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diff --git a/.gitattributes b/.gitattributes new file mode 100644 index 0000000..d7b82bc --- /dev/null +++ b/.gitattributes @@ -0,0 +1,4 @@ +*.txt text eol=lf +*.htm text eol=lf +*.html text eol=lf +*.md text eol=lf diff --git a/LICENSE.txt b/LICENSE.txt new file mode 100644 index 0000000..6312041 --- /dev/null +++ b/LICENSE.txt @@ -0,0 +1,11 @@ +This eBook, including all associated images, markup, improvements, +metadata, and any other content or labor, has been confirmed to be +in the PUBLIC DOMAIN IN THE UNITED STATES. + +Procedures for determining public domain status are described in +the "Copyright How-To" at https://www.gutenberg.org. + +No investigation has been made concerning possible copyrights in +jurisdictions other than the United States. Anyone seeking to utilize +this eBook outside of the United States should confirm copyright +status under the laws that apply to them. diff --git a/README.md b/README.md new file mode 100644 index 0000000..2cfec96 --- /dev/null +++ b/README.md @@ -0,0 +1,2 @@ +Project Gutenberg (https://www.gutenberg.org) public repository for +eBook #50458 (https://www.gutenberg.org/ebooks/50458) diff --git a/old/50458-8.txt b/old/50458-8.txt deleted file mode 100644 index 8b7aacf..0000000 --- a/old/50458-8.txt +++ /dev/null @@ -1,3326 +0,0 @@ -The Project Gutenberg EBook of The Toxins and Venoms and their Antibodies, by -Em. Pozzi-Escot - -This eBook is for the use of anyone anywhere in the United States and most -other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms of -the Project Gutenberg License included with this eBook or online at -www.gutenberg.org. If you are not located in the United States, you'll have -to check the laws of the country where you are located before using this ebook. - -Title: The Toxins and Venoms and their Antibodies - -Author: Em. Pozzi-Escot - -Translator: Alfred I. Cohn - -Release Date: November 14, 2015 [EBook #50458] - -Language: English - -Character set encoding: ISO-8859-1 - -*** START OF THIS PROJECT GUTENBERG EBOOK TOXINS, VENOMS, THEIR ANTIBODIES *** - - - - -Produced by The Online Distributed Proofreading Team at -http://www.pgdp.net (This file was produced from images -generously made available by The Internet Archive) - - - - - - - - THE - TOXINS AND VENOMS - AND THEIR ANTIBODIES - - BY - EM. POZZI-ESCOT - - AUTHORIZED TRANSLATION - BY - ALFRED I. COHN, PHAR. D. - - _FIRST EDITION_ - FIRST THOUSAND - - NEW YORK - JOHN WILEY & SONS - LONDON: CHAPMAN & HALL, LIMITED - 1906 - - - - - Copyright, 1906 - BY - ALFRED I. COHN - - ROBERT DRUMMOND, PRINTER, NEW YORK - - - - -INTRODUCTION. - - -Our knowledge of the toxins is of quite recent date. It is hardly -twenty years since we began to acquire a knowledge of the facts that -are detailed in this volume, and to which modern medicine owes its most -recent and marvelous progress, particularly in serotherapy. - -In this volume we have studied, besides the true toxins--substances of -cellular origin and of albuminoid nature and unknown composition--other -toxic substances, the nitrogenized alkaloidal bases introduced into -science through the researches of Selmi, Armand Gautier, and von -Behring, and which are highly hydrogenized nitrogenous crystallizable -principles of definite chemical composition--the products of the more -or less advanced breaking down of albuminoids. - -Although these principles differ widely, by reason of their -physiological properties as a whole, from the toxic albuminoids, or -true toxins, it appears proper to consider them as products of the -advanced decomposition of these toxins--and in this respect their study -becomes imperative, the more so as they are very frequently encountered -together with the toxins, particularly in serpent-venoms, where their -action is exerted in addition to that of the true toxins. - -In the first volume of this collection we dwelt on the essentially -reducing nature of the cellular functionation. To this -functionation--causing the splitting up or decomposition by hydrolysis -of nitrogenized albuminoid foods--is due the formation of these toxic -basic products within the organism, whether normally, or because of -certain pathological conditions. - -This alone suffices to show that, during physiological life, oxygen -plays an essentially antitoxic rôle within the organism. - -It is hoped that this succinct résumé, which it has been sought to -make as clear as possible, will be of service to those who, while -not scientists actively engaged in scientific progress, desire to be -abreast of the knowledge of modern evolution, but yet are not in a -position to consult original papers or large treatises. - - - - -CONTENTS. - - - PAGE - - INTRODUCTION iii - - - PART I. - - _GENERALITIES REGARDING TOXINS AND - ANTITOXINS._ - - CHAPTER I. - - ALKALOIDAL TOXINS, PTOMAINES, AND LEUCOMAINES. - - Alkaloidal products of cellular life 1 - Ptomaines 4 - Physiological action 5 - Extraction 5 - Classification, etc. 7 - Leucomaines 10 - Xanthic leucomaines 12 - Creatinic leucomaines 13 - Neurinic leucomaines 13 - Indeterminate leucomaines 14 - - CHAPTER II. - - TOXINS AND ANTITOXINS. - - Toxins 15 - Action of pathogenic bacteria 16 - Action of toxins 17 - Nature of toxins 18 - Origin of toxins 20 - Autointoxications 21 - General mode of action 23 - Constitution of toxins; Ehrlich's theory 24 - Means of defense possessed by the organism - against the action of toxins 28 - Pasteur's vaccination method 30 - Virus action 30 - Phagocytosis 32 - Antitoxins 33 - Mode of action 35 - Formation; Ehrlich's theory 38 - Serotherapy 41 - - - PART II. - - _THE TOXINS PROPER._ - - CHAPTER III. - - I. VEGETABLE AND ANIMAL TOXINS. 42 - Abrin 42 - Ricin 44 - Robin 45 - Toxicity of the vegetable diastases 45 - - II. TOXINS FROM MUSHROOMS 46 - Phalline 48 - Symptomatology 49 - Antidiastases 51 - - III. ANIMAL TOXINS 53 - Peptotoxin 53 - Alimentary Intoxications 55 - Urinary toxins 57 - Variation of urinary toxicity 59 - Autointoxications (animal) 60 - Glandular secretions 62 - Suprarenal capsules 63 - - CHAPTER IV. - - THE MICROBIAL TOXINS. - - Pyogenic and pyretogenic properties 66 - Anthrax toxin 67 - Tubercular toxin 69 - Diphtheria toxin 71 - Tetanus toxin 76 - Mallein 79 - Typhoid toxin 80 - Cholera toxin 82 - - CHAPTER V. - - THE VENOMS. - - General nature of venoms 85 - Venomous serpents 87 - Nature of serpent-venoms 88 - Natural immunity towards serpent-venoms 90 - Artificial immunity towards serpent venoms 91 - Venoms of batrachians and saurians 92 - Fish-poisons 95 - Poisons of the hymenoptera 96 - Poisons of scorpions 97 - Poisonous blood and serums 98 - Poisonous meats 100 - - - - -TOXINS AND VENOMS. - - - - -PART I. - -_GENERALITIES REGARDING TOXINS AND ANTITOXINS._ - - - - -CHAPTER I. - -ALKALOIDAL TOXINS, PTOMAINES AND LEUCOMAINES. - - -=Alkaloidal Products of Cellular Life.= - -Before entering upon the study of the true toxins, which are products -of an alkaloidal nature and of unknown composition, it is necessary to -say a few words regarding the most definite of the toxic alkaloidal -principles that are frequently encountered under various conditions, -conjointly with the true toxins, particularly in venoms, and which, -furthermore, are closely allied to these albuminoid toxins. - -These principles are formed in essentially reducing media, whether it -be within the body of the organism, and by the simple exercise of its -normal function, in which case the principles bear the generic name -_leucomaines_[1]; or whether due to the action of anaerobic microbes, -when they are designated as ptomaines.[2] These basic principles, which -are essentially the products of cellular secretion, are usually toxic, -and sometimes even extremely so. - - [1] ARMAND GAUTIER: Sur les leucomaines, nouveaux alcaloides, dérivés - de la transformation des substances protéiques des tissus vivants. - _Bull. Soc. Chim._, 2e série, XLIII, p. 158. - - [2] ARMAND GAUTIER: "Communication sur les bases d'origine - putréfactive." _Bull. Soc. Chim._ (2), XXXVII, p. 305. - -As we shall presently see, ptomaines are essentially products formed -during putrefactive fermentation. The toxic properties of extracts from -the cadaveric fluids have long been known. Already in 1838 Panum[3] had -met with these products in snake venoms. Bergmann and Schmiedberg[4] -in 1868 isolated from septic pus a toxic substance which they named -_sepsin_; and almost at the same time Zuelzer and Sonnenschein[5] -reported having isolated from anatomical preparations an alkaloid -possessing mydriatic properties. It is, however, due particularly to -the researches of Selmi and Armand Gautier that we are now so well -informed regarding these toxic principles. - - [3] _Virchow Archiv._, X, p. 301. - - [4] _Medic. Centralblatt_, 1868, p. 497. - - [5] _Berlin. Klin. Woch._, 1869, No. 2. - -The labors of Armand Gautier were first published in his _Traité de -Chimie Appliquée à la Physiologie_; those of Selmi in the _Actes de -l'Académie de Bologne_. - -At first sight, there appears to be a great difference between these -alkaloidal bases, the ptomaines and leucomaines, and the albuminoid -toxins proper. The toxic bases of the first two groups are quite -definite chemical products which can be generally obtained quite pure, -and frequently in crystalline form. The toxins proper, on the other -hand, are highly complex albuminoid substances which greatly resemble -the true diastases in all their properties. - -Nevertheless, between the toxic alkaloids, ptomaines and leucomaines, -and the toxic albuminoids, or more properly toxins, there exists no -absolutely sharp line of demarcation, but there is a gradual passage -from the one to the other by every intermediary grade, as a result of -the breaking down of the albuminoid molecule. - -We shall see, moreover, as we proceed, that these substances are -formed under coexistent circumstances, and that they are, hence, found -together, whether it be in virus or in snake venom. - -We will first consider the ptomaines, and then the leucomaines. - -=Ptomaines.= - -This name is more specially reserved to designate those alkaloidal -substances, generally highly hydrogenized, that are formed outside -the organism, from the fermentative action of anaerobic microbes on -albuminoid substances. - -These bases are generally volatile, with an intense and tenacious -purulent odor; often, however, they possess a floral odor (aubépine, -syringa), and even like that of musk. They combine readily with acids -and with the chlorides of the heavy metals, yielding crystallizable -salts. - -The ptomaines afford no specific reaction whereby they may be readily -identified; and their identification is effected only after a -painstaking analysis. - -We must here call attention, however, to several of their more common -properties, beginning with their basic character, their oxidizability -by the air and consequently their well-defined reducing power--a -property that led Selmi to propose a mixture of ferric chloride and -potassium ferricyanide as a reagent for their detection.[6] They are -precipitated by all the general reagents for the vegetable alkaloids. -Selmi has given several reactions, such as those afforded by sulphuric, -hydrochloric, and nitric acids, which appear, however, to apply much -more to the impurities present than to the bases themselves. - - [6] Sulle ptomaïne od alcaloïdi cadaverici. Bologne, CLXXXVII, p. 11. - -The physiological action of these bases varies greatly; in some -the action is an extremely toxic one, as in the case of neurine -and muscarine, which are true ptomaines; there are others, such as -cadaverine and putrescine, which are quite innocuous. The physiological -action of these bases, like that of the true toxins, is studied by -making hypodermic injections of solutions of the bases in healthy -animals, such as guinea-pigs, rabbits, and dogs. - -In animals, the principal phenomena observed by Selmi to follow the -injection of the substances are the following: At first dilatation -of the pupil, then constriction; tetanic convulsions, soon followed -by muscular relaxation, and retardation, rarely acceleration, of -heart-beat; absolute loss of cutaneous sensibility; loss of muscular -contractility; paralysis of the vasomotors; greatly retarded -respiration; stupor, followed by death with the heart in systole. - -It must be observed that in a number of cases where toxic researches -had been made in the past, these bases had been mistaken for poisons -which were believed to have been introduced into the organism with -criminal intent. No one will ever know how many have fallen victims in -the past to ignorance regarding the cellular mechanism! - -The extraction of these bases is a tedious and difficult operation. -The materials must first be exhausted with water slightly acidulated; -then, after precipitating the albuminoids by boiling and defecating by -adding lead acetate, the liquid is evaporated to one-half its volume -and dialyzed in a vacuum.[7] - - [7] ARMAND GAUTIER: _C. rend. de l'Académie des Sciences_, CXIV, p. - 1256. _Ibid._, XCVII, p. 264, and XCIV, p. 1600. - -Phosphomolybdate is then added to the dialyzed liquid, and the -precipitate formed, which now contains all the bases, decomposed by -boiling with lead acetate. After removing the excess of lead, there is -thus obtained a limpid solution of all the alkaloidal bases in the form -of acetates. These are separated by alcohol and by means of fractional -precipitations with various metallic salts, depending upon the known -properties of the bases. - -In order to facilitate their study, the ptomaines have been grouped -under two distinct classes, the one embracing the cadaveric or -putrefactive ptomaines, of undetermined microbial origin, the other -containing the ptomaines formed by microbes of known character. Each -of these two groups is itself divided into subgroups, as shown in the -following table: - - GROUP I. - -=CADAVERIC PTOMAINES OF UNDETERMINED MICROBIAL ORIGIN.= - - _a._ Amines. - _b._ Guanidines. - _c._ Oxamines (fatty or aromatic). - _d._ Amido Acids. - _e._ Carbopyridic Acids and analogues. - _f._ Undetermined Ptomaines. - - - GROUP II. - -=PTOMAINES OF KNOWN MICROBIAL ORIGIN.= - - _a._ Ptomaines extracted from microbial cells. - _b._ Ptomaines from pathological urines. - -We will not here enter upon a detailed study of the bases belonging -to each of these groups. This subject is a vast one, requiring for -its treatment a volume devoted to it alone. We will here simply touch -upon the principal properties of several of the bases of each of the -subgroups named. - - - BASES OF GROUP I. - -_a._ =Amines.=--Among these we find nearly all the fatty amines, such -as the methylamines and the cyclic alkaloids such as pyridine. They are -formed particularly by the putrefaction of fish. - -Certain of these bases are very toxic, for instance trimethylene -diamine, the collidines, and the parvolines. - -_b._ =Guanidines.=--Among the products of ordinary putrefaction there -has been found so far only methylguanidine, C{2}H{7}N{3}. This is a -highly toxic base of which 0.2 Gm. is fatal to a guinea-pig. - -_c._ =Oxamines.=--Under this designation the following bases are -comprised: 1. Neurine bases; 2. oxygenized aromatic bases; 3. bases of -unknown constitution. Amongst them we find neurine and choline, which -are toxic, and betaine, which is innocuous. They are found particularly -in putrid fish. - -_d._ =Amido Acids.=--These ptomaines, which are usually innocuous in -small quantities, are particularly the products of the decomposition -of albuminoid substances. Among them we find glycocoll, leucine, and -tyrosine, as members of this group. - -_e._ =Carbopyridic and Carboquinoleic Acids.=--So far only one base -is known belonging to this group, and that is morrhuic acid, which is -found in the decomposed livers of codfish, and which is a powerful -appetizer and stimulant in disassimilation. - -_f._ =Undetermined Ptomaines.=--Under this heading are classed certain -undetermined bases, such as those found in normal urines, and in -spoiled meats and bread. - - BASES OF GROUP II. - -_a._ =Ptomaines Isolated from Cultures of Pathogenic -Bacteria.=--Bacterial cultures contain, besides the true toxins, a -certain number of alkaloidal bases which sometimes possess considerable -toxicity. - -In the cultures of streptococcus pyogenes there are found -trimethylamine and xanthic bases; in those of staphylococcus pyogenes -aureus are found xanthic bases and creatinine; while pyocyanine and -pyoxanthine are found in the cultures of bacillus pyocyaneus, etc. - -_b._ =Ptomaines Isolated from Pathological Urines.=--Toxic ptomaine -bases have been found in the urines of a large number of diseases.[8] -It is quite probable that these bases are the results of a general -pathological condition due to some bacterial disease, the toxic -products of which are eliminated by the kidneys. - - [8] GRIFFITHS: _C. rend. de l'Académie des Sciences_, CXV, pp. 285 and - 667. - -From the urines of epileptics Griffiths[9] isolated a colorless base -crystallizing in prisms having the formula C{12}H{15}N{5}O{7}, and -which was found to be exceedingly toxic; the same investigator isolated -from the urines of eczematous subjects a ptomaine which he named -_eczemine_,[10] and which is also highly toxic. - - [9] E. POUCHET: Contribution à l'étude des matières extractives de - l'urine, _Thèse_, Paris, 1880; _Ibid._, _C. rend. de l'Académie des - Sc._, XCVII, p. 1560; BOUCHARD: _C. rend. Soc. de Biolog._, Aug. 12, - 1882. - - [10] GRIFFITHS: _C. rend. de l'Académie des Sciences_, CXVI, p. 1206. - -In certain cases of cystinuria there are found in the urine sulphurized -ptomaines, and in measles the urine contains an undetermined ptomaine, -_rubedine_, which is very poisonous. _Typhotoxine_, a very toxic -ptomaine, has been isolated from the urine of typhoid patients; -_erysipeline_, a hardly less toxic base, exists in the urine of -erysipelatic subjects; while _spasmotoxine_, _tetanotoxine_, and -_tetanine_, exceedingly active alkaloids, are found in the urines of -tetanus patients.[11] - - [11] BRIEGER: Untersuchungen über die Ptomaine, dritten Teil, p. 93; - _Berichte d. D. Chem. Gesellschaft_, 1886, p. 3159; 1887, p. 69. - -As a general rule, all abnormal urines contain toxic bases; the kidneys -appear, in fact, to serve as a means of eliminating the toxic products -that form in large quantity whenever, and for whatever cause, the -organism ceases to functionate normally, whether it be as a whole, or -in any one of its parts.[12] - - [12] CHARRIN: _Les poisons de l'urine_: Encyclopédie Léauté. - - - =Leucomaines.=[13] - - [13] ARMAND GAUTIER: _Bull. Acad. de Médecin_ (2), XV, p. 115. - -The leucomaines are basic substances, nearly allied to the ptomaines, -but still more closely related to the ureides. They are formed -directly or indirectly by the breaking down of protoplasmal -albuminoids. The agents that effect the breaking down are the -hydrolyzing ferments of the economy. It is well to recall here that -these phenomena of hydrolyzation occur within the cell itself and in -a practically reducing medium, as we have already stated. The inmost -mechanism of these phenomena cannot here be detailed; it will be found -described by Armand Gautier in the _Chimie Biologique_, and in his work -_Chimie de la Cellule Vivante_.[14] - - [14] ARMAND GAUTIER: Leçons de chimie biologique. Published by Masson; - _Ibid._, Chimie de la cellule vivante. Also published by Masson. - -The extraction of these bases is an extremely delicate operation. It is -necessary to operate with a large quantity of substance, say 50 kilos. -The substance is finely chopped, then exhausted with twice its weight -of water acidulated with acetic acid (0.2 Cc. per liter) and containing -a trace of oil of mustard, which is intended to act as an antiseptic. -The albuminoids are precipitated by boiling, the solution then -filtered, evaporated in a vacuum at 60° C., and the bases extracted -with 95-per cent. alcohol. - -The alkaloidal bases obtained in this manner are separated by -crystallization from alcohol or by various other chemical methods, the -description of which we will not enter upon here. - -In order to facilitate the study of the leucomaines they are classed -under three groups, according to their chemical affinities. These -groups are as follows: - -1. =Xanthic Leucomaines.=--The bases of this group appear to have a -composition resembling that of uric acid. When hydrolyzed, they yield -urea and guanidine. They are weak bases, and exhibit both basic and -weakly acid properties. They all possess the common characteristic of -being precipitated by copper acetate in acid solution with heat, and by -ammoniacal silver nitrate in the cold. - -According to Kossel, these bases are derived from the nucleo-albumins -which are found in the cell nuclei, and which are, as we know, -substances rich in nitrogen and phosphorus. - -Among the bases of this group may be mentioned _adenine_, -C{5}H{5}N{5}, which is obtained from infusions of tea.[15] This base -is non-toxic; it was discovered by Kossel,[16] and it crystallizes -easily. - - [15] KRUGER: _Bull. Soc. Chim._ (3), VIII, p. 687. - - [16] KOSSEL: _Zeitschrift für physiol. Chim._, X, p. 248; and _Bull. - Soc. Chim._ (3), III, p. 239. - -Some others of this group are: - -_Guanine_, C{5}H{5}N{5}O, non-toxic, discovered by Unger; -_pseudo-xanthine_, obtained from muscular tissues; _sarcine_, -C{5}H{4}N{4}O, also but slightly toxic, discovered by Scherer; -_xanthine_, C{5}H{4}N{4}O{2}, which is found in many urines, and -which acts as a stimulant on the cardiac muscles; _paraxanthine_, -C{7}H{8}N{4}O{2}, a toxic base found in certain pathological -urines; _caffeine_ and _theobromine_, powerful diuretic bases; and -_carnine_, C{7}H{8}N{4}O{3}, from meat, a muscular stimulant like -caffeine. - -2. =Creatinic Leucomaines.=--These have for their type guanidine; they -differ from the xanthic bases in that they are not precipitated by -copper acetate, but frequently are by ammoniacal silver nitrate. They -yield double salts with the chlorides of zinc and cadmium. To this -group belong _glycocyanine_, C{3}H{7}N{3}O{2}, and _glycocyanidine_, -C{3}H{7}N{3}O, both very toxic; _creatine_, C{4}H{9}N{3}O{2}, only -slightly toxic; _creatinine_, C{4}H{7}N{3}O; _lysatine_, which very -easily decomposes to form urea; _lysatinine_, _xanthocreatine_; -_arginine_, a vegetable base, etc. - -3. =Neurinic Leucomaines.=--These have none of the characteristics of -the preceding bases; their type is neurine, a highly toxic base found -in the brain, nerves, and certain fish ova. These bases are sometimes -normally produced by the animal economy, and are also frequently the -result of microbic action. They are the result of the simple phenomena -of fermentative hydrolyzation of protagons and lecithins. Among these -bases are _choline_, a weak alkaloid, and _betaine_, which appears to -be non-toxic. - -The former has the formula C{5}H{15}NO{2}; it was discovered -by Stocker. Wurtz synthesized it by combining trimethylamine and -glycol-monochlorhydrine, and treating the resulting hydrochloride with -silver oxide. Betaine, C{5}H{11}NO{2}, is found in beets; it was -discovered by Scheibler. Neurine is, chemically, trimethylvinylammonium -hydrate. - -4. =Undetermined Leucomaines.=--Among these bases several are -important in more than one respect. For instance _spermine_, which is -found in the sperm, is a strong base possessing a powerfully dynamic -and tonic action on the nerves. It acts as an oxidizer. Spermine -was first obtained by Schreiner[17] from the sperm of mammifers in -which it occurs as a phosphate. It has the formula C{5}H{14}N{2}. -It was physiologically studied by Poehl, Tarchanoff, Weljaminoff, -and Joffroy.[18] _Plasmaine_, a toxic base found in the blood and -discovered by R. Wurtz,[19] has the formula C{5}H{15}N{5}; -_protamine_, from fish milt, was discovered by Micocher.[20] - - [17] _Liebig's Ann. der Chemie_, CXCIV, p. 68. - - [18] _Journ. Soc. Phys. Chim. Russe_, 1893, No. 2; and _Bull. Soc. - Chim._ (3), XII, p. 243. - - [19] _Leucomaines du Sang Normal_, Thèse, Paris, 1889. - - [20] _Joh reab. de Thiérchen_, 1874, p. 341; Picard, _Ibid._, p. 355. - - - - -CHAPTER II. - -TOXINS AND ANTITOXINS. - - -We have already seen, in the preceding chapter, that the microbes -and the cells of various organisms are capable of secreting definite -products of a toxic nature to which the names "ptomaines" and -"leucomaines" have been given. Researches, which were begun scarcely -twenty years ago, have shown that, besides these crystallizable and -definite products, we meet with basic non-crystallizable substances of -unknown composition, possessing special toxic properties, sometimes -even of extreme violence. These substances have been named "toxins." - -At first this generic name was extended toward indefinite basic organic -products that could be isolated from tissues and tumors both normal and -abnormal; later on, however, the name was applied to toxic substances, -equally indefinite, isolated from the culture media of microbes and the -active constituent of various venoms. - -It is only since 1885, when Charrin called attention to them, that -investigations began to be made regarding them. In 1888 Roux and -Yersin,[21] in their beautiful researches on diphtheria, pointed out -the diastatic nature of the properties of the active albuminoid matter -existing in the cultures of the specific bacilli of this disease. From -that period, these products began to take a more and more prominent -place, from year to year, in the study of pathological affections, and, -by developing the knowledge of immunity, they have opened a new path to -the investigations of therapeutic technic. - - [21] ROUX and YERSIN; Mémoire sur Diphtérie. _Ann. Inst. Pasteur_, - 1888-1889. - -It is due to the knowledge of these principles that we have learned -that the infectious microbes, far from acting as they were believed to -do only a few years ago, and which Pasteur strongly maintained to be -by vital parasitism--such as would be the case with the carbonizing -bacteria which, according to Pasteur, act by diverting the oxygen, -or causing capillary embolisms--owe their pathogenic action to the -toxic substances which are the products of their secretion, and which -spread throughout the organism, even though the microbe frequently is -localized in a very circumscribed spot, as in tetanus and in diphtheria. - -The idea of intoxication by these products has now replaced the idea of -the direct action of the microbe on the elements or the liquids of the -organism. - -The occurrence that takes place in diphtheria and tetanus is one of the -best examples to cite in support of this view. - -Here, in fact, the pathogenic microbe is found only in a very limited -area in the organism attacked--the false membrane, in the case of -diphtheria, or frequently only a slight wound in the case of tetanus, -and the microbe becomes localized there only. Now, in both cases, -there are general phenomena of toxic effects. There must hence be a -diffusion of toxic substances which, distributed by the blood, affect -the different systems and exert a toxic action on the entire organism. - -It must be observed that the toxins act as toxic agents only when in -a condition to be introduced into the circulation subcutaneously. -The cause of this innocuousness of the toxins when given per os -has frequently been studied. It appears to be quite probable that -the cause of the attenuation of the morbid properties is due to -the intervention of the digestive microbes. Such is the opinion of -Levaditi and Charrin[22]; it is also the conclusion that is to be -drawn from the experiments of Mme. Metchnikoff and of Calmette[23] on -the modifications undergone by a vegetable toxalbumin, abrin, and by -serpent venoms, when these toxalbumins are inoculated with the bacillus -subtilis chromogenus. Moreover, Charrin and Lefèvre,[24] on the one -hand, and Nencki, Sieber and Somanowsky,[25] and Carrière,[26] on the -other hand, have discovered that the digestive ferments, particularly -trypsin, destroy, even though but little, the toxins secreted by -the Loeffler and Nicolaier bacilli. This is practically contrary to -the opinion of Behring and of Rauson,[27] according to which the -innocuousness of the microbial poisons when administered per os is due -exclusively to the lack of absorption. - - [22] CHARRIN and LEVADITI: Le sort de toxines introduites dans le tube - digestif. _Journal de Physiologie et de Pathologie Générales_, 1898, p. - 226. - - [23] Citing Metchnikoff. - - [24] _C. rend. de la Soc. de Biologie_, 1898. - - [25] _Centralblatt für Bakt._, 1898. - - [26] _C. rend. de la Soc. de Biologie_, 1899. - - [27] _Deutsche Med. Wochenschr._, 1898, No. 8. - -=Nature of the Toxins.=--The molecules of the toxins are very nearly -like those of the diastases. Like these, the toxins appear to have -a very complex, and very unstable, internal structure. Their mode -of action frequently depends, as in the case of the diastases, upon -the medium in which they occur. Again, like the diastases, they are -generally destroyed by the action of sufficiently prolonged heat, but -less easily, for there are certain toxins that resist a temperature -of 100° C. for an indefinite period. They are, like the diastatic -albuminoids, insoluble in strong alcohol, and are precipitated from -their solutions on the addition of this reagent. They easily adhere -to precipitates that form in liquids in which they occur in solution, -and possess the remarkable property of diastases in that imponderable -masses produce considerable results.[28] - - [28] See POZZI-ESCOT: Les diastases et leurs applications, published by - Masson, 1900; and _Traité de Physico-chimie_. - -Although closely allied to certain alkaloidal bases, the toxins are -sharply distinguished by the remarkable fact that their action is never -immediate, but is always preceded by a period of incubation, which may -be quite long. - -Like the alkaloidal bases, they appear to result from the hydrolyzing -breaking down of albuminoids and nucleo-albumins, and they appear to -be intermediary, from a chemical point of view, between these bodies, -the general characters of which they retain, and the alkaloids proper, -or ptomaines, to which we have called attention, and the principal -chemical and physiological properties of which they possess. - -No absolutely precise knowledge is had regarding the chemical nature -and constitution of these remarkable substances. A number of analyses -of these substances have been published which, in general, permit no -definite conclusion to be drawn.[29] I have, however, elaborated -several speculative ideas regarding this subject.[30] - - [29] Regarding this see the works by KOCH and BRIEGER, _Deutsche - Medicin. Wochenschr._, Oct. 22, 1891. - - [30] POZZI-ESCOT: Nature des Diastases. Published by J. Rousset, - Paris, 1903. See also Recherches de la Nature Chimique des Diastases - Oxydantes. _Revue génér. de chimie_, VII, pp. 129-136; and Aperçus - sur la nature chimique des Diastases, _Bulletin de l'Association - de Chimistes_, 1904, p. 769.--Propriétés Catalytiques de Quelques - Diastases; _Ibid._, 1904, p. 1247. - -We must here call particular attention to the ideas of Ehrlich -regarding the constitution of the toxins. According to this scientist, -their molecules contain two functional groups; the one, to which he -has given the name "haptophore," is that which enables the toxin to -attach itself to any cellular element whatever, and which it then -renders non-toxic by means of the other, or "toxophore," group. We will -particularize farther on regarding this very important conception. - -=Origin of the Toxins.=--These toxic bodies result either as the -products of the secretion of microbial life, or as the result of the -normal functionation of cellular life in the higher vegetable or animal -organisms. - -They are the direct products of life, and do not result, as was -formerly believed, from a more or less profound modification of the -more or less complex albuminoids that serve as a food for the various -species of microbes, or for the cellular elements. - -The vegetable toxins are less numerous than the animal toxins. -They are met with, nevertheless, in almost all mushrooms which are -reputed or known to be toxic; the seed of the castor plant contains a -very toxic vegetable albuminoid, as is likewise the case with Abrus -precatorius (jequirity-bean), and certain others. - -The true physiological toxins occupy a very important place in the -realization of the conditions that govern health, sickness, and death. - -We will see later on that they are met with in quite large number -in the bladder, whence they are voided in the urine. Their number -varies considerably, according to diverse influences (waking, slumber, -eating, fasting, fatigue, oxygen, brainwork, health, disease, etc.). -It is necessary here to observe that the renal system serves for the -purification of the entire organism, and that in the case of normal -life we will find in the renal system a large portion of the products -of the cellular secretion of the organism, and among the number there -are found, as we know, a certain number of alkaloidal bases. We will -take up later the subject of urinary toxicity. - -=Autointoxications.=--The toxins are also encountered, and often in -some number, in the muscular tissues and in the blood, particularly -in those of batrachians, mureids, and saurians. In the organism these -toxins, developed by the activity of the various cells, may cause -autointoxication whenever, for one cause or another, their normal -elimination ceases. "Although there are an infinity of diseases," -remarked Prof. Bouchard, "there are but a few ways of becoming ill." Of -these ways that of autointoxication is the most frequent. "What else -is it, then," says Prof. Charrin, "in the last analysis, but to die -from affections of the kidney, the liver, the heart, the lung, etc., if -it be not to succumb because of the lack of oxygen, the accumulation -of carbonic acid, the influence of the numerous urinary poisons, the -action of acids, of salts, of biliary pigments, or the effect of -noxious principles, which the hepatic cell must normally destroy or at -least attenuate." - -These autointoxications, always due to poor elimination of toxic -principles, toxins formed in very great number in the organism, and -which the normal modes of evacuation or destruction do not eliminate, -are always found to be the cause of all diseases, even those that are -manifested by attacks of the cerebro-spinal axis, and that exhibit -variously mania, insanity, symptoms of hyperexcitability, etc. - -These autointoxications are controlled by the nervous system, and -the latter alone is the cause of a larger number of maladies than -is generally believed; in fact, if the mechanism of nutrition be -reduced to its most simple elements, it will be seen to consist of the -penetration of the foods, of the plasmatic principles, to the cells; -of their transformation within the interior of the cells, and finally -the rejection of all the matter that could not be utilized. It is the -nervous system that commands or dominates this mechanism, that controls -the taking-up of assimilable elements and the elimination of toxic -principles, the fruit of assimilation or disassimilation, and in such a -manner, in fact, that this same nervous system can, at its will, cause -starvation, or intoxicate. - -The marvelous cures obtained by magnetic methods are due to no other -causes than favorable changes in the nervous system. - -=General Mode of Action.=--The toxins, of whatever kind, always behave -like diastases, in the sense that their definite action appears to be -absolutely independent of their mass, and that imponderable quantities -suffice to cause serious morbid affections and profound modifications -in nutrition. - -Koch has shown that tuberculin is capable of affecting 60 trillion -times its weight of the living human being. According to Vaillard one -milligramme of tetanus toxin will kill a horse weighing 600 kilos. -These two examples show what an enormous power the toxins possess. - -My views regarding the manner in which diastases act I have developed -at length in my work _Nature des Diastases_. The close analogy between -these substances and the toxins, an analogy upon which, moreover, -I have dwelt at some length, permits me to refer the reader who is -desirous of fuller details to the small work just mentioned. - -The mode of action of diastases resembles singularly closely that of -the catalytic substances, and we will admit, for the moment, that they -act by intermediary combination, resulting in their rapid decomposition. - -We owe to Ehrlich[31] a new conception relative to the nature and mode -of action of the diastases, and which to-day plays an important rôle in -all our conceptions regarding immunity.[32] - - [31] EHRLICH: _Klinisches Jahrbuch_, 1897, VI. _Proceedings of - the Royal Society_, 1900, No. 482, p. 424. _Nothnagles' specielle - Pathologie und Therapie_, 1901, VIII, Schlussbetrachtungen, p. 163. - - [32] To have a complete exposé regarding this question, it will be - profitable to consult No. 4 of this collection on _Sérums Immunisants_. - -According to this scientist, the complex molecule of albuminoid -substances is constituted by a fixed central nucleus, and by a number -of lateral chains or receptors, fixed to this nucleus, which possess -diverse accessory functions, and which serve, particularly, for the -nutrition of the cells. These receptors have a great affinity for the -various substances necessary for the support of the living elements, -and they seize upon the alimentary substances, in normal life, just as -a leaf of the _Dionæa_ seizes a fly which serves as its food. - -In these special conditions the receptors may attach themselves to -the complex molecules of albuminoid substances, such as the different -toxins. - -Ehrlich supposes, as we have already seen, that a toxin contains two -special groups--a _toxophore_ group, which poisons, and a _haptophore_ -group, which combines with the receptor. According to this theory, -the toxophore group of a toxin can act on an organism _only_ when the -haptophore group of the toxin encounters a suitable attachment or -receptor. - -The receptors attached to the living protoplasmic molecule attract the -toxin, just as a lightning-rod attracts the lightning. - -It is hence clearly proved that the toxigenic poisons exert their -noxious action on the cellular elements of sensitive organisms, by -entering into combination with these. - -Experience has shown that they attach themselves, in a most rigorously -elective manner, to the tissues, and rapidly disappear from the general -circulation. Numerous facts, clearly established, attest the reality of -this fixation or attachment. - -It is thus that von Behring and Wernicke[33] sought to ascertain -the quantity of antitoxin (we will see farther on that this name is -given to those substances which neutralize the activity of toxins -under certain conditions) which, introduced a certain time after the -introduction of the poison, will save the life of the animal. They -have experimented with diphtheria toxin, which we will study later, -and they have demonstrated that, if the antitoxic serum be introduced -immediately after the toxin, a dose of antitoxin twice as large as that -of the toxin suffices to effect a cure. - - [33] VON BEHRING and WERNICKE: Zeitschrift für Hygiene, XII. - -Eight hours after the administration of the toxin the dose must be -trebled, while after thirty-six hours it is necessary to have recourse -to a quantity of antitoxin eight times as great. These experiments -show that the curative action of the antitoxin is so much the less the -longer the period of time that has elapsed between the introduction -of the toxin and the antitoxin. This is because the toxin has become -so intimately attached to the tissues that the antitoxin introduced -has not the power to destroy the combination. These facts have been -confirmed by Donitz[34] and by the classic experiments of Decroly and -Rousse.[35] - - [34] DONITZ: Ueber die Grenzen der Wirksamkeit des Diphtheria - Heilserums. _Deutsche Med. Woch._, No. 27, 1897. - - [35] DECROLY et ROUSSE: _Arch. Int. de Pharmacodyn._, III and VI; - Masoin: _Arch. Intern. de Pharmacodyn._, II, 1903. - - This is not, however, the case with cold-blooded animals, which, - generally, are not affected by injections of poisonous toxins. Thus - Metchnikoff[36] and his pupils have been able to show that the toxins - introduced into certain cold-blooded animals (Oryetes nasicorius) may - remain for several months without alteration in their circulation. - - [36] METCHNIKOFF: _L'Immunité_, Paris, 1902; MORGENROTH: Zur Kenntniss - des Tetanus des Frosches. _Deutsche Med. Woch._, No. 35, 1898. - -If we consider the facts of the theory of Ehrlich's lateral chains, -which we have mentioned, we are led to well-defined conclusions -regarding the mode of action of the toxins. In fact, since these toxins -exhibit a pronounced chemical affinity for the tissues, and while, on -the other hand, they can attach themselves only because of the presence -of certain functional groups of the protoplasmic molecules, this union -can take place only in certain specific centers. This has been fully -confirmed by experiments _in vitro_. - -It is known, since the researches of Ehrlich,[37] Wassermann and -Takaki,[38] Marie,[39] Metchnikoff,[40] and a host of other scientists, -that this fixation is due to a clearly elective property. It is for -this reason that the tetanus toxin fixes itself only upon the nervous -tissue, and that in this action all passes as if the nervous tissue had -been provided with functional groups possessing an elective affinity -for the tetanic poison. - - [37] EHRLICH: _Berl. Klin. Woch._, No. 12, 1898. - - [38] WASSERMANN and TAKAKI: _Berl. Klin. Woch._, _Med._, p. 5, 1898. - - [39] MARIE: Sur les Propriétés Antitoxiques aux Centres Nerveux de - l'Animal Sain. _Ann. Inst. Past._, 1898, p. 1. - - [40] METCHNIKOFF: Recherches sur l'Influence de l'Organism sur les - Toxines. _Ann. Inst. Past._, 1899, p. 82. - -=Means of Defense Possessed by the Organism against the Action of -Toxins.=--We have already seen that the renal organs serve for the -elimination of the toxins normally produced in the organism by the -simple play of its cellular mechanism. Experience has shown that the -toxins introduced from without into the circulation are generally -finally eliminated, even though in the meantime the modifications they -have imprinted on the economy may be transmitted hereditarily; and that -their influence on the general nutrition and the normal functionation -of the entire organism persists even after their elimination. - -Much has been said regarding the elimination of these toxins by the -urine, but the experiments made by Métin, at the Institut Pasteur, have -shown the inaccuracy of this assumption, and it has been necessary to -seek another. - -It has been remarked that oxidation destroys the toxins _in vitro_, and -it has been thought that a process resembling disinfection may well -take place within the tissues of the animal economy, but no decision -has been arrived at regarding the possible mechanism of this action, -which some attribute to the action of the oxidizing ferments of the -organism, or to the action of certain special cells. - -According to Poehl, there is developed as destroyer a substance -possessing energetic oxidizing properties, which he has isolated and -named _spermine_, and which is found in most of the organic fluids -and particularly in the leucocytes, the special rôle of which we will -presently study. - -There develops still another cause of elimination, or, to be more -exact, of the neutralization of the toxic principles in defense of the -organism against the toxins, and that is the formation of _antitoxins_. - -It is well known that the term _virus_ has been reserved to designate -physiological liquids which were characterized, when first they were -known, by their property of transmitting to an organism certain -functional affections, but the true character of which is to expend -their toxicity upon the microbes which occur and are reproduced in the -organism, or upon the organized plastidulary granulations, as in the -case of the rabic virus, the special microbe of which has not as yet -been isolated. - -Pasteur, when studying rabies, found that the brain and spinal marrow -of rabid animals contained the pure rabic virus in considerable -quantity, and that every particle of the marrow was capable of -imparting rabies to a perfectly healthy dog. After having ascertained -this fact, he found that he could _attenuate the action of the virus_, -either by passing the virus through certain animal organisms, such -as the monkey or rabbit, by gently heating, or even by allowing it to -oxidize and partially dry in the air, or else by submitting it to the -action of antiseptics or alternating electric currents of very high -tension. - -Experiments have shown that a deadly virus, attenuated by one of the -means mentioned, may be injected, without danger of death, into the -living animal; and what is still better, the animal thus treated -acquires the power of resisting large doses of the virus, less and less -attenuated, and that it is possible to reach a point where the animal -economy may become habituated to very large doses of a highly virulent -virus without the organism experiencing any visible illness--that is, -the organism has been _vaccinated_ with regard to the particular virus. - -Experiments have shown that this property is not peculiar to microbial -virus alone, but that it is common to the venoms the toxicity of which -is essentially due to some toxins, with the exception of those agents -noted. - -The attenuated viruses act, as vaccins, through their soluble -constituents, which, either directly, by modifying the nutrition of -certain cells, or indirectly, by inducing reactions of the nervous -centers which preside over this nutrition, profoundly change the -conditions of life and give rise to the pathological condition--the -vaccined state. - -Experiments by Behring and Kitasato[41] have shown that the tumors of -a vaccinated animal, freed from all organized matter visible under the -microscope by filtration through porcelain, contains principles capable -of directly or indirectly protecting other animals from the disease -caused by the corresponding virus. Meanwhile, experiments have shown -that the vaccinating matters are totally eliminated; nevertheless, -after their elimination, the immunity acquired remains with the animal, -which then continues to be protected against the corresponding virus. - - [41] _Deutsche Med. Wochenschr._, 1890, p. 1113. - -Interest in this subject has incited numerous researches with a regard -to bringing to light the mechanism of this immunization; and this will -form the subject of another volume of this collection. We may state -here, however, that there have been recognized two concurrent causes of -this preservative action; the one, called _phagocytosis_, results from -the fact that the microbe introduced into the vaccined organism becomes -incapable of producing its usual toxins, while on the other hand the -immunization renders the organism capable of secreting substances -possessing an activity contrary to that of the virus, in fact true -counter-poisons, comprised under the general name _antitoxins_. - -=Phagocytosis.=--We have seen that an organism subjected to a toxic -invasion tends to protect itself by proper means of defense; and one -of those is the direct putting into activity of the living cellular -elements themselves, and in particular, the leucocytes, or white -corpuscles, found in more or less number, according to pathological -conditions, in the blood and lymphatic fluids.[42] - - [42] It is necessary here to consult the work by LEVADITI: Le Leucocyte - et ses Granulations. _Scientia_, Naud, publisher, Paris, 1903; also - METCHNIKOFF: L'Immunité, Paris, 1902, Masson, publisher. - -Metchnikoff has shown that the moment a foreign element, particularly -a microbe, enters the organism, these leucocytes come flocking from -all parts of the body, collect around the bacterial element, penetrate -it, and begin to digest it. These elements have received the name -_phagocytes_. The name _chemotaxis_ has been given to the property by -virtue of which they approach (positive chemotaxis) or move away from -(negative chemotaxis) certain substances which affect them powerfully. - -Experiments have shown that the leucocytes are attracted by the -products secreted by pathogenic microbes, or saprophytes. Attracted by -the latter, the white corpuscles surround, envelop, and finally digest -them; and when it happens that all the pathogenic microbes within an -organism are absorbed, the organism survives, while in the contrary -case it succumbs. - -Attention must be called to this attack by the white corpuscles within -the limits where they are normally confined. It is a pathologic -diapedesis--a leucocytosis provoked by the irritation of the -tissues--and caused either by the presence alone of foreign elements, -or by the soluble products secreted by them. - -When, for any reason whatever, this phagocytic action is impeded, -the resistance of the organism to pathogenic infection ceases to be -effective, and the organism may therefore be invaded by the microbe. -Numerous causes may contribute to impede this action. - - - =The Antitoxins.= - -We have seen that the second means of defense possessed by the organism -resides in the action of special products, true defensive secretions, -possessing an activity contrary to that of the toxins, and which are -secreted by the cells of the organism under the influence of the -vaccins. - -This is a property common to every organism, and which is observed even -in non-vaccinated subjects, although in this case the secretion forms -with great difficulty and in small quantity. - -When an organism subjected to the toxic action of a bacterial infection -does not succumb to the intoxication, it emerges from the test gifted -with a new property, which may be augmented by habituation, and which -borders on immunity. - -At first we were content to vaccinate small animals in the laboratory, -but in proportion as the discoveries in this domain extended, and there -developed a need for large quantities of antitoxins, recourse was had -to the larger animals, particularly horses and cattle. From the moment -that large quantities of blood and antitoxic serum were at command, -search was made for a means of isolating the antitoxin and determining -its properties. - -Experiments so far made have shown that the antitoxins are substances -of an albuminoid nature, of unknown composition, and which are very -closely united to the albuminoid substances of the serum. It must -be observed, however, that Behring and Knorr oppose the assertion -regarding the albuminoid nature of tetanic antitoxin, but their reasons -for this do not appear to be well founded. - -In general, these antitoxins are precipitable with the globulins, and -possess quite considerable powers of resistance towards physical and -chemical agents. Thus they are destroyed only at a temperature above -60-65° C. Kept in the dry state, in the residue of evaporated serum, -and away from the light and all oxidizing action, it is possible to -preserve their activity for a very long time. - -They are essentially humoral substances; they are found in the blood -of vaccinated animals, from which may be obtained antitoxic serums -with a specific but transient immunity; and they are also found in the -plasmas of the lymph and exudates, in aqueous tumors, and in the milk. -They are seldom found in the cells. - -=Mode of Action.=--Frequent attention has been paid to the mode of -action of the antitoxins upon the toxins, a phenomenon of great -importance in relation to the phenomenon of immunity acquired against -the toxins. At the beginning of our knowledge on this subject, the idea -of a destruction of the toxin immediately suggested itself, and was -advanced by von Behring.[43] According to this scientist the antibody -inhibits the morbigenic action of the toxin by neutralizing the toxin, -combining with the latter to form a compound of a chemical nature which -is devoid of toxicity and without action on the organism. According to -this theory, the influence of the antitoxin on the toxin is direct, and -does not require the intervention of the living cellular protoplasm. -Such was also the belief of Prof. Ehrlich.[44] - - [43] VON BEHRING and KITASATO: _Deutsch. med. Wochenschr._, 1890, p. - 1113. - - [44] EHRLICH: _Klin. Jahrb._ 1897, VI, p. 292. - -Buchner, a little later, believed that the antitoxin, instead of acting -directly on the toxin, exercised a direct influence on the living -elements of the organism, preserving them from intoxication.[45] - - [45] BUCHNER: _Münchener med. Wochenschr._, 1893, p. 480. - -Such was also the opinion of Roux[46]; and Calmette demonstrated that a -mixture of venom and of a non-toxic antivenom recovered its toxicity on -being heated to 68° C, whereby the antivenom was destroyed (Calmette: -_Le Venin des Serpents_, Paris, 1897, p. 58); and Wassermann arrived at -the same result.[47] - - [46] ROUX: _Annales de l'Institut Pasteur_, 1894, VIII, p. 724. - - [47] WASSERMANN: _Zeitschr. für Hygiene_. - -The array of proofs offered by these scientists, which we cannot here -enlarge upon without uselessly extending our subject, would tend to -make one believe, at first glance, that the antitoxin does not act -directly on the toxin, but at the present time Buchner's theory appears -untenable. Numerous researches have proved conclusively that the toxin -and the antitoxin have a specific affinity for each other, by virtue -of which these principles combine to form a substance free from all -toxicity, but unstable, and which may be decomposed by heat or certain -other factors.[48] - - [48] J. DANZSY: _Annales de l'Institut Pasteur_, XVI, p. 331. - -Some recent experiments by J. Martin and Cherry (_Proceedings of the -Royal Society_, 1898, LXIII, p. 423) have clearly brought out this -fact. These authors made mixtures of serpent venom with its antivenom, -which they filtered through a layer of gelatin, under the supposition -that, if the venom and its antivenom were not chemically combined, -the former alone would be able to pass through into the filtrate, -because its molecules are so much smaller. Martin and Cherry allowed -the venom and its antivenom to remain in contact for varying periods -before filtering. As the result of a series of experiments carried -out with this idea, they have demonstrated that the filtrate obtained -after allowing a few minutes' contact between the two substances, -was decidedly toxic, while that obtained after a contact of half an -hour was absolutely non-toxic. From this the authors conclude that -the antitoxin enters into chemical union with the venom, but that the -combination does not take place immediately, and requires a certain -length of time for its accomplishment. - -Ehrlich and Knorr have demonstrated that the neutralization is less -rapid in dilute solutions than in concentrated ones. - -Prof. Svante Arrhenius has completed our knowledge regarding the mode -of combination between the toxins and the antitoxins, by demonstrating -the occurrence of limited reactions analogous to the etherification of -an alcohol by an acid, and in such a manner that there always exists, -in a mixture of these two substances, a certain quantity of free toxin -and antitoxin. This is an important modification of the general ideas -held in this respect.[49] - - [49] SVANTE ARRHENIUS: La Physico-chimie des Toxines et des - Antitoxines. _Conférences de la Société chimique de Paris_, May 20, - 1904. See also MADSEN AND ARRHENIUS: Testkrift red indivulsen of - Stotens Serum Institut. Copenhagen, 1902. - -It appears necessary to bring here more clearly in evidence the fact -that _the antitoxin inhibits the noxious action of the toxin, even -outside the living organism, by uniting with it to form a compound in -identically the same manner as when a strong base and a strong acid are -brought together_. As we have seen, all the conditions of environment -that favor or retard the formation of salts, in a like sense influence -the neutralization of the toxin by its antitoxin. - -=Formation of Antitoxins.=--Ehrlich's theory of side chains, to which -reference has already been made, furnishes us with an explanation of -the formation of the antitoxins in tumors. Let us suppose that, in -the organism, a cell had come into contact only with certain toxic -molecules incapable of compromising its life, and that the only result -was the immobilization of the receptors which are united with the -haptophore groups of the opposing toxins. It is known that, by virtue -of a property inherent in all living organisms, during the phenomena -of reparation, there is generally an overproduction of the neoformed -parts. In the case we here speak of, as the receptors fill an important -function in the nutrition of the opposing cellular elements, once they -become united with the toxic haptophores, they become incapable of -filling their normal function of nutrition. Under these conditions the -cells develop so large a quantity of receptors that, filling the cells, -and not finding any more room, they spread into the blood and other -liquids of the organism. - -Under these conditions, every new injection of toxin into the organism -is absorbed into the blood where it meets with the free receptors which -possess great avidity for the haptophore group of its molecule, and the -two groups immediately unite, before the haptophore group of the toxin -has been able to attack and intoxicate a cellular element. - -We thus see that the receptors which, when in a free state in tumors, -play the rôle of antitoxics or antitoxins, become, within the cellular -elements themselves, the vehicle of intoxications. Figuratively -speaking, so long as these fixators are attached to the molecule of the -living protoplasm they attract the toxin. - -According to this ingenious conception, the formation of antitoxins is -hence absolutely independent of the action of the toxophore elements on -the cellular elements, and it suffices that these possess receptors or -side chains capable of uniting with the haptophore groups of the toxin. -This explains why it has been possible to produce antitoxins from -toxins which have lost some of their toxic properties, but which have -preserved their property of uniting with antitoxic substances. Ehrlich -gives the name _toxoids_ to those modified toxins that have lost their -toxophore groups, while the haptophore group, the producer of the -immunizing substance, is still preserved intact. - -According to Metchnikoff's theory, which is very similar, it seems -quite possible that the phagocytes, thanks to the facility with -which they absorb poisons, occupy an important place as producers of -antitoxins. It has not been possible so far to verify this theory in -our at present imperfect knowledge regarding this subject. The domain -of immunity has, however, made brilliant conquests during these last -few years, so that we should not despair of arriving at a definite -solution before long. - -In the vaccinated animal the antitoxin is reproduced, and it is -possible to obtain several times, from the vaccinated animals, -successive portions of antitoxic serum.[50] The protective power -of these antitoxins is absolutely marvelous. An animal accustomed -gradually to the tetanic virus yields a serum containing an antitoxin a -thousand times more active than the virus. - - [50] CH. SALMONSEN et TH. MADSEN: Réproduction de la substance - antitoxique. _Ann. Inst. Pasteur_, XII, p. 762. ROUX et VAILLARD: - _Ibid._, 1893, p. 83. - -According to Vaillard, a quintillionth of a cubic centimeter of this -antitetanic serum suffices to preserve one gramme of living mouse from -the effects of a dose of tetanic serum that would otherwise be surely -fatal. - -In the animal, the antitoxins are eliminated mostly by the fluids of -the body, and particularly by the urine. Ehrlich has demonstrated that -they also pass into the milk, and this fact is confirmed by a large -number of observers. It explains the immunity acquired by nurslings, -and which is transmitted by the milk. - -=Serotherapy.=--The search for antitoxins and their rôle in the -etiology of infectious diseases are fundamental points in actual -therapy. It has been demonstrated that the serums of certain vaccinated -animals enjoy very extended antitoxic therapeutic properties; for -instance, the serum of vaccinated rabbits is an antivenom towards -erysipelas; and the sterilized cultures of the pneumococcus or of the -Bacillus pyocyaneus prevents infection of carbuncle (anthrax). - -The antivenomous serum of the ass immunized by injections of increasing -doses of the venom of the terrible naja is a perfect prophylactic and -curative, not only as regards the venom of this serpent, but also -against that of the crotalus, trigonocephalus, and viper. - -We shall take up the study of serotherapeutics in another volume of -this collection. - - - - -PART II. - -_THE TOXINS PROPER._ - - - - -CHAPTER III. - - -I. VEGETABLE AND ANIMAL TOXINS. - -The vegetable toxins possess the characteristic property of being -innocuous, and of being almost completely devoid of poisonousness, when -they are absorbed by the intestines; we can see, from this, how greatly -they differ from the poisons proper.[51] - - [51] It is understood that the active principles of mushrooms are not - comprised under this definition, but they will be studied under the - next heading. - -The vegetable toxins known are quite numerous; nevertheless our -knowledge regarding them is very incomplete. Our review of them will be -chiefly descriptive. - -Many of the leguminous plants are poisonous, either because of -emanations exhaled by them, or by reason of their alkaloids, or because -of some toxins contained in them. We shall commence with these. - -=Abrin.=--This toxin, which was studied in particular by Warden -and Waddell,[52] then by Kobert[53] and de Hellin,[54] is found -in the fruit of the Leguminosæ, Abrus precatorius (wild licorice, -or jequirity). Its name was given it by Warden and Waddell, who -discovered both its toxic nature and the vegetable toxin; the toxin -is found only in the seeds. To extract it, the seeds are macerated -in water, and the solution filtered and precipitated with alcohol; -the precipitate which forms is collected and dissolved in distilled -water, from which it is again precipitated by adding powdered ammonium -sulphate. The precipitate is then collected and submitted to dialysis -in order to eliminate the ammonium sulphate. The abrin so obtained -forms an albuminoid substance[55] stable at 100° C., and possessing -rotatory power; it liquefies starch paste, and is extremely toxic. One -milligramme suffices to kill a rabbit within several hours. It must -be observed, however, that, as is the case with all the toxins, abrin -acts or kills only after a period of incubation which generally exceeds -twenty-four hours. - - [52] WARDEN and WADDELL: _Non-bacillar Nature of Abrus Poison_. - Calcutta, 1884. - - [53] KOBERT: _Arbeit. aus dem Pharmak. Institut._ Dorpat, 1893. - - [54] HELLIN: _Inaug. Dissert._ Dorpat, 1891. - - [55] EHRLICH: Experiment. Untersuchungen über Immunität. _Deutsch. Med. - Woch._, 1891. - -It is possible to vaccinate an organism so as to withstand a lethal -dose of abrin, but it requires quite a long time; it is effected by -injecting into a suitable animal very small doses of the substance, -and increasing the quantity gradually. Rabbits which have been -rendered highly immune towards venoms are capable of resisting without -inconvenience doses of abrin which are ordinarily fatal; and the blood -serum afforded by them contains a specific antibody for the substance. - -=Ricin.=--This vegetable toxalbumin has been studied particularly by -Stillmark,[56] by Dixon,[57] and Thuson.[58] It is found in the seeds -of the castor plant; three or four of the seeds suffice to cause a -gastroenteritis accompanied by serious symptoms and even by death. - - [56] STILLMARK: _Arbeit. aus dem pharmacol. Inst. Dorpat_, 1889. - - [57] DIXON: _Austr. Med. Gazette_, 1887. - - [58] THUSON: _Journ. f. prakt. Chem._, XCIV, p. 444. - -It was first isolated by P. Ehrlich, by treating the seeds with -lukewarm water, and precipitating the aqueous solution with alcohol. -The toxalbumin is soluble in water, but on boiling the solution, the -substance loses in great measure its activity. - -Ricin possesses considerable activity. 0.00003 Gm. suffice to kill a -rabbit when injected hypodermically; 0.2 Gm. are fatal to man. The -action is not immediate, but follows a period of incubation. Ehrlich -has shown that, exercising precaution, it is possible to create, as -with abrin, a condition of tolerance or habituation, and in consequence -to cause the formation of a specific antibody. - -=Robin.=--This toxic albuminoid was obtained from the bark of an Acacia -(Robinia Pseudacacia) by Power and Cambier,[59] by exhausting with -water at a temperature of about 30° C., and precipitating the infusion -with alcohol. The substance is analogous to ricin, and like this, -possesses powerful toxic properties. - - [59] POWER and CAMBIER: _Pharm. Journ. and Transact._, 1890. - -=Toxicity of the Vegetable Diastases.=--The diastases, which have been -treated of in a volume of the Encyclopédie Léauté,[60] and to which -we would refer the reader who is desirous of more complete details, -develop powerfully energetic toxic properties when injected into -the organism. Thus _amylase_ causes, when injected subcutaneously, -a considerable rise of temperature, but without any other toxic -symptoms. _Invertin_ or _sucrase_ was studied by Roussy under the name -_pyretogenin_, but it appears probable that this diastase was not the -only substance present in the product, but that there were present -reducing diastases, as we have already shown in the first volume of -this collection, devoted to the phenomena of reduction within the -living organism. - - [60] POZZI-ESCOT: _Les Diastases et leurs Applications_, Masson, 1900. - -The pyretogenin of Roussy gives rise to an attack of violent fever, but -it loses all activity when heated to 80-100° C. - -Through his researches, Roussy clearly demonstrated,[61] for the -first time, that the fever may cause the formation within the blood -of a substance clearly belonging to the class of soluble ferments or -zymases. Now, it is well known that within the animal economy there -exist many ferments of this character; and experiment has shown that -they can, at a given period and under various influences, leave the -cells in which they are normally localized, pass into the blood plasma, -and reach the nervous centers, where they cause serious effects. We -have already dwelt upon the mechanism of autointoxication of the -organism. The toxic action of certain digestive diastases has been -shown by Hildebrandt, who has demonstrated that 0.1 Gm. of pepsin is -capable of killing a rabbit in two or three days. - - [61] ROUSSY: _Aperçu historique sur les ferments et fermentations_. - Paris, 1901. J. Rousset, publ. - - - II. TOXINS FROM MUSHROOMS. - -Mushrooms are alimentary substances of the highest order, causing -a general stimulation of the entire organism. The substances -met with belong, according to their composition, to different -classes--celluloses, sugars, and amylaceous substances, alcohols, -acids, fats, astringents, essential oils, resins, alkaloids, and -albuminoids. The study of the last only, the albuminoids and diastases, -interests us here. The most important of these albuminoid substances, -_phallin_, was discovered in 1890 by Kobert. Pouchet also has isolated -a whole series of other toxic albuminoids, particularly from Amanita -muscaria (Fly Agaric). - -There are alimentary as well as toxic species in every possible variety -among mushrooms, some species consisting chiefly of the edible kind, -others consisting of the poisonous variety. - -In consequence of the toxicity of mushrooms, great attention must be -given to the treatment to which they are subjected when it is desired -to utilize them for alimentary purposes. Thus the toxic principles of -several varieties can be removed, and the mushrooms rendered edible by -very simple means. - -Pouchet has made a very ingenious comparison between the ethereal, -alcoholic, saline, and aqueous extracts of mushrooms, and bacterial -cultures. The analogy is striking as to the presence of toxin, -toxalbumose, and albumoses more or less toxic; it is moreover not -exaggerated, since, according to the classification generally admitted, -mushrooms are nothing more than the very advanced representatives of a -group the more simple members of which constitute the bacteria. - -The same author has shown that phallin obtained from the juice of the -Fly Agaric will kill a guinea-pig weighing 600 grammes in one hour. - -As we have already stated, it is the phalline to which the ordinary -disorders which mushrooms cause are due. According to Kobert, a 1:250 -000 solution of this substance causes an intense hemolysis, with all -its disastrous consequences. - -According to Pouchet, the flesh of mushrooms must be compared with meat -that has been kept for some time to become tender, and it is well known -that though this "tendering" process renders the meat more digestible, -it may also allow the meat to acquire noxious properties, due to the -presence of toxins. - -Phallin is the type of those toxic albuminoids of unknown composition -which exist in mushrooms, and which are comprised under the name -_sapotoxins_. The intravenous injection of phallin into an animal, in -the proportion of 1 part to 1 000 000 parts of body weight, causes -sudden death within one minute; in the proportion of 1:5 000 000, death -occurs in about three minutes; in the proportion of 1:50 000 000, death -also occurs, but is greatly retarded. An injection of 0.0005 Gm. per -kilo of body weight of animal causes solution of the blood corpuscles -to such an extent that thirty minutes later the blood serum is strongly -colored red, as well as the veins. - -Instead of being easily altered under the influence of an elevated -temperature, as are many of the albuminoid substances, whereby their -toxic power is lost, phallin may be boiled for half an hour with water -without undergoing any noticeable alteration. Pellegrini has observed -that the dried juice of Amanita Phalloides (Death-cup) preserves its -properties for more than a year. - -According to a recent paper by Gillot, the symptoms of poisoning by -mushrooms must be ascribed to albuminoids (phallin and albumose), -alkaloids (muscarine, choline, or betaine), or to resinoids (cambogic -and agaricic acids). - -The _alkaloids_ found in mushrooms are: _Muscaridine_ (an oxyneurine), -which possesses considerable toxicity, and of which 0.00005 Gm. -suffices to kill a frog; _neurine_ (trimethylethylammonium hydroxide); -_choline_ (trimethyloxyethylammonium hydroxide); _mycetomuscarine_; -_anhydromuscarine_ (an oxyneurine); and a whole series of various -betaines. - -=Symptomology.=--It is quite natural to divide this symptomology into -three different periods; that of incubation, that of manifestation of -symptoms, and that of termination. - -The duration of the first period, that of incubation, is exceedingly -variable; it very rarely lasts more than forty-eight hours, and becomes -general only a few hours after absorption. Certain conditions influence -the duration; firstly the quantity of mushrooms ingested, then the -manner in which they were prepared; and, to some extent, the nature of -the organism, whether child or adult, healthy or in poor health. - -When it is a question of the more particularly alkaloid-containing -mushrooms, especially when the poisoning is due to muscarine, the toxic -symptoms generally develop rapidly, the first symptoms appearing about -one hour after the ingestion of the mushrooms. On the other hand, if -the poisoning is due to one of the albuminoid group, and particularly -in the case of phallin, the period of incubation is longer, and may -last ten, twenty, thirty, or even forty-eight hours and more. - -The symptoms begin with dizziness and an indefinable sensation of being -ill. - -The second period is characterized chiefly by digestive and by nervous -derangements. The digestive derangements are evidenced by very violent -and painful vomiting, and diarrheas of choleraic or dysenteric -character. The nervous derangements vary according to whether they are -developed by an alkaloid, which causes delirium with hallucination, or -by albuminoids, which cause depression, ataxo-adynamia, and stupor, -these being particularly characteristic of the action of the toxic -albuminoids. - -As for the period of termination, it results either in death or a cure. -If the poisoning is due to phallin, death appears to be an almost -inevitable consequence, as it occurs in 80 per cent. or more of the -cases. The poisoning by the alkaloids is less dangerous, and the cure, -when it does occur, is very rapid, almost immediate, in fact, while in -the case of the toxic albuminoids the cure is very slow, and attended -by relapses. - -One characteristic of these toxalbumins is that they are apt to develop -specific antitoxalbumins. This fact has been verified not only in the -case of abrin, ricin, robin, and their analogues, but also in that -of the vegetable and animal diastases possessing toxic properties -even in the slightest degree only. These antibodies generally exhibit -their action _in vitro_. Thus antiricin exerts its antiagglutinative -action on the erythrocytes _in vitro_ in a saline medium in which the -erythrocytes cannot live. - -Here, again, as in the case of the antitoxins, it must be admitted that -the antitoxalbumin possesses a specific affinity by virtue of which it -unites chemically with the toxalbumin to give rise to a new substance -which is devoid of toxicity. - -The first antidiastase obtained by immunization methods, and according -to the mechanism we have already seen, was _antiemulsin_, obtained by -Hildebrandt.[62] This antiemulsin counteracts, both _in vivo_ and -_in vitro_, the specific action of emulsin. These studies have been -followed by a large number of scientists, particularly by Camus and -Gley,[63] Carnot, Mesnil,[64] and Charron and Levaditi,[65] in the case -of trypsin; and Sachs[66] in the case of animal pepsin. Gessard[67] -obtained a very active _antityrosinase_, and Mohl an _antiurease_. - - [62] HILDEBRANDT: Weiteres über hydrolyt. Fermente, etc. _Virch. - Arch._, CXXXI, 1895, P. 5. - - [63] CAMUS and GLEY: _Compt. rend. de la Soc. de Biolog._, 1897. - - [64] MESNIL: Sur la digestion des actinies. _Annales de l'Institut - Pasteur_, 1901. - - [65] CHARRIN and LEVADITI: _Compt. rend. de l'Académie dest Sciences_, - 1900. - - [66] SACHS: Ueber Antiseptika. _Zeitschr. f. Biolog._, 1901, XXVI. - - [67] GESSARD: _Annales de l'Institut Pasteur_, 1901, p. 609; _Comp. - rend. de la Société de Biologie_, May, 1902. - -The most important researches regarding this subject have been -published by Morgenroth, Briot,[68] and Korschum[69] on _antilab_ (or -_antirennet_). The researches of these authors have fully demonstrated -that there is considerable difference between the various rennets, -which had heretofore been confounded under one head; thus there is no -difference whatever between animal rennet and the rennet extracted -by Rosetti[70] from Cynara cardunculus (cardoon) so far as their -coagulant action on milk is concerned, yet each yields an antibody -which is strictly specific to itself. From a scientific point of -view we see, therefore, that the preparation of antidiastases permits -us to differentiate certain diastases that could otherwise not be -differentiated. - - [68] BRIOT: Thèse de Doctorat ès-Sciences, Paris, 1900. - - [69] KORSCHUM: _Zeitschr. f. physiolog. Chemie_, 1902, XXXI. - - [70] ROSETTI: _L'Orosi, giorn. di chemica, farmacia et scienza affini_, - 1898. - - - III. ANIMAL TOXINS. - -As we have shown at the beginning of this chapter, certain diastases, -and particularly those that are concerned with the digestive processes, -pepsin, trypsin, etc., and which are produced in abundance by the -entire living organism, possess quite clearly defined toxic properties, -and sometimes to even a considerable extent.[71] - - [71] GUSTAVE SAUX: De la toxicité des produits de la digestion - peptique. _Thèse de doctorat_, Bordeaux, 1902. - -Hemialbumose, from which peptones are formed, is itself a dangerous -toxin. It is generally believed that the toxic action of the peptones -and of the products of digestion of the albuminoids is due not to -the peptone itself, but to the more advanced products of digestion, -alkaloidal products unquestionably closely allied to the ptomaines. - -Nevertheless, the true peptones behave just like true poisons, when -they are introduced hypodermically into the blood.[72] - - [72] SCHMIDT: _Mühlheim, Arch. de physiol._, 1880. - -Brieger has made us acquainted with a non-proteid substance, under -the name of "peptotoxin," which is met with at the beginning of the -putrefaction of albuminoids. This toxin, which is not a protein, is -nothing else but a ptomaine. It is not altered by heat, and possesses a -very high toxicity. Brieger claims that it is a hydroxylized derivative -of an aromatic amide.[73] - - [73] BRIEGER: _Berichte d. D. chem. Gesellsch._, XIX, p. 3120; and - _Verhandl. d. Congress f. innere Med._, II, p. 277. - -Besides these facts, experiment has shown that the leucocytes, or white -corpuscles, the defensive rôle of which we have noted in phagocytosis, -owe their properties to the ferments which they secrete, and -particularly to some of the digestive ferments. These white corpuscles -are very rich in ferments of all kinds. Rossbach found in them amylase; -Achalme found lipase, casease, and trypsin; and the study of immunity -has brought to light a series of other ferments, the alexins or cytases -(microcytase and macrocytase), which have an exceedingly important rôle -to play. - -It may easily be conceived that under certain circumstances a part or -the whole of these ferments can pass into the blood of the fluids of -the body, when they give rise to serious disturbances in certain cases, -or confer immunity in others. - -It is thus that, according to Gautier, the rise of temperature which -characterizes fever is a consequence of the abnormal transudation of -these normal ferments into the blood, and their transmission by the -general circulation to the nervous centers. - -However, it is not only in the leucocytes that we meet with these -toxic digestive ferments; it appears quite probable, and has even been -partially demonstrated, that they occur in a large number of other -cellular elements. - -It is not necessary here to dwell upon the formation of the antibodies -of this group of active substances. The animal toxins are animal -diastases, and we have seen in the preceding paragraph that these -substances yield specific antibodies with great facility. For the rest, -we will dwell more fully on these antibodies of the animal toxins in -another volume of this collection, specially devoted to the study of -these substances, and entitled "_Les Serums Immunisants_," to which we -refer the reader who is desirous of obtaining more complete details -than he can obtain in the present volume. - -=Alimentary Intoxications.=--What we have already stated permits -us to understand the phenomena of indigestion and botulism. The -toxic substances form within the digestive tract when the nervous -conditions modify the composition of the gastric juice, and arrest -the flow of hydrochloric acid, the presence of which normally checks -the development of the microbial flora, so rich within the stomach. -The result is the production, within the organism, of all kinds of -dangerous toxins. The same thing happens when the liver does not -functionate normally, and this, affords us a knowledge of the mechanism -by which foods that are most wholesome may become toxic by reason of -poor digestion or poor assimilation. - -The absorption of spoiled viands may, _a fortiori_, produce serious -results. The alteration may be due not only to a bacterial infection, -as in tainted meat, but it has also been proved that the flesh of an -animal that has died of terror or madness may be very dangerous as a -food, even after cooking, because, although there are toxins which are -destroyed by a sufficient heat, there are ptomaines and certain toxins -that resist destruction under these conditions.[74] - - [74] POLLIN and LABIT: _Examens des aliments suspects_, Masson, - publisher. - -The use of preserved but spoiled beef, preserved ham or birds, sausages -frequently, and pieces of pork tainted by sausage poison, gives rise to -a succession of toxic symptoms the principal ones of which are dryness, -constriction of the pharynx, bilious vomiting, diarrhea, dyspnea with -pulmonary edema, etc. Fish and eggs are foods quite frequently capable -of developing serious results; the same is the case with molluscs, -mussels, oysters, lobsters, and snails. Lastly, moldy bread, spoiled -cheese, putrid water, and spoiled vegetables themselves, are proper -agents for determining attacks of botulic poisoning. - -We have seen, at the beginning of this volume, that putrid meats -contain ptomaines, which are among the most toxic alkaloidal bases. We -have shown that Brieger has isolated from them neuridine, putrescine, -muscarine, and guanidine; that Nencki has isolated hydrocollidine; -and that Gautier and Etard have obtained from them parvoline--only to -mention a few of them. - -Lastly, there may develop within the gastrointestinal tract dangerous -putrefactions, the products of which may enter the veins and arteries -from the ileum (a portion of the small intestine) and be distributed -throughout the organism. Although such poisonings occur, they do not -immediately follow the ingestion of the spoiled or toxic foods, but -they are always preceded by a period of incubation varying from several -hours to several days. - -These alimentary poisonings are recognized by a great physical -depression, accompanied by vomiting and paralysis of the lower -extremities, sweats, and diarrheas. In some cases there occur cutaneous -eruptions; and when death happens, this occurs only several days later, -and generally without being preceded by any great pain. - -=Urinary Toxins.=--As we have already remarked several times, it is by -the renal way that the organism voids its principal waste products. - -We have seen also that it is by the kidneys that the toxins are -eliminated in all pathological conditions. As a general rule, the -urines are always more or less toxic. This toxicity of the urines -must be attributed in the first place to the crystallizable organic -principles (ptomaines and leucomaines[75]) which they contain; -secondly, to the non-crystallizable[76] extractive matters not so well -known; and lastly, to the saline substances, among which the potassium -salts are the most active. We find these mineral salts particularly -abundant under normal conditions in the urines of the herbivora. -According to Bouchard, 0.18 Gm. of potassium chloride are sufficient -to prove fatal to 1000 Gm. of living organism; a man excretes on the -average 2.5 Gm. of this salt, and a rabbit excretes about double this -quantity, weight for weight. - - [75] ADDUCO: _Arch. Ital. de biolog._, 1891. - - [76] POUCHET: _Thèse de Doctorat en Médecine_, Paris, 1878. - -A very large number of hypotheses have been advanced regarding the -toxicity of the urines. Wilson considers the urea as being responsible -for it; Stadthagen[77] believes it to be due to the potassium salts, -etc. Bouchard[78] was the first to recognize that the toxicity of the -urines is due to a number of causes. We will not dwell further on these -active principles which, in the last analysis, are no other than -those that form in the various portions of the organism, and which are -eliminated by the urine. - - [77] STADTHAGEN: _Zeitschr. f. Klin. Med._, XV. - - [78] BOUCHARD: _Leçons sur les Autointoxications_. - -It is self-evident, and it has already been shown, that the toxicity -of the urines varies greatly according to the malady, in consequence -of the elimination of toxins by the urines. According to Bouchard, in -infectious maladies the urines are twelve times more highly charged -with toxins than is blood serum. Moreover, the toxicity of the urines -is considerably augmented the moment there is the least febrile -condition, no matter what the cause is.[79] - - [79] Regarding this point see the excellent work by A. CHARRIN: - _Poisons de l'Organism_. Masson, publ. - -Even in the normal condition, the urinary toxicity varies greatly; and -this is easily conceived since the physiological phenomena that control -this secretion undergo incessant rise and fall. Thus, for example, the -urines eliminated during sleep are less active than those produced -during waking, because during sleep the elimination of cellular poisons -is at a minimum. Exercise, walking, physical and intellectual labor, -exert their portion of influence on these oscillations of toxicity; -and this variation of toxicity is due not to any one variation in the -mineral extractive matters, but rather more or less to the organic -toxic products. We will not dwell further on this subject, but will -simply refer to the work by Charrin, already mentioned, for all -supplementary details. - -=Autointoxications.=[80]--The cells of the organism having, as a whole, -a life very much like that of the microbes, it is quite natural that -among the excreted products of the living tissues there should be found -the same substances formed as a result of the anaerobic fermentation of -albuminoids. Experiment has demonstrated that this is so, and Armand -Gautier has irrefutably proven the existence of these principles.[81] -Bouchard was the first to demonstrate the toxic nature of muscle -extract,[82] and Roger[83] established the fact that the toxicity of -this extract is due to ferment-toxins; it has since been recognized -that after death these toxins accumulate in the muscles. - - [80] CH. BOUCHARD: _Des Autointoxications_. Paris, 1887. - - [81] _Bull. Acad, de Médecine_ (2), X, p. 947, and XX, p. 115. - - [82] BOUCHARD: _Leçons sur les Autointoxications_, Paris, 1887. - - [83] ROGER: Toxicité des Extraits des Tissus Normaux. _Soc. de - Biolog._, 1891, p. 728. - -The extract of kidney made rapidly by cold process by triturating the -washed kidney with glycerin, and precipitating the glycerinic solution -with alcohol, contains toxic ferments to which the name "_hystozymes_" -has been given.[84] These ferments split up hippuric acid into benzoic -acid and glycocoll. Lépine has likewise discovered in the kidney a -very toxic pyrogenic substance.[85] Roger has given us evidence of the -toxic properties of the liver, washed and pulped, and then sterilized -by filtration through a porous diaphragm. This scientist has shown that -the toxic properties are due to albuminoids, which lose their activity -when heated to 100°C.[86] - - [84] It is well to recall here that the kidneys contain both reducing - and oxidizing ferments, as has been demonstrated by de Rey-Pailhade, - and later by Abelous and Gérard. - - [85] LÉPINE: _Compt. rend. de l'Acad. des Sciences_, May 13, 1889; - _Soc. de Biol._, 1891, p. 724. - - [86] ROGER: _Compt. rend. Soc. Biol._, 1891, p. 727. - -It must be remarked that the organs we have studied are essentially -reducers, and that the more powerful reducers yield the most toxic -extracts. We find here a confirmation of Armand Gautier's views -regarding the anaerobic origin of the toxic substances formed within -the organism.[87] - - [87] POZZI-ESCOT: _Compt. rend. de l'Acad. de Médecine_ (3), XLVII, p. - 400. See also POZZI-ESCOT: _Etat actuel de nos Connaissances sur les - Oxydases et les Réductases_. Dunod, publ., Paris. 1902. - -Blood serum precipitated by alcohol affords products which possess very -marked toxic power. It would appear that the toxic products we speak -of here are thermogenic diastatic substances derived from the white -blood corpuscles. In certain diseases the blood serum may acquire a -high degree of toxicity. We will recur again presently to this property -as a normal characteristic of the blood of various animal species, and -will study it in greater detail in a future volume of this collection, -devoted to the immunizing active principles. - -=Glandular Secretions.=--On studying the venoms we will see that a -certain number of these products are the result of glandular secretion. -This is a general property of the glands; and it was Brown-Sequard who -first drew attention to the rôle played by these glands, and to the -importance of the products that they throw into the blood.[88] - - [88] _Compt. rend. de l'Acad. des Sciences_, CXIV, pp. 1237, 1318, - 1399, and 1534; CXV, p. 375; and CXVI, p. 856. - -P. Noel showed later that the testicular juice possesses a high degree -of activity, which he attributed to an oxidizing ferment, and which we -have already mentioned, _spermine_. - -The greater number of the other glands contain proteid matters and -various peptones, more or less toxic, with amides and alkaloids. - -Particular mention must be made of the thyroid gland, the secretions -of which exercise a powerful action on the nervous centers and on -nutrition.[89] It appears reasonable to attribute to the secretions -of this gland a very powerful antitoxic action, and the first proof -of this fact is that the organisms deprived of this gland become the -seat of serious derangements; the urines of such organisms become -particularly toxic, while, on the other hand, the hypodermic injections -of the aqueous extract of the gland, when the derangements spoken of -exist, cause the immediate disappearance of the derangements caused by -the excision of the gland.[90] - - [89] LAULANIÉ: _Compt. rend. Soc. de Biol._, 1894, p. 187. - - [90] GLEY: _Compt. rend. Soc. de Biol._, 1891, p. 250. - -Attempts have been made to isolate the active principle of the glands. -Notkine isolated a _tyroproteid_,[91] which is not sensibly toxic to -animals who still retain the gland, but which becomes toxic when the -gland is excised. It seems probable, however, that this product is not -the principal agent of the thyroid gland. - - [91] _Semaine Médicale_, Apr. 3, 1895, p. 138. - -From the researches of Schaeffer, Roos, and Sigmund Fraenkel[92] it -results that the active principle of the gland is not a toxin, but a -purely chemical substance, a true leucomaine, which has received the -name _thyroantitoxin_. - - [92] _Wiener Med. Blätter_, No. 48; and _Gesellsch. d. Aerzte in Wien_, - Nov. 22, 1895. - -On the other hand, Baumann quite recently extracted from the thyroid -gland an iodized substance, which he named _thyroiodine_.[93] - - [93] _Zeitschr. f. Physiol. Chem._, XXI, pp. 319 and 481; and XXII, p. - 1. ARMAND GAUTIER: Chimie Biologique, 2d edit., pp. 330-332. Masson, - publ. - -The suprarenal capsules also possess properties that have often -attracted the attention of physiologists during the last few years. -They are considered as being, just like the thyroid gland, producers -of antitoxins; they destroy, or seem to destroy, toxins that are -artificially introduced into the circulation. - -Albanèse[94] maintains that the function of the suprarenal capsules -is to neutralize neurine, the toxic product of the disassimilation of -the nervous system; this view, however, is opposed by Boinet[95] and -Langlois.[96] On the contrary, it has been definitely proven that the -suprarenal glands exert a specific action on the poisons of muscular -origin. Abelous and Langlois[97] have in fact demonstrated that the -alcoholic extract of the muscle of a decapsulated animal has the same -properties as the extract of tetanized muscle; the decapsulated animal -gives ergographic tracings analogous to those afforded by tetanized -animals. The removal of the suprarenal capsule from an animal brings -results, hence, analogous to those of fatigue--that is to say, that -the toxic substances which accumulate as a result of the decapsulation -resemble those that result from muscular exertion. The suprarenal -capsules exert their action furthermore on other toxic products as -well, as Guieysse[98] has shown, and particularly on the exogenous -poisons. In conclusion, it may be said that the matter concerns a -most important rôle, and we cannot do better in this respect than -to refer the reader to the memoir presented by Sergent and Bernard -to the Académie de Médecine in 1902 and entitled _l'Insuffisance -Surrénale_.[99] - - [94] ALBANÈSE: Recherches sur les fonctions des capsules surrénales. - _Arch. Italiennes Biol._, 1892. - - [95] BOINET: _Compt. rend. Soc. de Biol._, Mch. 1896. - - [96] See _Compt. rend. de Biol. et Arch. Physiologie_, 1891-1897. - - [97] LANGLOIS: Thèse de doctorat en Méd., Paris, 1897. - - [98] GUIEYSSE: _Les capsules surrénales du cobaye_, Thèse, Paris, 1901. - - [99] Encyclopédie Léauté, CCCXIV, Masson, publ., Paris, 1904. - - - - -CHAPTER IV. - -THE MICROBIAL TOXINS. - - -There is but one way of characterizing the toxic poisons secreted -by microbes, and that is to apply to them the name of the microbes -generating them; thus the soluble and toxic poison of the tetanus -bacilli has received the name _tetanus toxin_. - -In toxic microbial cultures it is necessary to distinguish the toxins -proper from the toxic alkaloids (ptomaines) which generally accompany -them; this is easily accomplished by evaporating the solution in a -vacuum at about 30°C., and then treating with alcohol and ether, in -which the alkaloids are soluble, while the true toxins are insoluble. -By fractional precipitation with alcohol it is easy to isolate the -peptones and true toxins. - -The microbial toxins possess two essential properties; one the pyogenic -property, thanks to which the toxins first attract, then destroy the -white blood corpuscles or leucocytes, and transform them into pus, and -the other the pyretogenic property, which appears to belong only quite -indirectly to the pyogenic substance. The toxins in general retard the -heart action. - -We will not speak of the distinctions it has been sought to establish -between the substances which possess these different properties, but -will at once take up the discussion of several of the microbial toxins. - -=Anthrax Toxin=[100] (from Bacillus Anthracis).--We will describe the -preparation of this toxin as a type. - - [100] ARLOING, CORNEVIN, THOMAS: _Le Charbon Symptomatique_, 1st edit., - Paris; and LE DANTEC: _La Bactéridie du Charbon_, Masson, publ.; - STRAUS: _Le Charbon des Animaux et de l'Homme_, Paris, 1887. - -The cultures of the bacillus are made in Liebig's bouillon, to which -has been added 0.1% of fibrin, the whole being carefully sterilized -for a long time at 110° C. The cultures medium is inoculated with a -drop of blood taken from the heart or spleen of an animal that has -died of anthrax. At the end of a week, the culture is filtered, and -the filtrate acidulated with a little acetic acid and precipitated -by adding powdered ammonium sulphate. The flocculent precipitate -is collected, washed, dissolved in distilled water, and dialyzed. -The dialyzed solution is concentrated in vacuo at 40-45° C., and -precipitated by adding to it alcohol. The precipitate formed is then -collected and dried.[101] - - [101] HANKIN: _British Medical Journal_, Oct. 12, 1889, and July 12, - 1890. - -In this manner there is obtained a grayish-white substance which is -soluble in water, and which is fatal in large doses, but which, given -in repeated small doses, confers immunity against anthrax. - -According to Hankin, it seems that the toxic property of this toxin is -due to an albumose. - -Marchoux[102] has been able to confer immunity upon sheep by injecting -first small quantities of the filtered culture of the anthrax bacilli, -and then the virulent anthrax itself. - - [102] _Annal. Instit. Pasteur_, IX, p. 785. - -The animals thus rendered immune yield a serum which may be used as a -vaccin against anthrax, and which even possesses curative properties -under certain conditions. - -In every case the acquired immunity is only temporary. We will recall -to recollection the method employed by Pasteur for vaccinating against -anthrax, using attenuated cultures, a method which is practiced daily -at the present time.[103] - - [103] CHAMBERLAND: _Le Charbon et la Vaccination Charbonneuse_, Paris, - 1887. PETERMANN: _Annal. Instit. Pasteur_, VI, p. 32. - -From the cultures of symptomatic anthrax (Bacillus Chauvæ) Chauvée -extracted a very active toxin which can withstand without impairment -a temperature of 110°C.[104] Roux[105] has shown that the serum of -animals that have succumbed to the symptomatic anthrax is capable -of vaccinating against this disease; we have here a new proof that -the antitoxin is in fact a product of the defense of the cells of -the organism, and the author mentioned has been able to vaccinate -guinea-pigs by injecting into the peritoneum culture bouillon -sterilized by heating to 115° C. or by filtering through porcelain. - - [104] DEUTSCHMANN: _Annal. Instit. Pasteur_, VIII, p. 403. - - [105] _Annal. Inst. Pasteur_, Feb. 1888. - -=Tubercular Toxin.=--The culture bouillons of Koch's bacillus contain -one or more active substances which constitute, and which is at the -present designated as, tuberculin.[106] Koch's therapeutic tuberculin -is obtained by evaporating to one-tenth its volume a culture bouillon -of Koch's tubercle bacilli prepared from a 4-per cent. glycerinic -mutton bouillon, and filtering through porcelain. By fractional -precipitation it is possible to obtain from the crude tuberculin so -prepared a product which is considered as pure tuberculin, and which -possesses considerable activity. - - [106] AUCLAIR: _Thèse de doctorat_, Paris, 1897; and _Arch. de - Médecine_, exp. 1898. - -Prolonged boiling on the water-bath completely destroys the activity -of this tuberculin, which moreover hardly ever keeps longer than three -weeks. It has been found possible to preserve it for an indefinite -period, however, by adding to it 30 to 40 per cent. of glycerin. It -possesses all the general reactions of albuminoids. - -Tuberculin is not toxic in the proper sense of the word. Injected in -small quantities into the healthy human being[107] and into healthy -animals, it exerts no effect; on the other hand, however, in tubercular -organisms, even in incipient stages of the disease, even where it is -almost impossible to make a clinical diagnosis, the injection of very -small quantities develops a lively and characteristic reaction.[108] - - [107] KOCH: _Deutsch. Med. Woch._, Nov. 13, 1890-1897, No. 14, p. 209. - - [108] _Annal. de l'Instit. Pasteur_, V, p. 191; _Arch. de la Soc. Biol. - de Saint-Pétersbourg_, I, p. 213. - -Grasset and Vedel consider the tuberculin as an excellent means of -diagnosing tuberculosis in man, but in such a case it is necessary -to operate with the greatest caution, with very small quantities of -the tuberculin, and to feel, in some sort, the sensitiveness of the -patient, particularly in the case of children. - -It is chiefly for the diagnosis of tuberculosis in cattle, however, -that tuberculin is valuable. Thanks to Nocard, the procedure has to-day -become a common practice. The injection of a fairly large dose, 0.3 -to 0.4 Gm., according to the size of the animal, causes, in about ten -hours or so, if the animal is tuberculous, a strong febrile reaction -with an elevation of temperature of 1.5 to 3° C., whereas if the animal -is not tuberculous no such reaction takes place. - -Cases in which tuberculosis is far advanced, and in which the organism -is impregnated with tuberculin, do not react after the injection of -tuberculin.[109] - - [109] NOCARD and LECLAINCHE: _Les Maladies Microbiennes des Animaux_. - -Tuberculin does not confer immunity, and the bacillus retains all its -virulence, even in injected tissues; nevertheless, the return to health -of animals in which injections have been recently made may be due to -the action of large doses of the serum; and on the other hand the -tuberculin, in large quantities, may render the location unsuitable for -the development of the tubercle bacilli. - -=Diphtheria Toxin.=--The most characteristic property of the diphtheria -bacillus is the production, in culture media, of a special toxic -substance which has been named _diphtheritic toxin_; this name, -however, has come to be also extended to a liquid in which the bacilli -have lived, and which has been sterilized by filtration or by any other -suitable process. - -Roux and Yersin[110] were the first to affirm that diphtheria is an -autointoxication caused by a very active poison formed by the microbe -in the restricted locality where it develops. In order to obtain this -toxin[111] a culture of the bacillus is first made in a mutton bouillon -made strongly alkaline with sodium carbonate (10 grams per liter), and -with the addition of 2 per cent. of peptone. At the end of about one -month, the culture being kept at about 37° C., the liquid is filtered -through porcelain. It is indispensable to employ a very virulent -bacillus; it is hence frequently advantageous to increase the virulence -and toxigenic power of the bacilli it is desired to use. - - [110] _Annal. de l'Instit. Pasteur_, II, p. 632, and VIII, p. 611. - - [111] See SPRONK: _Annal. de l'Instit. Pasteur_, IX, p. 785; _Ibid._, - X, p. 333; MARTIN, _Ibid._, XII, p. 26; SPRONK, _Ibid._, XII, p. 711. - -The toxic liquid obtained is exceedingly powerful: 0.1 Cc. kills a -rabbit in forty-eight hours. This toxin is very sensitive to the -effects of heat. When heated to 65° C. it loses almost all its -toxicity; at 70º C. it becomes innocuous; and it only requires to be -heated to 100° C. for fifteen minutes in order to lose all immediate -activity even in large doses. Nevertheless toxins thus weakened are -capable of proving fatal to an animal even after five or six months. - -Light, oxygen, ozone and all oxidizers destroy the active principle of -the diphtheria toxin, which is, moreover, rendered almost inactive by -organic acids. - -This toxin is capable of diffusing through animal membranes, a fact -that is in agreement with the toxic effect seen in a subject attacked -with diphtheria, and due to the toxin passing through the mucosa. In -spite of this property, however, the diphtheritic poison may be taken -into the stomach without any pernicious results. - -Roux and Yersin have shown that, like all the diastases, it may be -precipitated from its solutions by the development, within these, -of certain precipitates, particularly calcium phosphate. It is -precipitated from its solutions by alcohol, as has been observed -also in the case of diastatic solutions. All the toxic substance -is contained in the albuminous precipitate thus obtained; but the -prolonged action of alcohol, or repeated successive precipitations, -alter it finally. Diphtheria toxin is likewise precipitated by the -reagents for albumoses, particularly sodium sulphate in saturated -solution. This procedure has been utilized by Brieger and Fraenkel -for preparing the pure toxin, which they obtained in the form of very -light, brilliant white, amorphous flocks, affording all the principal -reactions of the soluble albumoses (biuret, xanthoproteic, Millon's), -and which they characterized as a toxalbumin. - -On injecting into healthy animals this diphtheria toxin attenuated -by sufficiently heating at 70° C, employing at first small doses, -and gradually increasing, it is possible to immunize them against -diphtheria, as was first demonstrated by Carl Fraenkel. - -Roux and Martin, who have specially studied this procedure,[112] have -shown that a horse may be easily immunized by injecting into the animal -the toxin diluted with a third of its volume of Gram's iodine solution, -and in successively increasing doses. The initial dose is 0.25 Cc.; -then, after two days, 0.5 Cc. of the same toxin is injected, and in -like manner the dose is increased up to the eighteenth day, when the -pure toxin is injected, at first in small doses, which are gradually -increased so that at the end of two or three months injections of 80 -Cc. of the pure toxin may be given without danger; the animal is then -completely immunized. - - [112] Contribution à l'Étude de la Diphtérie. _Annal. de l'Instit. - Pasteur_, VIII, p. 609; _Ibid._, p. 640. - -The serum of an animal rendered immune in this manner contains a -diphtheria antitoxin which possesses high power. A guinea-pig which -has received an injection of 0.01 Cc. of the antitoxin is perfectly -capable of withstanding a lethal dose of 0.5 Cc. of the toxin. The -antidiphtheria serum thus obtained, and in almost limitless quantities, -from an immunized animal, is capable of saturating the therapeutic -diphtheritic toxin, and has to-day taken rank in therapeutics as the -most efficacious remedy in diphtheria. Injected in varying doses, it -confers a temporary but immediate immunity. - -Nevertheless antidiphtheria serum must not be considered as an -antidote; and in pathological diphtheria, the more serum is required -the later it is used.[113] In certain cases, if employed too late, it -may prove ineffective. - - [113] BAYEUX: _Thèse de Doctorat_, Paris, 1899. - -The preventive action of the serum is remarkable. In 10 000 inoculated -cases Behring and Ehrlich have had but 10 cases of diphtheria, and -these were, moreover, of a benign character. The duration of the -immunizing action appears to be from three weeks to two months. - -This diphtheria antitoxin was first prepared by Guérin and Macé[114] by -adding to the antidiphtheria serum a large volume of alcohol, washing -the precipitate, and drying it in a vacuum. It is soluble in water, and -loses its activity when heated to 65° C. Wassermann[115] has proposed -to extract it from the milk of immunized animals, by first coagulating -the milk by rennet in the presence of sodium chloride, filtering, and -removing the fat from the clear liquid by means of chloroform. After -decanting, the clear solution obtained is precipitated by adding to it -30 to 33 per cent. of ammonium sulphate. The precipitate is dried in a -vacuum on a polished porcelain slab after having first been strongly -expressed. It is then dissolved in water.[116] - - [114] _Compt. rend. de l'Acad. des Sc._, Apr. 5, 1895. - - [115] _Zeitschr. für Hygiene_, XVIII, p. 235. - - [116] ROUX and MARTIN: Contribution à l'Étude de la Diphtérie. _Annal. - de l'Instit. Pasteur_, VIII, p. 512. - -=Tetanus Toxin.=--The fact that the tetanus bacillus never penetrates -to the interior of the organism enabled us long ago to foretell that -it secretes a very powerful toxin capable of dialyzing and diffusing -through the economy. Kuno Faber was the first to fully recognize the -fact that the culture bouillon of this bacillus, fully sterilized by -filtration through porcelain, possesses an exceedingly high toxicity, -and exerts a toxic effect on 50 000 000 times its own weight of living -organism. Brieger had previously, however, extracted three ptomaines -from the cultures of the bacillus--_tetanin_, _tetanotoxin_, and -_spasmotoxin_.[117] In order to obtain a highly active liquid, the same -culture medium is inoculated several times in succession, but filtering -each time before the new inoculation; the microbes greatly increase in -number after each fresh inoculation, and the toxic substance developed -by them accumulates.[118] - - [117] Die Pathogenese des Tetanus. _Berlin. Klin. Wochenschr._, 1890, - No. 31. - - [118] NAILLARD: _Compt. rend. de l'Acad. des Sciences_, CXX, p. 1181. - -Experiment has shown that the culture bouillon thus obtained contains -two kinds of toxic substances[119]--highly toxic alkaloidal bases -(ptomaines, tetanin, tetanotoxin, etc.), and a true toxin, possessing -diastatic properties, and of almost incredible toxic power. - - [119] _Annal. Instit. Pasteur_, V, 15. - -This toxin had already been isolated by Kitasato. It is a toxalbumin, -and is very sensitive to the action of heat. A temperature of 65° C., -maintained for 30 minutes, renders it quite inactive; and it becomes -oxidized and is destroyed by the action of the air in the presence of -light. - -Brieger and Boer,[120] by precipitating with zinc chloride the filtered -culture bouillon, obtained a pure, amorphous tetanus toxin, which they -also considered as a toxalbumin, and which possesses exceedingly toxic -properties. - - [120] _Deutsche Med. Wochenschr._, No. 49, Dec. 3, 1896. - -If a precipitate be caused to form in these toxic solutions, as, for -instance, a precipitate of calcium phosphate, this carries down with it -all the toxin present in the liquid. 0.0005 Gm. of this precipitate is -surely fatal to a guinea-pig. - -Dozon and Cournemont have observed that even in doses of 300 to 400 Gm. -of the filtered culture liquid, this toxin is not immediately toxic -to a horse, but kills the animal only after a period of incubation -of at least twenty-four hours. The blood of such an animal, however, -is immediately and directly fatal to animals into which it is -injected.[121] - - [121] _Compt. rend. Soc. Biol._, 1893, p. 294; _Ibid._, 1894, p. 878. - -Experiment has shown that animals that have been cured of tetanus -possess no immunity whatever against tetanus; nevertheless Behring and -Kitasato[122] first, and Wassermann and Kitasato later on, succeeded -in preparing a _tetanus antitoxin_. To obtain this, the immunization -of the animal, horse or cow, is effected by injecting increasing -quantities of the toxin, more or less attenuated by mixing it with -Gramm's iodine solution; the immunization is easily and rapidly -accomplished by the process devised by Roux and Vaillard.[123] - - [122] _Deutsch. Med. Wochenschr._, 1890. - - [123] _Annal. Instit. Pasteur_, VII, p. 64. - -The immunized animals yield a serum which, mixed with tetanus cultures, -renders these innocuous, and which enjoys an antitoxic power that -borders on the marvelous.[124] A quintillionth of a cubic centimeter -of the serum per gramme weight of a live mouse suffices to protect the -animal from an otherwise fatal quantity of tetanus toxin.[125] - - [124] NOCARD: _Bull. de l'Acad. de Médecine_, Oct. 22, 1895. - - [125] NAILLARD: _Compt. rend. de l'Acad. de Sciences_, CXX, p. 1181. - -This serum is nevertheless powerless to preserve man in cases of acute -tetanus; it confers an immediate, but only transitory, immunity. - -As to its mode of action, it appears to cause a permanent condition -of excitation or of nutritive reaction of the cells, which makes -these resistant to the poison. As in the case of the other toxins, -the quantity of antitoxin necessary to protect an organism is so much -greater the later the treatment is applied. - -=Mallein (Toxin of Glanders).=--Among the soluble products secreted -in the culture media by the glanders bacilli, there are found true -toxins to which are ascribed certain symptoms of glanders infection. -These toxins have been isolated and designated by the name _mallein_. -First prepared by Helman and Kalmino, mallein was later on specially -studied by Roux and Nocard, and, in consequence of the researches of -the last-mentioned scientist, it has acquired great importance.[126] It -is obtained by sterilizing at 110° C. cultures of the glanders bacillus -made with mutton bouillon with the addition of salt, glycerin, and -peptones. To isolate the toxin the culture bouillon is first sterilized -by heating for half an hour in an autoclave at 100° C. It is then -filtered, concentrated to one-tenth its volume on a water-bath, and -filtered through a Chardin filter. The mallein is thus obtained in the -form of a brown syrupy liquid containing half its weight of glycerin. - - [126] NOCARD: _Les Maladies microbiennes des animaux_, Paris. - -This solution keeps well when kept from air, light, and heat. In -practice it is employed in 10-per cent. solution in phenolated water -(5:1000). The mallein may be precipitated from the crude solution by -the addition of alcohol, as recommended by Foth. Foth's mallein occurs -as a white, light powder, very easily soluble in water. - -Mallein enjoys a very important rôle in veterinary therapeutics, a rôle -analogous to that of tuberculin, permitting the diagnosis of incipient -glanders.[127] - - [127] STRAUSS: _Arch. de Médic. expériment_, 1886. - -Experience has shown that in animals already attacked by glanders, -even if ever so slightly, the thermic reaction never fails when 0.25 -Cc. of the mallein solution is injected. In healthy animals, however, -the injection of mallein, even in much larger quantities, causes no -apparent effect. In animals attacked by glanders the reaction attains -its maximum in twelve hours, and several days are required for the -temperature to return to normal.[128] - - [128] CADIOT and ROGER: _Compt. rend. Soc. Biol._, 1895, p. 770; - WLADIMIROW: _Arch. des Sciences Biol. de St.-Pétersbourg_, IV, p. 30; - BOURGES and MÉRY: _Soc. de Biol._, Feb. 5, 1878. - -According to Nocard, mallein possesses no immunizing properties -whatever.[129] - - [129] GALTIER: _Compt. rend. de l'Acad. des Sciences_, XCII, p. 303; - STRAUSS: _Arch. de Médic. expériment_, I, p. 489. - -=Typhoid Toxin.=--This is obtained, like the other microbial toxins, -from a culture, prepared with more or less difficulty, from Eberth's -typhoid bacillus. This toxin, injected into guinea-pigs, develops in -them typhoid fever. - -In the solution there occurs a ptomaine, which has been isolated by -Brieger, and which gives rise to almost all the phenomena of typhoid -fever; this ptomaine is called _typhotoxin_.[130] - - [130] BRIEGER: _Microbes, Ptomaïnes et Maladies_, Doin, publ., Paris, - 1887; LUFF: _Brit. Med. Journ._, 1889. - -The same author, in collaboration with Fraenkel,[131] later on isolated -a toxalbumin from the culture bouillon of the typhoid bacillus. -Sanarelli[132] obtained an active toxin by macerating for several days -at 60° C. a month-old culture of the typhoid bacillus made with a 2-per -cent. glycerin-bouillon. Chantemesse has also published a process which -yields a highly virulent toxin.[133] - - [131] _Berlin. Klin. Wochenschr._, 1890. - - [132] _Annal. de l'Instit. Pasteur_, VIII, p. 103. - - [133] _Compt. rend. Soc. de Biol._, p. 232, Jan. 30, 1897. _Congrès - d'Hygiène de Madrid_, 1898. - -Chantemesse and Widal[134] have shown that on injecting into an -organism increasing quantities of the sterilized cultures of Eberth's -Bacillus, it is possible to fully immunize an animal against the -bacillus itself, and even also against the Bacillus coli communis. The -operation, however, is tedious and painful. The serum of immunized -animals possesses preventive and curative properties respecting the -effects of typhoid bacilli. - - [134] _Annal. l'Instit. Pasteur_, VI, p. 755; SANARELLI: _Ibid._, p. - 721. - -A dose of the filtered culture, which is fatal to a guinea-pig, -becomes innocuous when mixed with 0.5 Cc. of the serum of a vaccinated -guinea-pig; 6 Cc. of the serum injected six hours after an injection -of the virulent culture, hence when this is in full action, suffice -to save the animal.[135] So far as the human being is concerned, the -results obtained have not been sufficiently satisfactory. - - [135] FUNCK: _La Sérothérapie de la Fièvre Typhoïde_, I, Brussels, 1896. - -The culture bouillon of the Bacillus coli communis, which is closely -allied to Eberth's bacillus, also contains soluble toxic substances -which have been named coli-bacillus toxin. This substance, which is -produced only in small quantity by the microbe, is fatal only in very -large doses. - -=Cholera Toxin.=--Very little is known regarding the toxic products of -the spirillium choleræ; nevertheless, the fact that typical cholera -exhibits every symptom of the action of a toxic agent demonstrates -quite clearly the elaboration of some toxic substance within the -cultures of this microbe. - -Villiers[136] found in it a liquid ptomaine; Klebs[137] found another -and crystallizable ptomaine; while Pitai discovered in it a toxin -unalterable by heat, and which he considered as a toxopeptone. -According to Gamaleia[138] there is present a true toxin, alterable -by heat, and the reactions of which entitle it to be considered as a -nucleo-albumin; he has also found in it a toxic nuclein. - - [136] _Compt. rend. de l'Acad. des Sciences_, Jan. 12, 1885. - - [137] KLEBS: _Allgem. Wien. Med. Zeit._, 1887. - - [138] _Arch. de Méd. Expérim._, IV, p. 173. - -These toxic substances are found, according to Gamaleia, Pfeiffer, -and Sanarelli,[139] confined during the life of the microbe within -its cellular envelope, and does not diffuse through this. Metchnikoff -and Roux are of the contrary opinion,[140] however, and they have -prepared a toxin almost insensitive to a temperature of 100° C., and -precipitable from its solutions by ammonium sulphate or strong alcohol; -the toxin is a toxalbumin. This toxin is quite toxic; one-third of a -cubic centimeter suffices to kill 100 Gm. of guinea-pig in 18 hours; -with larger doses, death is almost immediate. - - [139] _Annal. de l'Instit. Pasteur_, IX, p. 129. - - [140] _Ibid._, X, p. 257. - -By immunizing guinea-pigs, rabbits, and horses with this cholera toxin, -Metchnikoff and Roux obtained a serum which is distinctly antitoxic for -rabbits. Nothing absolutely certain has been found as to its action on -man.[141] - - [141] HAFFKINE: _Compt. rend. de l'Acad. des Sciences_, 1892; - METCHNIKOFF: _Annal. de l'Instit. Pasteur_, VII, p. 403; and ROUX: - _Ibid._, X, p. 253. - - * * * * * - -We will not dwell longer here on the toxins of microbial origin. It -appears evident, however, from what has been stated above, that the -great majority, if not all, of the virulent microbes manifest their -virulence by means of toxic secretions. Almost every one of these -toxins has been the subject of study. They would otherwise not have -interested us here, where our main object was but to dwell upon the -general properties. - - - - -CHAPTER V. - -THE VENOMS. - - -=General Nature of Venoms.=--The venoms are more or less toxic products -secreted by certain reptiles, batrachians, and fish; by a large number -of invertebrates; by arachnids, apids, scorpionids, araneids, and a -large number of other insects. - -The venoms are toxic principles very closely allied to the microbial -toxins; like the latter, they form two classes, the one alkaloidal, -the other proteid, possessing a true diastatic character. They -closely resemble the microbial toxins, moreover, by the fact that -they are capable of being transformed into vaccins by attenuation of -their virulence, by the action of heat or chemical reagents, and of -leading to habituation of use and the conference of immunity.[142] -Moreover, like the various viruses, the serum of immunized animals is -antivenomous, so that if injected into the veins or beneath the skin of -non-immunized animals, the serum confers upon them an immunity against -venom which lasts for some time. - - [142] _Annal. de l'Instit. Pasteur_, VIII, p. 281; _Journ. of - Physiol._, VIII, p. 203; and _Soc. de Biol._, 1894, p. 111. - -These venoms, like the microbial toxins, possess but slight toxicity -when absorbed via the stomach. Fraser, utilizing a method previously -advocated, succeeded, by following this method, in vaccinating against -serpent-venom by causing the absorption by animals of constantly -increasing doses of venom. - -It was thus possible to make the animals withstand doses a thousand -times greater than the ordinary lethal dose; the blood and serums -of these animals at this point possessed immunizing properties, and -this property passed by heredity to the offspring, to which it is -transmitted by the blood itself, and by the milk during feeding. - -Along with these resemblances between the venoms and toxins, attention -must be called to a very important difference. As we have already -seen, the action of the toxins on the organism is always preceded -by a certain period of incubation; the action of the venoms, on the -contrary, is almost instantaneous, and in this respect they behave like -chemical agents and alkaloidal toxins. - -If the venoms are preserved in a moist condition, they change because -they undergo putrefaction, which is generally the case with all -diastatic substances, and particularly the toxins. - -It is interesting to note that animals which have been bitten by a -venomous serpent, but which, for some reason or other, have not -succumbed to the venom, never recover their former condition; if they -were young, their functions cease to develop, and they droop; if they -are adults, their general condition remains that of stupefaction. - -=Venomous Serpents.=--Among the venomous serpents,[143] the most -important as well as the most dangerous are the following: Cobra di -capello (Naja tripudians, the hooded cobra) and its analogues, the -black Naja, Naja hagé, etc.; the elops (coral serpent); the bungurus -of Bengal and Burmah; the Platycercus proteroglyphia, which is found -chiefly in the waters of the Indian Ocean; the crotalian solenoglyphs -of the two Americas, and among which in particular are the rattlesnake, -the fer-de-lance (the yellow viper) of Martinique; the surucucu of -Guiana; and the moccasins and copperheads of Texas and Florida. Lastly, -the entire group of viperian solenoglyphs, among which are the Echidnæ, -the bite of some of which, for instance the daboia or echidna, is -dreadful; the African vipers, among which may be mentioned the horned -viper, the bite of which will kill a camel; the springing viper of -Congo, and the rhinoceros-viper of Gabun; the European vipers, the most -dangerous of which is certainly the asp of France, which is exceedingly -numerous in certain regions. - - [143] CALMETTE: _Le Venin des Serpents_, Paris, 1896. - -The effects of the bites of venomous serpents on man and animals -are generally well known to the public; it is well to recall them, -nevertheless. From the moment the bite has been inflicted, complete -symptoms of poisoning develop, attended by a condition of extreme and -increasing weakness, with vomiting, hemorrhage, and decomposition of -the blood. There are, besides, particular effects which vary with every -venom. - -The following table by Calmette[144] gives the comparative toxicity -of various venoms, taking as the standard of comparison the quantity -sufficient to kill a rabbit in three or four hours: - - Naja tripudians 0.00047 - Naja hagé 0.0003-0.0007 - Acanthophis antarctica 0.001 - Ceraste 0.0017-0.0021 - Haplocephalus variegatus 0.0025 - Trigonocephalus 0.0025 - - [144] CALMETTE: _Annal. Instit. Pasteur_, VIII, p. 276; IX, p. 229. - -=Nature of Serpent-venoms.=--These venoms are homogeneous liquids, -somewhat more dense than water, in which they are soluble, slightly -colored green or yellow, transparent, and insoluble in alcohol; they -contain from 30 to 35 per cent. of solid matter. When fresh, they have -a slightly acid reaction. Towards chemical reagents, and particularly -acids, they behave like albuminoids; almost all the combinations they -afford with the various albuminoid reagents are active, despite their -insolubility. According to Gautier, they are decomposed by caustic -potash. - -According to numerous researches, oxidizers like potassium -permanganate, the hypochlorites, hydrogen peroxide, and gold chloride -(in 1% solution) destroy the venoms; in certain cases when immediately -injected hypodermically in the poisoned region, these substances are -excellent antidotes _in vivo_.[145] - - [145] WINTER and BLYTH: _The Analyst_, 1877, p. 204; LACERDA: _Compt. - rend. de l'Acad. des Sciences_, XCIII, p. 466; CALMETTE: _Annal. - Instit. Pasteur_, VI, p. 175, and VIII, p. 278. - -We shall not here enter upon a detailed study of the toxic albuminoid -principles of serpent-venoms; moreover, our knowledge is rather vague, -as it is, on a number of points. It will suffice us to know that, taken -altogether, the active albuminoids of these venoms are numerous, and -that each venom has its own particular active constituents, differing -according to the species and variety of the snake. - -Each one of these substances acts more or less rapidly, and may be -associated with different principles which give rise to the variability -of the action of these toxic agents. Among these toxic albuminoids, the -most virulent appear to be true albumins and globulins, followed by -the nucleo-albumins, as we have already stated; there are also found -in venoms alkaloidal bases, but these principles are present only in -very slight quantity. These bases are but very slightly toxic compared -with the toxins that accompany them. - -=Natural Immunity towards Serpent-venoms.=--Certain animals exhibit -a natural immunity toward snake-bites; among them are the snakes -themselves, the hog, the hedgehog, and the mongoos (an Egyptian rat); -the blood of these animals contains apparently an antitoxin.[146] - - [146] _Compt. rend. de l'Acad. des Sciences_, CXXI, p. 745; JACODOT: - _Arch. de Médecine Navale_, VII, p. 390. - -Fontana[147] had remarked that snakes were quite unaffected by the -bite of the viper, even when inoculated with the venom hypodermically. -Physalix and Bertrand[148] confirmed these statements, and showed -that the snake perfectly resisted quantities of viper-venom capable -of killing at least 20 guinea-pigs. According to these scientists, -this natural immunity is due to the existence in the blood of toxic -principles analogous to those of viper's venom--principles that exist -in the labial glands of the snake, and pass into the blood and the -fluids via the internal secretions. These writers, and also Calmette, -have shown that the blood of venomous serpents becomes antitoxic when -heated. - - [147] _Traité sur le Venin de la Vipère_, Florence, 1781. - - [148] _Archives de Physiologie_, 1894, p. 423. - -It has been known for a long time that the hedgehog and the mongoos -eat certain venomous reptiles, and eagerly hunt for the vipers in -particular. When the hedgehog is bitten, which happens quite often -despite its dexterity, it resists the viper-venom quite well. Physalix -and Bertrand[149] have experimentally demonstrated that the hedgehog -withstands a dose of viper-venom capable of killing at least 40 -guinea-pigs. Levin[150] has shown that young individuals are less -resistant, and it is concluded from this, and perhaps incorrectly so, -that the immunity of the hedgehog is naturally acquired, rather than -inherent. Bertrand and Physalix have nevertheless shown that on heating -the blood of the hedgehog to 88° C. it manifests an antitoxic power -toward serpent-venom _in vitro_. - - [149] _Bull. Muséum Histoire Naturelle_, I, p. 294; _Compt. rend. Soc. - de Biol._, 1899. p. 77. - - [150] _Deutsche med. Woch._, 1898, p. 629. - -=Artificial Immunity toward Serpent-venom.=--Immunity may be conferred -upon every individual by utilizing the method of habituation. This -fact was simultaneously elicited by Calmette, Bertrand, and Physalix. -To effect the immunity these scientists prepare an antivenomous serum -and inject it into animals, giving at first very small quantities of -the diluted venom, and gradually increasing the doses, and the periods -intervening between the injections. At the end of about two months of -this treatment, the immunity has reached its maximum. Certain rabbits, -thus slowly inoculated, have been able to withstand 0.04 Gm. of the -venom of the naja at a single injection; such rabbits then yield a -vaccinal serum.[151] - - [151] _Annal. de l'Instit. Pasteur_, 1895, p. 229; _Compt. rend. de - l'Acad. des Sciences_, CXXII, p. 203. - -At the Institut Pasteur at Lille there is prepared in this manner an -antivenomous serum from the horse; it is capable of acting upon 20 000 -times its own weight. This has rendered great service in the treatment -of snake-bites, particularly in hot countries, where the accidents are -of daily occurrence. _In vitro_ it acts quite as well preventively -as therapeutically. It arrests the effects of the naja, the horned -ceraste, the trigonocephalus, the rattlesnake, and of almost every one -of the venomous serpents known. - -The relatively considerable immunity possessed by certain -snake-charmers, and which passes for a magical gift, is due to nothing -else but a natural immunity, acquired perhaps by heredity, and it -always appears to follow as a result of a nonfatal snake-bite. - -=Venoms of Batrachians and Saurians.=--We observe here a fundamental -difference between these poisons and those of snakes, as we shall see. -These latter, in fact, appear to owe all their toxicity to true toxins -which they contain, while the poisons of batrachians and saurians are -chiefly composed of alkaloidal bases.[152] - - [152] CLOEZ: _Compt. rend. de l'Acad. des Sciences_, XXXIV, p. 592. - -The poison of toads and frogs (studied by Faust, Bertrand, and -Physalix) is chiefly secreted by the glands of the subcutaneous tissues -of these animals; it has but a very slight action on the unbroken skin, -but it rapidly inflames the nasal and buccal conjunctival mucosa. The -poison is a yellowish liquid, milky and viscid, with a waxy odor and -an insupportably bitter taste. It is strongly acid and caustic. When -dried, the poison yields to ether a fatty matter which, when absorbed -by an animal, plunges the latter into a coma that may end in death. - -The residue insoluble in ether contains the non-toxic albuminoids, and -ptomaines, such as methylcarbylamine,[153] and isocyanacetic acid, -resulting from the decomposition of a lecithin that appears to be -soluble in ether. - - [153] _Ibid._, XCVIII, p. 538. - -To obtain this venom, Physalix and Bertrand[154] skin the toads, first -chloroformed, and dry the skins in a vacuum over sulphuric acid; the -skins are then cleaned by treating with carbon disulphide to remove -fatty matters, and the toxic principles removed by means of 95-per -cent. alcohol; the poison so obtained, however, is impure. A better -procedure is to express the parotid glands which have been placed in -distilled water. Faust found in this venom a principle which he named -_bufonin_. Physalix and Bertrand isolated from it also a resinoid -substance soluble in alcohol and in a large excess of water; this -substance, which they named _bufotaline_, acts upon the heart. These -authors have also obtained another substance which has a paralyzing -action, and which they have named _bufotenin_. - - [154] _Ibid._, CXXVIII, pp. 45-48. - -The poison of the common toad acts as a paralyzant upon the heart and -on the spinal marrow[155]; that of the common frog possesses similar -properties. The poison of the tritons is quite analogous to that of the -toads; it contains a lecithin hydrolyzable by water with the formation -of alanin, formic acid, and alpha-isocyanopropionic acid. - - [155] P. BERT: _Compt. rend. de la Soc. de Biologie_, 1885, p. 524. - -Zalnosky[156] isolated from the glands of the skin of the salamander a -white, thick, bitter and alkaline liquid poison, containing a highly -poisonous alkaloid, _salamandrine_, or _samandarine_, which acts on -the brain, the medulla, and the spinal cord, and which has the formula -C{54}H{60}N{2}O{5}; it is a strong base and yields crystallizable -salts. - - [156] _Bull. Soc. Chim._ [2], VI, p. 344. - -=Fish-poisons.=[157]--Very little accurate knowledge is extant -regarding these. Many fish are poisonous, and among them are the -synanceia, found in the Indian Ocean between the Netherland Isles and -New Caledonia; considerable numbers are found in the neighborhood of -the latter locality. These fish are provided with spiny rays which are -in direct communication with a poisonous system having its seat in the -dorsal fin. The prick of one of the spiny rays of this fish may under -certain circumstances result fatally, and in every case it causes a -rapid and painful gangrene. - - [157] BOFFORD: _Thèse de doctorat en Médecine--Les Poissons venimeux_, - Paris, 1889; O. ARCOS: _Thèse de doctorat--Essais sur les accidents - causés par les poissons venimeux_, Paris, 1887. - -From the reservoir the poison is conducted to the sharp extremity of -the spines by a deep channel with which each spiny ray is provided; the -animal has 26 poison-sacs, two for each ray, and the sacs burst when -the corresponding sting is in any manner compressed. - -The poison is an odorless liquid having a slight styptic or acidulous -taste, and exhibiting a bluish fluorescence; it rapidly becomes turbid. - -The weevers, which are numerous on the shores of the Mediterranean Sea, -and which are also met with in the northeastern portion of the Atlantic -Ocean, are likewise very dangerous, which explains their popular names -"viper-weever," "spiderweever," etc. These fish are provided with a -double set of poisonous apparatus, the one opercular, which is the -more dangerous, and the other dorsal. The opercular spine has a double -channel in connection with a conical cavity hollowed out in the base of -the opercular bone. The bottom of this cavity is provided with special -cells which secrete the poison. The dorsal glands have a similar -structure. - -The poison of the weever is a liquid, limpid when the fish is alive, -and turbid when dead; it has a slight bluish fluorescence, is neutral -in reaction, and is coagulated by acids and bases. It acts as a -paralyzant, its action being exerted on the medulla and spinal cord; it -retards the heart's action. - -These examples will suffice; and we will not dilate further on this -subject, because, as already stated, but little is accurately known -regarding the subject, and what is known may be summed up as follows: -Fish-poisons always give rise to an intense pain, frequently with motor -paralysis, followed by paralysis of sensation; they affect the heart, -arresting it in diastole; and they are more dangerous to fish and -cold-blooded animals than to mammifers. - -=Poisons of the Hymenoptera.=[158]--The poison system of the bee, and -of such insects as the wasps, bumblebees, etc., is known to consist of -a hollow sting consisting of two sharp needles communicating with two -poison-bearing glands, and forming a flexible tube. One of these glands -secretes an acid liquid (formic acid); the other secretes an alkaline -fluid. - - [158] PHILOUZE: Venin des Abeilles. _Annales de la Société Linn. du - Maine-et-Loire_, IV. - -The action of the bee-poison is very often benign, but there have been -cases where death followed the infliction of numerous stings. - -Our information regarding the poison of the cantharides and flies is -very vague[159]; the same is true of the poisons of various arachnids, -acarides, and myriapoda. So far as spiders are concerned, it is known -that their poison is an oily liquid having an acid and bitter taste, -and containing a toxalbumin derived from the skin of the insect. The -bite of the ordinary spider occasions simply a slight local pain, with -redness; that of the large poisonous spider, however, may kill the -larger animals, and even man. - - [159] JOYEUX-LAFFRIÉE: _Thèse de doctorat en Médecine_, Paris, 1883; P. - BERT: _Compt. rend. de la Soc. de Biol._, II [4], p. 136. - -=Poison of Scorpions.=[160]--This poison is a colorless, acid liquid, -having a higher specific gravity than water, in which liquid it is -soluble. The famed legend of the suicide of scorpions is well known to -all. It is stated that when the insect finds itself in a position where -its death is inevitable, it stings itself, and dies from the effects of -its own poison. A simple method has even been described of bringing -this result about experimentally by surrounding the insect with a -circle of fire. Bounne, of Madras,[161] who has studied the procedure, -has demonstrated its entire falsity by showing, first of all, that the -insect dies from the effects of the excessive heat, and further, that -the poison of the scorpion is harmless to individuals of the species -that furnish it. - - [160] CALMETTE: _Annales de l'Instit. Pasteur_, X, p. 232. - - [161] _Proceedings of the Royal Society_, XLII, p. 17. - -Metchinkoff[162] has confirmed these facts, and has moreover -demonstrated that the blood of the scorpion possesses an undoubted -antitoxic power against the poison of the insect. - - [162] METCHNIKOFF: _L'Immunité_, p. 344. - -The poison of the scorpion serves it to kill the insects which are its -prey. Frogs and birds stung by the scorpion also generally die. A dose -of 0.0005 Gm. kills a guinea-pig in less than one hour; and according -to Calmette[163] less than 0.0005 will kill a white mouse in two hours. -Oxidizers destroy the toxicity of the poison. Guinea-pigs immunized -against the poison of the scorpion resist perfectly very large doses of -the poison. - - [163] CALMETTE: _Annal. de l'Instit. Pasteur_, X, p. 232. - -=Poisonous Blood and Serums.=--It is an almost general fact that the -blood and blood serum of batrachians, eels, lampreys, snakes (even -non-poisonous ones), and hedgehogs are very poisonous. Mosso has -found in the blood serum of the lamprey a toxin possessing a strong -hemolytic power, and which he has named _ichthyotoxin_. O.5 Cc. of this -serum injected into a dog kills it in a few minutes. He also observed, -in 1888, that the blood of the eel, in like dose, kills a dog almost -immediately, and that the blood contains an ichthyotoxin analogous to -that of the lamprey. - -This substance, which appears to be closely allied to the sero-albumin -of the blood, has a phosphorus-like, sharp, and burning taste. By -digestion it loses its toxicity, as well as by heating at 68° to 70° C. -It is easily obtained by precipitating with ammonium sulphate the serum -of eels, and dialyzing the precipitate dissolved in water. The power of -this substance is almost as great as that of the cobra poison, 0.002 -Gm. being instantly fatal per kilo of dog. - -The blood of snakes is likewise very toxic; the same is true of the -blood of the viper, as 0.02 Cc. will kill a guinea-pig in two hours. -All these bloods lose their toxicity when heated above 70° C. The serum -of the hedgehog is peculiar in this respect; when heated at 38° C. -for fifteen minutes it loses its toxicity, but it then possesses an -immunizing power against the poisons. - -The subject possesses great interest, because it was in studying -these immunizing properties that Camus and Gley,[164] and later -on Kossel[165] and Tchistowitch,[166] discovered the first -anticytotoxin,[167] which they obtained by treating the animals with -increasing quantities of the serum of eels. On mixing the antitoxic -serum of these animals _in vitro_ with the red blood-corpuscles of the -species furnishing the serum and of the hemolytic serum of eels, it is -found that the blood-corpuscles kept quite well. - - [164] _Archives internat. de Pharmacodynamie_, III and IV. - - [165] _Berliner Klin. Wochenschr._, 1895, No. 7. - - [166] _Annal. de l'Instit. Pasteur_, XIII, p. 406. - - [167] The name "cytases" or "alexins" has been given to hemolyzing - diastatic substances which are found in certain serums. It has been - known for a long time that the serum of the blood of many animals - destroys the red blood-corpuscles of other and different species. The - chemical composition of these cytases or alexins is not yet definitely - known, but the substances rank among the albuminoids; they are - destroyed by a temperature of 55° to 56° C., and act only in saline - solutions (Ehrlich and Morgenroth, _Berlin. Klin. Woch._, pp. 6 and - 481). The cytases or alexins, which will be studied in another volume - of this collection, and which will discuss the active principles - of the immunizing serums, constitute one of the numerous soluble - intraleucocytary ferments, and they pass into the serous liquids of the - organism only as the result of a rupture of or injury to the phagocytes. - -As to the blood of the hedgehog, we have already seen that Physalix -and Bertrand have shown that it may be a counter-poison towards -serpent-venom under certain conditions. In its normal condition it is -highly toxic. - -=Poisonous Meats.=--It is particularly among the fish that we find -these normally present, and it is a singular fact that, for a given -species, the toxicity frequently depends upon the period of the -year. Thus, at the period of spawning, certain fish may be extremely -poisonous, or, on the contrary, may entirely cease to be so. The -anchovy ballassa from the shores of India occasions death even in -very small quantity; the poisonous meltite of the same seas causes -violent vomiting; the fugu of the Japanese seas possesses an extreme -poisonousness at the spawning period, while, on the contrary, it is -perfectly innocuous at all other periods. - -Numerous cases of poisoning have been chronicled every year by the -journals, due to the ingestion of mussels; in the flesh of these -crustaceæ is found a dangerous toxin, _methylotoxin_. The flesh of -oysters is also unwholesome at the spawning period. - -The toxic symptoms caused by these animals become apparent in not -less than twenty-four hours after ingestion. The poisoning due to -these fresh meats must not, however, be confounded with that caused by -tainted or spoiled meats. - - - - -WORKS OF ALFRED I. COHN - -PUBLISHED BY - -JOHN WILEY & SONS. - - -=Indicators and Test-papers.= - -Their Source, Preparation, Application, and Tests for Sensitiveness. -With Tabular Summary of the Application of Indicators. Second Edition, -Revised and Enlarged. 12mo, ix + 267 pages. Cloth, $2.00. - -=Tests and Reagents.= - -Chemical and Microscopical, known by their Authors' Names; together -with an Index of Subjects. 8vo, iii + 383 pages. Cloth, $3.00. - - -_TRANSLATIONS._ - -=Fresenius's Quantitative Chemical Analysis.= - -New Authorized Translation of the latest German Edition. In two -volumes. By Alfred I. Cohn, Phar.D. Recalculated on the basis of the -latest atomic weights, and also greatly amplified by the translator. -8vo, 2 vols., upwards of 2000 pages, 280 figures. Cloth, $12.50. - -=Techno-Chemical Analysis.= - -By Dr. G. LUNGE, Professor at the Eidgenössische Polytechnische Schule, -Zurich. Authorized Translation by Alfred I. Cohn, Phar.D. 12mo, vii + -136 pages, 16 figures. Cloth, $1.00. - -=Toxins and Venoms and Their Antibodies.= - -By EM. POZZI-ESCOT. Authorized Translation by Alfred I. Cohn, Phar.D. -12mo, vii + 101 pages. Cloth, $1.00, _net_. - - - - - Transcriber's Notes - -Obvious typographical errors have been silently corrected, but all -other variations in spelling, punctuation and accents are as in the -original, with the exception of Symptomatology (in the contents -list) and symptomology (in the text) which has been corrected to -symptomatology. - -Variations between the treatment and phrasing of headings in the table -of contents and in the text have not been changed. - -Italics are represent thus _italic_ and bold thus =bold=. Subscripts -are represented thus {2} - -The book begins with a page of adverts for works by the translator, -this has been moved to the end. - - - - - - - - -End of the Project Gutenberg EBook of The Toxins and Venoms and their -Antibodies, by Em. 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Pozzi-Escot - -This eBook is for the use of anyone anywhere in the United States and most -other parts of the world at no cost and with almost no restrictions -whatsoever. You may copy it, give it away or re-use it under the terms of -the Project Gutenberg License included with this eBook or online at -www.gutenberg.org. If you are not located in the United States, you'll have -to check the laws of the country where you are located before using this ebook. - -Title: The Toxins and Venoms and their Antibodies - -Author: Em. Pozzi-Escot - -Translator: Alfred I. Cohn - -Release Date: November 14, 2015 [EBook #50458] - -Language: English - -Character set encoding: ISO-8859-1 - -*** START OF THIS PROJECT GUTENBERG EBOOK TOXINS, VENOMS, THEIR ANTIBODIES *** - - - - -Produced by The Online Distributed Proofreading Team at -http://www.pgdp.net (This file was produced from images -generously made available by The Internet Archive) - - - - - - -</pre> - - - -<p><span class="pagenum"><a name="Page_1" id="Page_1">[Pg 1]</a><br /><a name="Page_2" id="Page_2">[Pg 2]</a></span></p> - - -<div class="box"> - -<p class="center"><b>WORKS OF ALFRED I. COHN</b></p> - -<p class="center"><small>PUBLISHED BY</small></p> - -<p class="center">JOHN WILEY & SONS.</p> -<hr class="small" /> -<div class="small"> -<p><b>Indicators and Test-papers.</b><br /> - -Their Source, Preparation, Application, and Tests -for Sensitiveness. With Tabular Summary of the Application -of Indicators. Second Edition, Revised and -Enlarged. 12mo, ix + 267 pages. Cloth, $2.00.</p> - -<p><b>Tests and Reagents.</b><br /> - -Chemical and Microscopical, known by their -Authors' Names; together with an Index of Subjects. -8vo, iii + 383 pages. Cloth, $3.00.</p> - - -<p class="center"><i>TRANSLATIONS.</i></p> - -<p><b>Fresenius's Quantitative Chemical Analysis.</b><br /> - -New Authorized Translation of the latest German -Edition. In two volumes. By Alfred I. Cohn, -Phar.D. Recalculated on the basis of the latest atomic -weights, and also greatly amplified by the translator. -8vo, 2 vols., upwards of 2000 pages, 280 figures. Cloth, -$12.50.</p> - -<p><b>Techno-Chemical Analysis.</b><br /> - -By Dr. <span class="smcap">G. Lunge</span>, Professor at the Eidgenössische -Polytechnische Schule, Zurich. Authorized Translation -by Alfred I. Cohn, Phar.D. 12mo, vii + 136 pages, -16 figures. Cloth, $1.00.</p> - -<p><b>Toxins and Venoms and Their Antibodies.</b><br /> - -By <span class="smcap">Em. Pozzi-Escot</span>. Authorized Translation by -Alfred I. Cohn, Phar.D. 12mo, vii + 101 pages. Cloth, -$1.00, <i>net</i>.</p> -</div></div> -<hr class="chap" /> - -<p><span class="pagenum" id="Page_3">3</span></p> - - - - - -<h1><small>THE</small><br /> - TOXINS AND VENOMS<br /> - <small>AND THEIR ANTIBODIES</small></h1> - - <p class="center"><span class="xs">BY</span><br /> - EM. POZZI-ESCOT</p> - - <p class="center space-above"><small>AUTHORIZED TRANSLATION</small><br /> - <span class="xs">BY</span><br /> - ALFRED I. COHN, <span class="smcap">Phar. D.</span></p> - - <p class="center space-above"><i><small>FIRST EDITION</small></i><br /> - <span class="xs">FIRST THOUSAND</span></p> - - <p class="center space-above"><small>NEW YORK</small><br /> - JOHN WILEY & SONS<br /> - <small><span class="smcap">London</span>: CHAPMAN & HALL, <span class="smcap">Limited</span><br /> - 1906</small></p> -<p><span class="pagenum" id="Page_4">4</span></p> - - - - -<p class="center spaced"><span class="xs"> - Copyright, 1906<br /> - BY<br /> - ALFRED I. COHN</span></p> - - -<p class="center spaced"><span class="xs">ROBERT DRUMMOND, PRINTER, NEW YORK</span> -<span class="pagenum" id="Page_5">5</span></p> - -<hr class="chap" /><div class="chapter"></div> - - - -<h2><a name="INTRODUCTION" id="INTRODUCTION">INTRODUCTION.</a></h2> - - -<p>Our knowledge of the toxins is of quite recent -date. It is hardly twenty years since we began to -acquire a knowledge of the facts that are detailed -in this volume, and to which modern medicine owes -its most recent and marvelous progress, particularly -in serotherapy.</p> - -<p>In this volume we have studied, besides the true -toxins—substances of cellular origin and of albuminoid -nature and unknown composition—other -toxic substances, the nitrogenized alkaloidal bases -introduced into science through the researches of -Selmi, Armand Gautier, and von Behring, and -which are highly hydrogenized nitrogenous crystallizable -principles of definite chemical composition—the -products of the more or less advanced -breaking down of albuminoids.</p> - -<p>Although these principles differ widely, by reason -of their physiological properties as a whole, -from the toxic albuminoids, or true toxins, it -appears proper to consider them as products of<span class="pagenum" id="Page_6">6</span> -the advanced decomposition of these toxins—and -in this respect their study becomes imperative, the -more so as they are very frequently encountered -together with the toxins, particularly in serpent-venoms, -where their action is exerted in addition -to that of the true toxins.</p> - -<p>In the first volume of this collection we dwelt -on the essentially reducing nature of the cellular -functionation. To this functionation—causing the -splitting up or decomposition by hydrolysis of -nitrogenized albuminoid foods—is due the formation -of these toxic basic products within the organism, -whether normally, or because of certain pathological -conditions.</p> - -<p>This alone suffices to show that, during physiological -life, oxygen plays an essentially antitoxic -rôle within the organism.</p> - -<p>It is hoped that this succinct résumé, which it -has been sought to make as clear as possible, will -be of service to those who, while not scientists -actively engaged in scientific progress, desire to -be abreast of the knowledge of modern evolution, -but yet are not in a position to consult original -papers or large treatises.</p> - - -<hr class="chap" /> - -<p><span class="pagenum" id="Page_7">7</span></p> - - - -<div class="chapter"></div> -<h2><a name="CONTENTS" id="CONTENTS">CONTENTS.</a></h2> - - - - - - -<div class="center"> -<table border="0" cellpadding="4" cellspacing="0" summary=""> -<col width="5%" /><col width="70%" /> -<tr><td></td><td></td><td class="tdrb xs"><span class="smcap">Page</span></td></tr> -<tr><td class="tdlt" colspan="2"> <span class="smcap">Introduction</span></td><td class="tdrb">iii</td></tr> -<tr><td class="tdc" colspan="3"> <a href="#PART_I">PART I</a>.</td></tr> -<tr><td class="tdc" colspan="3"> <i>GENERALITIES REGARDING TOXINS AND ANTITOXINS.</i></td></tr> -<tr><td class="tdc" colspan="3"> <a href="#CHAPTER_I">CHAPTER I</a>.</td></tr> -<tr><td class="tdc" colspan="3"><span class="smcap">Alkaloidal Toxins, Ptomaines, and Leucomaines.</span></td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Alkaloidal_Products">Alkaloidal products of cellular life</a></td><td class="tdrb">1</td></tr> -<tr><td class="tdlt" colspan="2"><a href="#Ptomaines">Ptomaines</a></td><td class="tdrb">4</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#physiological_action">Physiological actio</a>n</td><td class="tdrb">5</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#extraction">Extraction</a></td><td class="tdrb">5</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#In_order_to_facilitate">Classification, etc</a>.</td><td class="tdrb">7</td></tr> -<tr><td class="tdlt" colspan="2"><a href="#Leucomaines">Leucomaines</a></td><td class="tdrb">10</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Xanthic_Leucomaines">Xanthic leucomaines</a></td><td class="tdrb">12</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Creatinic_Leucomaines">Creatinic leucomaines</a></td><td class="tdrb">13</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Neurinic_Leucomaines">Neurinic leucomaines</a></td><td class="tdrb">13</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Undetermined_Leucomaines">Indeterminate leucomaines</a></td><td class="tdrb">14</td></tr> -<tr><td class="tdc" colspan="3"> <a href="#CHAPTER_II">CHAPTER II</a>.</td></tr> -<tr><td class="tdct" colspan="3"> <span class="smcap">Toxins and Antitoxins.</span></td></tr> -<tr><td class="tdlt" colspan="2"> Toxins</td><td class="tdrb">15</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#It_is_due">Action of pathogenic bacteria</a></td><td class="tdrb">16</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#the_toxins_act">Action of toxins</a></td><td class="tdrb">17</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Nature_of_the_Toxins">Nature of toxins</a></td><td class="tdrb">18<span class="pagenum" id="Page_8">8</span></td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Origin_of_the_Toxins">Origin of toxins</a></td><td class="tdrb">20</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Autointoxications">Autointoxications</a></td><td class="tdrb">21</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#General_Mode">General mode of action</a></td><td class="tdrb">23</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#We_owe_to_Ehrlich">Constitution of toxins; Ehrlich's theory</a></td><td class="tdrb">24</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Means_of_Defense">Means of defense possessed by the organism against the action of toxins</a></td><td class="tdrb">28</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Pasteur">Pasteur's vaccination method</a></td><td class="tdrb">30</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#viruses_act">Virus action</a></td><td class="tdrb">30</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Phagocytosis">Phagocytosis</a></td><td class="tdrb">32</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#The_Antitoxins">Antitoxins</a></td><td class="tdrb">33</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Mode_of_Action">Mode of action</a></td><td class="tdrb">35</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Formation_of_Antitoxins">Formation; Ehrlich's theory</a></td><td class="tdrb">38</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Serotherapy">Serotherapy</a></td><td class="tdrb">41</td></tr> -<tr><td class="tdc" colspan="3"> <a href="#PART_II">PART II</a>.</td></tr> -<tr><td class="tdc" colspan="3"> <i>THE TOXINS PROPER.</i></td></tr> -<tr><td class="tdc" colspan="3"> <a href="#CHAPTER_III">CHAPTER III</a>.</td></tr> -<tr><td class="tdlt" colspan="2"> I. <span class="smcap"><a href="#VEGETABLE_AND_ANIMAL_TOXINS">Vegetable and Animal Toxins</a>.</span></td><td class="tdrb">42</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Abrin">Abrin</a></td><td class="tdrb">42</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Ricin">Ricin</a></td><td class="tdrb">44</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Robin">Robin</a></td><td class="tdrb">45</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Toxicity_of_the_Vegetable">Toxicity of the vegetable diastases</a></td><td class="tdrb">45</td></tr> -<tr><td class="tdlt" colspan="2"> II. <span class="smcap"><a href="#TOXINS_FROM_MUSHROOMS">Toxins from Mushrooms</a></span></td><td class="tdrb">46</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#phalline">Phalline</a></td><td class="tdrb">48</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#symptomatology">Symptomatology</a></td><td class="tdrb">49</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#antidiastase">Antidiastases</a></td><td class="tdrb">51</td></tr> -<tr><td class="tdlt" colspan="2"> III. <span class="smcap"><a href="#ANIMAL_TOXINS">Animal Toxins</a></span></td><td class="tdrb">53</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#ANIMAL_TOXINS"><q>Peptotoxin</q></a></td><td class="tdrb">53</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Alimentary_Intoxications">Alimentary Intoxications</a></td><td class="tdrb">55</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Urinary_Toxins">Urinary toxins</a></td><td class="tdrb">57</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#urinary_toxicity">Variation of urinary toxicity</a></td><td class="tdrb">59</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Autointoxications">Autointoxications (animal)</a></td><td class="tdrb">60</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#Glandular_Secretions">Glandular secretions</a></td><td class="tdrb">62</td></tr> -<tr><td class="tdrb"></td><td class="tdlt"><a href="#suprarenal_capsules">Suprarenal capsules</a></td><td class="tdrb">63<span class="pagenum" id="Page_9">9</span></td></tr> -<tr><td class="tdc" colspan="3"><a href="#CHAPTER_IV"> CHAPTER IV</a>.</td></tr> -<tr><td class="tdc" colspan="3"> <span class="smcap">The Microbial Toxins.</span></td></tr> -<tr><td class="tdlt" colspan="2"><a href="#CHAPTER_IV">Pyogenic and pyretogenic properties</a></td><td class="tdrb">66</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Anthrax_Toxin">Anthrax toxin</a></td><td class="tdrb">67</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Tubercular_Toxin">Tubercular toxin</a></td><td class="tdrb">69</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Diphtheria_Toxin">Diphtheria toxin</a></td><td class="tdrb">71</td></tr> -<tr><td class="tdlt" colspan="2"><a href="#Tetanus_Toxin"> Tetanus toxin</a></td><td class="tdrb">76</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Mallein">Mallein</a></td><td class="tdrb">79</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Typhoid_Toxin">Typhoid toxin</a></td><td class="tdrb">80</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Cholera_Toxin">Cholera toxin</a></td><td class="tdrb">82</td></tr> -<tr><td class="tdc" colspan="3"> <a href="#CHAPTER_V">CHAPTER V</a>.</td></tr> -<tr><td class="tdc" colspan="3"> <span class="smcap">The Venoms.</span></td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#General_Nature">General nature of venoms</a></td><td class="tdrb">85</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Venomous_Serpents">Venomous serpents</a></td><td class="tdrb">87</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Serpent-venoms">Nature of serpent-venoms</a></td><td class="tdrb">88</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Natural_Immunity">Natural immunity towards serpent-venoms</a></td><td class="tdrb">90</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Artificial_Immunity">Artificial immunity towards serpent venoms</a></td><td class="tdrb">91</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Venoms_of_Batrachians">Venoms of batrachians and saurians</a></td><td class="tdrb">92</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Fish-poisons">Fish-poisons</a></td><td class="tdrb">95</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Hymenoptera">Poisons of the hymenoptera</a></td><td class="tdrb">96</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Poison_of_Scorpions">Poisons of scorpions</a></td><td class="tdrb">97</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Poisonous_Blood">Poisonous blood and serums</a></td><td class="tdrb">98</td></tr> -<tr><td class="tdlt" colspan="2"> <a href="#Poisonous_Meats">Poisonous meats</a></td><td class="tdrb">100</td></tr> -</table></div> -<p><span class="pagenum"><a name="Page_10" id="Page_10">[Pg 10]</a><br /><a name="Page_11" id="Page_11">[Pg 11]</a></span></p> -<hr class="chap" /><div class="chapter"></div> - - - -<p class="half-title">TOXINS AND VENOMS.</p> -<hr class="small" /> - - - -<h2><a name="PART_I" id="PART_I">PART I.</a><br /><br /> - -<i>GENERALITIES REGARDING TOXINS AND -ANTITOXINS.</i></h2> - -<hr class="small" /> - - -<h3><a name="CHAPTER_I" id="CHAPTER_I">CHAPTER I.</a><br /> - -<small>ALKALOIDAL TOXINS, PTOMAINES AND -LEUCOMAINES</small>.</h3> - - -<p class="sub-title"><a id="Alkaloidal_Products"></a>Alkaloidal Products of Cellular Life.</p> - -<p>Before entering upon the study of the true -toxins, which are products of an alkaloidal nature -and of unknown composition, it is necessary to -say a few words regarding the most definite of -the toxic alkaloidal principles that are frequently -encountered under various conditions, conjointly -with the true toxins, particularly in venoms, and -which, furthermore, are closely allied to these albuminoid -toxins.</p> - -<p><span class="pagenum" id="Page_12">12</span></p> - -<p>These principles are formed in essentially reducing -media, whether it be within the body of the -organism, and by the simple exercise of its normal -function, in which case the principles bear -the generic name <em>leucomaines</em><a id="FNanchor_1" href="#Footnote_1" class="fnanchor">1</a>; or whether due to -the action of anaerobic microbes, when they are -designated as ptomaines.<a id="FNanchor_2" href="#Footnote_2" class="fnanchor">2</a> These basic principles, -which are essentially the products of cellular secretion, -are usually toxic, and sometimes even extremely -so.</p> - -<p>As we shall presently see, ptomaines are essentially -products formed during putrefactive fermentation. -The toxic properties of extracts from the -cadaveric fluids have long been known. Already -in 1838 Panum<a id="FNanchor_3" href="#Footnote_3" class="fnanchor">3</a> had met with these products -in snake venoms. Bergmann and Schmiedberg<a id="FNanchor_4" href="#Footnote_4" class="fnanchor">4</a> in -1868 isolated from septic pus a toxic substance -which they named <em>sepsin</em>; and almost at the same -time Zuelzer and Sonnenschein<a id="FNanchor_5" href="#Footnote_5" class="fnanchor">5</a> reported having -isolated from anatomical preparations an alkaloid -possessing mydriatic properties. It is, however, -due particularly to the researches of Selmi and<span class="pagenum" id="Page_13">13</span> -Armand Gautier that we are now so well informed -regarding these toxic principles.</p> - -<p>The labors of Armand Gautier were first published -in his <cite>Traité de Chimie Appliquée à la Physiologie</cite>; -those of Selmi in the <cite>Actes de l'Académie -de Bologne</cite>.</p> - -<p>At first sight, there appears to be a great difference -between these alkaloidal bases, the ptomaines and -leucomaines, and the albuminoid toxins proper. -The toxic bases of the first two groups are quite -definite chemical products which can be generally -obtained quite pure, and frequently in crystalline -form. The toxins proper, on the other -hand, are highly complex albuminoid substances -which greatly resemble the true diastases in all -their properties.</p> - -<p>Nevertheless, between the toxic alkaloids, -ptomaines and leucomaines, and the toxic albuminoids, -or more properly toxins, there exists no -absolutely sharp line of demarcation, but there is -a gradual passage from the one to the other by -every intermediary grade, as a result of the breaking -down of the albuminoid molecule.</p> - -<p>We shall see, moreover, as we proceed, that -these substances are formed under coexistent circumstances, -and that they are, hence, found together, -whether it be in virus or in snake venom.</p> - -<p>We will first consider the ptomaines, and then -the leucomaines.</p> - -<p><span class="pagenum" id="Page_14">14</span></p> - -<p class="sub-title"><a id="Ptomaines"></a>Ptomaines.</p> - -<p>This name is more specially reserved to designate -those alkaloidal substances, generally highly -hydrogenized, that are formed outside the organism, -from the fermentative action of anaerobic microbes -on albuminoid substances.</p> - -<p>These bases are generally volatile, with an intense -and tenacious purulent odor; often, however, they -possess a floral odor (aubépine, syringa), and even -like that of musk. They combine readily with -acids and with the chlorides of the heavy metals, -yielding crystallizable salts.</p> - -<p>The ptomaines afford no specific reaction whereby -they may be readily identified; and their identification -is effected only after a painstaking analysis.</p> - -<p>We must here call attention, however, to several -of their more common properties, beginning with -their basic character, their oxidizability by the air -and consequently their well-defined reducing power—a -property that led Selmi to propose a mixture -of ferric chloride and potassium ferricyanide as a -reagent for their detection.<a id="FNanchor_6" href="#Footnote_6" class="fnanchor">6</a> They are precipitated -by all the general reagents for the vegetable alkaloids. -Selmi has given several reactions, such as -those afforded by sulphuric, hydrochloric, and -nitric acids, which appear, however, to apply much<span class="pagenum" id="Page_15">15</span> -more to the impurities present than to the bases -themselves.</p> - -<p>The <a id="physiological_action"></a>physiological action of these bases varies -greatly; in some the action is an extremely toxic -one, as in the case of neurine and muscarine, -which are true ptomaines; there are others, such -as cadaverine and putrescine, which are quite -innocuous. The physiological action of these bases, -like that of the true toxins, is studied by making -hypodermic injections of solutions of the bases in -healthy animals, such as guinea-pigs, rabbits, and -dogs.</p> - -<p>In animals, the principal phenomena observed by -Selmi to follow the injection of the substances are -the following: At first dilatation of the pupil, then -constriction; tetanic convulsions, soon followed by -muscular relaxation, and retardation, rarely acceleration, -of heart-beat; absolute loss of cutaneous sensibility; -loss of muscular contractility; paralysis of -the vasomotors; greatly retarded respiration; stupor, -followed by death with the heart in systole.</p> - -<p>It must be observed that in a number of cases -where toxic researches had been made in the past, -these bases had been mistaken for poisons which -were believed to have been introduced into the -organism with criminal intent. No one will ever -know how many have fallen victims in the past to -ignorance regarding the cellular mechanism!</p> - -<p>The <a id="extraction"></a>extraction of these bases is a tedious and<span class="pagenum" id="Page_16">16</span> -difficult operation. The materials must first be -exhausted with water slightly acidulated; then, -after precipitating the albuminoids by boiling and -defecating by adding lead acetate, the liquid is evaporated -to one-half its volume and dialyzed in a -vacuum.<a id="FNanchor_7" href="#Footnote_7" class="fnanchor">7</a></p> - -<p>Phosphomolybdate is then added to the dialyzed -liquid, and the precipitate formed, which now contains -all the bases, decomposed by boiling with -lead acetate. After removing the excess of lead, -there is thus obtained a limpid solution of all the -alkaloidal bases in the form of acetates. These -are separated by alcohol and by means of fractional -precipitations with various metallic salts, -depending upon the known properties of the bases.</p> - -<p><a id="In_order_to_facilitate"></a>In order to facilitate their study, the ptomaines -have been grouped under two distinct classes, the -one embracing the cadaveric or putrefactive -ptomaines, of undetermined microbial origin, the -other containing the ptomaines formed by microbes -of known character. Each of these two groups is -itself divided into subgroups, as shown in the -following table:</p> - -<p><span class="pagenum" id="Page_17">17</span></p> - -<p class="center">GROUP I.</p> - -<p class="sub-title">CADAVERIC PTOMAINES OF UNDETERMINED MICROBIAL -ORIGIN.</p> - -<p> -<i>a.</i> Amines.<br /> -<i>b.</i> Guanidines.<br /> -<i>c.</i> Oxamines (fatty or aromatic).<br /> -<i>d.</i> Amido Acids.<br /> -<i>e.</i> Carbopyridic Acids and analogues.<br /> -<i>f.</i> Undetermined Ptomaines.<br /> -</p> - - -<p class="center">GROUP II.</p> - -<p class="sub-title">PTOMAINES OF KNOWN MICROBIAL ORIGIN.</p> - -<p><i>a.</i> Ptomaines extracted from microbial cells.</p> -<p><i>b.</i> Ptomaines from pathological urines.</p> - -<p>We will not here enter upon a detailed study of -the bases belonging to each of these groups. This -subject is a vast one, requiring for its treatment -a volume devoted to it alone. We will here simply -touch upon the principal properties of several of -the bases of each of the subgroups named.</p> - - -<p class="center"><span class="smcap">Bases of Group I.</span></p> - -<p><i>a.</i> <b><a id="Amines"></a>Amines.</b>—Among these we find nearly all the -fatty amines, such as the methylamines and the -cyclic alkaloids such as pyridine. They are formed -particularly by the putrefaction of fish.</p> - -<p>Certain of these bases are very toxic, for in<span class="pagenum" id="Page_18">18</span>stance -trimethylene diamine, the collidines, and -the parvolines.</p> - -<p><i>b.</i> <b><a id="Guanidines"></a>Guanidines.</b>—Among the products of ordinary -putrefaction there has been found so far only methylguanidine, -C<sub>2</sub>H<sub>7</sub>N<sub>3</sub>. This is a highly toxic base -of which 0.2 Gm. is fatal to a guinea-pig.</p> - -<p><i>c.</i> <b><a id="Oxamines"></a>Oxamines.</b>—Under this designation the following -bases are comprised: 1. Neurine bases; -2. oxygenized aromatic bases; 3. bases of unknown -constitution. Amongst them we find neurine -and choline, which are toxic, and betaine, which -is innocuous. They are found particularly in -putrid fish.</p> - -<p><i>d.</i> <b><a id="Amido_Acids"></a>Amido Acids.</b>—These ptomaines, which are -usually innocuous in small quantities, are particularly -the products of the decomposition of albuminoid -substances. Among them we find glycocoll, -leucine, and tyrosine, as members of this -group.</p> - -<p><i>e.</i> <b><a id="Carbopyridic"></a>Carbopyridic and Carboquinoleic Acids.</b>—So -far only one base is known belonging to this -group, and that is morrhuic acid, which is found -in the decomposed livers of codfish, and which -is a powerful appetizer and stimulant in disassimilation.</p> - -<p><i>f.</i> <b><a id="Undetermined_Ptomaines"></a>Undetermined Ptomaines.</b>—Under this heading -are classed certain undetermined bases, such as -those found in normal urines, and in spoiled meats -and bread.</p> - -<p><span class="pagenum" id="Page_19">19</span></p> - -<p class="center"><span class="smcap">Bases of Group II.</span></p> - -<p><i>a.</i> <b><a id="Ptomaines_Isolated_cultures"></a>Ptomaines Isolated from Cultures of Pathogenic -Bacteria.</b>—Bacterial cultures contain, besides -the true toxins, a certain number of alkaloidal -bases which sometimes possess considerable toxicity.</p> - -<p>In the cultures of streptococcus pyogenes there -are found trimethylamine and xanthic bases; in -those of staphylococcus pyogenes aureus are found -xanthic bases and creatinine; while pyocyanine -and pyoxanthine are found in the cultures of -bacillus pyocyaneus, etc.</p> - -<p><i>b.</i> <b><a id="Ptomaines_Isolated_Urines"></a>Ptomaines Isolated from Pathological Urines.</b>—Toxic -ptomaine bases have been found in the urines -of a large number of diseases.<a id="FNanchor_8" href="#Footnote_8" class="fnanchor">8</a> It is quite probable -that these bases are the results of a general -pathological condition due to some bacterial disease, -the toxic products of which are eliminated by the -kidneys.</p> - -<p>From the urines of epileptics Griffiths<a id="FNanchor_9" href="#Footnote_9" class="fnanchor">9</a> isolated -a colorless base crystallizing in prisms having the -formula C<sub>12</sub>H<sub>15</sub>N<sub>5</sub>O<sub>7</sub>, and which was found to be -exceedingly toxic; the same investigator isolated -from the urines of eczematous subjects a ptomaine<span class="pagenum" id="Page_20">20</span> -which he named <em>eczemine</em>,<a id="FNanchor_10" href="#Footnote_10" class="fnanchor">10</a> and which is also highly -toxic.</p> - -<p>In certain cases of cystinuria there are found in -the urine sulphurized ptomaines, and in measles -the urine contains an undetermined ptomaine, -<em>rubedine</em>, which is very poisonous. <em>Typhotoxine</em>, a -very toxic ptomaine, has been isolated from the -urine of typhoid patients; <em>erysipeline</em>, a hardly less -toxic base, exists in the urine of erysipelatic subjects; -while <em>spasmotoxine</em>, <em>tetanotoxine</em>, and <em>tetanine</em>, -exceedingly active alkaloids, are found in the -urines of tetanus patients.<a id="FNanchor_11" href="#Footnote_11" class="fnanchor">11</a></p> - -<p>As a general rule, all abnormal urines contain -toxic bases; the kidneys appear, in fact, to serve -as a means of eliminating the toxic products that -form in large quantity whenever, and for whatever -cause, the organism ceases to functionate normally, -whether it be as a whole, or in any one of -its parts.<a id="FNanchor_12" href="#Footnote_12" class="fnanchor">12</a></p> - - -<p class="sub-title1"><a id="Leucomaines"></a>Leucomaines.<a id="FNanchor_13" href="#Footnote_13" class="fnanchor">13</a></p> - -<p>The leucomaines are basic substances, nearly -allied to the ptomaines, but still more closely related -to the ureides. They are formed directly<span class="pagenum" id="Page_21">21</span> -or indirectly by the breaking down of protoplasmal -albuminoids. The agents that effect the breaking -down are the hydrolyzing ferments of the -economy. It is well to recall here that these -phenomena of hydrolyzation occur within the cell -itself and in a practically reducing medium, as we -have already stated. The inmost mechanism of -these phenomena cannot here be detailed; it will -be found described by Armand Gautier in the -<cite>Chimie Biologique</cite>, and in his work <cite>Chimie de la -Cellule Vivante</cite>.<a id="FNanchor_14" href="#Footnote_14" class="fnanchor">14</a></p> - -<p>The extraction of these bases is an extremely delicate -operation. It is necessary to operate with a -large quantity of substance, say 50 kilos. The substance -is finely chopped, then exhausted with twice -its weight of water acidulated with acetic acid (0.2 -Cc. per liter) and containing a trace of oil of mustard, -which is intended to act as an antiseptic. The albuminoids -are precipitated by boiling, the solution then -filtered, evaporated in a vacuum at 60° C., and the -bases extracted with 95-per cent. alcohol.</p> - -<p>The alkaloidal bases obtained in this manner are -separated by crystallization from alcohol or by -various other chemical methods, the description of -which we will not enter upon here.</p> - -<p>In order to facilitate the study of the leuco<span class="pagenum" id="Page_22">22</span>maines -they are classed under three groups, according -to their chemical affinities. These groups are -as follows:</p> - -<p>1. <b><a id="Xanthic_Leucomaines"></a>Xanthic Leucomaines.</b>—The bases of this -group appear to have a composition resembling -that of uric acid. When hydrolyzed, they yield -urea and guanidine. They are weak bases, and -exhibit both basic and weakly acid properties. -They all possess the common characteristic of being -precipitated by copper acetate in acid solution with -heat, and by ammoniacal silver nitrate in the cold.</p> - -<p>According to Kossel, these bases are derived -from the nucleo-albumins which are found in -the cell nuclei, and which are, as we know, substances -rich in nitrogen and phosphorus.</p> - -<p>Among the bases of this group may be mentioned -<em>adenine</em>, C<sub>5</sub>H<sub>5</sub>N<sub>5</sub>, which is obtained from -infusions of tea.<a id="FNanchor_15" href="#Footnote_15" class="fnanchor">15</a> This base is non-toxic; it was -discovered by Kossel,<a id="FNanchor_16" href="#Footnote_16" class="fnanchor">16</a> and it crystallizes easily.</p> - -<p>Some others of this group are:</p> - -<p><em>Guanine</em>, C<sub>5</sub>H<sub>5</sub>N<sub>5</sub>O, non-toxic, discovered by -Unger; <em>pseudo-xanthine</em>, obtained from muscular -tissues; <em>sarcine</em>, C<sub>5</sub>H<sub>4</sub>N<sub>4</sub>O, also but slightly toxic, -discovered by Scherer; <em>xanthine</em>, C<sub>5</sub>H<sub>4</sub>N<sub>4</sub>O<sub>2</sub>, -which is found in many urines, and which acts as a -stimulant on the cardiac muscles; <em>paraxanthine</em>,<span class="pagenum" id="Page_23">23</span> -C<sub>7</sub>H<sub>8</sub>N<sub>4</sub>O<sub>2</sub>, a toxic base found in certain pathological -urines; <em>caffeine</em> and <em>theobromine</em>, powerful -diuretic bases; and <em>carnine</em>, C<sub>7</sub>H<sub>8</sub>N<sub>4</sub>O<sub>3</sub>, from meat, -a muscular stimulant like caffeine.</p> - -<p>2. <b><a id="Creatinic_Leucomaines"></a>Creatinic Leucomaines.</b>—These have for their -type guanidine; they differ from the xanthic bases -in that they are not precipitated by copper acetate, -but frequently are by ammoniacal silver nitrate. -They yield double salts with the chlorides of zinc -and cadmium. To this group belong <em>glycocyanine</em>, -C<sub>3</sub>H<sub>7</sub>N<sub>3</sub>O<sub>2</sub>, and <em>glycocyanidine</em>, C<sub>3</sub>H<sub>7</sub>N<sub>3</sub>O, both very -toxic; <em>creatine</em>, C<sub>4</sub>H<sub>9</sub>N<sub>3</sub>O<sub>2</sub>, only slightly toxic; -<em>creatinine</em>, C<sub>4</sub>H<sub>7</sub>N<sub>3</sub>O; <em>lysatine</em>, which very easily -decomposes to form urea; <em>lysatinine</em>, <em>xanthocreatine</em>; -<em>arginine</em>, a vegetable base, etc.</p> - -<p>3. <b><a id="Neurinic_Leucomaines"></a>Neurinic Leucomaines.</b>—These have none of -the characteristics of the preceding bases; their -type is neurine, a highly toxic base found in the -brain, nerves, and certain fish ova. These bases -are sometimes normally produced by the animal -economy, and are also frequently the result of -microbic action. They are the result of the simple -phenomena of fermentative hydrolyzation of protagons -and lecithins. Among these bases are -<em>choline</em>, a weak alkaloid, and <em>betaine</em>, which appears -to be non-toxic.</p> - -<p>The former has the formula C<sub>5</sub>H<sub>15</sub>NO<sub>2</sub>; it was -discovered by Stocker. Wurtz synthesized it by -combining trimethylamine and glycol-monochlor<span class="pagenum" id="Page_24">24</span>hydrine, -and treating the resulting hydrochloride -with silver oxide. Betaine, C<sub>5</sub>H<sub>11</sub>NO<sub>2</sub>, is found in -beets; it was discovered by Scheibler. Neurine is, -chemically, trimethylvinylammonium hydrate.</p> - -<p>4. <b><a id="Undetermined_Leucomaines"></a>Undetermined Leucomaines.</b>—Among these -bases several are important in more than one -respect. For instance <em>spermine</em>, which is found in -the sperm, is a strong base possessing a powerfully -dynamic and tonic action on the nerves. It acts -as an oxidizer. Spermine was first obtained by -Schreiner<a id="FNanchor_17" href="#Footnote_17" class="fnanchor">17</a> from the sperm of mammifers in which -it occurs as a phosphate. It has the formula -C<sub>5</sub>H<sub>14</sub>N<sub>2</sub>. It was physiologically studied by Poehl, -Tarchanoff, Weljaminoff, and Joffroy.<a id="FNanchor_18" href="#Footnote_18" class="fnanchor">18</a> <em>Plasmaine</em>, -a toxic base found in the blood and discovered -by R. Wurtz,<a id="FNanchor_19" href="#Footnote_19" class="fnanchor">19</a> has the formula C<sub>5</sub>H<sub>15</sub>N<sub>5</sub>; <em>protamine</em>, -from fish milt, was discovered by Micocher.<a id="FNanchor_20" href="#Footnote_20" class="fnanchor">20</a></p> - -<hr class="chap" /> - -<p><span class="pagenum" id="Page_25">25</span></p> - -<div class="chapter"></div> -<h3><a name="CHAPTER_II" id="CHAPTER_II">CHAPTER II.</a><br /> - -<small>TOXINS AND ANTITOXINS</small>.</h3> - - -<p>We have already seen, in the preceding chapter, -that the microbes and the cells of various organisms -are capable of secreting definite products of a -toxic nature to which the names "ptomaines" and -"leucomaines" have been given. Researches, -which were begun scarcely twenty years ago, -have shown that, besides these crystallizable -and definite products, we meet with basic non-crystallizable -substances of unknown composition, -possessing special toxic properties, sometimes even -of extreme violence. These substances have been -named "toxins."</p> - -<p>At first this generic name was extended toward -indefinite basic organic products that could be -isolated from tissues and tumors both normal and -abnormal; later on, however, the name was applied -to toxic substances, equally indefinite, isolated -from the culture media of microbes and the active -constituent of various venoms.</p> - -<p>It is only since 1885, when Charrin called attention -to them, that investigations began to be<span class="pagenum" id="Page_26">26</span> -made regarding them. In 1888 Roux and Yersin,<a id="FNanchor_21" href="#Footnote_21" class="fnanchor">21</a> -in their beautiful researches on diphtheria, pointed -out the diastatic nature of the properties of the -active albuminoid matter existing in the cultures -of the specific bacilli of this disease. From -that period, these products began to take a more -and more prominent place, from year to year, in -the study of pathological affections, and, by developing -the knowledge of immunity, they have opened -a new path to the investigations of therapeutic -technic.</p> - -<p><a id="It_is_due"></a>It is due to the knowledge of these principles that -we have learned that the infectious microbes, far -from acting as they were believed to do only a few -years ago, and which Pasteur strongly maintained -to be by vital parasitism—such as would be the -case with the carbonizing bacteria which, according -to Pasteur, act by diverting the oxygen, or causing -capillary embolisms—owe their pathogenic action -to the toxic substances which are the products -of their secretion, and which spread throughout -the organism, even though the microbe frequently -is localized in a very circumscribed spot, as in -tetanus and in diphtheria.</p> - -<p>The idea of intoxication by these products has -now replaced the idea of the direct action of the<span class="pagenum" id="Page_27">27</span> -microbe on the elements or the liquids of the organism.</p> - -<p>The occurrence that takes place in diphtheria -and tetanus is one of the best examples to cite in -support of this view.</p> - -<p>Here, in fact, the pathogenic microbe is found -only in a very limited area in the organism attacked—the -false membrane, in the case of diphtheria, or -frequently only a slight wound in the case of -tetanus, and the microbe becomes localized there -only. Now, in both cases, there are general -phenomena of toxic effects. There must hence be -a diffusion of toxic substances which, distributed -by the blood, affect the different systems and -exert a toxic action on the entire organism.</p> - -<p>It must be observed that<a id="the_toxins_act"></a> the toxins act as toxic -agents only when in a condition to be introduced -into the circulation subcutaneously. The -cause of this innocuousness of the toxins when -given per os has frequently been studied. It -appears to be quite probable that the cause of -the attenuation of the morbid properties is due -to the intervention of the digestive microbes. -Such is the opinion of Levaditi and Charrin<a id="FNanchor_22" href="#Footnote_22" class="fnanchor">22</a>; it -is also the conclusion that is to be drawn from the -experiments of Mme. Metchnikoff and of Cal<span class="pagenum" id="Page_28">28</span>mette<a id="FNanchor_23" href="#Footnote_23" class="fnanchor">23</a> -on the modifications undergone by a -vegetable toxalbumin, abrin, and by serpent -venoms, when these toxalbumins are inoculated -with the bacillus subtilis chromogenus. Moreover, -Charrin and Lefèvre,<a id="FNanchor_24" href="#Footnote_24" class="fnanchor">24</a> on the one hand, and -Nencki, Sieber and Somanowsky,<a id="FNanchor_25" href="#Footnote_25" class="fnanchor">25</a> and Carrière,<a id="FNanchor_26" href="#Footnote_26" class="fnanchor">26</a> -on the other hand, have discovered that the digestive -ferments, particularly trypsin, destroy, even -though but little, the toxins secreted by the Loeffler -and Nicolaier bacilli. This is practically contrary -to the opinion of Behring and of Rauson,<a id="FNanchor_27" href="#Footnote_27" class="fnanchor">27</a> according -to which the innocuousness of the microbial poisons -when administered per os is due exclusively to the -lack of absorption.</p> - -<p><b><a id="Nature_of_the_Toxins"></a>Nature of the Toxins.</b>—The molecules of the toxins -are very nearly like those of the diastases. Like -these, the toxins appear to have a very complex, -and very unstable, internal structure. Their mode -of action frequently depends, as in the case of the -diastases, upon the medium in which they occur. -Again, like the diastases, they are generally destroyed -by the action of sufficiently prolonged heat, -but less easily, for there are certain toxins that -resist a temperature of 100° C. for an indefinite -period. They are, like the diastatic albuminoids,<span class="pagenum" id="Page_29">29</span> -insoluble in strong alcohol, and are precipitated -from their solutions on the addition of this reagent. -They easily adhere to precipitates that form in -liquids in which they occur in solution, and possess -the remarkable property of diastases in that imponderable -masses produce considerable results.<a id="FNanchor_28" href="#Footnote_28" class="fnanchor">28</a></p> - -<p>Although closely allied to certain alkaloidal bases, -the toxins are sharply distinguished by the remarkable -fact that their action is never immediate, but -is always preceded by a period of incubation, which -may be quite long.</p> - -<p>Like the alkaloidal bases, they appear to result -from the hydrolyzing breaking down of albuminoids -and nucleo-albumins, and they appear to -be intermediary, from a chemical point of view, -between these bodies, the general characters of -which they retain, and the alkaloids proper, or -ptomaines, to which we have called attention, and -the principal chemical and physiological properties -of which they possess.</p> - -<p>No absolutely precise knowledge is had regarding -the chemical nature and constitution of these -remarkable substances. A number of analyses of -these substances have been published which, in -general, permit no definite conclusion to be drawn.<a id="FNanchor_29" href="#Footnote_29" class="fnanchor">29</a><span class="pagenum" id="Page_30">30</span> -I have, however, elaborated several speculative -ideas regarding this subject.<a id="FNanchor_30" href="#Footnote_30" class="fnanchor">30</a></p> - -<p>We must here call particular attention to the -ideas of Ehrlich regarding the constitution of the -toxins. According to this scientist, their molecules -contain two functional groups; the one, to which -he has given the name "haptophore," is that -which enables the toxin to attach itself to any -cellular element whatever, and which it then -renders non-toxic by means of the other, or "toxophore," -group. We will particularize farther on -regarding this very important conception.</p> - -<p><b><a id="Origin_of_the_Toxins"></a>Origin of the Toxins.</b>—These toxic bodies result -either as the products of the secretion of microbial -life, or as the result of the normal functionation of -cellular life in the higher vegetable or animal -organisms.</p> - -<p>They are the direct products of life, and do -not result, as was formerly believed, from a more -or less profound modification of the more or less -complex albuminoids that serve as a food for the -various species of microbes, or for the cellular elements.</p> - -<p>The vegetable toxins are less numerous than<span class="pagenum" id="Page_31">31</span> -the animal toxins. They are met with, nevertheless, -in almost all mushrooms which are reputed -or known to be toxic; the seed of the castor plant -contains a very toxic vegetable albuminoid, as is -likewise the case with Abrus precatorius (jequirity-bean), -and certain others.</p> - -<p>The true physiological toxins occupy a very -important place in the realization of the conditions -that govern health, sickness, and death.</p> - -<p>We will see later on that they are met with in -quite large number in the bladder, whence they -are voided in the urine. Their number varies considerably, -according to diverse influences (waking, -slumber, eating, fasting, fatigue, oxygen, brainwork, -health, disease, etc.). It is necessary here to -observe that the renal system serves for the purification -of the entire organism, and that in the -case of normal life we will find in the renal system -a large portion of the products of the cellular secretion -of the organism, and among the number there -are found, as we know, a certain number of alkaloidal -bases. We will take up later the subject of -urinary toxicity.</p> - -<p><b><a id="Autointoxications"></a>Autointoxications.</b>—The toxins are also encountered, -and often in some number, in the muscular -tissues and in the blood, particularly in those -of batrachians, mureids, and saurians. In the -organism these toxins, developed by the activity -of the various cells, may cause autointoxication<span class="pagenum" id="Page_32">32</span> -whenever, for one cause or another, their normal -elimination ceases. "Although there are an -infinity of diseases," remarked Prof. Bouchard, -"there are but a few ways of becoming ill." Of -these ways that of autointoxication is the most -frequent. "What else is it, then," says Prof. -Charrin, "in the last analysis, but to die from -affections of the kidney, the liver, the heart, the -lung, etc., if it be not to succumb because of the -lack of oxygen, the accumulation of carbonic acid, -the influence of the numerous urinary poisons, -the action of acids, of salts, of biliary pigments, or -the effect of noxious principles, which the hepatic -cell must normally destroy or at least attenuate."</p> - -<p>These autointoxications, always due to poor -elimination of toxic principles, toxins formed in -very great number in the organism, and which -the normal modes of evacuation or destruction do -not eliminate, are always found to be the cause -of all diseases, even those that are manifested by -attacks of the cerebro-spinal axis, and that exhibit -variously mania, insanity, symptoms of hyperexcitability, -etc.</p> - -<p>These autointoxications are controlled by the -nervous system, and the latter alone is the cause -of a larger number of maladies than is generally -believed; in fact, if the mechanism of nutrition be -reduced to its most simple elements, it will be -seen to consist of the penetration of the foods, of<span class="pagenum" id="Page_33">33</span> -the plasmatic principles, to the cells; of their -transformation within the interior of the cells, -and finally the rejection of all the matter that -could not be utilized. It is the nervous system -that commands or dominates this mechanism, that -controls the taking-up of assimilable elements and -the elimination of toxic principles, the fruit of -assimilation or disassimilation, and in such a manner, -in fact, that this same nervous system can, -at its will, cause starvation, or intoxicate.</p> - -<p>The marvelous cures obtained by magnetic -methods are due to no other causes than favorable -changes in the nervous system.</p> - -<p><b><a id="General_Mode"></a>General Mode of Action.</b>—The toxins, of whatever -kind, always behave like diastases, in the sense -that their definite action appears to be absolutely -independent of their mass, and that imponderable -quantities suffice to cause serious morbid affections -and profound modifications in nutrition.</p> - -<p>Koch has shown that tuberculin is capable of affecting -60 trillion times its weight of the living human -being. According to Vaillard one milligramme of -tetanus toxin will kill a horse weighing 600 kilos. -These two examples show what an enormous power -the toxins possess.</p> - -<p>My views regarding the manner in which diastases -act I have developed at length in my work -<cite>Nature des Diastases</cite>. The close analogy between -these substances and the toxins, an analogy upon<span class="pagenum" id="Page_34">34</span> -which, moreover, I have dwelt at some length, permits -me to refer the reader who is desirous of fuller -details to the small work just mentioned.</p> - -<p>The mode of action of diastases resembles singularly -closely that of the catalytic substances, -and we will admit, for the moment, that they -act by intermediary combination, resulting in their -rapid decomposition.</p> - -<p><a id="We_owe_to_Ehrlich"></a>We owe to Ehrlich<a id="FNanchor_31" href="#Footnote_31" class="fnanchor">31</a> a new conception relative -to the nature and mode of action of the diastases, -and which to-day plays an important rôle in all -our conceptions regarding immunity.<a id="FNanchor_32" href="#Footnote_32" class="fnanchor">32</a></p> - -<p>According to this scientist, the complex molecule -of albuminoid substances is constituted by -a fixed central nucleus, and by a number of lateral -chains or receptors, fixed to this nucleus, which -possess diverse accessory functions, and which -serve, particularly, for the nutrition of the cells. -These receptors have a great affinity for the various -substances necessary for the support of the -living elements, and they seize upon the alimentary -substances, in normal life, just as a leaf of the -<em>Dionæa</em> seizes a fly which serves as its food.</p> - -<p>In these special conditions the receptors may<span class="pagenum" id="Page_35">35</span> -attach themselves to the complex molecules of -albuminoid substances, such as the different -toxins.</p> - -<p>Ehrlich supposes, as we have already seen, that -a toxin contains two special groups—a <em>toxophore</em> -group, which poisons, and a <em>haptophore</em> group, -which combines with the receptor. According to -this theory, the toxophore group of a toxin can act -on an organism <em>only</em> when the haptophore group -of the toxin encounters a suitable attachment or -receptor.</p> - -<p>The receptors attached to the living protoplasmic -molecule attract the toxin, just as a lightning-rod -attracts the lightning.</p> - -<p>It is hence clearly proved that the toxigenic -poisons exert their noxious action on the cellular -elements of sensitive organisms, by entering into -combination with these.</p> - -<p>Experience has shown that they attach themselves, -in a most rigorously elective manner, to the -tissues, and rapidly disappear from the general -circulation. Numerous facts, clearly established, attest -the reality of this fixation or attachment.</p> - -<p>It is thus that von Behring and Wernicke<a id="FNanchor_33" href="#Footnote_33" class="fnanchor">33</a> -sought to ascertain the quantity of antitoxin (we -will see farther on that this name is given to those -substances which neutralize the activity of toxins<span class="pagenum" id="Page_36">36</span> -under certain conditions) which, introduced a certain -time after the introduction of the poison, -will save the life of the animal. They have experimented -with diphtheria toxin, which we will study -later, and they have demonstrated that, if the -antitoxic serum be introduced immediately after -the toxin, a dose of antitoxin twice as large as -that of the toxin suffices to effect a cure.</p> - -<p>Eight hours after the administration of the toxin -the dose must be trebled, while after thirty-six hours -it is necessary to have recourse to a quantity of -antitoxin eight times as great. These experiments -show that the curative action of the antitoxin is -so much the less the longer the period of time -that has elapsed between the introduction of the toxin -and the antitoxin. This is because the toxin has -become so intimately attached to the tissues that -the antitoxin introduced has not the power to -destroy the combination. These facts have been -confirmed by Donitz<a id="FNanchor_34" href="#Footnote_34" class="fnanchor">34</a> and by the classic experiments -of Decroly and Rousse.<a id="FNanchor_35" href="#Footnote_35" class="fnanchor">35</a></p> - -<p>This is not, however, the case with cold-blooded -animals, which, generally, are not affected by injections -of poisonous toxins. Thus Metchnikoff<a id="FNanchor_36" href="#Footnote_36" class="fnanchor">36</a> and<span class="pagenum" id="Page_37">37</span> -his pupils have been able to show that the toxins -introduced into certain cold-blooded animals -(Oryetes nasicorius) may remain for several months -without alteration in their circulation.</p> - -<p>If we consider the facts of the theory of Ehrlich's -lateral chains, which we have mentioned, we are -led to well-defined conclusions regarding the mode -of action of the toxins. In fact, since these toxins -exhibit a pronounced chemical affinity for the tissues, -and while, on the other hand, they can attach -themselves only because of the presence of certain -functional groups of the protoplasmic molecules, -this union can take place only in certain specific -centers. This has been fully confirmed by experiments -<i lang="la">in vitro</i>.</p> - -<p>It is known, since the researches of Ehrlich,<a id="FNanchor_37" href="#Footnote_37" class="fnanchor">37</a> -Wassermann and Takaki,<a id="FNanchor_38" href="#Footnote_38" class="fnanchor">38</a> Marie,<a id="FNanchor_39" href="#Footnote_39" class="fnanchor">39</a> Metchnikoff,<a id="FNanchor_40" href="#Footnote_40" class="fnanchor">40</a> -and a host of other scientists, that this fixation is -due to a clearly elective property. It is for this -reason that the tetanus toxin fixes itself only upon -the nervous tissue, and that in this action all passes -as if the nervous tissue had been provided with<span class="pagenum" id="Page_38">38</span> -functional groups possessing an elective affinity -for the tetanic poison.</p> - -<p><b><a id="Means_of_Defense"></a>Means of Defense Possessed by the Organism -against the Action of Toxins.</b>—We have already seen -that the renal organs serve for the elimination of -the toxins normally produced in the organism by the -simple play of its cellular mechanism. Experience -has shown that the toxins introduced from without -into the circulation are generally finally eliminated, -even though in the meantime the modifications -they have imprinted on the economy may -be transmitted hereditarily; and that their influence -on the general nutrition and the normal functionation -of the entire organism persists even after -their elimination.</p> - -<p>Much has been said regarding the elimination of -these toxins by the urine, but the experiments made -by Métin, at the Institut Pasteur, have shown the -inaccuracy of this assumption, and it has been -necessary to seek another.</p> - -<p>It has been remarked that oxidation destroys -the toxins <i lang="la">in vitro</i>, and it has been thought that -a process resembling disinfection may well take -place within the tissues of the animal economy, -but no decision has been arrived at regarding the -possible mechanism of this action, which some -attribute to the action of the oxidizing ferments -of the organism, or to the action of certain special -cells.</p> - -<p><span class="pagenum" id="Page_39">39</span></p> - -<p>According to Poehl, there is developed as -destroyer a substance possessing energetic oxidizing -properties, which he has isolated and named -<em>spermine</em>, and which is found in most of the organic -fluids and particularly in the leucocytes, the special -rôle of which we will presently study.</p> - -<p>There develops still another cause of elimination, -or, to be more exact, of the neutralization of -the toxic principles in defense of the organism -against the toxins, and that is the formation of -<em>antitoxins</em>.</p> - -<p>It is well known that the term <em>virus</em> has been -reserved to designate physiological liquids which -were characterized, when first they were known, -by their property of transmitting to an organism -certain functional affections, but the true character -of which is to expend their toxicity upon the -microbes which occur and are reproduced in the -organism, or upon the organized plastidulary granulations, -as in the case of the rabic virus, the special -microbe of which has not as yet been isolated.</p> - -<p><a id="Pasteur"></a>Pasteur, when studying rabies, found that the -brain and spinal marrow of rabid animals contained -the pure rabic virus in considerable quantity, and -that every particle of the marrow was capable of -imparting rabies to a perfectly healthy dog. After -having ascertained this fact, he found that he -could <em>attenuate the action of the virus</em>, either by passing -the virus through certain animal organisms, such<span class="pagenum" id="Page_40">40</span> -as the monkey or rabbit, by gently heating, or even -by allowing it to oxidize and partially dry in the -air, or else by submitting it to the action of antiseptics -or alternating electric currents of very high -tension.</p> - -<p>Experiments have shown that a deadly virus, -attenuated by one of the means mentioned, may -be injected, without danger of death, into the living -animal; and what is still better, the animal thus -treated acquires the power of resisting large doses -of the virus, less and less attenuated, and that it -is possible to reach a point where the animal -economy may become habituated to very large -doses of a highly virulent virus without the organism -experiencing any visible illness—that is, the -organism has been <em>vaccinated</em> with regard to the -particular virus.</p> - -<p>Experiments have shown that this property is -not peculiar to microbial virus alone, but that it -is common to the venoms the toxicity of which is -essentially due to some toxins, with the exception -of those agents noted.</p> - -<p>The attenuated <a id="viruses_act"></a>viruses act, as vaccins, through -their soluble constituents, which, either directly, by -modifying the nutrition of certain cells, or indirectly, -by inducing reactions of the nervous centers which -preside over this nutrition, profoundly change the -conditions of life and give rise to the pathological -condition—the vaccined state.</p> - -<p><span class="pagenum" id="Page_41">41</span></p> - -<p>Experiments by Behring and Kitasato<a id="FNanchor_41" href="#Footnote_41" class="fnanchor">41</a> have -shown that the tumors of a vaccinated animal, -freed from all organized matter visible under the -microscope by filtration through porcelain, contains -principles capable of directly or indirectly protecting -other animals from the disease caused by the -corresponding virus. Meanwhile, experiments have -shown that the vaccinating matters are totally -eliminated; nevertheless, after their elimination, -the immunity acquired remains with the animal, -which then continues to be protected against the -corresponding virus.</p> - -<p>Interest in this subject has incited numerous -researches with a regard to bringing to light the -mechanism of this immunization; and this will -form the subject of another volume of this collection. -We may state here, however, that there -have been recognized two concurrent causes of -this preservative action; the one, called <em>phagocytosis</em>, -results from the fact that the microbe introduced -into the vaccined organism becomes incapable -of producing its usual toxins, while on the other -hand the immunization renders the organism -capable of secreting substances possessing an -activity contrary to that of the virus, in fact true -counter-poisons, comprised under the general name -<em>antitoxins</em>.</p> - -<p><span class="pagenum" id="Page_42">42</span></p> - -<p><b><a id="Phagocytosis"></a>Phagocytosis.</b>—We have seen that an organism -subjected to a toxic invasion tends to protect itself -by proper means of defense; and one of those is -the direct putting into activity of the living cellular -elements themselves, and in particular, the leucocytes, -or white corpuscles, found in more or less -number, according to pathological conditions, in -the blood and lymphatic fluids.<a id="FNanchor_42" href="#Footnote_42" class="fnanchor">42</a></p> - -<p>Metchnikoff has shown that the moment a -foreign element, particularly a microbe, enters the -organism, these leucocytes come flocking from -all parts of the body, collect around the bacterial -element, penetrate it, and begin to digest it. -These elements have received the name <em>phagocytes</em>. -The name <em>chemotaxis</em> has been given to the property -by virtue of which they approach (positive -chemotaxis) or move away from (negative chemotaxis) -certain substances which affect them powerfully.</p> - -<p>Experiments have shown that the leucocytes -are attracted by the products secreted by pathogenic -microbes, or saprophytes. Attracted by -the latter, the white corpuscles surround, envelop, -and finally digest them; and when it happens that -all the pathogenic microbes within an organism<span class="pagenum" id="Page_43">43</span> -are absorbed, the organism survives, while in the -contrary case it succumbs.</p> - -<p>Attention must be called to this attack by the -white corpuscles within the limits where they are -normally confined. It is a pathologic diapedesis—a -leucocytosis provoked by the irritation of the -tissues—and caused either by the presence alone -of foreign elements, or by the soluble products -secreted by them.</p> - -<p>When, for any reason whatever, this phagocytic -action is impeded, the resistance of the organism -to pathogenic infection ceases to be effective, -and the organism may therefore be invaded by -the microbe. Numerous causes may contribute to -impede this action.</p> - - -<p class="sub-title1"><a id="The_Antitoxins"></a>The Antitoxins.</p> - -<p>We have seen that the second means of defense -possessed by the organism resides in the action of -special products, true defensive secretions, possessing -an activity contrary to that of the toxins, -and which are secreted by the cells of the organism -under the influence of the vaccins.</p> - -<p>This is a property common to every organism, -and which is observed even in non-vaccinated -subjects, although in this case the secretion forms -with great difficulty and in small quantity.</p> - -<p>When an organism subjected to the toxic action -of a bacterial infection does not succumb to the<span class="pagenum" id="Page_44">44</span> -intoxication, it emerges from the test gifted with a -new property, which may be augmented by habituation, -and which borders on immunity.</p> - -<p>At first we were content to vaccinate small -animals in the laboratory, but in proportion as the -discoveries in this domain extended, and there -developed a need for large quantities of antitoxins, -recourse was had to the larger animals, particularly -horses and cattle. From the moment that large -quantities of blood and antitoxic serum were at -command, search was made for a means of isolating -the antitoxin and determining its properties.</p> - -<p>Experiments so far made have shown that the -antitoxins are substances of an albuminoid nature, -of unknown composition, and which are very closely -united to the albuminoid substances of the serum. -It must be observed, however, that Behring and -Knorr oppose the assertion regarding the albuminoid -nature of tetanic antitoxin, but their reasons for -this do not appear to be well founded.</p> - -<p>In general, these antitoxins are precipitable with -the globulins, and possess quite considerable powers -of resistance towards physical and chemical agents. -Thus they are destroyed only at a temperature -above 60-65° C. Kept in the dry state, in the -residue of evaporated serum, and away from the -light and all oxidizing action, it is possible to preserve -their activity for a very long time.</p> - -<p>They are essentially humoral substances; they<span class="pagenum" id="Page_45">45</span> -are found in the blood of vaccinated animals, from -which may be obtained antitoxic serums with a -specific but transient immunity; and they are also -found in the plasmas of the lymph and exudates, -in aqueous tumors, and in the milk. They are -seldom found in the cells.</p> - -<p><b><a id="Mode_of_Action"></a>Mode of Action.</b>—Frequent attention has been -paid to the mode of action of the antitoxins upon -the toxins, a phenomenon of great importance in -relation to the phenomenon of immunity acquired -against the toxins. At the beginning of our -knowledge on this subject, the idea of a destruction -of the toxin immediately suggested itself, and was -advanced by von Behring.<a id="FNanchor_43" href="#Footnote_43" class="fnanchor">43</a> According to this -scientist the antibody inhibits the morbigenic action -of the toxin by neutralizing the toxin, combining -with the latter to form a compound of a chemical -nature which is devoid of toxicity and without -action on the organism. According to this theory, -the influence of the antitoxin on the toxin is direct, -and does not require the intervention of the living -cellular protoplasm. Such was also the belief of -Prof. Ehrlich.<a id="FNanchor_44" href="#Footnote_44" class="fnanchor">44</a></p> - -<p>Buchner, a little later, believed that the antitoxin, -instead of acting directly on the toxin, -exercised a direct influence on the living elements<span class="pagenum" id="Page_46">46</span> -of the organism, preserving them from intoxication.<a id="FNanchor_45" href="#Footnote_45" class="fnanchor">45</a></p> - -<p>Such was also the opinion of Roux<a id="FNanchor_46" href="#Footnote_46" class="fnanchor">46</a>; and Calmette -demonstrated that a mixture of venom and -of a non-toxic antivenom recovered its toxicity on -being heated to 68° C, whereby the antivenom -was destroyed (Calmette: <cite>Le Venin des Serpents</cite>, -Paris, 1897, p. 58); and Wassermann arrived at -the same result.<a id="FNanchor_47" href="#Footnote_47" class="fnanchor">47</a></p> - -<p>The array of proofs offered by these scientists, -which we cannot here enlarge upon without uselessly -extending our subject, would tend to make -one believe, at first glance, that the antitoxin does -not act directly on the toxin, but at the present -time Buchner's theory appears untenable. Numerous -researches have proved conclusively that the -toxin and the antitoxin have a specific affinity -for each other, by virtue of which these principles -combine to form a substance free from all toxicity, -but unstable, and which may be decomposed by -heat or certain other factors.<a id="FNanchor_48" href="#Footnote_48" class="fnanchor">48</a></p> - -<p>Some recent experiments by J. Martin and Cherry -(<cite>Proceedings of the Royal Society</cite>, 1898, <span class="smcap">LXIII</span>, p. -423) have clearly brought out this fact. These -authors made mixtures of serpent venom with its<span class="pagenum" id="Page_47">47</span> -antivenom, which they filtered through a layer of -gelatin, under the supposition that, if the venom -and its antivenom were not chemically combined, -the former alone would be able to pass through -into the filtrate, because its molecules are so much -smaller. Martin and Cherry allowed the venom -and its antivenom to remain in contact for varying -periods before filtering. As the result of a series -of experiments carried out with this idea, they -have demonstrated that the filtrate obtained after -allowing a few minutes' contact between the two -substances, was decidedly toxic, while that obtained -after a contact of half an hour was absolutely non-toxic. -From this the authors conclude that the -antitoxin enters into chemical union with the -venom, but that the combination does not take -place immediately, and requires a certain length -of time for its accomplishment.</p> - -<p>Ehrlich and Knorr have demonstrated that the -neutralization is less rapid in dilute solutions than -in concentrated ones.</p> - -<p>Prof. Svante Arrhenius has completed our knowledge -regarding the mode of combination between -the toxins and the antitoxins, by demonstrating the -occurrence of limited reactions analogous to the -etherification of an alcohol by an acid, and in -such a manner that there always exists, in a mixture -of these two substances, a certain quantity of -free toxin and antitoxin. This is an important<span class="pagenum" id="Page_48">48</span> -modification of the general ideas held in this -respect.<a id="FNanchor_49" href="#Footnote_49" class="fnanchor">49</a></p> - -<p>It appears necessary to bring here more clearly -in evidence the fact that <em>the antitoxin inhibits the -noxious action of the toxin, even outside the living -organism, by uniting with it to form a compound -in identically the same manner as when a strong base -and a strong acid are brought together</em>. As we have -seen, all the conditions of environment that favor -or retard the formation of salts, in a like sense -influence the neutralization of the toxin by its -antitoxin.</p> - -<p><b><a id="Formation_of_Antitoxins"></a>Formation of Antitoxins.</b>—Ehrlich's theory of -side chains, to which reference has already been -made, furnishes us with an explanation of the -formation of the antitoxins in tumors. Let us -suppose that, in the organism, a cell had come -into contact only with certain toxic molecules incapable -of compromising its life, and that the only -result was the immobilization of the receptors -which are united with the haptophore groups of -the opposing toxins. It is known that, by virtue -of a property inherent in all living organisms, -during the phenomena of reparation, there is -generally an overproduction of the neoformed<span class="pagenum" id="Page_49">49</span> -parts. In the case we here speak of, as the receptors -fill an important function in the nutrition of the -opposing cellular elements, once they become united -with the toxic haptophores, they become incapable -of filling their normal function of nutrition. Under -these conditions the cells develop so large a quantity -of receptors that, filling the cells, and not finding -any more room, they spread into the blood and -other liquids of the organism.</p> - -<p>Under these conditions, every new injection of toxin -into the organism is absorbed into the blood where -it meets with the free receptors which possess great -avidity for the haptophore group of its molecule, -and the two groups immediately unite, before the -haptophore group of the toxin has been able to -attack and intoxicate a cellular element.</p> - -<p>We thus see that the receptors which, when in a -free state in tumors, play the rôle of antitoxics or -antitoxins, become, within the cellular elements -themselves, the vehicle of intoxications. Figuratively -speaking, so long as these fixators are -attached to the molecule of the living protoplasm -they attract the toxin.</p> - -<p>According to this ingenious conception, the -formation of antitoxins is hence absolutely independent -of the action of the toxophore elements -on the cellular elements, and it suffices that these -possess receptors or side chains capable of uniting with -the haptophore groups of the toxin. This explains<span class="pagenum" id="Page_50">50</span> -why it has been possible to produce antitoxins from -toxins which have lost some of their toxic properties, -but which have preserved their property of -uniting with antitoxic substances. Ehrlich gives -the name <em>toxoids</em> to those modified toxins that -have lost their toxophore groups, while the haptophore -group, the producer of the immunizing substance, -is still preserved intact.</p> - -<p>According to Metchnikoff's theory, which is -very similar, it seems quite possible that the -phagocytes, thanks to the facility with which they -absorb poisons, occupy an important place as -producers of antitoxins. It has not been possible -so far to verify this theory in our at present imperfect -knowledge regarding this subject. The -domain of immunity has, however, made brilliant -conquests during these last few years, so that we -should not despair of arriving at a definite solution -before long.</p> - -<p>In the vaccinated animal the antitoxin is reproduced, -and it is possible to obtain several -times, from the vaccinated animals, successive -portions of antitoxic serum.<a id="FNanchor_50" href="#Footnote_50" class="fnanchor">50</a> The protective power -of these antitoxins is absolutely marvelous. An -animal accustomed gradually to the tetanic virus -yields a serum containing an antitoxin a thousand -times more active than the virus.</p> -<p><span class="pagenum" id="Page_51">51</span></p> -<p>According to Vaillard, a quintillionth of a cubic -centimeter of this antitetanic serum suffices to -preserve one gramme of living mouse from the -effects of a dose of tetanic serum that would otherwise -be surely fatal.</p> - -<p>In the animal, the antitoxins are eliminated -mostly by the fluids of the body, and particularly -by the urine. Ehrlich has demonstrated that they -also pass into the milk, and this fact is confirmed -by a large number of observers. It explains the -immunity acquired by nurslings, and which is -transmitted by the milk.</p> - -<p><b><a id="Serotherapy"></a>Serotherapy.</b>—The search for antitoxins and their -rôle in the etiology of infectious diseases are fundamental -points in actual therapy. It has been demonstrated -that the serums of certain vaccinated animals -enjoy very extended antitoxic therapeutic properties; -for instance, the serum of vaccinated rabbits is an -antivenom towards erysipelas; and the sterilized cultures -of the pneumococcus or of the Bacillus pyocyaneus -prevents infection of carbuncle (anthrax).</p> - -<p>The antivenomous serum of the ass immunized -by injections of increasing doses of the venom of -the terrible naja is a perfect prophylactic and curative, -not only as regards the venom of this serpent, -but also against that of the crotalus, trigonocephalus, -and viper.</p> - -<p>We shall take up the study of serotherapeutics in -another volume of this collection.</p> - -<hr class="chap" /> - -<p><span class="pagenum" id="Page_52">52</span></p> - - -<div class="chapter"></div> - -<h2><a name="PART_II" id="PART_II">PART II.</a><br /> - -<i><small>THE TOXINS PROPER</small>.</i></h2> - - - -<hr class="small" /> -<h3><a name="CHAPTER_III" id="CHAPTER_III">CHAPTER III.</a></h3> - - -<p class="center">I. <a id="VEGETABLE_AND_ANIMAL_TOXINS"></a>VEGETABLE AND ANIMAL TOXINS.</p> - -<p>The vegetable toxins possess the characteristic -property of being innocuous, and of being almost -completely devoid of poisonousness, when they are -absorbed by the intestines; we can see, from this, -how greatly they differ from the poisons proper.<a id="FNanchor_51" href="#Footnote_51" class="fnanchor">51</a></p> - -<p>The vegetable toxins known are quite numerous; -nevertheless our knowledge regarding them is very -incomplete. Our review of them will be chiefly -descriptive.</p> - -<p>Many of the leguminous plants are poisonous, -either because of emanations exhaled by them, or -by reason of their alkaloids, or because of some -toxins contained in them. We shall commence -with these.</p> - -<p><b><a id="Abrin"></a>Abrin.</b>—This toxin, which was studied in par<span class="pagenum" id="Page_53">53</span>ticular -by Warden and Waddell,<a id="FNanchor_52" href="#Footnote_52" class="fnanchor">52</a> then by Kobert<a id="FNanchor_53" href="#Footnote_53" class="fnanchor">53</a> -and de Hellin,<a id="FNanchor_54" href="#Footnote_54" class="fnanchor">54</a> is found in the fruit of the Leguminosæ, -Abrus precatorius (wild licorice, or jequirity). -Its name was given it by Warden and Waddell, who -discovered both its toxic nature and the vegetable -toxin; the toxin is found only in the seeds. To -extract it, the seeds are macerated in water, and -the solution filtered and precipitated with alcohol; -the precipitate which forms is collected and dissolved -in distilled water, from which it is again precipitated -by adding powdered ammonium sulphate. -The precipitate is then collected and submitted -to dialysis in order to eliminate the ammonium -sulphate. The abrin so obtained forms an albuminoid -substance<a id="FNanchor_55" href="#Footnote_55" class="fnanchor">55</a> stable at 100° C., and possessing -rotatory power; it liquefies starch paste, and is -extremely toxic. One milligramme suffices to kill -a rabbit within several hours. It must be observed, -however, that, as is the case with all the toxins, -abrin acts or kills only after a period of incubation -which generally exceeds twenty-four hours.</p> - -<p>It is possible to vaccinate an organism so as to -withstand a lethal dose of abrin, but it requires -quite a long time; it is effected by injecting into<span class="pagenum" id="Page_54">54</span> -a suitable animal very small doses of the substance, -and increasing the quantity gradually. Rabbits -which have been rendered highly immune towards -venoms are capable of resisting without inconvenience -doses of abrin which are ordinarily fatal; -and the blood serum afforded by them contains a -specific antibody for the substance.</p> - -<p><b><a id="Ricin"></a>Ricin.</b>—This vegetable toxalbumin has been -studied particularly by Stillmark,<a id="FNanchor_56" href="#Footnote_56" class="fnanchor">56</a> by Dixon,<a id="FNanchor_57" href="#Footnote_57" class="fnanchor">57</a> -and Thuson.<a id="FNanchor_58" href="#Footnote_58" class="fnanchor">58</a> It is found in the seeds of the -castor plant; three or four of the seeds suffice to -cause a gastroenteritis accompanied by serious -symptoms and even by death.</p> - -<p>It was first isolated by P. Ehrlich, by treating -the seeds with lukewarm water, and precipitating -the aqueous solution with alcohol. The toxalbumin -is soluble in water, but on boiling the solution, the -substance loses in great measure its activity.</p> - -<p>Ricin possesses considerable activity. 0.00003 Gm. -suffice to kill a rabbit when injected hypodermically; -0.2 Gm. are fatal to man. The action is not immediate, -but follows a period of incubation. Ehrlich -has shown that, exercising precaution, it is possible -to create, as with abrin, a condition of tolerance -or habituation, and in consequence to cause the -formation of a specific antibody.</p> - -<p><span class="pagenum" id="Page_55">55</span></p> - -<p><b><a id="Robin"></a>Robin.</b>—This toxic albuminoid was obtained -from the bark of an Acacia (Robinia Pseudacacia) -by Power and Cambier,<a id="FNanchor_59" href="#Footnote_59" class="fnanchor">59</a> by exhausting with water -at a temperature of about 30° C., and precipitating -the infusion with alcohol. The substance is analogous -to ricin, and like this, possesses powerful -toxic properties.</p> - -<p><b><a id="Toxicity_of_the_Vegetable"></a>Toxicity of the Vegetable Diastases.</b>—The diastases, -which have been treated of in a volume of -the Encyclopédie Léauté,<a id="FNanchor_60" href="#Footnote_60" class="fnanchor">60</a> and to which we would -refer the reader who is desirous of more complete -details, develop powerfully energetic toxic properties -when injected into the organism. Thus <em>amylase</em> -causes, when injected subcutaneously, a considerable -rise of temperature, but without any other -toxic symptoms. <em>Invertin</em> or <em>sucrase</em> was studied -by Roussy under the name <em>pyretogenin</em>, but it -appears probable that this diastase was not the -only substance present in the product, but that -there were present reducing diastases, as we have -already shown in the first volume of this collection, -devoted to the phenomena of reduction within the -living organism.</p> - -<p>The pyretogenin of Roussy gives rise to an -attack of violent fever, but it loses all activity when -heated to 80-100° C.</p> - -<p><span class="pagenum" id="Page_56">56</span></p> - -<p>Through his researches, Roussy clearly demonstrated,<a id="FNanchor_61" href="#Footnote_61" class="fnanchor">61</a> -for the first time, that the fever may -cause the formation within the blood of a substance -clearly belonging to the class of soluble -ferments or zymases. Now, it is well known that -within the animal economy there exist many ferments -of this character; and experiment has shown -that they can, at a given period and under various -influences, leave the cells in which they are normally -localized, pass into the blood plasma, and -reach the nervous centers, where they cause serious -effects. We have already dwelt upon the -mechanism of autointoxication of the organism. -The toxic action of certain digestive diastases has -been shown by Hildebrandt, who has demonstrated -that 0.1 Gm. of pepsin is capable of killing a -rabbit in two or three days.</p> - - -<p class="center">II. <a id="TOXINS_FROM_MUSHROOMS"></a>TOXINS FROM MUSHROOMS.</p> - -<p>Mushrooms are alimentary substances of the -highest order, causing a general stimulation of the -entire organism. The substances met with belong, -according to their composition, to different classes—celluloses, -sugars, and amylaceous substances, alcohols, -acids, fats, astringents, essential oils, resins,<span class="pagenum" id="Page_57">57</span> -alkaloids, and albuminoids. The study of the last -only, the albuminoids and diastases, interests us -here. The most important of these albuminoid -substances, <em>phallin</em>, was discovered in 1890 by -Kobert. Pouchet also has isolated a whole series -of other toxic albuminoids, particularly from Amanita -muscaria (Fly Agaric).</p> - -<p>There are alimentary as well as toxic species in -every possible variety among mushrooms, some -species consisting chiefly of the edible kind, others -consisting of the poisonous variety.</p> - -<p>In consequence of the toxicity of mushrooms, -great attention must be given to the treatment to -which they are subjected when it is desired to -utilize them for alimentary purposes. Thus the -toxic principles of several varieties can be removed, -and the mushrooms rendered edible by very simple -means.</p> - -<p>Pouchet has made a very ingenious comparison -between the ethereal, alcoholic, saline, and aqueous -extracts of mushrooms, and bacterial cultures. The -analogy is striking as to the presence of toxin, -toxalbumose, and albumoses more or less toxic; -it is moreover not exaggerated, since, according to -the classification generally admitted, mushrooms -are nothing more than the very advanced representatives -of a group the more simple members of -which constitute the bacteria.</p> - -<p>The same author has shown that phallin obtained<span class="pagenum" id="Page_58">58</span> -from the juice of the Fly Agaric will kill a guinea-pig -weighing 600 grammes in one hour.</p> - -<p><a id="phalline"></a>As we have already stated, it is the phalline to -which the ordinary disorders which mushrooms -cause are due. According to Kobert, a 1:250 000 -solution of this substance causes an intense hemolysis, -with all its disastrous consequences.</p> - -<p>According to Pouchet, the flesh of mushrooms -must be compared with meat that has been kept -for some time to become tender, and it is well -known that though this "tendering" process -renders the meat more digestible, it may also allow -the meat to acquire noxious properties, due to the -presence of toxins.</p> - -<p>Phallin is the type of those toxic albuminoids -of unknown composition which exist in mushrooms, -and which are comprised under the name -<em>sapotoxins</em>. The intravenous injection of phallin -into an animal, in the proportion of 1 part to -1 000 000 parts of body weight, causes sudden -death within one minute; in the proportion of -1:5 000 000, death occurs in about three minutes; -in the proportion of 1:50 000 000, death also occurs, -but is greatly retarded. An injection of 0.0005 Gm. -per kilo of body weight of animal causes solution -of the blood corpuscles to such an extent that -thirty minutes later the blood serum is strongly -colored red, as well as the veins.</p> - -<p>Instead of being easily altered under the influ<span class="pagenum" id="Page_59">59</span>ence -of an elevated temperature, as are many of -the albuminoid substances, whereby their toxic -power is lost, phallin may be boiled for half an -hour with water without undergoing any noticeable -alteration. Pellegrini has observed that the dried -juice of Amanita Phalloides (Death-cup) preserves -its properties for more than a year.</p> - -<p>According to a recent paper by Gillot, the symptoms -of poisoning by mushrooms must be ascribed -to albuminoids (phallin and albumose), alkaloids -(muscarine, choline, or betaine), or to resinoids -(cambogic and agaricic acids).</p> - -<p>The <em>alkaloids</em> found in mushrooms are: <em>Muscaridine</em> -(an oxyneurine), which possesses considerable -toxicity, and of which 0.00005 Gm. suffices to kill -a frog; <em>neurine</em> (trimethylethylammonium hydroxide); -<em>choline</em> (trimethyloxyethylammonium hydroxide); -<em>mycetomuscarine</em>; <em>anhydromuscarine</em> (an oxyneurine); -and a whole series of various betaines.</p> - -<p><b><a id="symptomatology"></a>symptomatology.</b>—It is quite natural to divide -this symptomatology into three different periods; -that of incubation, that of manifestation of symptoms, -and that of termination.</p> - -<p>The duration of the first period, that of incubation, -is exceedingly variable; it very rarely -lasts more than forty-eight hours, and becomes -general only a few hours after absorption. Certain -conditions influence the duration; firstly the quantity -of mushrooms ingested, then the manner in<span class="pagenum" id="Page_60">60</span> -which they were prepared; and, to some extent, -the nature of the organism, whether child or adult, -healthy or in poor health.</p> - -<p>When it is a question of the more particularly -alkaloid-containing mushrooms, especially when the -poisoning is due to muscarine, the toxic symptoms -generally develop rapidly, the first symptoms -appearing about one hour after the ingestion of the -mushrooms. On the other hand, if the poisoning -is due to one of the albuminoid group, and particularly -in the case of phallin, the period of incubation -is longer, and may last ten, twenty, thirty, -or even forty-eight hours and more.</p> - -<p>The symptoms begin with dizziness and an -indefinable sensation of being ill.</p> - -<p>The second period is characterized chiefly by -digestive and by nervous derangements. The digestive -derangements are evidenced by very violent -and painful vomiting, and diarrheas of choleraic or -dysenteric character. The nervous derangements -vary according to whether they are developed by -an alkaloid, which causes delirium with hallucination, -or by albuminoids, which cause depression, -ataxo-adynamia, and stupor, these being particularly -characteristic of the action of the toxic albuminoids.</p> - -<p>As for the period of termination, it results either -in death or a cure. If the poisoning is due to phallin, -death appears to be an almost inevitable con<span class="pagenum" id="Page_61">61</span>sequence, -as it occurs in 80 per cent. or more of the -cases. The poisoning by the alkaloids is less dangerous, -and the cure, when it does occur, is very -rapid, almost immediate, in fact, while in the case -of the toxic albuminoids the cure is very slow, and -attended by relapses.</p> - -<p>One characteristic of these toxalbumins is that -they are apt to develop specific antitoxalbumins. -This fact has been verified not only in the case of -abrin, ricin, robin, and their analogues, but also -in that of the vegetable and animal diastases possessing -toxic properties even in the slightest degree -only. These antibodies generally exhibit their -action <i lang="la">in vitro</i>. Thus antiricin exerts its antiagglutinative -action on the erythrocytes <i lang="la">in vitro</i> -in a saline medium in which the erythrocytes cannot -live.</p> - -<p>Here, again, as in the case of the antitoxins, it -must be admitted that the antitoxalbumin possesses -a specific affinity by virtue of which it unites -chemically with the toxalbumin to give rise to a -new substance which is devoid of toxicity.</p> - -<p><a id="antidiastase"></a>The first antidiastase obtained by immunization -methods, and according to the mechanism we have -already seen, was <em>antiemulsin</em>, obtained by Hildebrandt.<a id="FNanchor_62" href="#Footnote_62" class="fnanchor">62</a> -This antiemulsin counteracts, both <i lang="la">in<span class="pagenum" id="Page_62">62</span> -vivo</i> and <i lang="la">in vitro</i>, the specific action of emulsin. -These studies have been followed by a large number -of scientists, particularly by Camus and Gley,<a id="FNanchor_63" href="#Footnote_63" class="fnanchor">63</a> -Carnot, Mesnil,<a id="FNanchor_64" href="#Footnote_64" class="fnanchor">64</a> and Charron and Levaditi,<a id="FNanchor_65" href="#Footnote_65" class="fnanchor">65</a> in the -case of trypsin; and Sachs<a id="FNanchor_66" href="#Footnote_66" class="fnanchor">66</a> in the case of animal -pepsin. Gessard<a id="FNanchor_67" href="#Footnote_67" class="fnanchor">67</a> obtained a very active <em>antityrosinase</em>, -and Mohl an <em>antiurease</em>.</p> - -<p>The most important researches regarding this -subject have been published by Morgenroth, Briot,<a id="FNanchor_68" href="#Footnote_68" class="fnanchor">68</a> -and Korschum<a id="FNanchor_69" href="#Footnote_69" class="fnanchor">69</a> on <em>antilab</em> (or <em>antirennet</em>). The -researches of these authors have fully demonstrated -that there is considerable difference between the -various rennets, which had heretofore been confounded -under one head; thus there is no difference -whatever between animal rennet and the rennet -extracted by Rosetti<a id="FNanchor_70" href="#Footnote_70" class="fnanchor">70</a> from Cynara cardunculus -(cardoon) so far as their coagulant action on milk -is concerned, yet each yields an antibody which -is strictly specific to itself. From a scientific point<span class="pagenum" id="Page_63">63</span> -of view we see, therefore, that the preparation of -antidiastases permits us to differentiate certain -diastases that could otherwise not be differentiated.</p> - - -<p class="center">III. <a id="ANIMAL_TOXINS"></a>ANIMAL TOXINS.</p> - -<p>As we have shown at the beginning of this chapter, -certain diastases, and particularly those that are -concerned with the digestive processes, pepsin, -trypsin, etc., and which are produced in abundance -by the entire living organism, possess quite clearly -defined toxic properties, and sometimes to even a -considerable extent.<a id="FNanchor_71" href="#Footnote_71" class="fnanchor">71</a></p> - -<p>Hemialbumose, from which peptones are formed, -is itself a dangerous toxin. It is generally believed -that the toxic action of the peptones and of the -products of digestion of the albuminoids is due not -to the peptone itself, but to the more advanced -products of digestion, alkaloidal products unquestionably -closely allied to the ptomaines.</p> - -<p>Nevertheless, the true peptones behave just -like true poisons, when they are introduced hypodermically -into the blood.<a id="FNanchor_72" href="#Footnote_72" class="fnanchor">72</a></p> - -<p>Brieger has made us acquainted with a non-proteid -substance, under the name of "peptotoxin," -which is met with at the beginning of the putre<span class="pagenum" id="Page_64">64</span>faction -of albuminoids. This toxin, which is not a -protein, is nothing else but a ptomaine. It is not -altered by heat, and possesses a very high toxicity. -Brieger claims that it is a hydroxylized derivative -of an aromatic amide.<a id="FNanchor_73" href="#Footnote_73" class="fnanchor">73</a></p> - -<p>Besides these facts, experiment has shown that -the leucocytes, or white corpuscles, the defensive -rôle of which we have noted in phagocytosis, owe -their properties to the ferments which they secrete, -and particularly to some of the digestive ferments. -These white corpuscles are very rich in ferments -of all kinds. Rossbach found in them amylase; -Achalme found lipase, casease, and trypsin; and -the study of immunity has brought to light a -series of other ferments, the alexins or cytases -(microcytase and macrocytase), which have an -exceedingly important rôle to play.</p> - -<p>It may easily be conceived that under certain -circumstances a part or the whole of these ferments -can pass into the blood of the fluids of the body, -when they give rise to serious disturbances in -certain cases, or confer immunity in others.</p> - -<p>It is thus that, according to Gautier, the rise of -temperature which characterizes fever is a consequence -of the abnormal transudation of these -normal ferments into the blood, and their trans<span class="pagenum" id="Page_65">65</span>mission -by the general circulation to the nervous -centers.</p> - -<p>However, it is not only in the leucocytes that -we meet with these toxic digestive ferments; it -appears quite probable, and has even been partially -demonstrated, that they occur in a large number of -other cellular elements.</p> - -<p>It is not necessary here to dwell upon the formation -of the antibodies of this group of active substances. -The animal toxins are animal diastases, -and we have seen in the preceding paragraph that -these substances yield specific antibodies with -great facility. For the rest, we will dwell more -fully on these antibodies of the animal toxins in -another volume of this collection, specially devoted -to the study of these substances, and entitled -"<cite>Les Serums Immunisants</cite>," to which we refer -the reader who is desirous of obtaining more -complete details than he can obtain in the present -volume.</p> - -<p><b><a id="Alimentary_Intoxications"></a>Alimentary Intoxications.</b>—What we have -already stated permits us to understand the -phenomena of indigestion and botulism. The toxic -substances form within the digestive tract when -the nervous conditions modify the composition of -the gastric juice, and arrest the flow of hydrochloric -acid, the presence of which normally checks -the development of the microbial flora, so rich -within the stomach. The result is the production,<span class="pagenum" id="Page_66">66</span> -within the organism, of all kinds of dangerous -toxins. The same thing happens when the liver -does not functionate normally, and this, affords us -a knowledge of the mechanism by which foods that -are most wholesome may become toxic by reason of -poor digestion or poor assimilation.</p> - -<p>The absorption of spoiled viands may, <i lang="la">a fortiori</i>, -produce serious results. The alteration may be -due not only to a bacterial infection, as in tainted -meat, but it has also been proved that the flesh of -an animal that has died of terror or madness may -be very dangerous as a food, even after cooking, -because, although there are toxins which are -destroyed by a sufficient heat, there are ptomaines -and certain toxins that resist destruction under -these conditions.<a id="FNanchor_74" href="#Footnote_74" class="fnanchor">74</a></p> - -<p>The use of preserved but spoiled beef, preserved -ham or birds, sausages frequently, and pieces of -pork tainted by sausage poison, gives rise to a -succession of toxic symptoms the principal ones of -which are dryness, constriction of the pharynx, -bilious vomiting, diarrhea, dyspnea with pulmonary -edema, etc. Fish and eggs are foods quite -frequently capable of developing serious results; -the same is the case with molluscs, mussels, oysters, -lobsters, and snails. Lastly, moldy bread, spoiled -cheese, putrid water, and spoiled vegetables them<span class="pagenum" id="Page_67">67</span>selves, -are proper agents for determining attacks of -botulic poisoning.</p> - -<p>We have seen, at the beginning of this volume, -that putrid meats contain ptomaines, which are -among the most toxic alkaloidal bases. We have -shown that Brieger has isolated from them neuridine, -putrescine, muscarine, and guanidine; that Nencki -has isolated hydrocollidine; and that Gautier and -Etard have obtained from them parvoline—only to -mention a few of them.</p> - -<p>Lastly, there may develop within the gastrointestinal -tract dangerous putrefactions, the products -of which may enter the veins and arteries from -the ileum (a portion of the small intestine) and be -distributed throughout the organism. Although -such poisonings occur, they do not immediately -follow the ingestion of the spoiled or toxic foods, -but they are always preceded by a period of incubation -varying from several hours to several days.</p> - -<p>These alimentary poisonings are recognized by -a great physical depression, accompanied by vomiting -and paralysis of the lower extremities, sweats, -and diarrheas. In some cases there occur cutaneous -eruptions; and when death happens, this -occurs only several days later, and generally without -being preceded by any great pain.</p> - -<p><b><a id="Urinary_Toxins"></a>Urinary Toxins.</b>—As we have already remarked -several times, it is by the renal way that the -organism voids its principal waste products.</p> - -<p><span class="pagenum" id="Page_68">68</span></p> - -<p>We have seen also that it is by the kidneys that the -toxins are eliminated in all pathological conditions. -As a general rule, the urines are always more or less -toxic. This toxicity of the urines must be attributed -in the first place to the crystallizable organic -principles (ptomaines and leucomaines<a id="FNanchor_75" href="#Footnote_75" class="fnanchor">75</a>) which they -contain; secondly, to the non-crystallizable<a id="FNanchor_76" href="#Footnote_76" class="fnanchor">76</a> extractive -matters not so well known; and lastly, to -the saline substances, among which the potassium -salts are the most active. We find these mineral -salts particularly abundant under normal conditions -in the urines of the herbivora. According -to Bouchard, 0.18 Gm. of potassium chloride are -sufficient to prove fatal to 1000 Gm. of living organism; -a man excretes on the average 2.5 Gm. of this -salt, and a rabbit excretes about double this quantity, -weight for weight.</p> - -<p>A very large number of hypotheses have been -advanced regarding the toxicity of the urines. -Wilson considers the urea as being responsible for -it; Stadthagen<a id="FNanchor_77" href="#Footnote_77" class="fnanchor">77</a> believes it to be due to the potassium -salts, etc. Bouchard<a id="FNanchor_78" href="#Footnote_78" class="fnanchor">78</a> was the first to recognize -that the toxicity of the urines is due to a -number of causes. We will not dwell further on -these active principles which, in the last analysis,<span class="pagenum" id="Page_69">69</span> -are no other than those that form in the various -portions of the organism, and which are eliminated -by the urine.</p> - -<p>It is self-evident, and it has already been shown, -that the toxicity of the urines varies greatly -according to the malady, in consequence of the -elimination of toxins by the urines. According -to Bouchard, in infectious maladies the urines -are twelve times more highly charged with toxins -than is blood serum. Moreover, the toxicity of -the urines is considerably augmented the moment -there is the least febrile condition, no matter what -the cause is.<a id="FNanchor_79" href="#Footnote_79" class="fnanchor">79</a></p> - -<p><a id="urinary_toxicity"></a>Even in the normal condition, the urinary toxicity -varies greatly; and this is easily conceived since the -physiological phenomena that control this secretion -undergo incessant rise and fall. Thus, for -example, the urines eliminated during sleep are -less active than those produced during waking, -because during sleep the elimination of cellular -poisons is at a minimum. Exercise, walking, -physical and intellectual labor, exert their portion -of influence on these oscillations of toxicity; and -this variation of toxicity is due not to any one -variation in the mineral extractive matters, but -rather more or less to the organic toxic products. -We will not dwell further on this subject, but will<span class="pagenum" id="Page_70">70</span> -simply refer to the work by Charrin, already mentioned, -for all supplementary details.</p> - -<p><b><a id="Autointoxication"></a>Autointoxications.</b><a id="FNanchor_80" href="#Footnote_80" class="fnanchor">80</a>—The cells of the organism -having, as a whole, a life very much like that of -the microbes, it is quite natural that among the -excreted products of the living tissues there should -be found the same substances formed as a result -of the anaerobic fermentation of albuminoids. -Experiment has demonstrated that this is so, -and Armand Gautier has irrefutably proven the -existence of these principles.<a id="FNanchor_81" href="#Footnote_81" class="fnanchor">81</a> Bouchard was the -first to demonstrate the toxic nature of muscle -extract,<a id="FNanchor_82" href="#Footnote_82" class="fnanchor">82</a> and Roger<a id="FNanchor_83" href="#Footnote_83" class="fnanchor">83</a> established the fact that -the toxicity of this extract is due to ferment-toxins; -it has since been recognized that after death these -toxins accumulate in the muscles.</p> - -<p>The extract of kidney made rapidly by cold -process by triturating the washed kidney with -glycerin, and precipitating the glycerinic solution -with alcohol, contains toxic ferments to which the -name "<em>hystozymes</em>" has been given.<a id="FNanchor_84" href="#Footnote_84" class="fnanchor">84</a> These ferments -split up hippuric acid into benzoic acid and -glycocoll. Lépine has likewise discovered in the<span class="pagenum" id="Page_71">71</span> -kidney a very toxic pyrogenic substance.<a id="FNanchor_85" href="#Footnote_85" class="fnanchor">85</a> Roger -has given us evidence of the toxic properties of -the liver, washed and pulped, and then sterilized -by filtration through a porous diaphragm. This -scientist has shown that the toxic properties are -due to albuminoids, which lose their activity when -heated to 100°C.<a id="FNanchor_86" href="#Footnote_86" class="fnanchor">86</a></p> - -<p>It must be remarked that the organs we have -studied are essentially reducers, and that the -more powerful reducers yield the most toxic extracts. -We find here a confirmation of Armand -Gautier's views regarding the anaerobic origin -of the toxic substances formed within the organism.<a id="FNanchor_87" href="#Footnote_87" class="fnanchor">87</a></p> - -<p>Blood serum precipitated by alcohol affords products -which possess very marked toxic power. It -would appear that the toxic products we speak of -here are thermogenic diastatic substances derived -from the white blood corpuscles. In certain diseases -the blood serum may acquire a high degree of -toxicity. We will recur again presently to this -property as a normal characteristic of the blood of -various animal species, and will study it in greater<span class="pagenum" id="Page_72">72</span> -detail in a future volume of this collection, devoted -to the immunizing active principles.</p> - -<p><b><a id="Glandular_Secretions"></a>Glandular Secretions.</b>—On studying the venoms -we will see that a certain number of these products -are the result of glandular secretion. This is a -general property of the glands; and it was Brown-Sequard -who first drew attention to the rôle played -by these glands, and to the importance of the -products that they throw into the blood.<a id="FNanchor_88" href="#Footnote_88" class="fnanchor">88</a></p> - -<p>P. Noel showed later that the testicular juice -possesses a high degree of activity, which he -attributed to an oxidizing ferment, and which we -have already mentioned, <em>spermine</em>.</p> - -<p>The greater number of the other glands contain -proteid matters and various peptones, more or less -toxic, with amides and alkaloids.</p> - -<p>Particular mention must be made of the thyroid -gland, the secretions of which exercise a powerful -action on the nervous centers and on nutrition.<a id="FNanchor_89" href="#Footnote_89" class="fnanchor">89</a> -It appears reasonable to attribute to the secretions -of this gland a very powerful antitoxic action, and -the first proof of this fact is that the organisms -deprived of this gland become the seat of serious -derangements; the urines of such organisms become -particularly toxic, while, on the other hand, the -hypodermic injections of the aqueous extract of<span class="pagenum" id="Page_73">73</span> -the gland, when the derangements spoken of exist, -cause the immediate disappearance of the derangements -caused by the excision of the gland.<a id="FNanchor_90" href="#Footnote_90" class="fnanchor">90</a></p> - -<p>Attempts have been made to isolate the active -principle of the glands. Notkine isolated a <em>tyroproteid</em>,<a id="FNanchor_91" href="#Footnote_91" class="fnanchor">91</a> -which is not sensibly toxic to animals -who still retain the gland, but which becomes toxic -when the gland is excised. It seems probable, -however, that this product is not the principal -agent of the thyroid gland.</p> - -<p>From the researches of Schaeffer, Roos, and Sigmund -Fraenkel<a id="FNanchor_92" href="#Footnote_92" class="fnanchor">92</a> it results that the active principle -of the gland is not a toxin, but a purely -chemical substance, a true leucomaine, which has -received the name <em>thyroantitoxin</em>.</p> - -<p>On the other hand, Baumann quite recently -extracted from the thyroid gland an iodized substance, -which he named <em>thyroiodine</em>.<a id="FNanchor_93" href="#Footnote_93" class="fnanchor">93</a></p> - -<p>The <a id="suprarenal_capsules"></a>suprarenal capsules also possess properties -that have often attracted the attention of physiologists -during the last few years. They are considered -as being, just like the thyroid gland, producers -of antitoxins; they destroy, or seem to<span class="pagenum" id="Page_74">74</span> -destroy, toxins that are artificially introduced into -the circulation.</p> - -<p>Albanèse<a id="FNanchor_94" href="#Footnote_94" class="fnanchor">94</a> maintains that the function of the -suprarenal capsules is to neutralize neurine, the -toxic product of the disassimilation of the nervous -system; this view, however, is opposed by Boinet<a id="FNanchor_95" href="#Footnote_95" class="fnanchor">95</a> -and Langlois.<a id="FNanchor_96" href="#Footnote_96" class="fnanchor">96</a> On the contrary, it has been definitely -proven that the suprarenal glands exert a -specific action on the poisons of muscular origin. -Abelous and Langlois<a id="FNanchor_97" href="#Footnote_97" class="fnanchor">97</a> have in fact demonstrated -that the alcoholic extract of the muscle -of a decapsulated animal has the same properties -as the extract of tetanized muscle; the decapsulated -animal gives ergographic tracings analogous to those -afforded by tetanized animals. The removal of the -suprarenal capsule from an animal brings results, -hence, analogous to those of fatigue—that is to say, -that the toxic substances which accumulate as a -result of the decapsulation resemble those that -result from muscular exertion. The suprarenal -capsules exert their action furthermore on other -toxic products as well, as Guieysse<a id="FNanchor_98" href="#Footnote_98" class="fnanchor">98</a> has shown, -and particularly on the exogenous poisons. In<span class="pagenum" id="Page_75">75</span> -conclusion, it may be said that the matter concerns -a most important rôle, and we cannot do better in -this respect than to refer the reader to the memoir -presented by Sergent and Bernard to the Académie -de Médecine in 1902 and entitled <cite>l'Insuffisance -Surrénale</cite>.<a id="FNanchor_99" href="#Footnote_99" class="fnanchor">99</a></p> - -<hr class="chap" /> - -<p><span class="pagenum" id="Page_76">76</span></p> - -<div class="chapter"></div> -<h3><a name="CHAPTER_IV" id="CHAPTER_IV">CHAPTER IV.</a><br /> - -<small>THE MICROBIAL TOXINS</small>.</h3> - - -<p>There is but one way of characterizing the toxic -poisons secreted by microbes, and that is to apply -to them the name of the microbes generating them; -thus the soluble and toxic poison of the tetanus -bacilli has received the name <em>tetanus toxin</em>.</p> - -<p>In toxic microbial cultures it is necessary to -distinguish the toxins proper from the toxic -alkaloids (ptomaines) which generally accompany -them; this is easily accomplished by evaporating -the solution in a vacuum at about 30°C., and -then treating with alcohol and ether, in which the -alkaloids are soluble, while the true toxins are -insoluble. By fractional precipitation with alcohol -it is easy to isolate the peptones and true toxins.</p> - -<p>The microbial toxins possess two essential properties; -one the pyogenic property, thanks to -which the toxins first attract, then destroy the -white blood corpuscles or leucocytes, and transform -them into pus, and the other the pyretogenic -property, which appears to belong only quite<span class="pagenum" id="Page_77">77</span> -indirectly to the pyogenic substance. The toxins -in general retard the heart action.</p> - -<p>We will not speak of the distinctions it has been -sought to establish between the substances which -possess these different properties, but will at once -take up the discussion of several of the microbial -toxins.</p> - -<p><b><a id="Anthrax_Toxin"></a>Anthrax Toxin</b><a id="FNanchor_100" href="#Footnote_100" class="fnanchor">100</a> (from Bacillus Anthracis).—We -will describe the preparation of this toxin as a -type.</p> - -<p>The cultures of the bacillus are made in Liebig's -bouillon, to which has been added 0.1% of fibrin, -the whole being carefully sterilized for a long time -at 110° C. The cultures medium is inoculated with -a drop of blood taken from the heart or spleen of an -animal that has died of anthrax. At the end of a -week, the culture is filtered, and the filtrate acidulated -with a little acetic acid and precipitated by -adding powdered ammonium sulphate. The flocculent -precipitate is collected, washed, dissolved in -distilled water, and dialyzed. The dialyzed solution -is concentrated in vacuo at 40-45° C., and -precipitated by adding to it alcohol. The precipitate -formed is then collected and dried.<a id="FNanchor_101" href="#Footnote_101" class="fnanchor">101</a></p> -<p><span class="pagenum" id="Page_78">78</span></p> -<p>In this manner there is obtained a grayish-white -substance which is soluble in water, and -which is fatal in large doses, but which, given in -repeated small doses, confers immunity against -anthrax.</p> - -<p>According to Hankin, it seems that the toxic -property of this toxin is due to an albumose.</p> - -<p>Marchoux<a id="FNanchor_102" href="#Footnote_102" class="fnanchor">102</a> has been able to confer immunity -upon sheep by injecting first small quantities of -the filtered culture of the anthrax bacilli, and then -the virulent anthrax itself.</p> - -<p>The animals thus rendered immune yield a serum -which may be used as a vaccin against anthrax, -and which even possesses curative properties under -certain conditions.</p> - -<p>In every case the acquired immunity is only -temporary. We will recall to recollection the -method employed by Pasteur for vaccinating -against anthrax, using attenuated cultures, a -method which is practiced daily at the present time.<a id="FNanchor_103" href="#Footnote_103" class="fnanchor">103</a></p> - -<p>From the cultures of symptomatic anthrax -(Bacillus Chauvæ) Chauvée extracted a very active -toxin which can withstand without impairment -a temperature of 110°C.<a id="FNanchor_104" href="#Footnote_104" class="fnanchor">104</a> Roux<a id="FNanchor_105" href="#Footnote_105" class="fnanchor">105</a> has shown that<span class="pagenum" id="Page_79">79</span> -the serum of animals that have succumbed to the -symptomatic anthrax is capable of vaccinating -against this disease; we have here a new proof -that the antitoxin is in fact a product of the defense -of the cells of the organism, and the author mentioned -has been able to vaccinate guinea-pigs by -injecting into the peritoneum culture bouillon -sterilized by heating to 115° C. or by filtering -through porcelain.</p> - -<p><b><a id="Tubercular_Toxin"></a>Tubercular Toxin.</b>—The culture bouillons of -Koch's bacillus contain one or more active substances -which constitute, and which is at the -present designated as, tuberculin.<a id="FNanchor_106" href="#Footnote_106" class="fnanchor">106</a> Koch's therapeutic -tuberculin is obtained by evaporating to -one-tenth its volume a culture bouillon of Koch's -tubercle bacilli prepared from a 4-per cent. glycerinic -mutton bouillon, and filtering through porcelain. -By fractional precipitation it is possible to -obtain from the crude tuberculin so prepared a -product which is considered as pure tuberculin, and -which possesses considerable activity.</p> - -<p>Prolonged boiling on the water-bath completely -destroys the activity of this tuberculin, which -moreover hardly ever keeps longer than three -weeks. It has been found possible to preserve it -for an indefinite period, however, by adding to<span class="pagenum" id="Page_80">80</span> -it 30 to 40 per cent. of glycerin. It possesses all -the general reactions of albuminoids.</p> - -<p>Tuberculin is not toxic in the proper sense of -the word. Injected in small quantities into the -healthy human being<a id="FNanchor_107" href="#Footnote_107" class="fnanchor">107</a> and into healthy animals, it -exerts no effect; on the other hand, however, in -tubercular organisms, even in incipient stages of -the disease, even where it is almost impossible to -make a clinical diagnosis, the injection of very small -quantities develops a lively and characteristic -reaction.<a id="FNanchor_108" href="#Footnote_108" class="fnanchor">108</a></p> - -<p>Grasset and Vedel consider the tuberculin as an -excellent means of diagnosing tuberculosis in man, -but in such a case it is necessary to operate with -the greatest caution, with very small quantities -of the tuberculin, and to feel, in some sort, the -sensitiveness of the patient, particularly in the -case of children.</p> - -<p>It is chiefly for the diagnosis of tuberculosis in -cattle, however, that tuberculin is valuable. -Thanks to Nocard, the procedure has to-day become -a common practice. The injection of a fairly -large dose, 0.3 to 0.4 Gm., according to the size -of the animal, causes, in about ten hours or so, -if the animal is tuberculous, a strong febrile reac<span class="pagenum" id="Page_81">81</span>tion -with an elevation of temperature of 1.5 to -3° C., whereas if the animal is not tuberculous -no such reaction takes place.</p> - -<p>Cases in which tuberculosis is far advanced, and -in which the organism is impregnated with tuberculin, -do not react after the injection of tuberculin.<a id="FNanchor_109" href="#Footnote_109" class="fnanchor">109</a></p> - -<p>Tuberculin does not confer immunity, and the -bacillus retains all its virulence, even in injected -tissues; nevertheless, the return to health of animals -in which injections have been recently made -may be due to the action of large doses of the -serum; and on the other hand the tuberculin, in -large quantities, may render the location unsuitable -for the development of the tubercle bacilli.</p> - -<p><b><a id="Diphtheria_Toxin"></a>Diphtheria Toxin.</b>—The most characteristic property -of the diphtheria bacillus is the production, in -culture media, of a special toxic substance which -has been named <em>diphtheritic toxin</em>; this name, -however, has come to be also extended to a liquid -in which the bacilli have lived, and which has -been sterilized by filtration or by any other suitable -process.</p> - -<p>Roux and Yersin<a id="FNanchor_110" href="#Footnote_110" class="fnanchor">110</a> were the first to affirm that -diphtheria is an autointoxication caused by a very -active poison formed by the microbe in the restricted -locality where it develops. In order to obtain this<span class="pagenum" id="Page_82">82</span> -toxin<a id="FNanchor_111" href="#Footnote_111" class="fnanchor">111</a> a culture of the bacillus is first made in a -mutton bouillon made strongly alkaline with sodium -carbonate (10 grams per liter), and with the -addition of 2 per cent. of peptone. At the end -of about one month, the culture being kept at -about 37° C., the liquid is filtered through porcelain. -It is indispensable to employ a very virulent -bacillus; it is hence frequently advantageous -to increase the virulence and toxigenic power of -the bacilli it is desired to use.</p> - -<p>The toxic liquid obtained is exceedingly powerful: -0.1 Cc. kills a rabbit in forty-eight hours. -This toxin is very sensitive to the effects of heat. -When heated to 65° C. it loses almost all its toxicity; -at 70º C. it becomes innocuous; and it only requires -to be heated to 100° C. for fifteen minutes -in order to lose all immediate activity even in large -doses. Nevertheless toxins thus weakened are -capable of proving fatal to an animal even after -five or six months.</p> - -<p>Light, oxygen, ozone and all oxidizers destroy the -active principle of the diphtheria toxin, which is, -moreover, rendered almost inactive by organic acids.</p> - -<p>This toxin is capable of diffusing through animal -membranes, a fact that is in agreement with the -toxic effect seen in a subject attacked with diph<span class="pagenum" id="Page_83">83</span>theria, -and due to the toxin passing through the -mucosa. In spite of this property, however, the -diphtheritic poison may be taken into the stomach -without any pernicious results.</p> - -<p>Roux and Yersin have shown that, like all the -diastases, it may be precipitated from its solutions -by the development, within these, of certain precipitates, -particularly calcium phosphate. It is -precipitated from its solutions by alcohol, as has -been observed also in the case of diastatic solutions. -All the toxic substance is contained in the albuminous -precipitate thus obtained; but the prolonged -action of alcohol, or repeated successive precipitations, -alter it finally. Diphtheria toxin is likewise -precipitated by the reagents for albumoses, particularly -sodium sulphate in saturated solution. -This procedure has been utilized by Brieger and -Fraenkel for preparing the pure toxin, which -they obtained in the form of very light, brilliant -white, amorphous flocks, affording all the principal -reactions of the soluble albumoses (biuret, xanthoproteic, -Millon's), and which they characterized -as a toxalbumin.</p> - -<p>On injecting into healthy animals this diphtheria -toxin attenuated by sufficiently heating at 70° C, -employing at first small doses, and gradually -increasing, it is possible to immunize them against -diphtheria, as was first demonstrated by Carl -Fraenkel.</p> - -<p><span class="pagenum" id="Page_84">84</span></p> - -<p>Roux and Martin, who have specially studied -this procedure,<a id="FNanchor_112" href="#Footnote_112" class="fnanchor">112</a> have shown that a horse may be -easily immunized by injecting into the animal the -toxin diluted with a third of its volume of Gram's -iodine solution, and in successively increasing -doses. The initial dose is 0.25 Cc.; then, after -two days, 0.5 Cc. of the same toxin is injected, -and in like manner the dose is increased up to the -eighteenth day, when the pure toxin is injected, -at first in small doses, which are gradually increased -so that at the end of two or three months -injections of 80 Cc. of the pure toxin may be given -without danger; the animal is then completely -immunized.</p> - -<p>The serum of an animal rendered immune in this -manner contains a diphtheria antitoxin which -possesses high power. A guinea-pig which has -received an injection of 0.01 Cc. of the antitoxin is -perfectly capable of withstanding a lethal dose of -0.5 Cc. of the toxin. The antidiphtheria serum -thus obtained, and in almost limitless quantities, -from an immunized animal, is capable of saturating -the therapeutic diphtheritic toxin, and has to-day -taken rank in therapeutics as the most efficacious -remedy in diphtheria. Injected in varying doses, -it confers a temporary but immediate immunity.</p> - -<p><span class="pagenum" id="Page_85">85</span></p> - -<p>Nevertheless antidiphtheria serum must not be -considered as an antidote; and in pathological -diphtheria, the more serum is required the later -it is used.<a id="FNanchor_113" href="#Footnote_113" class="fnanchor">113</a> In certain cases, if employed too late, -it may prove ineffective.</p> - -<p>The preventive action of the serum is remarkable. -In 10 000 inoculated cases Behring and Ehrlich -have had but 10 cases of diphtheria, and these -were, moreover, of a benign character. The duration -of the immunizing action appears to be from -three weeks to two months.</p> - -<p>This diphtheria antitoxin was first prepared -by Guérin and Macé<a id="FNanchor_114" href="#Footnote_114" class="fnanchor">114</a> by adding to the antidiphtheria -serum a large volume of alcohol, washing -the precipitate, and drying it in a vacuum. -It is soluble in water, and loses its activity when -heated to 65° C. Wassermann<a id="FNanchor_115" href="#Footnote_115" class="fnanchor">115</a> has proposed -to extract it from the milk of immunized animals, -by first coagulating the milk by rennet in the -presence of sodium chloride, filtering, and removing -the fat from the clear liquid by means of chloroform. -After decanting, the clear solution obtained is -precipitated by adding to it 30 to 33 per cent. of -ammonium sulphate. The precipitate is dried in -a vacuum on a polished porcelain slab after having<span class="pagenum" id="Page_86">86</span> -first been strongly expressed. It is then dissolved -in water.<a id="FNanchor_116" href="#Footnote_116" class="fnanchor">116</a></p> - -<p><b><a id="Tetanus_Toxin"></a>Tetanus Toxin.</b>—The fact that the tetanus -bacillus never penetrates to the interior of the -organism enabled us long ago to foretell that it -secretes a very powerful toxin capable of dialyzing -and diffusing through the economy. Kuno -Faber was the first to fully recognize the fact that -the culture bouillon of this bacillus, fully sterilized -by filtration through porcelain, possesses an -exceedingly high toxicity, and exerts a toxic -effect on 50 000 000 times its own weight of living -organism. Brieger had previously, however, extracted -three ptomaines from the cultures of the -bacillus—<em>tetanin</em>, <em>tetanotoxin</em>, and <em>spasmotoxin</em>.<a id="FNanchor_117" href="#Footnote_117" class="fnanchor">117</a> -In order to obtain a highly active liquid, the same -culture medium is inoculated several times in -succession, but filtering each time before the new -inoculation; the microbes greatly increase in -number after each fresh inoculation, and the toxic -substance developed by them accumulates.<a id="FNanchor_118" href="#Footnote_118" class="fnanchor">118</a></p> - -<p>Experiment has shown that the culture bouillon -thus obtained contains two kinds of toxic sub<span class="pagenum" id="Page_87">87</span>stances<a id="FNanchor_119" href="#Footnote_119" class="fnanchor">119</a>—highly -toxic alkaloidal bases (ptomaines, -tetanin, tetanotoxin, etc.), and a true toxin, possessing -diastatic properties, and of almost incredible -toxic power.</p> - -<p>This toxin had already been isolated by Kitasato. -It is a toxalbumin, and is very sensitive to the -action of heat. A temperature of 65° C., maintained -for 30 minutes, renders it quite inactive; -and it becomes oxidized and is destroyed by the -action of the air in the presence of light.</p> - -<p>Brieger and Boer,<a id="FNanchor_120" href="#Footnote_120" class="fnanchor">120</a> by precipitating with zinc -chloride the filtered culture bouillon, obtained -a pure, amorphous tetanus toxin, which they also -considered as a toxalbumin, and which possesses -exceedingly toxic properties.</p> - -<p>If a precipitate be caused to form in these toxic -solutions, as, for instance, a precipitate of calcium -phosphate, this carries down with it all the -toxin present in the liquid. 0.0005 Gm. of this -precipitate is surely fatal to a guinea-pig.</p> - -<p>Dozon and Cournemont have observed that -even in doses of 300 to 400 Gm. of the filtered culture -liquid, this toxin is not immediately toxic -to a horse, but kills the animal only after a period -of incubation of at least twenty-four hours. The -blood of such an animal, however, is immediately<span class="pagenum" id="Page_88">88</span> -and directly fatal to animals into which it is -injected.<a id="FNanchor_121" href="#Footnote_121" class="fnanchor">121</a></p> - -<p>Experiment has shown that animals that have -been cured of tetanus possess no immunity whatever -against tetanus; nevertheless Behring and -Kitasato<a id="FNanchor_122" href="#Footnote_122" class="fnanchor">122</a> first, and Wassermann and Kitasato later -on, succeeded in preparing a <em>tetanus antitoxin</em>. To -obtain this, the immunization of the animal, horse -or cow, is effected by injecting increasing quantities -of the toxin, more or less attenuated by mixing -it with Gramm's iodine solution; the immunization -is easily and rapidly accomplished by the process -devised by Roux and Vaillard.<a id="FNanchor_123" href="#Footnote_123" class="fnanchor">123</a></p> - -<p>The immunized animals yield a serum which, -mixed with tetanus cultures, renders these innocuous, -and which enjoys an antitoxic power that -borders on the marvelous.<a id="FNanchor_124" href="#Footnote_124" class="fnanchor">124</a> A quintillionth of a -cubic centimeter of the serum per gramme weight -of a live mouse suffices to protect the animal from -an otherwise fatal quantity of tetanus toxin.<a id="FNanchor_125" href="#Footnote_125" class="fnanchor">125</a></p> - -<p>This serum is nevertheless powerless to preserve -man in cases of acute tetanus; it confers an immediate, -but only transitory, immunity.</p> - -<p>As to its mode of action, it appears to cause -a permanent condition of excitation or of nutri<span class="pagenum" id="Page_89">89</span>tive -reaction of the cells, which makes these resistant -to the poison. As in the case of the other -toxins, the quantity of antitoxin necessary to -protect an organism is so much greater the later -the treatment is applied.</p> - -<p><b><a id="Mallein"></a>Mallein (Toxin of Glanders).</b>—Among the soluble -products secreted in the culture media by the -glanders bacilli, there are found true toxins to -which are ascribed certain symptoms of glanders -infection. These toxins have been isolated and -designated by the name <em>mallein</em>. First prepared -by Helman and Kalmino, mallein was later on -specially studied by Roux and Nocard, and, in -consequence of the researches of the last-mentioned -scientist, it has acquired great importance.<a id="FNanchor_126" href="#Footnote_126" class="fnanchor">126</a> -It is obtained by sterilizing at 110° C. cultures of -the glanders bacillus made with mutton bouillon -with the addition of salt, glycerin, and peptones. -To isolate the toxin the culture bouillon is first -sterilized by heating for half an hour in an autoclave -at 100° C. It is then filtered, concentrated -to one-tenth its volume on a water-bath, and filtered -through a Chardin filter. The mallein is -thus obtained in the form of a brown syrupy -liquid containing half its weight of glycerin.</p> - -<p>This solution keeps well when kept from air, -light, and heat. In practice it is employed in 10-per<span class="pagenum" id="Page_90">90</span> -cent. solution in phenolated water (5:1000). The -mallein may be precipitated from the crude solution -by the addition of alcohol, as recommended -by Foth. Foth's mallein occurs as a white, light -powder, very easily soluble in water.</p> - -<p>Mallein enjoys a very important rôle in veterinary -therapeutics, a rôle analogous to that of -tuberculin, permitting the diagnosis of incipient -glanders.<a id="FNanchor_127" href="#Footnote_127" class="fnanchor">127</a></p> - -<p>Experience has shown that in animals already -attacked by glanders, even if ever so slightly, the -thermic reaction never fails when 0.25 Cc. of the -mallein solution is injected. In healthy animals, -however, the injection of mallein, even in much -larger quantities, causes no apparent effect. In -animals attacked by glanders the reaction attains -its maximum in twelve hours, and several days -are required for the temperature to return to -normal.<a id="FNanchor_128" href="#Footnote_128" class="fnanchor">128</a></p> - -<p>According to Nocard, mallein possesses no immunizing -properties whatever.<a id="FNanchor_129" href="#Footnote_129" class="fnanchor">129</a></p> - -<p><b><a id="Typhoid_Toxin"></a>Typhoid Toxin.</b>—This is obtained, like the other -microbial toxins, from a culture, prepared with -more or less difficulty, from Eberth's typhoid<span class="pagenum" id="Page_91">91</span> -bacillus. This toxin, injected into guinea-pigs, -develops in them typhoid fever.</p> - -<p>In the solution there occurs a ptomaine, which -has been isolated by Brieger, and which gives rise -to almost all the phenomena of typhoid fever; this -ptomaine is called <em>typhotoxin</em>.<a id="FNanchor_130" href="#Footnote_130" class="fnanchor">130</a></p> - -<p>The same author, in collaboration with Fraenkel,<a id="FNanchor_131" href="#Footnote_131" class="fnanchor">131</a> -later on isolated a toxalbumin from the culture -bouillon of the typhoid bacillus. Sanarelli<a id="FNanchor_132" href="#Footnote_132" class="fnanchor">132</a> obtained -an active toxin by macerating for several -days at 60° C. a month-old culture of the typhoid -bacillus made with a 2-per cent. glycerin-bouillon. -Chantemesse has also published a process which -yields a highly virulent toxin.<a id="FNanchor_133" href="#Footnote_133" class="fnanchor">133</a></p> - -<p>Chantemesse and Widal<a id="FNanchor_134" href="#Footnote_134" class="fnanchor">134</a> have shown that on -injecting into an organism increasing quantities -of the sterilized cultures of Eberth's Bacillus, it is -possible to fully immunize an animal against the -bacillus itself, and even also against the Bacillus -coli communis. The operation, however, is tedious -and painful. The serum of immunized animals -possesses preventive and curative properties respecting -the effects of typhoid bacilli.</p> -<p><span class="pagenum" id="Page_92">92</span></p> -<p>A dose of the filtered culture, which is fatal to -a guinea-pig, becomes innocuous when mixed with -0.5 Cc. of the serum of a vaccinated guinea-pig; -6 Cc. of the serum injected six hours after an -injection of the virulent culture, hence when this -is in full action, suffice to save the animal.<a id="FNanchor_135" href="#Footnote_135" class="fnanchor">135</a> So -far as the human being is concerned, the results -obtained have not been sufficiently satisfactory.</p> - -<p>The culture bouillon of the Bacillus coli communis, -which is closely allied to Eberth's bacillus, -also contains soluble toxic substances which have -been named coli-bacillus toxin. This substance, -which is produced only in small quantity by the -microbe, is fatal only in very large doses.</p> - -<p><b><a id="Cholera_Toxin"></a>Cholera Toxin.</b>—Very little is known regarding -the toxic products of the spirillium choleræ; -nevertheless, the fact that typical cholera exhibits -every symptom of the action of a toxic agent -demonstrates quite clearly the elaboration of some -toxic substance within the cultures of this microbe.</p> - -<p>Villiers<a id="FNanchor_136" href="#Footnote_136" class="fnanchor">136</a> found in it a liquid ptomaine; Klebs<a id="FNanchor_137" href="#Footnote_137" class="fnanchor">137</a> -found another and crystallizable ptomaine; while -Pitai discovered in it a toxin unalterable by heat, -and which he considered as a toxopeptone. According -to Gamaleia<a id="FNanchor_138" href="#Footnote_138" class="fnanchor">138</a> there is present a true toxin,<span class="pagenum" id="Page_93">93</span> -alterable by heat, and the reactions of which -entitle it to be considered as a nucleo-albumin; he -has also found in it a toxic nuclein.</p> - -<p>These toxic substances are found, according to -Gamaleia, Pfeiffer, and Sanarelli,<a id="FNanchor_139" href="#Footnote_139" class="fnanchor">139</a> confined during -the life of the microbe within its cellular envelope, -and does not diffuse through this. Metchnikoff -and Roux are of the contrary opinion,<a id="FNanchor_140" href="#Footnote_140" class="fnanchor">140</a> however, -and they have prepared a toxin almost insensitive -to a temperature of 100° C., and precipitable from -its solutions by ammonium sulphate or strong -alcohol; the toxin is a toxalbumin. This toxin is -quite toxic; one-third of a cubic centimeter suffices -to kill 100 Gm. of guinea-pig in 18 hours; with larger -doses, death is almost immediate.</p> - -<p>By immunizing guinea-pigs, rabbits, and horses -with this cholera toxin, Metchnikoff and Roux -obtained a serum which is distinctly antitoxic for -rabbits. Nothing absolutely certain has been found -as to its action on man.<a id="FNanchor_141" href="#Footnote_141" class="fnanchor">141</a></p> - -<hr class="tb" /> - -<p>We will not dwell longer here on the toxins of -microbial origin. It appears evident, however, -from what has been stated above, that the great<span class="pagenum" id="Page_94">94</span> -majority, if not all, of the virulent microbes manifest -their virulence by means of toxic secretions. Almost -every one of these toxins has been the subject of -study. They would otherwise not have interested -us here, where our main object was but to dwell -upon the general properties.</p> - -<hr class="chap" /> - -<p><span class="pagenum" id="Page_95">95</span></p> - - -<div class="chapter"></div> - -<h3><a name="CHAPTER_V" id="CHAPTER_V">CHAPTER V.</a><br /> - -<small>THE VENOMS</small>.</h3> - - -<p><b><a id="General_Nature"></a>General Nature of Venoms.</b>—The venoms are -more or less toxic products secreted by certain -reptiles, batrachians, and fish; by a large number -of invertebrates; by arachnids, apids, scorpionids, -araneids, and a large number of other insects.</p> - -<p>The venoms are toxic principles very closely -allied to the microbial toxins; like the latter, they -form two classes, the one alkaloidal, the other -proteid, possessing a true diastatic character. -They closely resemble the microbial toxins, moreover, -by the fact that they are capable of being -transformed into vaccins by attenuation of their -virulence, by the action of heat or chemical reagents, -and of leading to habituation of use and -the conference of immunity.<a id="FNanchor_142" href="#Footnote_142" class="fnanchor">142</a> Moreover, like the -various viruses, the serum of immunized animals -is antivenomous, so that if injected into the veins -or beneath the skin of non-immunized animals, the<span class="pagenum" id="Page_96">96</span> -serum confers upon them an immunity against -venom which lasts for some time.</p> - -<p>These venoms, like the microbial toxins, possess -but slight toxicity when absorbed via the stomach. -Fraser, utilizing a method previously advocated, -succeeded, by following this method, in vaccinating -against serpent-venom by causing the absorption -by animals of constantly increasing doses of venom.</p> - -<p>It was thus possible to make the animals withstand -doses a thousand times greater than the -ordinary lethal dose; the blood and serums of -these animals at this point possessed immunizing -properties, and this property passed by heredity -to the offspring, to which it is transmitted by -the blood itself, and by the milk during feeding.</p> - -<p>Along with these resemblances between the -venoms and toxins, attention must be called to a -very important difference. As we have already -seen, the action of the toxins on the organism is -always preceded by a certain period of incubation; -the action of the venoms, on the contrary, is almost -instantaneous, and in this respect they behave like -chemical agents and alkaloidal toxins.</p> - -<p>If the venoms are preserved in a moist condition, -they change because they undergo putrefaction, -which is generally the case with all diastatic substances, -and particularly the toxins.</p> - -<p>It is interesting to note that animals which have -been bitten by a venomous serpent, but which,<span class="pagenum" id="Page_97">97</span> -for some reason or other, have not succumbed to -the venom, never recover their former condition; -if they were young, their functions cease to develop, -and they droop; if they are adults, their general -condition remains that of stupefaction.</p> - -<p><b><a id="Venomous_Serpents"></a>Venomous Serpents.</b>—Among the venomous serpents,<a id="FNanchor_143" href="#Footnote_143" class="fnanchor">143</a> -the most important as well as the most -dangerous are the following: Cobra di capello -(Naja tripudians, the hooded cobra) and its analogues, -the black Naja, Naja hagé, etc.; the elops -(coral serpent); the bungurus of Bengal and -Burmah; the Platycercus proteroglyphia, which is -found chiefly in the waters of the Indian Ocean; -the crotalian solenoglyphs of the two Americas, -and among which in particular are the rattlesnake, -the fer-de-lance (the yellow viper) of Martinique; -the surucucu of Guiana; and the moccasins and -copperheads of Texas and Florida. Lastly, the -entire group of viperian solenoglyphs, among -which are the Echidnæ, the bite of some of which, -for instance the daboia or echidna, is dreadful; the -African vipers, among which may be mentioned -the horned viper, the bite of which will kill a camel; -the springing viper of Congo, and the rhinoceros-viper -of Gabun; the European vipers, the most -dangerous of which is certainly the asp of France, -which is exceedingly numerous in certain regions.</p> -<p><span class="pagenum" id="Page_98">98</span></p> -<p>The effects of the bites of venomous serpents on -man and animals are generally well known to the -public; it is well to recall them, nevertheless. -From the moment the bite has been inflicted, complete -symptoms of poisoning develop, attended by -a condition of extreme and increasing weakness, -with vomiting, hemorrhage, and decomposition of -the blood. There are, besides, particular effects -which vary with every venom.</p> - -<p>The following table by Calmette<a id="FNanchor_144" href="#Footnote_144" class="fnanchor">144</a> gives the -comparative toxicity of various venoms, taking as -the standard of comparison the quantity sufficient -to kill a rabbit in three or four hours:</p> - - - -<div class="center"> -<table border="0" cellpadding="4" cellspacing="0" summary=""> -<tr><td align="left">Naja tripudians</td><td align="left">0.00047</td></tr> -<tr><td align="left">Naja hagé</td><td align="left">0.0003-0.0007</td></tr> -<tr><td align="left">Acanthophis antarctica</td><td align="left">0.001</td></tr> -<tr><td align="left">Ceraste</td><td align="left">0.0017-0.0021</td></tr> -<tr><td align="left">Haplocephalus variegatus </td><td align="left">0.0025</td></tr> -<tr><td align="left">Trigonocephalus</td><td align="left">0.0025</td></tr> -</table></div> - - -<p><b>Nature of <a id="Serpent-venoms"></a>Serpent-venoms.</b>—These venoms are -homogeneous liquids, somewhat more dense than -water, in which they are soluble, slightly colored -green or yellow, transparent, and insoluble in -alcohol; they contain from 30 to 35 per cent. of -solid matter. When fresh, they have a slightly -acid reaction. Towards chemical reagents, and<span class="pagenum" id="Page_99">99</span> -particularly acids, they behave like albuminoids; -almost all the combinations they afford with the -various albuminoid reagents are active, despite -their insolubility. According to Gautier, they are -decomposed by caustic potash.</p> - -<p>According to numerous researches, oxidizers like -potassium permanganate, the hypochlorites, hydrogen -peroxide, and gold chloride (in 1% solution) -destroy the venoms; in certain cases when immediately -injected hypodermically in the poisoned -region, these substances are excellent antidotes -<i lang="la">in vivo</i>.<a id="FNanchor_145" href="#Footnote_145" class="fnanchor">145</a></p> - -<p>We shall not here enter upon a detailed study -of the toxic albuminoid principles of serpent-venoms; -moreover, our knowledge is rather vague, as it is, on -a number of points. It will suffice us to know that, -taken altogether, the active albuminoids of these -venoms are numerous, and that each venom has -its own particular active constituents, differing -according to the species and variety of the snake.</p> - -<p>Each one of these substances acts more or less -rapidly, and may be associated with different -principles which give rise to the variability of -the action of these toxic agents. Among these -toxic albuminoids, the most virulent appear to be -true albumins and globulins, followed by the<span class="pagenum" id="Page_100">100</span> -nucleo-albumins, as we have already stated; there -are also found in venoms alkaloidal bases, but -these principles are present only in very slight -quantity. These bases are but very slightly toxic -compared with the toxins that accompany them.</p> - -<p><b><a id="Natural_Immunity"></a>Natural Immunity towards Serpent-venoms.</b>—Certain -animals exhibit a natural immunity toward -snake-bites; among them are the snakes themselves, -the hog, the hedgehog, and the mongoos -(an Egyptian rat); the blood of these animals contains -apparently an antitoxin.<a id="FNanchor_146" href="#Footnote_146" class="fnanchor">146</a></p> - -<p>Fontana<a id="FNanchor_147" href="#Footnote_147" class="fnanchor">147</a> had remarked that snakes were quite -unaffected by the bite of the viper, even when -inoculated with the venom hypodermically. Physalix -and Bertrand<a id="FNanchor_148" href="#Footnote_148" class="fnanchor">148</a> confirmed these statements, -and showed that the snake perfectly resisted quantities -of viper-venom capable of killing at least -20 guinea-pigs. According to these scientists, -this natural immunity is due to the existence in -the blood of toxic principles analogous to those of -viper's venom—principles that exist in the labial -glands of the snake, and pass into the blood and -the fluids via the internal secretions. These writers, -and also Calmette, have shown that the blood of -venomous serpents becomes antitoxic when heated.</p> - -<p><span class="pagenum" id="Page_101">101</span></p> - -<p>It has been known for a long time that the -hedgehog and the mongoos eat certain venomous -reptiles, and eagerly hunt for the vipers in particular. -When the hedgehog is bitten, which -happens quite often despite its dexterity, it resists -the viper-venom quite well. Physalix and Bertrand<a id="FNanchor_149" href="#Footnote_149" class="fnanchor">149</a> -have experimentally demonstrated that the -hedgehog withstands a dose of viper-venom capable -of killing at least 40 guinea-pigs. Levin<a id="FNanchor_150" href="#Footnote_150" class="fnanchor">150</a> has -shown that young individuals are less resistant, -and it is concluded from this, and perhaps incorrectly -so, that the immunity of the hedgehog is -naturally acquired, rather than inherent. Bertrand -and Physalix have nevertheless shown that on -heating the blood of the hedgehog to 88° C. it -manifests an antitoxic power toward serpent-venom -<i lang="la">in vitro</i>.</p> - -<p><b><a id="Artificial_Immunity"></a>Artificial Immunity toward Serpent-venom.</b>—Immunity -may be conferred upon every individual -by utilizing the method of habituation. This -fact was simultaneously elicited by Calmette, -Bertrand, and Physalix. To effect the immunity -these scientists prepare an antivenomous serum -and inject it into animals, giving at first very small -quantities of the diluted venom, and gradually -increasing the doses, and the periods intervening<span class="pagenum" id="Page_102">102</span> -between the injections. At the end of about two -months of this treatment, the immunity has reached -its maximum. Certain rabbits, thus slowly inoculated, -have been able to withstand 0.04 Gm. -of the venom of the naja at a single injection; -such rabbits then yield a vaccinal serum.<a id="FNanchor_151" href="#Footnote_151" class="fnanchor">151</a></p> - -<p>At the Institut Pasteur at Lille there is prepared -in this manner an antivenomous serum from the -horse; it is capable of acting upon 20 000 times -its own weight. This has rendered great service -in the treatment of snake-bites, particularly in -hot countries, where the accidents are of daily -occurrence. <i lang="la">In vitro</i> it acts quite as well preventively -as therapeutically. It arrests the effects -of the naja, the horned ceraste, the trigonocephalus, -the rattlesnake, and of almost every one of the -venomous serpents known.</p> - -<p>The relatively considerable immunity possessed -by certain snake-charmers, and which passes for a -magical gift, is due to nothing else but a natural -immunity, acquired perhaps by heredity, and -it always appears to follow as a result of a nonfatal -snake-bite.</p> - -<p><b><a id="Venoms_of_Batrachians"></a>Venoms of Batrachians and Saurians.</b>—We -observe here a fundamental difference between -these poisons and those of snakes, as we shall<span class="pagenum" id="Page_103">103</span> -see. These latter, in fact, appear to owe all their -toxicity to true toxins which they contain, while -the poisons of batrachians and saurians are chiefly -composed of alkaloidal bases.<a id="FNanchor_152" href="#Footnote_152" class="fnanchor">152</a></p> - -<p>The poison of toads and frogs (studied by Faust, -Bertrand, and Physalix) is chiefly secreted by the -glands of the subcutaneous tissues of these animals; -it has but a very slight action on the unbroken -skin, but it rapidly inflames the nasal and buccal -conjunctival mucosa. The poison is a yellowish -liquid, milky and viscid, with a waxy odor and -an insupportably bitter taste. It is strongly acid -and caustic. When dried, the poison yields to -ether a fatty matter which, when absorbed by an -animal, plunges the latter into a coma that may -end in death.</p> - -<p>The residue insoluble in ether contains the non-toxic -albuminoids, and ptomaines, such as methylcarbylamine,<a id="FNanchor_153" href="#Footnote_153" class="fnanchor">153</a> -and isocyanacetic acid, resulting -from the decomposition of a lecithin that appears -to be soluble in ether.</p> - -<p>To obtain this venom, Physalix and Bertrand<a id="FNanchor_154" href="#Footnote_154" class="fnanchor">154</a> -skin the toads, first chloroformed, and dry the -skins in a vacuum over sulphuric acid; the skins -are then cleaned by treating with carbon disulphide -to remove fatty matters, and the toxic<span class="pagenum" id="Page_104">104</span> -principles removed by means of 95-per cent. alcohol; -the poison so obtained, however, is impure. A -better procedure is to express the parotid glands -which have been placed in distilled water. Faust -found in this venom a principle which he named -<em>bufonin</em>. Physalix and Bertrand isolated from it -also a resinoid substance soluble in alcohol and in -a large excess of water; this substance, which they -named <em>bufotaline</em>, acts upon the heart. These -authors have also obtained another substance -which has a paralyzing action, and which they have -named <em>bufotenin</em>.</p> - -<p>The poison of the common toad acts as a paralyzant -upon the heart and on the spinal marrow<a id="FNanchor_155" href="#Footnote_155" class="fnanchor">155</a>; -that of the common frog possesses similar properties. -The poison of the tritons is quite analogous to that -of the toads; it contains a lecithin hydrolyzable -by water with the formation of alanin, formic acid, -and alpha-isocyanopropionic acid.</p> - -<p>Zalnosky<a id="FNanchor_156" href="#Footnote_156" class="fnanchor">156</a> isolated from the glands of the -skin of the salamander a white, thick, bitter and -alkaline liquid poison, containing a highly poisonous -alkaloid, <em>salamandrine</em>, or <em>samandarine</em>, which -acts on the brain, the medulla, and the spinal cord, -and which has the formula C<sub>54</sub>H<sub>60</sub>N<sub>2</sub>O<sub>5</sub>; it is a -strong base and yields crystallizable salts.</p> -<p><span class="pagenum" id="Page_105">105</span></p> -<p><b><a id="Fish-poisons"></a>Fish-poisons.</b><a id="FNanchor_157" href="#Footnote_157" class="fnanchor">157</a>—Very little accurate knowledge -is extant regarding these. Many fish are poisonous, -and among them are the synanceia, found in -the Indian Ocean between the Netherland Isles and -New Caledonia; considerable numbers are found -in the neighborhood of the latter locality. These -fish are provided with spiny rays which are in direct -communication with a poisonous system having its -seat in the dorsal fin. The prick of one of the -spiny rays of this fish may under certain circumstances -result fatally, and in every case it causes a -rapid and painful gangrene.</p> - -<p>From the reservoir the poison is conducted to -the sharp extremity of the spines by a deep channel -with which each spiny ray is provided; the animal -has 26 poison-sacs, two for each ray, and the sacs -burst when the corresponding sting is in any manner -compressed.</p> - -<p>The poison is an odorless liquid having a slight -styptic or acidulous taste, and exhibiting a bluish -fluorescence; it rapidly becomes turbid.</p> - -<p>The weevers, which are numerous on the shores -of the Mediterranean Sea, and which are also met -with in the northeastern portion of the Atlantic -Ocean, are likewise very dangerous, which explains -their popular names "viper-weever," "spider<span class="pagenum" id="Page_106">106</span>weever," -etc. These fish are provided with a double -set of poisonous apparatus, the one opercular, -which is the more dangerous, and the other dorsal. -The opercular spine has a double channel in connection -with a conical cavity hollowed out in the -base of the opercular bone. The bottom of this -cavity is provided with special cells which secrete the -poison. The dorsal glands have a similar structure.</p> - -<p>The poison of the weever is a liquid, limpid when -the fish is alive, and turbid when dead; it has -a slight bluish fluorescence, is neutral in reaction, -and is coagulated by acids and bases. It acts as a -paralyzant, its action being exerted on the medulla -and spinal cord; it retards the heart's action.</p> - -<p>These examples will suffice; and we will not -dilate further on this subject, because, as already -stated, but little is accurately known regarding -the subject, and what is known may be summed -up as follows: Fish-poisons always give rise to an -intense pain, frequently with motor paralysis, followed -by paralysis of sensation; they affect the -heart, arresting it in diastole; and they are more -dangerous to fish and cold-blooded animals than -to mammifers.</p> - -<p><b>Poisons of the <a id="Hymenoptera"></a>Hymenoptera.</b><a id="FNanchor_158" href="#Footnote_158" class="fnanchor">158</a>—The poison system -of the bee, and of such insects as the wasps, -bumblebees, etc., is known to consist of a hollow<span class="pagenum" id="Page_107">107</span> -sting consisting of two sharp needles communicating -with two poison-bearing glands, and forming a -flexible tube. One of these glands secretes an acid -liquid (formic acid); the other secretes an alkaline -fluid.</p> - -<p>The action of the bee-poison is very often benign, -but there have been cases where death followed -the infliction of numerous stings.</p> - -<p>Our information regarding the poison of the -cantharides and flies is very vague<a id="FNanchor_159" href="#Footnote_159" class="fnanchor">159</a>; the same -is true of the poisons of various arachnids, acarides, -and myriapoda. So far as spiders are concerned, -it is known that their poison is an oily liquid having -an acid and bitter taste, and containing a toxalbumin -derived from the skin of the insect. The -bite of the ordinary spider occasions simply a -slight local pain, with redness; that of the large -poisonous spider, however, may kill the larger -animals, and even man.</p> - -<p><b><a id="Poison_of_Scorpions"></a>Poison of Scorpions.</b><a id="FNanchor_160" href="#Footnote_160" class="fnanchor">160</a>—This poison is a colorless, -acid liquid, having a higher specific gravity than -water, in which liquid it is soluble. The famed -legend of the suicide of scorpions is well known to -all. It is stated that when the insect finds itself -in a position where its death is inevitable, it stings -itself, and dies from the effects of its own poison.<span class="pagenum" id="Page_108">108</span> -A simple method has even been described of bringing -this result about experimentally by surrounding -the insect with a circle of fire. Bounne, of -Madras,<a id="FNanchor_161" href="#Footnote_161" class="fnanchor">161</a> who has studied the procedure, has -demonstrated its entire falsity by showing, first -of all, that the insect dies from the effects of the -excessive heat, and further, that the poison of the -scorpion is harmless to individuals of the species -that furnish it.</p> - -<p>Metchinkoff<a id="FNanchor_162" href="#Footnote_162" class="fnanchor">162</a> has confirmed these facts, and -has moreover demonstrated that the blood of the -scorpion possesses an undoubted antitoxic power -against the poison of the insect.</p> - -<p>The poison of the scorpion serves it to kill the -insects which are its prey. Frogs and birds stung -by the scorpion also generally die. A dose of -0.0005 Gm. kills a guinea-pig in less than one hour; -and according to Calmette<a id="FNanchor_163" href="#Footnote_163" class="fnanchor">163</a> less than 0.0005 will -kill a white mouse in two hours. Oxidizers destroy -the toxicity of the poison. Guinea-pigs immunized -against the poison of the scorpion resist perfectly -very large doses of the poison.</p> - -<p><b><a id="Poisonous_Blood"></a>Poisonous Blood and Serums.</b>—It is an almost -general fact that the blood and blood serum of -batrachians, eels, lampreys, snakes (even non-poisonous -ones), and hedgehogs are very poisonous.<span class="pagenum" id="Page_109">109</span> -Mosso has found in the blood serum of the -lamprey a toxin possessing a strong hemolytic -power, and which he has named <em>ichthyotoxin</em>. O.5 -Cc. of this serum injected into a dog kills it in -a few minutes. He also observed, in 1888, that -the blood of the eel, in like dose, kills a dog -almost immediately, and that the blood contains -an ichthyotoxin analogous to that of the -lamprey.</p> - -<p>This substance, which appears to be closely -allied to the sero-albumin of the blood, has a -phosphorus-like, sharp, and burning taste. By digestion -it loses its toxicity, as well as by heating at -68° to 70° C. It is easily obtained by precipitating -with ammonium sulphate the serum of eels, and -dialyzing the precipitate dissolved in water. The -power of this substance is almost as great as that -of the cobra poison, 0.002 Gm. being instantly -fatal per kilo of dog.</p> - -<p>The blood of snakes is likewise very toxic; the -same is true of the blood of the viper, as 0.02 Cc. -will kill a guinea-pig in two hours. All these -bloods lose their toxicity when heated above 70° C. -The serum of the hedgehog is peculiar in this -respect; when heated at 38° C. for fifteen minutes -it loses its toxicity, but it then possesses an immunizing -power against the poisons.</p> - -<p>The subject possesses great interest, because it -was in studying these immunizing properties that<span class="pagenum" id="Page_110">110</span> -Camus and Gley,<a id="FNanchor_164" href="#Footnote_164" class="fnanchor">164</a> and later on Kossel<a id="FNanchor_165" href="#Footnote_165" class="fnanchor">165</a> and -Tchistowitch,<a id="FNanchor_166" href="#Footnote_166" class="fnanchor">166</a> discovered the first anticytotoxin,<a id="FNanchor_167" href="#Footnote_167" class="fnanchor">167</a> -which they obtained by treating the animals with -increasing quantities of the serum of eels. On -mixing the antitoxic serum of these animals <i lang="la">in -vitro</i> with the red blood-corpuscles of the species -furnishing the serum and of the hemolytic serum -of eels, it is found that the blood-corpuscles kept -quite well.</p> - -<p>As to the blood of the hedgehog, we have already -seen that Physalix and Bertrand have shown that -it may be a counter-poison towards serpent-venom -under certain conditions. In its normal condition -it is highly toxic.</p> - -<p><b><a id="Poisonous_Meats"></a>Poisonous Meats.</b>—It is particularly among the -fish that we find these normally present, and it is<span class="pagenum" id="Page_111">111</span> -a singular fact that, for a given species, the toxicity -frequently depends upon the period of the year. -Thus, at the period of spawning, certain fish may -be extremely poisonous, or, on the contrary, may -entirely cease to be so. The anchovy ballassa -from the shores of India occasions death even in -very small quantity; the poisonous meltite of the -same seas causes violent vomiting; the fugu of -the Japanese seas possesses an extreme poisonousness -at the spawning period, while, on the contrary, -it is perfectly innocuous at all other periods.</p> - -<p>Numerous cases of poisoning have been chronicled -every year by the journals, due to the ingestion -of mussels; in the flesh of these crustaceæ is found -a dangerous toxin, <em>methylotoxin</em>. The flesh of -oysters is also unwholesome at the spawning period.</p> - -<p>The toxic symptoms caused by these animals -become apparent in not less than twenty-four -hours after ingestion. The poisoning due to these -fresh meats must not, however, be confounded -with that caused by tainted or spoiled meats.</p> - -<div class="chapter"></div> -<div class="footnotes"><h3>FOOTNOTES:</h3> - -<div class="footnote"> - -<p><a id="Footnote_1" href="#FNanchor_1" class="label">1</a> - <span class="smcap">Armand Gautier</span>: Sur les leucomaines, nouveaux alcaloides, -dérivés de la transformation des substances protéiques des tissus -vivants. <cite>Bull. Soc. Chim.</cite>, 2e série, <span class="smcap">XLIII</span>, p. 158.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_2" id="Footnote_2"></a><a href="#FNanchor_2"><span class="label">[2]</span></a> <span class="smcap">Armand Gautier</span>: "Communication sur les bases d'origine -putréfactive." <cite>Bull. Soc. Chim.</cite> (2), <span class="smcap">XXXVII</span>, p. 305.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_3" id="Footnote_3"></a><a href="#FNanchor_3"><span class="label">[3]</span></a> <cite>Virchow Archiv.</cite>, <span class="smcap">X</span>, p. 301.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_4" id="Footnote_4"></a><a href="#FNanchor_4"><span class="label">[4]</span></a> <cite>Medic. Centralblatt</cite>, 1868, p. 497.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_5" id="Footnote_5"></a><a href="#FNanchor_5"><span class="label">[5]</span></a> <cite>Berlin. Klin. Woch.</cite>, 1869, No. 2.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_6" id="Footnote_6"></a><a href="#FNanchor_6"><span class="label">[6]</span></a> Sulle ptomaïne od alcaloïdi cadaverici. Bologne, <span class="smcap">CLXXXVII</span>, -p. 11.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_7" id="Footnote_7"></a><a href="#FNanchor_7"><span class="label">[7]</span></a> <span class="smcap">Armand Gautier</span>: <cite>C. rend. de l'Académie des Sciences</cite>, <span class="smcap">CXIV</span>, -p. 1256. <cite>Ibid.</cite>, <span class="smcap">XCVII</span>, p. 264, and <span class="smcap">XCIV</span>, p. 1600.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_8" id="Footnote_8"></a><a href="#FNanchor_8"><span class="label">[8]</span></a> <span class="smcap">Griffiths</span>: <cite>C. rend. de l'Académie des Sciences</cite>, <span class="smcap">CXV</span>, pp. 285 -and 667.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_9" id="Footnote_9"></a><a href="#FNanchor_9"><span class="label">[9]</span></a> <span class="smcap">E. Pouchet</span>: Contribution à l'étude des matières extractives -de l'urine, <cite>Thèse</cite>, Paris, 1880; <cite>Ibid.</cite>, <cite>C. rend. de l'Académie -des Sc.</cite>, <span class="smcap">XCVII</span>, p. 1560; <span class="smcap">Bouchard</span>: <cite>C. rend. Soc. de Biolog.</cite>, -Aug. 12, 1882.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_10" id="Footnote_10"></a><a href="#FNanchor_10"><span class="label">[10]</span></a> <span class="smcap">Griffiths</span>: <cite>C. rend. de l'Académie des Sciences</cite>, <span class="smcap">CXVI</span>, p. 1206.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_11" id="Footnote_11"></a><a href="#FNanchor_11"><span class="label">[11]</span></a> <span class="smcap">Brieger</span>: Untersuchungen über die Ptomaine, dritten Teil, -p. 93; <cite>Berichte d. D. Chem. Gesellschaft</cite>, 1886, p. 3159; 1887, -p. 69.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_12" id="Footnote_12"></a><a href="#FNanchor_12"><span class="label">[12]</span></a> <span class="smcap">Charrin</span>: <cite>Les poisons de l'urine</cite>: Encyclopédie Léauté.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_13" id="Footnote_13"></a><a href="#FNanchor_13"><span class="label">[13]</span></a> <span class="smcap">Armand Gautier</span>: <cite>Bull. Acad. de Médecin</cite> (2), <span class="smcap">XV</span>, p. 115.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_14" id="Footnote_14"></a><a href="#FNanchor_14"><span class="label">[14]</span></a> <span class="smcap">Armand Gautier</span>: Leçons de chimie biologique. Published -by Masson; <cite>Ibid.</cite>, Chimie de la cellule vivante. Also published -by Masson.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_15" id="Footnote_15"></a><a href="#FNanchor_15"><span class="label">[15]</span></a> <span class="smcap">Kruger</span>: <cite>Bull. Soc. Chim.</cite> (3), <span class="smcap">VIII</span>, p. 687.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_16" id="Footnote_16"></a><a href="#FNanchor_16"><span class="label">[16]</span></a> <span class="smcap">Kossel</span>: <cite>Zeitschrift für physiol. Chim.</cite>, <span class="smcap">X</span>, p. 248; and -<cite>Bull. Soc. Chim.</cite> (3), <span class="smcap">III</span>, p. 239.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_17" id="Footnote_17"></a><a href="#FNanchor_17"><span class="label">[17]</span></a> <cite>Liebig's Ann. der Chemie</cite>, <span class="smcap">CXCIV</span>, p. 68.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_18" id="Footnote_18"></a><a href="#FNanchor_18"><span class="label">[18]</span></a> <cite>Journ. Soc. Phys. Chim. Russe</cite>, 1893, No. 2; and <cite>Bull. Soc. -Chim.</cite> (3), <span class="smcap">XII</span>, p. 243.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_19" id="Footnote_19"></a><a href="#FNanchor_19"><span class="label">[19]</span></a> <cite>Leucomaines du Sang Normal</cite>, Thèse, Paris, 1889.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_20" id="Footnote_20"></a><a href="#FNanchor_20"><span class="label">[20]</span></a> <cite>Joh reab. de Thiérchen</cite>, 1874, p. 341; Picard, <cite>Ibid.</cite>, p. 355.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_21" id="Footnote_21"></a><a href="#FNanchor_21"><span class="label">[21]</span></a> <span class="smcap">Roux</span> and <span class="smcap">Yersin</span>; Mémoire sur Diphtérie. <cite>Ann. Inst. -Pasteur</cite>, 1888-1889.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_22" id="Footnote_22"></a><a href="#FNanchor_22"><span class="label">[22]</span></a> <span class="smcap">Charrin</span> and <span class="smcap">Levaditi</span>: Le sort de toxines introduites dans -le tube digestif. <cite>Journal de Physiologie et de Pathologie Générales</cite>, -1898, p. 226.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_23" id="Footnote_23"></a><a href="#FNanchor_23"><span class="label">[23]</span></a> Citing Metchnikoff.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_24" id="Footnote_24"></a><a href="#FNanchor_24"><span class="label">[24]</span></a> <cite>C. rend. de la Soc. de Biologie</cite>, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_25" id="Footnote_25"></a><a href="#FNanchor_25"><span class="label">[25]</span></a> <cite>Centralblatt für Bakt.</cite>, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_26" id="Footnote_26"></a><a href="#FNanchor_26"><span class="label">[26]</span></a> <cite>C. rend. de la Soc. de Biologie</cite>, 1899.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_27" id="Footnote_27"></a><a href="#FNanchor_27"><span class="label">[27]</span></a> <cite>Deutsche Med. Wochenschr.</cite>, 1898, No. 8.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_28" id="Footnote_28"></a><a href="#FNanchor_28"><span class="label">[28]</span></a> See <span class="smcap">Pozzi-Escot</span>: Les diastases et leurs applications, published -by Masson, 1900; and <cite>Traité de Physico-chimie</cite>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_29" id="Footnote_29"></a><a href="#FNanchor_29"><span class="label">[29]</span></a> Regarding this see the works by <span class="smcap">Koch</span> and <span class="smcap">Brieger</span>, -<cite>Deutsche Medicin. Wochenschr.</cite>, Oct. 22, 1891.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_30" id="Footnote_30"></a><a href="#FNanchor_30"><span class="label">[30]</span></a> <span class="smcap">Pozzi-Escot</span>: Nature des Diastases. Published by J. -Rousset, Paris, 1903. See also Recherches de la Nature Chimique -des Diastases Oxydantes. <cite>Revue génér. de chimie</cite>, <span class="smcap">VII</span>, pp. -129-136; and Aperçus sur la nature chimique des Diastases, -<cite>Bulletin de l'Association de Chimistes</cite>, 1904, p. 769.—Propriétés -Catalytiques de Quelques Diastases; <cite>Ibid.</cite>, 1904, p. 1247.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_31" id="Footnote_31"></a><a href="#FNanchor_31"><span class="label">[31]</span></a> <span class="smcap">Ehrlich</span>: <cite>Klinisches Jahrbuch</cite>, 1897, <span class="smcap">VI</span>. <cite>Proceedings of the -Royal Society</cite>, 1900, No. 482, p. 424. <cite>Nothnagles' specielle Pathologie -und Therapie</cite>, 1901, <span class="smcap">VIII</span>, Schlussbetrachtungen, p. 163.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_32" id="Footnote_32"></a><a href="#FNanchor_32"><span class="label">[32]</span></a> To have a complete exposé regarding this question, it will -be profitable to consult No. 4 of this collection on <cite>Sérums -Immunisants</cite>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_33" id="Footnote_33"></a><a href="#FNanchor_33"><span class="label">[33]</span></a> <span class="smcap">Von Behring</span> and <span class="smcap">Wernicke</span>: Zeitschrift für Hygiene, <span class="smcap">XII</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_34" id="Footnote_34"></a><a href="#FNanchor_34"><span class="label">[34]</span></a> <span class="smcap">Donitz</span>: Ueber die Grenzen der Wirksamkeit des Diphtheria -Heilserums. <cite>Deutsche Med. Woch.</cite>, No. 27, 1897.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_35" id="Footnote_35"></a><a href="#FNanchor_35"><span class="label">[35]</span></a> <span class="smcap">Decroly</span> et <span class="smcap">Rousse</span>: <cite>Arch. Int. de Pharmacodyn.</cite>, <span class="smcap">III</span> and -<span class="smcap">VI</span>; Masoin: <cite>Arch. Intern. de Pharmacodyn.</cite>, <span class="smcap">II</span>, 1903.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_36" id="Footnote_36"></a><a href="#FNanchor_36"><span class="label">[36]</span></a> <span class="smcap">Metchnikoff</span>: <cite>L'Immunité</cite>, Paris, 1902; <span class="smcap">Morgenroth</span>: -Zur Kenntniss des Tetanus des Frosches. <cite>Deutsche Med. Woch.</cite>, -No. 35, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_37" id="Footnote_37"></a><a href="#FNanchor_37"><span class="label">[37]</span></a> <span class="smcap">Ehrlich</span>: <cite>Berl. Klin. Woch.</cite>, No. 12, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_38" id="Footnote_38"></a><a href="#FNanchor_38"><span class="label">[38]</span></a> <span class="smcap">Wassermann</span> and <span class="smcap">Takaki</span>: <cite>Berl. Klin. Woch.</cite>, <cite>Med.</cite>, p. 5, -1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_39" id="Footnote_39"></a><a href="#FNanchor_39"><span class="label">[39]</span></a> <span class="smcap">Marie</span>: Sur les Propriétés Antitoxiques aux Centres Nerveux -de l'Animal Sain. <cite>Ann. Inst. Past.</cite>, 1898, p. 1.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_40" id="Footnote_40"></a><a href="#FNanchor_40"><span class="label">[40]</span></a> <span class="smcap">Metchnikoff</span>: Recherches sur l'Influence de l'Organism -sur les Toxines. <cite>Ann. Inst. Past.</cite>, 1899, p. 82.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_41" id="Footnote_41"></a><a href="#FNanchor_41"><span class="label">[41]</span></a> <cite>Deutsche Med. Wochenschr.</cite>, 1890, p. 1113.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_42" id="Footnote_42"></a><a href="#FNanchor_42"><span class="label">[42]</span></a> It is necessary here to consult the work by <span class="smcap">Levaditi</span>: -Le Leucocyte et ses Granulations. <cite>Scientia</cite>, Naud, publisher, -Paris, 1903; also <span class="smcap">Metchnikoff</span>: L'Immunité, Paris, 1902, -Masson, publisher.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_43" id="Footnote_43"></a><a href="#FNanchor_43"><span class="label">[43]</span></a> <span class="smcap">Von Behring</span> and <span class="smcap">Kitasato</span>: <cite>Deutsch. med. Wochenschr.</cite>, -1890, p. 1113.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_44" id="Footnote_44"></a><a href="#FNanchor_44"><span class="label">[44]</span></a> <span class="smcap">Ehrlich</span>: <cite>Klin. Jahrb.</cite> 1897, <span class="smcap">VI</span>, p. 292.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_45" id="Footnote_45"></a><a href="#FNanchor_45"><span class="label">[45]</span></a> <span class="smcap">Buchner</span>: <cite>Münchener med. Wochenschr.</cite>, 1893, p. 480.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_46" id="Footnote_46"></a><a href="#FNanchor_46"><span class="label">[46]</span></a> <span class="smcap">Roux</span>: <cite>Annales de l'Institut Pasteur</cite>, 1894, <span class="smcap">VIII</span>, p. 724.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_47" id="Footnote_47"></a><a href="#FNanchor_47"><span class="label">[47]</span></a> <span class="smcap">Wassermann</span>: <cite>Zeitschr. für Hygiene</cite>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_48" id="Footnote_48"></a><a href="#FNanchor_48"><span class="label">[48]</span></a> <span class="smcap">J. Danzsy</span>: <cite>Annales de l'Institut Pasteur</cite>, <span class="smcap">XVI</span>, p. 331.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_49" id="Footnote_49"></a><a href="#FNanchor_49"><span class="label">[49]</span></a> <span class="smcap">Svante Arrhenius</span>: La Physico-chimie des Toxines et -des Antitoxines. <cite>Conférences de la Société chimique de Paris</cite>, -May 20, 1904. See also <span class="smcap">Madsen and Arrhenius</span>: Testkrift -red indivulsen of Stotens Serum Institut. Copenhagen, 1902.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_50" id="Footnote_50"></a><a href="#FNanchor_50"><span class="label">[50]</span></a> <span class="smcap">Ch. Salmonsen</span> et <span class="smcap">Th. Madsen</span>: Réproduction de la substance -antitoxique. <cite>Ann. Inst. Pasteur</cite>, <span class="smcap">XII</span>, p. 762. <span class="smcap">Roux</span> et -<span class="smcap">Vaillard</span>: <cite>Ibid.</cite>, 1893, p. 83.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_51" id="Footnote_51"></a><a href="#FNanchor_51"><span class="label">[51]</span></a> It is understood that the active principles of mushrooms -are not comprised under this definition, but they will be studied -under the next heading.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_52" id="Footnote_52"></a><a href="#FNanchor_52"><span class="label">[52]</span></a> <span class="smcap">Warden</span> and <span class="smcap">Waddell</span>: <cite>Non-bacillar Nature of Abrus Poison</cite>. -Calcutta, 1884.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_53" id="Footnote_53"></a><a href="#FNanchor_53"><span class="label">[53]</span></a> <span class="smcap">Kobert</span>: <cite>Arbeit. aus dem Pharmak. Institut.</cite> Dorpat, 1893.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_54" id="Footnote_54"></a><a href="#FNanchor_54"><span class="label">[54]</span></a> <span class="smcap">Hellin</span>: <cite>Inaug. Dissert.</cite> Dorpat, 1891.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_55" id="Footnote_55"></a><a href="#FNanchor_55"><span class="label">[55]</span></a> <span class="smcap">Ehrlich</span>: Experiment. Untersuchungen über Immunität. -<cite>Deutsch. Med. Woch.</cite>, 1891.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_56" id="Footnote_56"></a><a href="#FNanchor_56"><span class="label">[56]</span></a> <span class="smcap">Stillmark</span>: <cite>Arbeit. aus dem pharmacol. Inst. Dorpat</cite>, 1889.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_57" id="Footnote_57"></a><a href="#FNanchor_57"><span class="label">[57]</span></a> <span class="smcap">Dixon</span>: <cite>Austr. Med. Gazette</cite>, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_58" id="Footnote_58"></a><a href="#FNanchor_58"><span class="label">[58]</span></a> <span class="smcap">Thuson</span>: <cite>Journ. f. prakt. Chem.</cite>, <span class="smcap">XCIV</span>, p. 444.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_59" id="Footnote_59"></a><a href="#FNanchor_59"><span class="label">[59]</span></a> <span class="smcap">Power</span> and <span class="smcap">Cambier</span>: <cite>Pharm. Journ. and Transact.</cite>, 1890.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_60" id="Footnote_60"></a><a href="#FNanchor_60"><span class="label">[60]</span></a> <span class="smcap">Pozzi-Escot</span>: <cite>Les Diastases et leurs Applications</cite>, Masson, -1900.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_61" id="Footnote_61"></a><a href="#FNanchor_61"><span class="label">[61]</span></a> <span class="smcap">Roussy</span>: <cite>Aperçu historique sur les ferments et fermentations</cite>. -Paris, 1901. J. Rousset, publ.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_62" id="Footnote_62"></a><a href="#FNanchor_62"><span class="label">[62]</span></a> <span class="smcap">Hildebrandt</span>: Weiteres über hydrolyt. Fermente, etc. -<cite>Virch. Arch.</cite>, <span class="smcap">CXXXI</span>, 1895, P. 5.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_63" id="Footnote_63"></a><a href="#FNanchor_63"><span class="label">[63]</span></a> <span class="smcap">Camus</span> and <span class="smcap">Gley</span>: <cite>Compt. rend. de la Soc. de Biolog.</cite>, -1897.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_64" id="Footnote_64"></a><a href="#FNanchor_64"><span class="label">[64]</span></a> <span class="smcap">Mesnil</span>: Sur la digestion des actinies. <cite>Annales de l'Institut -Pasteur</cite>, 1901.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_65" id="Footnote_65"></a><a href="#FNanchor_65"><span class="label">[65]</span></a> <span class="smcap">Charrin</span> and <span class="smcap">Levaditi</span>: <cite>Compt. rend. de l'Académie dest -Sciences</cite>, 1900.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_66" id="Footnote_66"></a><a href="#FNanchor_66"><span class="label">[66]</span></a> <span class="smcap">Sachs</span>: Ueber Antiseptika. <cite>Zeitschr. f. Biolog.</cite>, 1901, <span class="smcap">XXVI</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_67" id="Footnote_67"></a><a href="#FNanchor_67"><span class="label">[67]</span></a> <span class="smcap">Gessard</span>: <cite>Annales de l'Institut Pasteur</cite>, 1901, p. 609; <cite>Comp. -rend. de la Société de Biologie</cite>, May, 1902.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_68" id="Footnote_68"></a><a href="#FNanchor_68"><span class="label">[68]</span></a> <span class="smcap">Briot</span>: Thèse de Doctorat ès-Sciences, Paris, 1900.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_69" id="Footnote_69"></a><a href="#FNanchor_69"><span class="label">[69]</span></a> <span class="smcap">Korschum</span>: <cite>Zeitschr. f. physiolog. Chemie</cite>, 1902, <span class="smcap">XXXI</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_70" id="Footnote_70"></a><a href="#FNanchor_70"><span class="label">[70]</span></a> <span class="smcap">Rosetti</span>: <cite>L'Orosi, giorn. di chemica, farmacia et scienza -affini</cite>, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_71" id="Footnote_71"></a><a href="#FNanchor_71"><span class="label">[71]</span></a> <span class="smcap">Gustave Saux</span>: De la toxicité des produits de la digestion -peptique. <cite>Thèse de doctorat</cite>, Bordeaux, 1902.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_72" id="Footnote_72"></a><a href="#FNanchor_72"><span class="label">[72]</span></a> <span class="smcap">Schmidt</span>: <cite>Mühlheim, Arch. de physiol.</cite>, 1880.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_73" id="Footnote_73"></a><a href="#FNanchor_73"><span class="label">[73]</span></a> <span class="smcap">Brieger</span>: <cite>Berichte d. D. chem. Gesellsch.</cite>, <span class="smcap">XIX</span>, p. 3120; and -<cite>Verhandl. d. Congress f. innere Med.</cite>, <span class="smcap">II</span>, p. 277.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_74" id="Footnote_74"></a><a href="#FNanchor_74"><span class="label">[74]</span></a> <span class="smcap">Pollin</span> and <span class="smcap">Labit</span>: <cite>Examens des aliments suspects</cite>, Masson, -publisher.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_75" id="Footnote_75"></a><a href="#FNanchor_75"><span class="label">[75]</span></a> <span class="smcap">Adduco</span>: <cite>Arch. Ital. de biolog.</cite>, 1891.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_76" id="Footnote_76"></a><a href="#FNanchor_76"><span class="label">[76]</span></a> <span class="smcap">Pouchet</span>: <cite>Thèse de Doctorat en Médecine</cite>, Paris, 1878.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_77" id="Footnote_77"></a><a href="#FNanchor_77"><span class="label">[77]</span></a> <span class="smcap">Stadthagen</span>: <cite>Zeitschr. f. Klin. Med.</cite>, <span class="smcap">XV</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_78" id="Footnote_78"></a><a href="#FNanchor_78"><span class="label">[78]</span></a> <span class="smcap">Bouchard</span>: <cite>Leçons sur les Autointoxications</cite>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_79" id="Footnote_79"></a><a href="#FNanchor_79"><span class="label">[79]</span></a> Regarding this point see the excellent work by <span class="smcap">A. Charrin</span>: -<cite>Poisons de l'Organism</cite>. Masson, publ.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_80" id="Footnote_80"></a><a href="#FNanchor_80"><span class="label">[80]</span></a> <span class="smcap">Ch. Bouchard</span>: <cite>Des Autointoxications</cite>. Paris, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_81" id="Footnote_81"></a><a href="#FNanchor_81"><span class="label">[81]</span></a> <cite>Bull. Acad, de Médecine</cite> (2), <span class="smcap">X</span>, p. 947, and <span class="smcap">XX</span>, p. 115.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_82" id="Footnote_82"></a><a href="#FNanchor_82"><span class="label">[82]</span></a> <span class="smcap">Bouchard</span>: <cite>Leçons sur les Autointoxications</cite>, Paris, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_83" id="Footnote_83"></a><a href="#FNanchor_83"><span class="label">[83]</span></a> <span class="smcap">Roger</span>: Toxicité des Extraits des Tissus Normaux. <cite>Soc. -de Biolog.</cite>, 1891, p. 728.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_84" id="Footnote_84"></a><a href="#FNanchor_84"><span class="label">[84]</span></a> It is well to recall here that the kidneys contain both -reducing and oxidizing ferments, as has been demonstrated -by de Rey-Pailhade, and later by Abelous and Gérard.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_85" id="Footnote_85"></a><a href="#FNanchor_85"><span class="label">[85]</span></a> <span class="smcap">Lépine</span>: <cite>Compt. rend. de l'Acad. des Sciences</cite>, May 13, 1889; -<cite>Soc. de Biol.</cite>, 1891, p. 724.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_86" id="Footnote_86"></a><a href="#FNanchor_86"><span class="label">[86]</span></a> <span class="smcap">Roger</span>: <cite>Compt. rend. Soc. Biol.</cite>, 1891, p. 727.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_87" id="Footnote_87"></a><a href="#FNanchor_87"><span class="label">[87]</span></a> <span class="smcap">Pozzi-Escot</span>: <cite>Compt. rend. de l'Acad. de Médecine</cite> (3), <span class="smcap">XLVII</span>, -p. 400. See also <span class="smcap">Pozzi-Escot</span>: <cite>Etat actuel de nos Connaissances -sur les Oxydases et les Réductases</cite>. Dunod, publ., Paris. -1902.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_88" id="Footnote_88"></a><a href="#FNanchor_88"><span class="label">[88]</span></a> <cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">CXIV</span>, pp. 1237, 1318, -1399, and 1534; <span class="smcap">CXV</span>, p. 375; and <span class="smcap">CXVI</span>, p. 856.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_89" id="Footnote_89"></a><a href="#FNanchor_89"><span class="label">[89]</span></a> <span class="smcap">Laulanié</span>: <cite>Compt. rend. Soc. de Biol.</cite>, 1894, p. 187.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_90" id="Footnote_90"></a><a href="#FNanchor_90"><span class="label">[90]</span></a> <span class="smcap">Gley</span>: <cite>Compt. rend. Soc. de Biol.</cite>, 1891, p. 250.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_91" id="Footnote_91"></a><a href="#FNanchor_91"><span class="label">[91]</span></a> <cite>Semaine Médicale</cite>, Apr. 3, 1895, p. 138.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_92" id="Footnote_92"></a><a href="#FNanchor_92"><span class="label">[92]</span></a> <cite>Wiener Med. Blätter</cite>, No. 48; and <cite>Gesellsch. d. Aerzte in -Wien</cite>, Nov. 22, 1895.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_93" id="Footnote_93"></a><a href="#FNanchor_93"><span class="label">[93]</span></a> <cite>Zeitschr. f. Physiol. Chem.</cite>, <span class="smcap">XXI</span>, pp. 319 and 481; and <span class="smcap">XXII</span>, -p. 1. <span class="smcap">Armand Gautier</span>: Chimie Biologique, 2d edit., pp. 330-332. -Masson, publ.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_94" id="Footnote_94"></a><a href="#FNanchor_94"><span class="label">[94]</span></a> <span class="smcap">Albanèse</span>: Recherches sur les fonctions des capsules -surrénales. <cite>Arch. Italiennes Biol.</cite>, 1892.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_95" id="Footnote_95"></a><a href="#FNanchor_95"><span class="label">[95]</span></a> <span class="smcap">Boinet</span>: <cite>Compt. rend. Soc. de Biol.</cite>, Mch. 1896.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_96" id="Footnote_96"></a><a href="#FNanchor_96"><span class="label">[96]</span></a> See <cite>Compt. rend. de Biol. et Arch. Physiologie</cite>, 1891-1897.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_97" id="Footnote_97"></a><a href="#FNanchor_97"><span class="label">[97]</span></a> <span class="smcap">Langlois</span>: Thèse de doctorat en Méd., Paris, 1897.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_98" id="Footnote_98"></a><a href="#FNanchor_98"><span class="label">[98]</span></a> <span class="smcap">Guieysse</span>: <cite>Les capsules surrénales du cobaye</cite>, Thèse, Paris, -1901.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_99" id="Footnote_99"></a><a href="#FNanchor_99"><span class="label">[99]</span></a> Encyclopédie Léauté, <span class="smcap">CCCXIV</span>, Masson, publ., Paris, 1904.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_100" id="Footnote_100"></a><a href="#FNanchor_100"><span class="label">[100]</span></a> <span class="smcap">Arloing</span>, <span class="smcap">Cornevin</span>, <span class="smcap">Thomas</span>: <cite>Le Charbon Symptomatique</cite>, -1st edit., Paris; and <span class="smcap">Le Dantec</span>: <cite>La Bactéridie du Charbon</cite>, -Masson, publ.; <span class="smcap">Straus</span>: <cite>Le Charbon des Animaux et de l'Homme</cite>, -Paris, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_101" id="Footnote_101"></a><a href="#FNanchor_101"><span class="label">[101]</span></a> <span class="smcap">Hankin</span>: <cite>British Medical Journal</cite>, Oct. 12, 1889, and July -12, 1890.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_102" id="Footnote_102"></a><a href="#FNanchor_102"><span class="label">[102]</span></a> <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">IX</span>, p. 785.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_103" id="Footnote_103"></a><a href="#FNanchor_103"><span class="label">[103]</span></a> <span class="smcap">Chamberland</span>: <cite>Le Charbon et la Vaccination Charbonneuse</cite>, -Paris, 1887. <span class="smcap">Petermann</span>: <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">VI</span>, p. 32.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_104" id="Footnote_104"></a><a href="#FNanchor_104"><span class="label">[104]</span></a> <span class="smcap">Deutschmann</span>: <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">VIII</span>, p. 403.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_105" id="Footnote_105"></a><a href="#FNanchor_105"><span class="label">[105]</span></a> <cite>Annal. Inst. Pasteur</cite>, Feb. 1888.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_106" id="Footnote_106"></a><a href="#FNanchor_106"><span class="label">[106]</span></a> <span class="smcap">Auclair</span>: <cite>Thèse de doctorat</cite>, Paris, 1897; and <cite>Arch. de -Médecine</cite>, exp. 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_107" id="Footnote_107"></a><a href="#FNanchor_107"><span class="label">[107]</span></a> <span class="smcap">Koch</span>: <cite>Deutsch. Med. Woch.</cite>, Nov. 13, 1890-1897, No. 14, -p. 209.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_108" id="Footnote_108"></a><a href="#FNanchor_108"><span class="label">[108]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">V</span>, p. 191; <cite>Arch. de la Soc. Biol. -de Saint-Pétersbourg</cite>, <span class="smcap">I</span>, p. 213.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_109" id="Footnote_109"></a><a href="#FNanchor_109"><span class="label">[109]</span></a> <span class="smcap">Nocard</span> and <span class="smcap">Leclainche</span>: <cite>Les Maladies Microbiennes -des Animaux</cite>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_110" id="Footnote_110"></a><a href="#FNanchor_110"><span class="label">[110]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">II</span>, p. 632, and <span class="smcap">VIII</span>, p. 611.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_111" id="Footnote_111"></a><a href="#FNanchor_111"><span class="label">[111]</span></a> See <span class="smcap">Spronk</span>: <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">IX</span>, p. 785; <cite>Ibid.</cite>, -<span class="smcap">X</span>, p. 333; <span class="smcap">Martin</span>, <cite>Ibid.</cite>, <span class="smcap">XII</span>, p. 26; <span class="smcap">Spronk</span>, <cite>Ibid.</cite>, <span class="smcap">XII</span>, p. 711.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_112" id="Footnote_112"></a><a href="#FNanchor_112"><span class="label">[112]</span></a> Contribution à l'Étude de la Diphtérie. <cite>Annal. de l'Instit. -Pasteur</cite>, <span class="smcap">VIII</span>, p. 609; <cite>Ibid.</cite>, p. 640.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_113" id="Footnote_113"></a><a href="#FNanchor_113"><span class="label">[113]</span></a> <span class="smcap">Bayeux</span>: <cite>Thèse de Doctorat</cite>, Paris, 1899.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_114" id="Footnote_114"></a><a href="#FNanchor_114"><span class="label">[114]</span></a> <cite>Compt. rend. de l'Acad. des Sc.</cite>, Apr. 5, 1895.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_115" id="Footnote_115"></a><a href="#FNanchor_115"><span class="label">[115]</span></a> <cite>Zeitschr. für Hygiene</cite>, <span class="smcap">XVIII</span>, p. 235.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_116" id="Footnote_116"></a><a href="#FNanchor_116"><span class="label">[116]</span></a> <span class="smcap">Roux</span> and <span class="smcap">Martin</span>: Contribution à l'Étude de la Diphtérie. -<cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">VIII</span>, p. 512.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_117" id="Footnote_117"></a><a href="#FNanchor_117"><span class="label">[117]</span></a> Die Pathogenese des Tetanus. <cite>Berlin. Klin. Wochenschr.</cite>, -1890, No. 31.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_118" id="Footnote_118"></a><a href="#FNanchor_118"><span class="label">[118]</span></a> <span class="smcap">Naillard</span>: <cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">CXX</span>, p. -1181.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_119" id="Footnote_119"></a><a href="#FNanchor_119"><span class="label">[119]</span></a> <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">V</span>, 15.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_120" id="Footnote_120"></a><a href="#FNanchor_120"><span class="label">[120]</span></a> <cite>Deutsche Med. Wochenschr.</cite>, No. 49, Dec. 3, 1896.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_121" id="Footnote_121"></a><a href="#FNanchor_121"><span class="label">[121]</span></a> <cite>Compt. rend. Soc. Biol.</cite>, 1893, p. 294; <cite>Ibid.</cite>, 1894, p. 878.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_122" id="Footnote_122"></a><a href="#FNanchor_122"><span class="label">[122]</span></a> <cite>Deutsch. Med. Wochenschr.</cite>, 1890.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_123" id="Footnote_123"></a><a href="#FNanchor_123"><span class="label">[123]</span></a> <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">VII</span>, p. 64.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_124" id="Footnote_124"></a><a href="#FNanchor_124"><span class="label">[124]</span></a> <span class="smcap">Nocard</span>: <cite>Bull. de l'Acad. de Médecine</cite>, Oct. 22, 1895.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_125" id="Footnote_125"></a><a href="#FNanchor_125"><span class="label">[125]</span></a> <span class="smcap">Naillard</span>: <cite>Compt. rend. de l'Acad. de Sciences</cite>, <span class="smcap">CXX</span>, p. 1181.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_126" id="Footnote_126"></a><a href="#FNanchor_126"><span class="label">[126]</span></a> <span class="smcap">Nocard</span>: <cite>Les Maladies microbiennes des animaux</cite>, Paris.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_127" id="Footnote_127"></a><a href="#FNanchor_127"><span class="label">[127]</span></a> <span class="smcap">Strauss</span>: <cite>Arch. de Médic. expériment</cite>, 1886.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_128" id="Footnote_128"></a><a href="#FNanchor_128"><span class="label">[128]</span></a> <span class="smcap">Cadiot</span> and <span class="smcap">Roger</span>: <cite>Compt. rend. Soc. Biol.</cite>, 1895, p. 770; -<span class="smcap">Wladimirow</span>: <cite>Arch. des Sciences Biol. de St.-Pétersbourg</cite>, <span class="smcap">IV</span>, -p. 30; <span class="smcap">Bourges</span> and <span class="smcap">Méry</span>: <cite>Soc. de Biol.</cite>, Feb. 5, 1878.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_129" id="Footnote_129"></a><a href="#FNanchor_129"><span class="label">[129]</span></a> <span class="smcap">Galtier</span>: <cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">XCII</span>, p. -303; <span class="smcap">Strauss</span>: <cite>Arch. de Médic. expériment</cite>, <span class="smcap">I</span>, p. 489.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_130" id="Footnote_130"></a><a href="#FNanchor_130"><span class="label">[130]</span></a> <span class="smcap">Brieger</span>: <cite>Microbes, Ptomaïnes et Maladies</cite>, Doin, publ., -Paris, 1887; <span class="smcap">Luff</span>: <cite>Brit. Med. Journ.</cite>, 1889.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_131" id="Footnote_131"></a><a href="#FNanchor_131"><span class="label">[131]</span></a> <cite>Berlin. Klin. Wochenschr.</cite>, 1890.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_132" id="Footnote_132"></a><a href="#FNanchor_132"><span class="label">[132]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">VIII</span>, p. 103.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_133" id="Footnote_133"></a><a href="#FNanchor_133"><span class="label">[133]</span></a> <cite>Compt. rend. Soc. de Biol.</cite>, p. 232, Jan. 30, 1897. <cite>Congrès -d'Hygiène de Madrid</cite>, 1898.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_134" id="Footnote_134"></a><a href="#FNanchor_134"><span class="label">[134]</span></a> <cite>Annal. l'Instit. Pasteur</cite>, <span class="smcap">VI</span>, p. 755; <span class="smcap">Sanarelli</span>: <cite>Ibid.</cite>, p. 721.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_135" id="Footnote_135"></a><a href="#FNanchor_135"><span class="label">[135]</span></a> <span class="smcap">Funck</span>: <cite>La Sérothérapie de la Fièvre Typhoïde</cite>, <span class="smcap">I</span>, Brussels, -1896.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_136" id="Footnote_136"></a><a href="#FNanchor_136"><span class="label">[136]</span></a> <cite>Compt. rend. de l'Acad. des Sciences</cite>, Jan. 12, 1885.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_137" id="Footnote_137"></a><a href="#FNanchor_137"><span class="label">[137]</span></a> <span class="smcap">Klebs</span>: <cite>Allgem. Wien. Med. Zeit.</cite>, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_138" id="Footnote_138"></a><a href="#FNanchor_138"><span class="label">[138]</span></a> <cite>Arch. de Méd. Expérim.</cite>, <span class="smcap">IV</span>, p. 173.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_139" id="Footnote_139"></a><a href="#FNanchor_139"><span class="label">[139]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">IX</span>, p. 129.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_140" id="Footnote_140"></a><a href="#FNanchor_140"><span class="label">[140]</span></a> <cite>Ibid.</cite>, <span class="smcap">X</span>, p. 257.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_141" id="Footnote_141"></a><a href="#FNanchor_141"><span class="label">[141]</span></a> <span class="smcap">Haffkine</span>: <cite>Compt. rend. de l'Acad. des Sciences</cite>, 1892; -<span class="smcap">Metchnikoff</span>: <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">VII</span>, p. 403; and -<span class="smcap">Roux</span>: <cite>Ibid.</cite>, <span class="smcap">X</span>, p. 253.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_142" id="Footnote_142"></a><a href="#FNanchor_142"><span class="label">[142]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">VIII</span>, p. 281; <cite>Journ. of Physiol.</cite>, -<span class="smcap">VIII</span>, p. 203; and <cite>Soc. de Biol.</cite>, 1894, p. 111.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_143" id="Footnote_143"></a><a href="#FNanchor_143"><span class="label">[143]</span></a> <span class="smcap">Calmette</span>: <cite>Le Venin des Serpents</cite>, Paris, 1896.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_144" id="Footnote_144"></a><a href="#FNanchor_144"><span class="label">[144]</span></a> <span class="smcap">Calmette</span>: <cite>Annal. Instit. Pasteur</cite>, <span class="smcap">VIII</span>, p. 276; <span class="smcap">IX</span>, p. 229.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_145" id="Footnote_145"></a><a href="#FNanchor_145"><span class="label">[145]</span></a> <span class="smcap">Winter</span> and <span class="smcap">Blyth</span>: <cite>The Analyst</cite>, 1877, p. 204; <span class="smcap">Lacerda</span>: -<cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">XCIII</span>, p. 466; <span class="smcap">Calmette</span>: -<cite>Annal. Instit. Pasteur</cite>, <span class="smcap">VI</span>, p. 175, and <span class="smcap">VIII</span>, p. 278.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_146" id="Footnote_146"></a><a href="#FNanchor_146"><span class="label">[146]</span></a> <cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">CXXI</span>, p. 745; <span class="smcap">Jacodot</span>: -<cite>Arch. de Médecine Navale</cite>, <span class="smcap">VII</span>, p. 390.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_147" id="Footnote_147"></a><a href="#FNanchor_147"><span class="label">[147]</span></a> <cite>Traité sur le Venin de la Vipère</cite>, Florence, 1781.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_148" id="Footnote_148"></a><a href="#FNanchor_148"><span class="label">[148]</span></a> <cite>Archives de Physiologie</cite>, 1894, p. 423.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_149" id="Footnote_149"></a><a href="#FNanchor_149"><span class="label">[149]</span></a> <cite>Bull. Muséum Histoire Naturelle</cite>, <span class="smcap">I</span>, p. 294; <cite>Compt. rend. -Soc. de Biol.</cite>, 1899. p. 77.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_150" id="Footnote_150"></a><a href="#FNanchor_150"><span class="label">[150]</span></a> <cite>Deutsche med. Woch.</cite>, 1898, p. 629.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_151" id="Footnote_151"></a><a href="#FNanchor_151"><span class="label">[151]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, 1895, p. 229; <cite>Compt. rend. de -l'Acad. des Sciences</cite>, <span class="smcap">CXXII</span>, p. 203.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_152" id="Footnote_152"></a><a href="#FNanchor_152"><span class="label">[152]</span></a> <span class="smcap">Cloez</span>: <cite>Compt. rend. de l'Acad. des Sciences</cite>, <span class="smcap">XXXIV</span>, p. 592.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_153" id="Footnote_153"></a><a href="#FNanchor_153"><span class="label">[153]</span></a> <cite>Ibid.</cite>, <span class="smcap">XCVIII</span>, p. 538.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_154" id="Footnote_154"></a><a href="#FNanchor_154"><span class="label">[154]</span></a> <cite>Ibid.</cite>, <span class="smcap">CXXVIII</span>, pp. 45-48.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_155" id="Footnote_155"></a><a href="#FNanchor_155"><span class="label">[155]</span></a> <span class="smcap">P. Bert</span>: <cite>Compt. rend. de la Soc. de Biologie</cite>, 1885, p. 524.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_156" id="Footnote_156"></a><a href="#FNanchor_156"><span class="label">[156]</span></a> <cite>Bull. Soc. Chim.</cite> [2], <span class="smcap">VI</span>, p. 344.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_157" id="Footnote_157"></a><a href="#FNanchor_157"><span class="label">[157]</span></a> <span class="smcap">Bofford</span>: <cite>Thèse de doctorat en Médecine—Les Poissons -venimeux</cite>, Paris, 1889; <span class="smcap">O. Arcos</span>: <cite>Thèse de doctorat—Essais -sur les accidents causés par les poissons venimeux</cite>, Paris, 1887.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_158" id="Footnote_158"></a><a href="#FNanchor_158"><span class="label">[158]</span></a> <span class="smcap">Philouze</span>: Venin des Abeilles. <cite>Annales de la Société Linn. -du Maine-et-Loire</cite>, <span class="smcap">IV</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_159" id="Footnote_159"></a><a href="#FNanchor_159"><span class="label">[159]</span></a> <span class="smcap">Joyeux-Laffriée</span>: <cite>Thèse de doctorat en Médecine</cite>, Paris, -1883; <span class="smcap">P. Bert</span>: <cite>Compt. rend. de la Soc. de Biol.</cite>, <span class="smcap">II</span> [4], p. 136.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_160" id="Footnote_160"></a><a href="#FNanchor_160"><span class="label">[160]</span></a> <span class="smcap">Calmette</span>: <cite>Annales de l'Instit. Pasteur</cite>, <span class="smcap">X</span>, p. 232.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_161" id="Footnote_161"></a><a href="#FNanchor_161"><span class="label">[161]</span></a> <cite>Proceedings of the Royal Society</cite>, <span class="smcap">XLII</span>, p. 17.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_162" id="Footnote_162"></a><a href="#FNanchor_162"><span class="label">[162]</span></a> <span class="smcap">Metchnikoff</span>: <cite>L'Immunité</cite>, p. 344.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_163" id="Footnote_163"></a><a href="#FNanchor_163"><span class="label">[163]</span></a> <span class="smcap">Calmette</span>: <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">X</span>, p. 232.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_164" id="Footnote_164"></a><a href="#FNanchor_164"><span class="label">[164]</span></a> <cite>Archives internat. de Pharmacodynamie</cite>, <span class="smcap">III</span> and <span class="smcap">IV</span>.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_165" id="Footnote_165"></a><a href="#FNanchor_165"><span class="label">[165]</span></a> <cite>Berliner Klin. Wochenschr.</cite>, 1895, No. 7.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_166" id="Footnote_166"></a><a href="#FNanchor_166"><span class="label">[166]</span></a> <cite>Annal. de l'Instit. Pasteur</cite>, <span class="smcap">XIII</span>, p. 406.</p></div> - -<div class="footnote"> - -<p><a name="Footnote_167" id="Footnote_167"></a><a href="#FNanchor_167"><span class="label">[167]</span></a> The name "cytases" or "alexins" has been given to -hemolyzing diastatic substances which are found in certain -serums. It has been known for a long time that the serum -of the blood of many animals destroys the red blood-corpuscles -of other and different species. The chemical composition of -these cytases or alexins is not yet definitely known, but the -substances rank among the albuminoids; they are destroyed -by a temperature of 55° to 56° C., and act only in saline -solutions (Ehrlich and Morgenroth, <cite>Berlin. Klin. Woch.</cite>, pp. -6 and 481). The cytases or alexins, which will be studied -in another volume of this collection, and which will discuss -the active principles of the immunizing serums, constitute one -of the numerous soluble intraleucocytary ferments, and they -pass into the serous liquids of the organism only as the result -of a rupture of or injury to the phagocytes.</p></div></div> - - -<div class="transnote"> -<h3>Transcriber's Notes</h3> - -<p>Obvious typographical errors have been silently corrected, but all -other variations in spelling, punctuation and accents are as in the -original, with the exception of Symptomatology (in the contents list) and -symptomology (in the text) which has been corrected to symptomatology.</p> - -<p>Variations between the treatment and phrasing of headings in the table -of contents and in the text have not been changed.</p> -</div> - - - - - - - -<pre> - - - - - -End of the Project Gutenberg EBook of The Toxins and Venoms and their -Antibodies, by Em. 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