,,the ,,toxins ,,and ,,venoms ,,and ,,their ,,antibodies ,,by ,,em4 ,,pozzi-,,escot ,,authorized ,,translation ,,by ,,alfred ,i4 ,,cohn1 ,,phar4 ,d4 ,,first ,,edition ,,first ,,thousand ,,new ,,york ,,john ,,wiley ,,sons ,,london3 ,,chapman ,,hall1 ,,limited #aijf ,copyright1 #aijf ,,by ,,alfred ,i4 ,,cohn ,,robert ,,drummond1 ,,printer1 ,,new ,,york ,,introduction4 ,our knowledge of the toxins is of quite recent date4 ,it is hardly twenty years since we began to acquire a knowledge of the facts that are detailed in this volume1 and to which modern medicine owes its most recent and marvelous progress1 particularly in serotherapy4 ,in this volume we have studied1 besides the true toxins--substances of cellular origin and of albuminoid nature and unknown composition--other toxic substances1 the nitrogenized alkaloidal bases introduced into science through the researches of ,selmi1 ,armand ,gautier1 and von ,behring1 and which are highly hydrogenized nitrogenous crystallizable principles of definite chemical composition--the products of the more or less advanced breaking down of albuminoids4 ,although these principles differ widely1 by reason of their physiological properties as a whole1 from the toxic albuminoids1 or true toxins1 it appears proper to consider them as products of the advanced decomposition of these toxins--and in this respect their study becomes imperative1 the more so as they are very frequently encountered together with the toxins1 particularly in serpent-venoms1 where their action is exerted in addition to that of the true toxins4 ,in the first volume of this collection we dwelt on the essentially reducing nature of the cellular functionation4 ,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 organism1 whether normally1 or because of certain pathological conditions4 ,this alone suffices to show that1 during physiological life1 oxygen plays an essentially antitoxic rle within the organism4 ,it is hoped that this succinct rsum1 which it has been sought to make as clear as possible1 will be of service to those who1 while not scientists actively engaged in scientific progress1 desire to be abreast of the knowledge of modern evolution1 but yet are not in a position to consult original papers or large treatises4 ,,contents4 ,,page ,,introduction iii ,,part ,i4 ,,generalities ,,regarding ,,toxins ,,and ,,antitoxins4 ,,chapter ,i4 ,,alkaloidal ,,toxins1 ,,ptomaines1 ,,and ,,leucomaines4 ,alkaloidal products of cellular life #a ,ptomaines #d ,physiological action #e ,extraction #e ,classification1 etc4 #g ,leucomaines #aj ,xanthic leucomaines #ab ,creatinic leucomaines #ac ,neurinic leucomaines #ac ,indeterminate leucomaines #ad ,,chapter ,,ii4 ,,toxins ,,and ,,antitoxins4 ,toxins #ae ,action of pathogenic bacteria #af ,action of toxins #ag ,nature of toxins #ah ,origin of toxins #bj ,autointoxications #ba ,general mode of action #bc ,constitution of toxins2 ,ehrlich's theory #bd ,means of defense possessed by the organism against the action of toxins #bh ,pasteur's vaccination method #cj ,virus action #cj ,phagocytosis #cb ,antitoxins #cc ,mode of action #ce ,formation2 ,ehrlich's theory #ch ,serotherapy #da ,,part ,,ii4 ,,the ,,toxins ,,proper4 ,,chapter ,,iii4 ,i4 ,,vegetable ,,and ,,animal ,,toxins4 #db ,abrin #db ,ricin #dd ,robin #de ,toxicity of the vegetable diastases #de ,,ii4 ,,toxins ,,from ,,mushrooms #df ,phalline #dh ,symptomatology #di ,antidiastases #ea ,,iii4 ,,animal ,,toxins #ec ,peptotoxin #ec ,alimentary ,intoxications #ee ,urinary toxins #eg ,variation of urinary toxicity #ei ,autointoxications 7animal7 #fj ,glandular secretions #fb ,suprarenal capsules #fc ,,chapter ,,iv4 ,,the ,,microbial ,,toxins4 ,pyogenic and pyretogenic properties #ff ,anthrax toxin #fg ,tubercular toxin #fi ,diphtheria toxin #ga ,tetanus toxin #gf ,mallein #gi ,typhoid toxin #hj ,cholera toxin #hb ,,chapter ,v4 ,,the ,,venoms4 ,general nature of venoms #he ,venomous serpents #hg ,nature of serpent-venoms #hh ,natural immunity towards serpent-venoms #ij ,artificial immunity towards serpent venoms #ia ,venoms of batrachians and saurians #ib ,fish-poisons #ie ,poisons of the hymenoptera #if ,poisons of scorpions #ig ,poisonous blood and serums #ih ,poisonous meats #ajj ,,toxins ,,and ,,venoms4 ,,part ,i4 ,,generalities ,,regarding ,,toxins ,,and ,,antitoxins4 ,,chapter ,i4 ,,alkaloidal ,,toxins1 ,,ptomaines ,,and ,,leucomaines4 ,alkaloidal ,products of ,cellular ,life4 ,before entering upon the study of the true toxins1 which are products of an alkaloidal nature and of unknown composition1 it is necessary to say a few words regarding the most definite of the toxic alkaloidal principles that are frequently encountered under various conditions1 conjointly with the true toxins1 particularly in venoms1 and which1 furthermore1 are closely allied to these albuminoid toxins4 ,these principles are formed in essentially reducing media1 whether it be within the body of the organism1 and by the simple exercise of its normal function1 in which case the principles bear the generic name leucomaines#a2 or whether due to the action of anaerobic microbes1 when they are designated as ptomaines4#b ,these basic principles1 which are essentially the products of cellular secretion1 are usually toxic1 and sometimes even extremely so4 #a ,,armand ,,gautier3 ,sur les leucomaines1 nouveaux alcaloides1 drivs de la transformation des substances protiques des tissus vivants4 ,bull4 ,soc4 ,chim41 #b;e srie1 ,,xliii1 p4 #aeh4 #b ,,armand ,,gautier3 ,communication sur les bases d'origine putrfactive4 ,bull4 ,soc4 ,chim4 7#b71 ,,xxxvii1 p4 #cje4 ,as we shall presently see1 ptomaines are essentially products formed during putrefactive fermentation4 ,the toxic properties of extracts from the cadaveric fluids have long been known4 ,already in #ahch ,panum#c had met with these products in snake venoms4 ,bergmann and ,schmiedberg#d in #ahfh isolated from septic pus a toxic substance which they named sepsin2 and almost at the same time ,zuelzer and ,sonnenschein#e reported having isolated from anatomical preparations an alkaloid possessing mydriatic properties4 ,it is1 however1 due particularly to the researches of ,selmi and ,armand ,gautier that we are now so well informed regarding these toxic principles4 #c ,virchow ,archiv41 ,x1 p4 #cja4 #d ,medic4 ,centralblatt1 #ahfh1 p4 #dig4 #e ,berlin4 ,klin4 ,woch41 #ahfi1 ,no4 #b4 ,the labors of ,armand ,gautier were first published in his ,trait de ,chimie ,applique la ,physiologie2 those of ,selmi in the ,actes de l',acadmie de ,bologne4 ,at first sight1 there appears to be a great difference between these alkaloidal bases1 the ptomaines and leucomaines1 and the albuminoid toxins proper4 ,the toxic bases of the first two groups are quite definite chemical products which can be generally obtained quite pure1 and frequently in crystalline form4 ,the toxins proper1 on the other hand1 are highly complex albuminoid substances which greatly resemble the true diastases in all their properties4 ,nevertheless1 between the toxic alkaloids1 ptomaines and leucomaines1 and the toxic albuminoids1 or more properly toxins1 there exists no absolutely sharp line of demarcation1 but there is a gradual passage from the one to the other by every intermediary grade1 as a result of the breaking down of the albuminoid molecule4 ,we shall see1 moreover1 as we proceed1 that these substances are formed under coexistent circumstances1 and that they are1 hence1 found together1 whether it be in virus or in snake venom4 ,we will first consider the ptomaines1 and then the leucomaines4 ,ptomaines4 ,this name is more specially reserved to designate those alkaloidal substances1 generally highly hydrogenized1 that are formed outside the organism1 from the fermentative action of anaerobic microbes on albuminoid substances4 ,these bases are generally volatile1 with an intense and tenacious purulent odor2 often1 however1 they possess a floral odor 7aubpine1 syringa71 and even like that of musk4 ,they combine readily with acids and with the chlorides of the heavy metals1 yielding crystallizable salts4 ,the ptomaines afford no specific reaction whereby they may be readily identified2 and their identification is effected only after a painstaking analysis4 ,we must here call attention1 however1 to several of their more common properties1 beginning with their basic character1 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 detection4#f ,they are precipitated by all the general reagents for the vegetable alkaloids4 ,selmi has given several reactions1 such as those afforded by sulphuric1 hydrochloric1 and nitric acids1 which appear1 however1 to apply much more to the impurities present than to the bases themselves4 #f ,sulle ptomane od alcalodi cadaverici4 ,bologne1 ,,clxxxvii1 p4 #aa4 ,the physiological action of these bases varies greatly2 in some the action is an extremely toxic one1 as in the case of neurine and muscarine1 which are true ptomaines2 there are others1 such as cadaverine and putrescine1 which are quite innocuous4 ,the physiological action of these bases1 like that of the true toxins1 is studied by making hypodermic injections of solutions of the bases in healthy animals1 such as guinea-pigs1 rabbits1 and dogs4 ,in animals1 the principal phenomena observed by ,selmi to follow the injection of the substances are the following3 ,at first dilatation of the pupil1 then constriction2 tetanic convulsions1 soon followed by muscular relaxation1 and retardation1 rarely acceleration1 of heart-beat2 absolute loss of cutaneous sensibility2 loss of muscular contractility2 paralysis of the vasomotors2 greatly retarded respiration2 stupor1 followed by death with the heart in systole4 ,it must be observed that in a number of cases where toxic researches had been made in the past1 these bases had been mistaken for poisons which were believed to have been introduced into the organism with criminal intent4 ,no one will ever know how many have fallen victims in the past to ignorance regarding the cellular mechanism6 ,the extraction of these bases is a tedious and difficult operation4 ,the materials must first be exhausted with water slightly acidulated2 then1 after precipitating the albuminoids by boiling and defecating by adding lead acetate1 the liquid is evaporated to one-half its volume and dialyzed in a vacuum4#g #g ,,armand ,,gautier3 ,c4 rend4 de l',acadmie des ,sciences1 ,,cxiv1 p4 #abef4 ,ibid41 ,,xcvii1 p4 #bfd1 and ,,xciv1 p4 #afjj4 ,phosphomolybdate is then added to the dialyzed liquid1 and the precipitate formed1 which now contains all the bases1 decomposed by boiling with lead acetate4 ,after removing the excess of lead1 there is thus obtained a limpid solution of all the alkaloidal bases in the form of acetates4 ,these are separated by alcohol and by means of fractional precipitations with various metallic salts1 depending upon the known properties of the bases4 ,in order to facilitate their study1 the ptomaines have been grouped under two distinct classes1 the one embracing the cadaveric or putrefactive ptomaines1 of undetermined microbial origin1 the other containing the ptomaines formed by microbes of known character4 ,each of these two groups is itself divided into subgroups1 as shown in the following table3 ,,group ,i4 ,,cadaveric ,,ptomaines ,,of ,,undetermined ,,microbial ,,origin4 a4 ,amines4 b4 ,guanidines4 c4 ,oxamines 7fatty or aromatic74 d4 ,amido ,acids4 e4 ,carbopyridic ,acids and analogues4 f4 ,undetermined ,ptomaines4 ,,group ,,ii4 ,,ptomaines ,,of ,,known ,,microbial ,,origin4 a4 ,ptomaines extracted from microbial cells4 b4 ,ptomaines from pathological urines4 ,we will not here enter upon a detailed study of the bases belonging to each of these groups4 ,this subject is a vast one1 requiring for its treatment a volume devoted to it alone4 ,we will here simply touch upon the principal properties of several of the bases of each of the subgroups named4 ,,bases ,,of ,,group ,i4 a4 ,amines4--,among these we find nearly all the fatty amines1 such as the methylamines and the cyclic alkaloids such as pyridine4 ,they are formed particularly by the putrefaction of fish4 ,certain of these bases are very toxic1 for instance trimethylene diamine1 the collidines1 and the parvolines4 b4 ,guanidines4--,among the products of ordinary putrefaction there has been found so far only methylguanidine1 ,c#b;,h#g,n#c4 ,this is a highly toxic base of which #j4b ,gm4 is fatal to a guinea-pig4 c4 ,oxamines4--,under this designation the following bases are comprised3 #a4 ,neurine bases2 #b4 oxygenized aromatic bases2 #c4 bases of unknown constitution4 ,amongst them we find neurine and choline1 which are toxic1 and betaine1 which is innocuous4 ,they are found particularly in putrid fish4 d4 ,amido ,acids4--,these ptomaines1 which are usually innocuous in small quantities1 are particularly the products of the decomposition of albuminoid substances4 ,among them we find glycocoll1 leucine1 and tyrosine1 as members of this group4 e4 ,carbopyridic and ,carboquinoleic ,acids4--,so far only one base is known belonging to this group1 and that is morrhuic acid1 which is found in the decomposed livers of codfish1 and which is a powerful appetizer and stimulant in disassimilation4 f4 ,undetermined ,ptomaines4--,under this heading are classed certain undetermined bases1 such as those found in normal urines1 and in spoiled meats and bread4 ,,bases ,,of ,,group ,,ii4 a4 ,ptomaines ,isolated from ,cultures of ,pathogenic ,bacteria4--,bacterial cultures contain1 besides the true toxins1 a certain number of alkaloidal bases which sometimes possess considerable toxicity4 ,in the cultures of streptococcus pyogenes there are found trimethylamine and xanthic bases2 in those of staphylococcus pyogenes aureus are found xanthic bases and creatinine2 while pyocyanine and pyoxanthine are found in the cultures of bacillus pyocyaneus1 etc4 b4 ,ptomaines ,isolated from ,pathological ,urines4--,toxic ptomaine bases have been found in the urines of a large number of diseases4#h ,it is quite probable that these bases are the results of a general pathological condition due to some bacterial disease1 the toxic products of which are eliminated by the kidneys4 #h ,,griffiths3 ,c4 rend4 de l',acadmie des ,sciences1 ,,cxv1 pp4 #bhe and #ffg4 ,from the urines of epileptics ,griffiths#i isolated a colorless base crystallizing in prisms having the formula ,c#ab;,h#ae,n#e,o#g1 and which was found to be exceedingly toxic2 the same investigator isolated from the urines of eczematous subjects a ptomaine which he named eczemine1#aj and which is also highly toxic4 #i ,e4 ,,pouchet3 ,contribution l'tude des matires extractives de l'urine1 ,thse1 ,paris1 #ahhj2 ,ibid41 ,c4 rend4 de l',acadmie des ,sc41 ,,xcvii1 p4 #aefj2 ,,bouchard3 ,c4 rend4 ,soc4 de ,biolog41 ,aug4 #ab1 #ahhb4 #aj ,,griffiths3 ,c4 rend4 de l',acadmie des ,sciences1 ,,cxvi1 p4 #abjf4 ,in certain cases of cystinuria there are found in the urine sulphurized ptomaines1 and in measles the urine contains an undetermined ptomaine1 rubedine1 which is very poisonous4 ,typhotoxine1 a very toxic ptomaine1 has been isolated from the urine of typhoid patients2 erysipeline1 a hardly less toxic base1 exists in the urine of erysipelatic subjects2 while spasmotoxine1 tetanotoxine1 and tetanine1 exceedingly active alkaloids1 are found in the urines of tetanus patients4#aa #aa ,,brieger3 ,untersuchungen ber die ,ptomaine1 dritten ,teil1 p4 #ic2 ,berichte d4 ,d4 ,chem4 ,gesellschaft1 #ahhf1 p4 #caei2 #ahhg1 p4 #fi4 ,as a general rule1 all abnormal urines contain toxic bases2 the kidneys appear1 in fact1 to serve as a means of eliminating the toxic products that form in large quantity whenever1 and for whatever cause1 the organism ceases to functionate normally1 whether it be as a whole1 or in any one of its parts4#ab #ab ,,charrin3 ,les poisons de l'urine3 ,encyclopdie ,laut4 ,leucomaines4#ac #ac ,,armand ,,gautier3 ,bull4 ,acad4 de ,mdecin 7#b71 ,,xv1 p4 #aae4 ,the leucomaines are basic substances1 nearly allied to the ptomaines1 but still more closely related to the ureides4 ,they are formed directly or indirectly by the breaking down of protoplasmal albuminoids4 ,the agents that effect the breaking down are the hydrolyzing ferments of the economy4 ,it is well to recall here that these phenomena of hydrolyzation occur within the cell itself and in a practically reducing medium1 as we have already stated4 ,the inmost mechanism of these phenomena cannot here be detailed2 it will be found described by ,armand ,gautier in the ,chimie ,biologique1 and in his work ,chimie de la ,cellule ,vivante4#ad #ad ,,armand ,,gautier3 ,leons de chimie biologique4 ,published by ,masson2 ,ibid41 ,chimie de la cellule vivante4 ,also published by ,masson4 ,the extraction of these bases is an extremely delicate operation4 ,it is necessary to operate with a large quantity of substance1 say #ej kilos4 ,the substance is finely chopped1 then exhausted with twice its weight of water acidulated with acetic acid 7#j4b ,cc4 per liter7 and containing a trace of oil of mustard1 which is intended to act as an antiseptic4 ,the albuminoids are precipitated by boiling1 the solution then filtered1 evaporated in a vacuum at #fj ,c41 and the bases extracted with #ie-per cent4 alcohol4 ,the alkaloidal bases obtained in this manner are separated by crystallization from alcohol or by various other chemical methods1 the description of which we will not enter upon here4 ,in order to facilitate the study of the leucomaines they are classed under three groups1 according to their chemical affinities4 ,these groups are as follows3 #a4 ,xanthic ,leucomaines4--,the bases of this group appear to have a composition resembling that of uric acid4 ,when hydrolyzed1 they yield urea and guanidine4 ,they are weak bases1 and exhibit both basic and weakly acid properties4 ,they all possess the common characteristic of being precipitated by copper acetate in acid solution with heat1 and by ammoniacal silver nitrate in the cold4 ,according to ,kossel1 these bases are derived from the nucleo-albumins which are found in the cell nuclei1 and which are1 as we know1 substances rich in nitrogen and phosphorus4 ,among the bases of this group may be mentioned adenine1 ,c#e;,h#e,n#e1 which is obtained from infusions of tea4#ae ,this base is non-toxic2 it was discovered by ,kossel1#af and it crystallizes easily4 #ae ,,kruger3 ,bull4 ,soc4 ,chim4 7#c71 ,,viii1 p4 #fhg4 #af ,,kossel3 ,zeitschrift fr physiol4 ,chim41 ,x1 p4 #bdh2 and ,bull4 ,soc4 ,chim4 7#c71 ,,iii1 p4 #bci4 ,some others of this group are3 ,guanine1 ,c#e;,h#e,n#e,o1 non-toxic1 discovered by ,unger2 pseudo-xanthine1 obtained from muscular tissues2 sarcine1 ,c#e;,h#d,n#d,o1 also but slightly toxic1 discovered by ,scherer2 xanthine1 ,c#e;,h#d,n#d,o#b1 which is found in many urines1 and which acts as a stimulant on the cardiac muscles2 paraxanthine1 ,c#g;,h#h,n#d,o#b1 a toxic base found in certain pathological urines2 caffeine and theobromine1 powerful diuretic bases2 and carnine1 ,c#g;,h#h,n#d,o#c1 from meat1 a muscular stimulant like caffeine4 #b4 ,creatinic ,leucomaines4--,these have for their type guanidine2 they differ from the xanthic bases in that they are not precipitated by copper acetate1 but frequently are by ammoniacal silver nitrate4 ,they yield double salts with the chlorides of zinc and cadmium4 ,to this group belong glycocyanine1 ,c#c;,h#g,n#c,o#b1 and glycocyanidine1 ,c#c;,h#g,n#c,o1 both very toxic2 creatine1 ,c#d;,h#i,n#c,o#b1 only slightly toxic2 creatinine1 ,c#d;,h#g,n#c,o2 lysatine1 which very easily decomposes to form urea2 lysatinine1 xanthocreatine2 arginine1 a vegetable base1 etc4 #c4 ,neurinic ,leucomaines4--,these have none of the characteristics of the preceding bases2 their type is neurine1 a highly toxic base found in the brain1 nerves1 and certain fish ova4 ,these bases are sometimes normally produced by the animal economy1 and are also frequently the result of microbic action4 ,they are the result of the simple phenomena of fermentative hydrolyzation of protagons and lecithins4 ,among these bases are choline1 a weak alkaloid1 and betaine1 which appears to be non-toxic4 ,the former has the formula ,c#e;,h#ae,,no#b2 it was discovered by ,stocker4 ,wurtz synthesized it by combining trimethylamine and glycol-monochlorhydrine1 and treating the resulting hydrochloride with silver oxide4 ,betaine1 ,c#e;,h#aa,,no#b1 is found in beets2 it was discovered by ,scheibler4 ,neurine is1 chemically1 trimethylvinylammonium hydrate4 #d4 ,undetermined ,leucomaines4--,among these bases several are important in more than one respect4 ,for instance spermine1 which is found in the sperm1 is a strong base possessing a powerfully dynamic and tonic action on the nerves4 ,it acts as an oxidizer4 ,spermine was first obtained by ,schreiner#ag from the sperm of mammifers in which it occurs as a phosphate4 ,it has the formula ,c#e;,h#ad,n#b4 ,it was physiologically studied by ,poehl1 ,tarchanoff1 ,weljaminoff1 and ,joffroy4#ah ,plasmaine1 a toxic base found in the blood and discovered by ,r4 ,wurtz1#ai has the formula ,c#e;,h#ae,n#e2 protamine1 from fish milt1 was discovered by ,micocher4#bj #ag ,liebig's ,ann4 der ,chemie1 ,,cxciv1 p4 #fh4 #ah ,journ4 ,soc4 ,phys4 ,chim4 ,russe1 #ahic1 ,no4 #b2 and ,bull4 ,soc4 ,chim4 7#c71 ,,xii1 p4 #bdc4 #ai ,leucomaines du ,sang ,normal1 ,thse1 ,paris1 #ahhi4 #bj ,joh reab4 de ,thirchen1 #ahgd1 p4 #cda2 ,picard1 ,ibid41 p4 #cee4 ,,chapter ,,ii4 ,,toxins ,,and ,,antitoxins4 ,we have already seen1 in the preceding chapter1 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 given4 ,researches1 which were begun scarcely twenty years ago1 have shown that1 besides these crystallizable and definite products1 we meet with basic non-crystallizable substances of unknown composition1 possessing special toxic properties1 sometimes even of extreme violence4 ,these substances have been named toxins4 ,at first this generic name was extended toward indefinite basic organic products that could be isolated from tissues and tumors both normal and abnormal2 later on1 however1 the name was applied to toxic substances1 equally indefinite1 isolated from the culture media of microbes and the active constituent of various venoms4 ,it is only since #ahhe1 when ,charrin called attention to them1 that investigations began to be made regarding them4 ,in #ahhh ,roux and ,yersin1#ba in their beautiful researches on diphtheria1 pointed out the diastatic nature of the properties of the active albuminoid matter existing in the cultures of the specific bacilli of this disease4 ,from that period1 these products began to take a more and more prominent place1 from year to year1 in the study of pathological affections1 and1 by developing the knowledge of immunity1 they have opened a new path to the investigations of therapeutic technic4 #ba ,,roux and ,,yersin2 ,mmoire sur ,diphtrie4 ,ann4 ,inst4 ,pasteur1 #ahhh-ahhi4 ,it is due to the knowledge of these principles that we have learned that the infectious microbes1 far from acting as they were believed to do only a few years ago1 and which ,pasteur strongly maintained to be by vital parasitism--such as would be the case with the carbonizing bacteria which1 according to ,pasteur1 act by diverting the oxygen1 or causing capillary embolisms--owe their pathogenic action to the toxic substances which are the products of their secretion1 and which spread throughout the organism1 even though the microbe frequently is localized in a very circumscribed spot1 as in tetanus and in diphtheria4 ,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 organism4 ,the occurrence that takes place in diphtheria and tetanus is one of the best examples to cite in support of this view4 ,here1 in fact1 the pathogenic microbe is found only in a very limited area in the organism attacked--the false membrane1 in the case of diphtheria1 or frequently only a slight wound in the case of tetanus1 and the microbe becomes localized there only4 ,now1 in both cases1 there are general phenomena of toxic effects4 ,there must hence be a diffusion of toxic substances which1 distributed by the blood1 affect the different systems and exert a toxic action on the entire organism4 ,it must be observed that the toxins act as toxic agents only when in a condition to be introduced into the circulation subcutaneously4 ,the cause of this innocuousness of the toxins when given per os has frequently been studied4 ,it appears to be quite probable that the cause of the attenuation of the morbid properties is due to the intervention of the digestive microbes4 ,such is the opinion of ,levaditi and ,charrin#bb2 it is also the conclusion that is to be drawn from the experiments of ,mme4 ,metchnikoff and of ,calmette#bc on the modifications undergone by a vegetable toxalbumin1 abrin1 and by serpent venoms1 when these toxalbumins are inoculated with the bacillus subtilis chromogenus4 ,moreover1 ,charrin and ,lefvre1#bd on the one hand1 and ,nencki1 ,sieber and ,somanowsky1#be and ,carrire1#bf on the other hand1 have discovered that the digestive ferments1 particularly trypsin1 destroy1 even though but little1 the toxins secreted by the ,loeffler and ,nicolaier bacilli4 ,this is practically contrary to the opinion of ,behring and of ,rauson1#bg according to which the innocuousness of the microbial poisons when administered per os is due exclusively to the lack of absorption4 #bb ,,charrin and ,,levaditi3 ,le sort de toxines introduites dans le tube digestif4 ,journal de ,physiologie et de ,pathologie ,gnrales1 #ahih1 p4 #bbf4 #bc ,citing ,metchnikoff4 #bd ,c4 rend4 de la ,soc4 de ,biologie1 #ahih4 #be ,centralblatt fr ,bakt41 #ahih4 #bf ,c4 rend4 de la ,soc4 de ,biologie1 #ahii4 #bg ,deutsche ,med4 ,wochenschr41 #ahih1 ,no4 #h4 ,nature of the ,toxins4--,the molecules of the toxins are very nearly like those of the diastases4 ,like these1 the toxins appear to have a very complex1 and very unstable1 internal structure4 ,their mode of action frequently depends1 as in the case of the diastases1 upon the medium in which they occur4 ,again1 like the diastases1 they are generally destroyed by the action of sufficiently prolonged heat1 but less easily1 for there are certain toxins that resist a temperature of #ajj ,c4 for an indefinite period4 ,they are1 like the diastatic albuminoids1 insoluble in strong alcohol1 and are precipitated from their solutions on the addition of this reagent4 ,they easily adhere to precipitates that form in liquids in which they occur in solution1 and possess the remarkable property of diastases in that imponderable masses produce considerable results4#bh #bh ,see ,,pozzi-,,escot3 ,les diastases et leurs applications1 published by ,masson1 #aijj2 and ,trait de ,physico-chimie4 ,although closely allied to certain alkaloidal bases1 the toxins are sharply distinguished by the remarkable fact that their action is never immediate1 but is always preceded by a period of incubation1 which may be quite long4 ,like the alkaloidal bases1 they appear to result from the hydrolyzing breaking down of albuminoids and nucleo-albumins1 and they appear to be intermediary1 from a chemical point of view1 between these bodies1 the general characters of which they retain1 and the alkaloids proper1 or ptomaines1 to which we have called attention1 and the principal chemical and physiological properties of which they possess4 ,no absolutely precise knowledge is had regarding the chemical nature and constitution of these remarkable substances4 ,a number of analyses of these substances have been published which1 in general1 permit no definite conclusion to be drawn4#bi ,i have1 however1 elaborated several speculative ideas regarding this subject4#cj #bi ,regarding this see the works by ,,koch and ,,brieger1 ,deutsche ,medicin4 ,wochenschr41 ,oct4 #bb1 #ahia4 #cj ,,pozzi-,,escot3 ,nature des ,diastases4 ,published by ,j4 ,rousset1 ,paris1 #aijc4 ,see also ,recherches de la ,nature ,chimique des ,diastases ,oxydantes4 ,revue gnr4 de chimie1 ,,vii1 pp4 #abi-acf2 and ,aperus sur la nature chimique des ,diastases1 ,bulletin de l',association de ,chimistes1 #aijd1 p4 #gfi4--,proprits ,catalytiques de ,quelques ,diastases2 ,ibid41 #aijd1 p4 #abdg4 ,we must here call particular attention to the ideas of ,ehrlich regarding the constitution of the toxins4 ,according to this scientist1 their molecules contain two functional groups2 the one1 to which he has given the name haptophore1 is that which enables the toxin to attach itself to any cellular element whatever1 and which it then renders non-toxic by means of the other1 or toxophore1 group4 ,we will particularize farther on regarding this very important conception4 ,origin of the ,toxins4--,these toxic bodies result either as the products of the secretion of microbial life1 or as the result of the normal functionation of cellular life in the higher vegetable or animal organisms4 ,they are the direct products of life1 and do not result1 as was formerly believed1 from a more or less profound modification of the more or less complex albuminoids that serve as a food for the various species of microbes1 or for the cellular elements4 ,the vegetable toxins are less numerous than the animal toxins4 ,they are met with1 nevertheless1 in almost all mushrooms which are reputed or known to be toxic2 the seed of the castor plant contains a very toxic vegetable albuminoid1 as is likewise the case with ,abrus precatorius 7jequirity-bean71 and certain others4 ,the true physiological toxins occupy a very important place in the realization of the conditions that govern health1 sickness1 and death4 ,we will see later on that they are met with in quite large number in the bladder1 whence they are voided in the urine4 ,their number varies considerably1 according to diverse influences 7waking1 slumber1 eating1 fasting1 fatigue1 oxygen1 brainwork1 health1 disease1 etc474 ,it is necessary here to observe that the renal system serves for the purification of the entire organism1 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 organism1 and among the number there are found1 as we know1 a certain number of alkaloidal bases4 ,we will take up later the subject of urinary toxicity4 ,autointoxications4--,the toxins are also encountered1 and often in some number1 in the muscular tissues and in the blood1 particularly in those of batrachians1 mureids1 and saurians4 ,in the organism these toxins1 developed by the activity of the various cells1 may cause autointoxication whenever1 for one cause or another1 their normal elimination ceases4 ,although there are an infinity of diseases1 remarked ,prof4 ,bouchard1 there are but a few ways of becoming ill4 ,of these ways that of autointoxication is the most frequent4 ,what else is it1 then1 says ,prof4 ,charrin1 in the last analysis1 but to die from affections of the kidney1 the liver1 the heart1 the lung1 etc41 if it be not to succumb because of the lack of oxygen1 the accumulation of carbonic acid1 the influence of the numerous urinary poisons1 the action of acids1 of salts1 of biliary pigments1 or the effect of noxious principles1 which the hepatic cell must normally destroy or at least attenuate4 ,these autointoxications1 always due to poor elimination of toxic principles1 toxins formed in very great number in the organism1 and which the normal modes of evacuation or destruction do not eliminate1 are always found to be the cause of all diseases1 even those that are manifested by attacks of the cerebro-spinal axis1 and that exhibit variously mania1 insanity1 symptoms of hyperexcitability1 etc4 ,these autointoxications are controlled by the nervous system1 and the latter alone is the cause of a larger number of maladies than is generally believed2 in fact1 if the mechanism of nutrition be reduced to its most simple elements1 it will be seen to consist of the penetration of the foods1 of the plasmatic principles1 to the cells2 of their transformation within the interior of the cells1 and finally the rejection of all the matter that could not be utilized4 ,it is the nervous system that commands or dominates this mechanism1 that controls the taking-up of assimilable elements and the elimination of toxic principles1 the fruit of assimilation or disassimilation1 and in such a manner1 in fact1 that this same nervous system can1 at its will1 cause starvation1 or intoxicate4 ,the marvelous cures obtained by magnetic methods are due to no other causes than favorable changes in the nervous system4 ,general ,mode of ,action4--,the toxins1 of whatever kind1 always behave like diastases1 in the sense that their definite action appears to be absolutely independent of their mass1 and that imponderable quantities suffice to cause serious morbid affections and profound modifications in nutrition4 ,koch has shown that tuberculin is capable of affecting #fj trillion times its weight of the living human being4 ,according to ,vaillard one milligramme of tetanus toxin will kill a horse weighing #fjj kilos4 ,these two examples show what an enormous power the toxins possess4 ,my views regarding the manner in which diastases act ,i have developed at length in my work ,nature des ,diastases4 ,the close analogy between these substances and the toxins1 an analogy upon which1 moreover1 ,i have dwelt at some length1 permits me to refer the reader who is desirous of fuller details to the small work just mentioned4 ,the mode of action of diastases resembles singularly closely that of the catalytic substances1 and we will admit1 for the moment1 that they act by intermediary combination1 resulting in their rapid decomposition4 ,we owe to ,ehrlich#ca a new conception relative to the nature and mode of action of the diastases1 and which to-day plays an important rle in all our conceptions regarding immunity4#cb #ca ,,ehrlich3 ,klinisches ,jahrbuch1 #ahig1 ,,vi4 ,proceedings of the ,royal ,society1 #aijj1 ,no4 #dhb1 p4 #dbd4 ,nothnagles' specielle ,pathologie und ,therapie1 #aija1 ,,viii1 ,schlussbetrachtungen1 p4 #afc4 #cb ,to have a complete expos regarding this question1 it will be profitable to consult ,no4 #d of this collection on ,srums ,immunisants4 ,according to this scientist1 the complex molecule of albuminoid substances is constituted by a fixed central nucleus1 and by a number of lateral chains or receptors1 fixed to this nucleus1 which possess diverse accessory functions1 and which serve1 particularly1 for the nutrition of the cells4 ,these receptors have a great affinity for the various substances necessary for the support of the living elements1 and they seize upon the alimentary substances1 in normal life1 just as a leaf of the ,diona seizes a fly which serves as its food4 ,in these special conditions the receptors may attach themselves to the complex molecules of albuminoid substances1 such as the different toxins4 ,ehrlich supposes1 as we have already seen1 that a toxin contains two special groups--a toxophore group1 which poisons1 and a haptophore group1 which combines with the receptor4 ,according to this theory1 the toxophore group of a toxin can act on an organism only when the haptophore group of the toxin encounters a suitable attachment or receptor4 ,the receptors attached to the living protoplasmic molecule attract the toxin1 just as a lightning-rod attracts the lightning4 ,it is hence clearly proved that the toxigenic poisons exert their noxious action on the cellular elements of sensitive organisms1 by entering into combination with these4 ,experience has shown that they attach themselves1 in a most rigorously elective manner1 to the tissues1 and rapidly disappear from the general circulation4 ,numerous facts1 clearly established1 attest the reality of this fixation or attachment4 ,it is thus that von ,behring and ,wernicke#cc sought to ascertain the quantity of antitoxin 7we will see farther on that this name is given to those substances which neutralize the activity of toxins under certain conditions7 which1 introduced a certain time after the introduction of the poison1 will save the life of the animal4 ,they have experimented with diphtheria toxin1 which we will study later1 and they have demonstrated that1 if the antitoxic serum be introduced immediately after the toxin1 a dose of antitoxin twice as large as that of the toxin suffices to effect a cure4 #cc ,,von ,,behring and ,,wernicke3 ,zeitschrift fr ,hygiene1 ,,xii4 ,eight hours after the administration of the toxin the dose must be trebled1 while after thirty-six hours it is necessary to have recourse to a quantity of antitoxin eight times as great4 ,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 antitoxin4 ,this is because the toxin has become so intimately attached to the tissues that the antitoxin introduced has not the power to destroy the combination4 ,these facts have been confirmed by ,donitz#cd and by the classic experiments of ,decroly and ,rousse4#ce #cd ,,donitz3 ,ueber die ,grenzen der ,wirksamkeit des ,diphtheria ,heilserums4 ,deutsche ,med4 ,woch41 ,no4 #bg1 #ahig4 #ce ,,decroly et ,,rousse3 ,arch4 ,int4 de ,pharmacodyn41 ,,iii and ,,vi2 ,masoin3 ,arch4 ,intern4 de ,pharmacodyn41 ,,ii1 #aijc4 ,this is not1 however1 the case with cold-blooded animals1 which1 generally1 are not affected by injections of poisonous toxins4 ,thus ,metchnikoff#cf and his pupils have been able to show that the toxins introduced into certain cold-blooded animals 7,oryetes nasicorius7 may remain for several months without alteration in their circulation4 #cf ,,metchnikoff3 ,l',immunit1 ,paris1 #aijb2 ,,morgenroth3 ,zur ,kenntniss des ,tetanus des ,frosches4 ,deutsche ,med4 ,woch41 ,no4 #ce1 #ahih4 ,if we consider the facts of the theory of ,ehrlich's lateral chains1 which we have mentioned1 we are led to well-defined conclusions regarding the mode of action of the toxins4 ,in fact1 since these toxins exhibit a pronounced chemical affinity for the tissues1 and while1 on the other hand1 they can attach themselves only because of the presence of certain functional groups of the protoplasmic molecules1 this union can take place only in certain specific centers4 ,this has been fully confirmed by experiments in vitro4 ,it is known1 since the researches of ,ehrlich1#cg ,wassermann and ,takaki1#ch ,marie1#ci ,metchnikoff1#dj and a host of other scientists1 that this fixation is due to a clearly elective property4 ,it is for this reason that the tetanus toxin fixes itself only upon the nervous tissue1 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 poison4 #cg ,,ehrlich3 ,berl4 ,klin4 ,woch41 ,no4 #ab1 #ahih4 #ch ,,wassermann and ,,takaki3 ,berl4 ,klin4 ,woch41 ,med41 p4 #e1 #ahih4 #ci ,,marie3 ,sur les ,proprits ,antitoxiques aux ,centres ,nerveux de l',animal ,sain4 ,ann4 ,inst4 ,past41 #ahih1 p4 #a4 #dj ,,metchnikoff3 ,recherches sur l',influence de l',organism sur les ,toxines4 ,ann4 ,inst4 ,past41 #ahii1 p4 #hb4 ,means of ,defense ,possessed by the ,organism against the ,action of ,toxins4--,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 mechanism4 ,experience has shown that the toxins introduced from without into the circulation are generally finally eliminated1 even though in the meantime the modifications they have imprinted on the economy may be transmitted hereditarily2 and that their influence on the general nutrition and the normal functionation of the entire organism persists even after their elimination4 ,much has been said regarding the elimination of these toxins by the urine1 but the experiments made by ,mtin1 at the ,institut ,pasteur1 have shown the inaccuracy of this assumption1 and it has been necessary to seek another4 ,it has been remarked that oxidation destroys the toxins in vitro1 and it has been thought that a process resembling disinfection may well take place within the tissues of the animal economy1 but no decision has been arrived at regarding the possible mechanism of this action1 which some attribute to the action of the oxidizing ferments of the organism1 or to the action of certain special cells4 ,according to ,poehl1 there is developed as destroyer a substance possessing energetic oxidizing properties1 which he has isolated and named spermine1 and which is found in most of the organic fluids and particularly in the leucocytes1 the special rle of which we will presently study4 ,there develops still another cause of elimination1 or1 to be more exact1 of the neutralization of the toxic principles in defense of the organism against the toxins1 and that is the formation of antitoxins4 ,it is well known that the term virus has been reserved to designate physiological liquids which were characterized1 when first they were known1 by their property of transmitting to an organism certain functional affections1 but the true character of which is to expend their toxicity upon the microbes which occur and are reproduced in the organism1 or upon the organized plastidulary granulations1 as in the case of the rabic virus1 the special microbe of which has not as yet been isolated4 ,pasteur1 when studying rabies1 found that the brain and spinal marrow of rabid animals contained the pure rabic virus in considerable quantity1 and that every particle of the marrow was capable of imparting rabies to a perfectly healthy dog4 ,after having ascertained this fact1 he found that he could attenuate the action of the virus1 either by passing the virus through certain animal organisms1 such as the monkey or rabbit1 by gently heating1 or even by allowing it to oxidize and partially dry in the air1 or else by submitting it to the action of antiseptics or alternating electric currents of very high tension4 ,experiments have shown that a deadly virus1 attenuated by one of the means mentioned1 may be injected1 without danger of death1 into the living animal2 and what is still better1 the animal thus treated acquires the power of resisting large doses of the virus1 less and less attenuated1 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 is1 the organism has been vaccinated with regard to the particular virus4 ,experiments have shown that this property is not peculiar to microbial virus alone1 but that it is common to the venoms the toxicity of which is essentially due to some toxins1 with the exception of those agents noted4 ,the attenuated viruses act1 as vaccins1 through their soluble constituents1 which1 either directly1 by modifying the nutrition of certain cells1 or indirectly1 by inducing reactions of the nervous centers which preside over this nutrition1 profoundly change the conditions of life and give rise to the pathological condition--the vaccined state4 ,experiments by ,behring and ,kitasato#da have shown that the tumors of a vaccinated animal1 freed from all organized matter visible under the microscope by filtration through porcelain1 contains principles capable of directly or indirectly protecting other animals from the disease caused by the corresponding virus4 ,meanwhile1 experiments have shown that the vaccinating matters are totally eliminated2 nevertheless1 after their elimination1 the immunity acquired remains with the animal1 which then continues to be protected against the corresponding virus4 #da ,deutsche ,med4 ,wochenschr41 #ahij1 p4 #aaac4 ,interest in this subject has incited numerous researches with a regard to bringing to light the mechanism of this immunization2 and this will form the subject of another volume of this collection4 ,we may state here1 however1 that there have been recognized two concurrent causes of this preservative action2 the one1 called phagocytosis1 results from the fact that the microbe introduced into the vaccined organism becomes incapable of producing its usual toxins1 while on the other hand the immunization renders the organism capable of secreting substances possessing an activity contrary to that of the virus1 in fact true counter-poisons1 comprised under the general name antitoxins4 ,phagocytosis4--,we have seen that an organism subjected to a toxic invasion tends to protect itself by proper means of defense2 and one of those is the direct putting into activity of the living cellular elements themselves1 and in particular1 the leucocytes1 or white corpuscles1 found in more or less number1 according to pathological conditions1 in the blood and lymphatic fluids4#db #db ,it is necessary here to consult the work by ,,levaditi3 ,le ,leucocyte et ses ,granulations4 ,scientia1 ,naud1 publisher1 ,paris1 #aijc2 also ,,metchnikoff3 ,l',immunit1 ,paris1 #aijb1 ,masson1 publisher4 ,metchnikoff has shown that the moment a foreign element1 particularly a microbe1 enters the organism1 these leucocytes come flocking from all parts of the body1 collect around the bacterial element1 penetrate it1 and begin to digest it4 ,these elements have received the name phagocytes4 ,the name chemotaxis has been given to the property by virtue of which they approach 7positive chemotaxis7 or move away from 7negative chemotaxis7 certain substances which affect them powerfully4 ,experiments have shown that the leucocytes are attracted by the products secreted by pathogenic microbes1 or saprophytes4 ,attracted by the latter1 the white corpuscles surround1 envelop1 and finally digest them2 and when it happens that all the pathogenic microbes within an organism are absorbed1 the organism survives1 while in the contrary case it succumbs4 ,attention must be called to this attack by the white corpuscles within the limits where they are normally confined4 ,it is a pathologic diapedesis--a leucocytosis provoked by the irritation of the tissues--and caused either by the presence alone of foreign elements1 or by the soluble products secreted by them4 ,when1 for any reason whatever1 this phagocytic action is impeded1 the resistance of the organism to pathogenic infection ceases to be effective1 and the organism may therefore be invaded by the microbe4 ,numerous causes may contribute to impede this action4 ,the ,antitoxins4 ,we have seen that the second means of defense possessed by the organism resides in the action of special products1 true defensive secretions1 possessing an activity contrary to that of the toxins1 and which are secreted by the cells of the organism under the influence of the vaccins4 ,this is a property common to every organism1 and which is observed even in non-vaccinated subjects1 although in this case the secretion forms with great difficulty and in small quantity4 ,when an organism subjected to the toxic action of a bacterial infection does not succumb to the intoxication1 it emerges from the test gifted with a new property1 which may be augmented by habituation1 and which borders on immunity4 ,at first we were content to vaccinate small animals in the laboratory1 but in proportion as the discoveries in this domain extended1 and there developed a need for large quantities of antitoxins1 recourse was had to the larger animals1 particularly horses and cattle4 ,from the moment that large quantities of blood and antitoxic serum were at command1 search was made for a means of isolating the antitoxin and determining its properties4 ,experiments so far made have shown that the antitoxins are substances of an albuminoid nature1 of unknown composition1 and which are very closely united to the albuminoid substances of the serum4 ,it must be observed1 however1 that ,behring and ,knorr oppose the assertion regarding the albuminoid nature of tetanic antitoxin1 but their reasons for this do not appear to be well founded4 ,in general1 these antitoxins are precipitable with the globulins1 and possess quite considerable powers of resistance towards physical and chemical agents4 ,thus they are destroyed only at a temperature above #fj-fe ,c4 ,kept in the dry state1 in the residue of evaporated serum1 and away from the light and all oxidizing action1 it is possible to preserve their activity for a very long time4 ,they are essentially humoral substances2 they are found in the blood of vaccinated animals1 from which may be obtained antitoxic serums with a specific but transient immunity2 and they are also found in the plasmas of the lymph and exudates1 in aqueous tumors1 and in the milk4 ,they are seldom found in the cells4 ,mode of ,action4--,frequent attention has been paid to the mode of action of the antitoxins upon the toxins1 a phenomenon of great importance in relation to the phenomenon of immunity acquired against the toxins4 ,at the beginning of our knowledge on this subject1 the idea of a destruction of the toxin immediately suggested itself1 and was advanced by von ,behring4#dc ,according to this scientist the antibody inhibits the morbigenic action of the toxin by neutralizing the toxin1 combining with the latter to form a compound of a chemical nature which is devoid of toxicity and without action on the organism4 ,according to this theory1 the influence of the antitoxin on the toxin is direct1 and does not require the intervention of the living cellular protoplasm4 ,such was also the belief of ,prof4 ,ehrlich4#dd #dc ,,von ,,behring and ,,kitasato3 ,deutsch4 med4 ,wochenschr41 #ahij1 p4 #aaac4 #dd ,,ehrlich3 ,klin4 ,jahrb4 #ahig1 ,,vi1 p4 #bib4 ,buchner1 a little later1 believed that the antitoxin1 instead of acting directly on the toxin1 exercised a direct influence on the living elements of the organism1 preserving them from intoxication4#de #de ,,buchner3 ,mnchener med4 ,wochenschr41 #ahic1 p4 #dhj4 ,such was also the opinion of ,roux#df2 and ,calmette demonstrated that a mixture of venom and of a non-toxic antivenom recovered its toxicity on being heated to #fh ,c1 whereby the antivenom was destroyed 7,calmette3 ,le ,venin des ,serpents1 ,paris1 #ahig1 p4 #eh72 and ,wassermann arrived at the same result4#dg #df ,,roux3 ,annales de l',institut ,pasteur1 #ahid1 ,,viii1 p4 #gbd4 #dg ,,wassermann3 ,zeitschr4 fr ,hygiene4 ,the array of proofs offered by these scientists1 which we cannot here enlarge upon without uselessly extending our subject1 would tend to make one believe1 at first glance1 that the antitoxin does not act directly on the toxin1 but at the present time ,buchner's theory appears untenable4 ,numerous researches have proved conclusively that the toxin and the antitoxin have a specific affinity for each other1 by virtue of which these principles combine to form a substance free from all toxicity1 but unstable1 and which may be decomposed by heat or certain other factors4#dh #dh ,j4 ,,danzsy3 ,annales de l',institut ,pasteur1 ,,xvi1 p4 #cca4 ,some recent experiments by ,j4 ,martin and ,cherry 7,proceedings of the ,royal ,society1 #ahih1 ,,lxiii1 p4 #dbc7 have clearly brought out this fact4 ,these authors made mixtures of serpent venom with its antivenom1 which they filtered through a layer of gelatin1 under the supposition that1 if the venom and its antivenom were not chemically combined1 the former alone would be able to pass through into the filtrate1 because its molecules are so much smaller4 ,martin and ,cherry allowed the venom and its antivenom to remain in contact for varying periods before filtering4 ,as the result of a series of experiments carried out with this idea1 they have demonstrated that the filtrate obtained after allowing a few minutes' contact between the two substances1 was decidedly toxic1 while that obtained after a contact of half an hour was absolutely non-toxic4 ,from this the authors conclude that the antitoxin enters into chemical union with the venom1 but that the combination does not take place immediately1 and requires a certain length of time for its accomplishment4 ,ehrlich and ,knorr have demonstrated that the neutralization is less rapid in dilute solutions than in concentrated ones4 ,prof4 ,svante ,arrhenius has completed our knowledge regarding the mode of combination between the toxins and the antitoxins1 by demonstrating the occurrence of limited reactions analogous to the etherification of an alcohol by an acid1 and in such a manner that there always exists1 in a mixture of these two substances1 a certain quantity of free toxin and antitoxin4 ,this is an important modification of the general ideas held in this respect4#di #di ,,svante ,,arrhenius3 ,la ,physico-chimie des ,toxines et des ,antitoxines4 ,confrences de la ,socit chimique de ,paris1 ,may #bj1 #aijd4 ,see also ,,madsen ,,and ,,arrhenius3 ,testkrift red indivulsen of ,stotens ,serum ,institut4 ,copenhagen1 #aijb4 ,it appears necessary to bring here more clearly in evidence the fact that the antitoxin inhibits the noxious action of the toxin1 even outside the living organism1 by uniting with it to form a compound in identically the same manner as when a strong base and a strong acid are brought together4 ,as we have seen1 all the conditions of environment that favor or retard the formation of salts1 in a like sense influence the neutralization of the toxin by its antitoxin4 ,formation of ,antitoxins4--,ehrlich's theory of side chains1 to which reference has already been made1 furnishes us with an explanation of the formation of the antitoxins in tumors4 ,let us suppose that1 in the organism1 a cell had come into contact only with certain toxic molecules incapable of compromising its life1 and that the only result was the immobilization of the receptors which are united with the haptophore groups of the opposing toxins4 ,it is known that1 by virtue of a property inherent in all living organisms1 during the phenomena of reparation1 there is generally an overproduction of the neoformed parts4 ,in the case we here speak of1 as the receptors fill an important function in the nutrition of the opposing cellular elements1 once they become united with the toxic haptophores1 they become incapable of filling their normal function of nutrition4 ,under these conditions the cells develop so large a quantity of receptors that1 filling the cells1 and not finding any more room1 they spread into the blood and other liquids of the organism4 ,under these conditions1 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 molecule1 and the two groups immediately unite1 before the haptophore group of the toxin has been able to attack and intoxicate a cellular element4 ,we thus see that the receptors which1 when in a free state in tumors1 play the rle of antitoxics or antitoxins1 become1 within the cellular elements themselves1 the vehicle of intoxications4 ,figuratively speaking1 so long as these fixators are attached to the molecule of the living protoplasm they attract the toxin4 ,according to this ingenious conception1 the formation of antitoxins is hence absolutely independent of the action of the toxophore elements on the cellular elements1 and it suffices that these possess receptors or side chains capable of uniting with the haptophore groups of the toxin4 ,this explains why it has been possible to produce antitoxins from toxins which have lost some of their toxic properties1 but which have preserved their property of uniting with antitoxic substances4 ,ehrlich gives the name toxoids to those modified toxins that have lost their toxophore groups1 while the haptophore group1 the producer of the immunizing substance1 is still preserved intact4 ,according to ,metchnikoff's theory1 which is very similar1 it seems quite possible that the phagocytes1 thanks to the facility with which they absorb poisons1 occupy an important place as producers of antitoxins4 ,it has not been possible so far to verify this theory in our at present imperfect knowledge regarding this subject4 ,the domain of immunity has1 however1 made brilliant conquests during these last few years1 so that we should not despair of arriving at a definite solution before long4 ,in the vaccinated animal the antitoxin is reproduced1 and it is possible to obtain several times1 from the vaccinated animals1 successive portions of antitoxic serum4#ej ,the protective power of these antitoxins is absolutely marvelous4 ,an animal accustomed gradually to the tetanic virus yields a serum containing an antitoxin a thousand times more active than the virus4 #ej ,,ch4 ,,salmonsen et ,,th4 ,,madsen3 ,rproduction de la substance antitoxique4 ,ann4 ,inst4 ,pasteur1 ,,xii1 p4 #gfb4 ,,roux et ,,vaillard3 ,ibid41 #ahic1 p4 #hc4 ,according to ,vaillard1 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 fatal4 ,in the animal1 the antitoxins are eliminated mostly by the fluids of the body1 and particularly by the urine4 ,ehrlich has demonstrated that they also pass into the milk1 and this fact is confirmed by a large number of observers4 ,it explains the immunity acquired by nurslings1 and which is transmitted by the milk4 ,serotherapy4--,the search for antitoxins and their rle in the etiology of infectious diseases are fundamental points in actual therapy4 ,it has been demonstrated that the serums of certain vaccinated animals enjoy very extended antitoxic therapeutic properties2 for instance1 the serum of vaccinated rabbits is an antivenom towards erysipelas2 and the sterilized cultures of the pneumococcus or of the ,bacillus pyocyaneus prevents infection of carbuncle 7anthrax74 ,the antivenomous serum of the ass immunized by injections of increasing doses of the venom of the terrible naja is a perfect prophylactic and curative1 not only as regards the venom of this serpent1 but also against that of the crotalus1 trigonocephalus1 and viper4 ,we shall take up the study of serotherapeutics in another volume of this collection4 ,,part ,,ii4 ,,the ,,toxins ,,proper4 ,,chapter ,,iii4 ,i4 ,,vegetable ,,and ,,animal ,,toxins4 ,the vegetable toxins possess the characteristic property of being innocuous1 and of being almost completely devoid of poisonousness1 when they are absorbed by the intestines2 we can see1 from this1 how greatly they differ from the poisons proper4#ea #ea ,it is understood that the active principles of mushrooms are not comprised under this definition1 but they will be studied under the next heading4 ,the vegetable toxins known are quite numerous2 nevertheless our knowledge regarding them is very incomplete4 ,our review of them will be chiefly descriptive4 ,many of the leguminous plants are poisonous1 either because of emanations exhaled by them1 or by reason of their alkaloids1 or because of some toxins contained in them4 ,we shall commence with these4 ,abrin4--,this toxin1 which was studied in particular by ,warden and ,waddell1#eb then by ,kobert#ec and de ,hellin1#ed is found in the fruit of the ,leguminos1 ,abrus precatorius 7wild licorice1 or jequirity74 ,its name was given it by ,warden and ,waddell1 who discovered both its toxic nature and the vegetable toxin2 the toxin is found only in the seeds4 ,to extract it1 the seeds are macerated in water1 and the solution filtered and precipitated with alcohol2 the precipitate which forms is collected and dissolved in distilled water1 from which it is again precipitated by adding powdered ammonium sulphate4 ,the precipitate is then collected and submitted to dialysis in order to eliminate the ammonium sulphate4 ,the abrin so obtained forms an albuminoid substance#ee stable at #ajj ,c41 and possessing rotatory power2 it liquefies starch paste1 and is extremely toxic4 ,one milligramme suffices to kill a rabbit within several hours4 ,it must be observed1 however1 that1 as is the case with all the toxins1 abrin acts or kills only after a period of incubation which generally exceeds twenty-four hours4 #eb ,,warden and ,,waddell3 ,non-bacillar ,nature of ,abrus ,poison4 ,calcutta1 #ahhd4 #ec ,,kobert3 ,arbeit4 aus dem ,pharmak4 ,institut4 ,dorpat1 #ahic4 #ed ,,hellin3 ,inaug4 ,dissert4 ,dorpat1 #ahia4 #ee ,,ehrlich3 ,experiment4 ,untersuchungen ber ,immunitt4 ,deutsch4 ,med4 ,woch41 #ahia4 ,it is possible to vaccinate an organism so as to withstand a lethal dose of abrin1 but it requires quite a long time2 it is effected by injecting into a suitable animal very small doses of the substance1 and increasing the quantity gradually4 ,rabbits which have been rendered highly immune towards venoms are capable of resisting without inconvenience doses of abrin which are ordinarily fatal2 and the blood serum afforded by them contains a specific antibody for the substance4 ,ricin4--,this vegetable toxalbumin has been studied particularly by ,stillmark1#ef by ,dixon1#eg and ,thuson4#eh ,it is found in the seeds of the castor plant2 three or four of the seeds suffice to cause a gastroenteritis accompanied by serious symptoms and even by death4 #ef ,,stillmark3 ,arbeit4 aus dem pharmacol4 ,inst4 ,dorpat1 #ahhi4 #eg ,,dixon3 ,austr4 ,med4 ,gazette1 #ahhg4 #eh ,,thuson3 ,journ4 f4 prakt4 ,chem41 ,,xciv1 p4 #ddd4 ,it was first isolated by ,p4 ,ehrlich1 by treating the seeds with lukewarm water1 and precipitating the aqueous solution with alcohol4 ,the toxalbumin is soluble in water1 but on boiling the solution1 the substance loses in great measure its activity4 ,ricin possesses considerable activity4 #j4jjjjc ,gm4 suffice to kill a rabbit when injected hypodermically2 #j4b ,gm4 are fatal to man4 ,the action is not immediate1 but follows a period of incubation4 ,ehrlich has shown that1 exercising precaution1 it is possible to create1 as with abrin1 a condition of tolerance or habituation1 and in consequence to cause the formation of a specific antibody4 ,robin4--,this toxic albuminoid was obtained from the bark of an ,acacia 7,robinia ,pseudacacia7 by ,power and ,cambier1#ei by exhausting with water at a temperature of about #cj ,c41 and precipitating the infusion with alcohol4 ,the substance is analogous to ricin1 and like this1 possesses powerful toxic properties4 #ei ,,power and ,,cambier3 ,pharm4 ,journ4 and ,transact41 #ahij4 ,toxicity of the ,vegetable ,diastases4--,the diastases1 which have been treated of in a volume of the ,encyclopdie ,laut1#fj and to which we would refer the reader who is desirous of more complete details1 develop powerfully energetic toxic properties when injected into the organism4 ,thus amylase causes1 when injected subcutaneously1 a considerable rise of temperature1 but without any other toxic symptoms4 ,invertin or sucrase was studied by ,roussy under the name pyretogenin1 but it appears probable that this diastase was not the only substance present in the product1 but that there were present reducing diastases1 as we have already shown in the first volume of this collection1 devoted to the phenomena of reduction within the living organism4 #fj ,,pozzi-,,escot3 ,les ,diastases et leurs ,applications1 ,masson1 #aijj4 ,the pyretogenin of ,roussy gives rise to an attack of violent fever1 but it loses all activity when heated to #hj-ajj ,c4 ,through his researches1 ,roussy clearly demonstrated1#fa for the first time1 that the fever may cause the formation within the blood of a substance clearly belonging to the class of soluble ferments or zymases4 ,now1 it is well known that within the animal economy there exist many ferments of this character2 and experiment has shown that they can1 at a given period and under various influences1 leave the cells in which they are normally localized1 pass into the blood plasma1 and reach the nervous centers1 where they cause serious effects4 ,we have already dwelt upon the mechanism of autointoxication of the organism4 ,the toxic action of certain digestive diastases has been shown by ,hildebrandt1 who has demonstrated that #j4a ,gm4 of pepsin is capable of killing a rabbit in two or three days4 #fa ,,roussy3 ,aperu historique sur les ferments et fermentations4 ,paris1 #aija4 ,j4 ,rousset1 publ4 ,,ii4 ,,toxins ,,from ,,mushrooms4 ,mushrooms are alimentary substances of the highest order1 causing a general stimulation of the entire organism4 ,the substances met with belong1 according to their composition1 to different classes--celluloses1 sugars1 and amylaceous substances1 alcohols1 acids1 fats1 astringents1 essential oils1 resins1 alkaloids1 and albuminoids4 ,the study of the last only1 the albuminoids and diastases1 interests us here4 ,the most important of these albuminoid substances1 phallin1 was discovered in #ahij by ,kobert4 ,pouchet also has isolated a whole series of other toxic albuminoids1 particularly from ,amanita muscaria 7,fly ,agaric74 ,there are alimentary as well as toxic species in every possible variety among mushrooms1 some species consisting chiefly of the edible kind1 others consisting of the poisonous variety4 ,in consequence of the toxicity of mushrooms1 great attention must be given to the treatment to which they are subjected when it is desired to utilize them for alimentary purposes4 ,thus the toxic principles of several varieties can be removed1 and the mushrooms rendered edible by very simple means4 ,pouchet has made a very ingenious comparison between the ethereal1 alcoholic1 saline1 and aqueous extracts of mushrooms1 and bacterial cultures4 ,the analogy is striking as to the presence of toxin1 toxalbumose1 and albumoses more or less toxic2 it is moreover not exaggerated1 since1 according to the classification generally admitted1 mushrooms are nothing more than the very advanced representatives of a group the more simple members of which constitute the bacteria4 ,the same author has shown that phallin obtained from the juice of the ,fly ,agaric will kill a guinea-pig weighing #fjj grammes in one hour4 ,as we have already stated1 it is the phalline to which the ordinary disorders which mushrooms cause are due4 ,according to ,kobert1 a #a3bej #jjj solution of this substance causes an intense hemolysis1 with all its disastrous consequences4 ,according to ,pouchet1 the flesh of mushrooms must be compared with meat that has been kept for some time to become tender1 and it is well known that though this tendering process renders the meat more digestible1 it may also allow the meat to acquire noxious properties1 due to the presence of toxins4 ,phallin is the type of those toxic albuminoids of unknown composition which exist in mushrooms1 and which are comprised under the name sapotoxins4 ,the intravenous injection of phallin into an animal1 in the proportion of #a part to #a #jjj #jjj parts of body weight1 causes sudden death within one minute2 in the proportion of #a3e #jjj #jjj1 death occurs in about three minutes2 in the proportion of #a3ej #jjj #jjj1 death also occurs1 but is greatly retarded4 ,an injection of #j4jjje ,gm4 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 red1 as well as the veins4 ,instead of being easily altered under the influence of an elevated temperature1 as are many of the albuminoid substances1 whereby their toxic power is lost1 phallin may be boiled for half an hour with water without undergoing any noticeable alteration4 ,pellegrini has observed that the dried juice of ,amanita ,phalloides 7,death-cup7 preserves its properties for more than a year4 ,according to a recent paper by ,gillot1 the symptoms of poisoning by mushrooms must be ascribed to albuminoids 7phallin and albumose71 alkaloids 7muscarine1 choline1 or betaine71 or to resinoids 7cambogic and agaricic acids74 ,the alkaloids found in mushrooms are3 ,muscaridine 7an oxyneurine71 which possesses considerable toxicity1 and of which #j4jjjje ,gm4 suffices to kill a frog2 neurine 7trimethylethylammonium hydroxide72 choline 7trimethyloxyethylammonium hydroxide72 mycetomuscarine2 anhydromuscarine 7an oxyneurine72 and a whole series of various betaines4 ,symptomology4--,it is quite natural to divide this symptomology into three different periods2 that of incubation1 that of manifestation of symptoms1 and that of termination4 ,the duration of the first period1 that of incubation1 is exceedingly variable2 it very rarely lasts more than forty-eight hours1 and becomes general only a few hours after absorption4 ,certain conditions influence the duration2 firstly the quantity of mushrooms ingested1 then the manner in which they were prepared2 and1 to some extent1 the nature of the organism1 whether child or adult1 healthy or in poor health4 ,when it is a question of the more particularly alkaloid-containing mushrooms1 especially when the poisoning is due to muscarine1 the toxic symptoms generally develop rapidly1 the first symptoms appearing about one hour after the ingestion of the mushrooms4 ,on the other hand1 if the poisoning is due to one of the albuminoid group1 and particularly in the case of phallin1 the period of incubation is longer1 and may last ten1 twenty1 thirty1 or even forty-eight hours and more4 ,the symptoms begin with dizziness and an indefinable sensation of being ill4 ,the second period is characterized chiefly by digestive and by nervous derangements4 ,the digestive derangements are evidenced by very violent and painful vomiting1 and diarrheas of choleraic or dysenteric character4 ,the nervous derangements vary according to whether they are developed by an alkaloid1 which causes delirium with hallucination1 or by albuminoids1 which cause depression1 ataxo-adynamia1 and stupor1 these being particularly characteristic of the action of the toxic albuminoids4 ,as for the period of termination1 it results either in death or a cure4 ,if the poisoning is due to phallin1 death appears to be an almost inevitable consequence1 as it occurs in #hj per cent4 or more of the cases4 ,the poisoning by the alkaloids is less dangerous1 and the cure1 when it does occur1 is very rapid1 almost immediate1 in fact1 while in the case of the toxic albuminoids the cure is very slow1 and attended by relapses4 ,one characteristic of these toxalbumins is that they are apt to develop specific antitoxalbumins4 ,this fact has been verified not only in the case of abrin1 ricin1 robin1 and their analogues1 but also in that of the vegetable and animal diastases possessing toxic properties even in the slightest degree only4 ,these antibodies generally exhibit their action in vitro4 ,thus antiricin exerts its antiagglutinative action on the erythrocytes in vitro in a saline medium in which the erythrocytes cannot live4 ,here1 again1 as in the case of the antitoxins1 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 toxicity4 ,the first antidiastase obtained by immunization methods1 and according to the mechanism we have already seen1 was antiemulsin1 obtained by ,hildebrandt4#fb ,this antiemulsin counteracts1 both in vivo and in vitro1 the specific action of emulsin4 ,these studies have been followed by a large number of scientists1 particularly by ,camus and ,gley1#fc ,carnot1 ,mesnil1#fd and ,charron and ,levaditi1#fe in the case of trypsin2 and ,sachs#ff in the case of animal pepsin4 ,gessard#fg obtained a very active antityrosinase1 and ,mohl an antiurease4 #fb ,,hildebrandt3 ,weiteres ber hydrolyt4 ,fermente1 etc4 ,virch4 ,arch41 ,,cxxxi1 #ahie1 ,p4 #e4 #fc ,,camus and ,,gley3 ,compt4 rend4 de la ,soc4 de ,biolog41 #ahig4 #fd ,,mesnil3 ,sur la digestion des actinies4 ,annales de l',institut ,pasteur1 #aija4 #fe ,,charrin and ,,levaditi3 ,compt4 rend4 de l',acadmie dest ,sciences1 #aijj4 #ff ,,sachs3 ,ueber ,antiseptika4 ,zeitschr4 f4 ,biolog41 #aija1 ,,xxvi4 #fg ,,gessard3 ,annales de l',institut ,pasteur1 #aija1 p4 #fji2 ,comp4 rend4 de la ,socit de ,biologie1 ,may1 #aijb4 ,the most important researches regarding this subject have been published by ,morgenroth1 ,briot1#fh and ,korschum#fi on antilab 7or antirennet74 ,the researches of these authors have fully demonstrated that there is considerable difference between the various rennets1 which had heretofore been confounded under one head2 thus there is no difference whatever between animal rennet and the rennet extracted by ,rosetti#gj from ,cynara cardunculus 7cardoon7 so far as their coagulant action on milk is concerned1 yet each yields an antibody which is strictly specific to itself4 ,from a scientific point of view we see1 therefore1 that the preparation of antidiastases permits us to differentiate certain diastases that could otherwise not be differentiated4 #fh ,,briot3 ,thse de ,doctorat s-,sciences1 ,paris1 #aijj4 #fi ,,korschum3 ,zeitschr4 f4 physiolog4 ,chemie1 #aijb1 ,,xxxi4 #gj ,,rosetti3 ,l',orosi1 giorn4 di chemica1 farmacia et scienza affini1 #ahih4 ,,iii4 ,,animal ,,toxins4 ,as we have shown at the beginning of this chapter1 certain diastases1 and particularly those that are concerned with the digestive processes1 pepsin1 trypsin1 etc41 and which are produced in abundance by the entire living organism1 possess quite clearly defined toxic properties1 and sometimes to even a considerable extent4#ga #ga ,,gustave ,,saux3 ,de la toxicit des produits de la digestion peptique4 ,thse de doctorat1 ,bordeaux1 #aijb4 ,hemialbumose1 from which peptones are formed1 is itself a dangerous toxin4 ,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 itself1 but to the more advanced products of digestion1 alkaloidal products unquestionably closely allied to the ptomaines4 ,nevertheless1 the true peptones behave just like true poisons1 when they are introduced hypodermically into the blood4#gb #gb ,,schmidt3 ,mhlheim1 ,arch4 de physiol41 #ahhj4 ,brieger has made us acquainted with a non-proteid substance1 under the name of peptotoxin1 which is met with at the beginning of the putrefaction of albuminoids4 ,this toxin1 which is not a protein1 is nothing else but a ptomaine4 ,it is not altered by heat1 and possesses a very high toxicity4 ,brieger claims that it is a hydroxylized derivative of an aromatic amide4#gc #gc ,,brieger3 ,berichte d4 ,d4 chem4 ,gesellsch41 ,,xix1 p4 #cabj2 and ,verhandl4 d4 ,congress f4 innere ,med41 ,,ii1 p4 #bgg4 ,besides these facts1 experiment has shown that the leucocytes1 or white corpuscles1 the defensive rle of which we have noted in phagocytosis1 owe their properties to the ferments which they secrete1 and particularly to some of the digestive ferments4 ,these white corpuscles are very rich in ferments of all kinds4 ,rossbach found in them amylase2 ,achalme found lipase1 casease1 and trypsin2 and the study of immunity has brought to light a series of other ferments1 the alexins or cytases 7microcytase and macrocytase71 which have an exceedingly important rle to play4 ,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 body1 when they give rise to serious disturbances in certain cases1 or confer immunity in others4 ,it is thus that1 according to ,gautier1 the rise of temperature which characterizes fever is a consequence of the abnormal transudation of these normal ferments into the blood1 and their transmission by the general circulation to the nervous centers4 ,however1 it is not only in the leucocytes that we meet with these toxic digestive ferments2 it appears quite probable1 and has even been partially demonstrated1 that they occur in a large number of other cellular elements4 ,it is not necessary here to dwell upon the formation of the antibodies of this group of active substances4 ,the animal toxins are animal diastases1 and we have seen in the preceding paragraph that these substances yield specific antibodies with great facility4 ,for the rest1 we will dwell more fully on these antibodies of the animal toxins in another volume of this collection1 specially devoted to the study of these substances1 and entitled ,les ,serums ,immunisants1 to which we refer the reader who is desirous of obtaining more complete details than he can obtain in the present volume4 ,alimentary ,intoxications4--,what we have already stated permits us to understand the phenomena of indigestion and botulism4 ,the toxic substances form within the digestive tract when the nervous conditions modify the composition of the gastric juice1 and arrest the flow of hydrochloric acid1 the presence of which normally checks the development of the microbial flora1 so rich within the stomach4 ,the result is the production1 within the organism1 of all kinds of dangerous toxins4 ,the same thing happens when the liver does not functionate normally1 and this1 affords us a knowledge of the mechanism by which foods that are most wholesome may become toxic by reason of poor digestion or poor assimilation4 ,the absorption of spoiled viands may1 a fortiori1 produce serious results4 ,the alteration may be due not only to a bacterial infection1 as in tainted meat1 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 food1 even after cooking1 because1 although there are toxins which are destroyed by a sufficient heat1 there are ptomaines and certain toxins that resist destruction under these conditions4#gd #gd ,,pollin and ,,labit3 ,examens des aliments suspects1 ,masson1 publisher4 ,the use of preserved but spoiled beef1 preserved ham or birds1 sausages frequently1 and pieces of pork tainted by sausage poison1 gives rise to a succession of toxic symptoms the principal ones of which are dryness1 constriction of the pharynx1 bilious vomiting1 diarrhea1 dyspnea with pulmonary edema1 etc4 ,fish and eggs are foods quite frequently capable of developing serious results2 the same is the case with molluscs1 mussels1 oysters1 lobsters1 and snails4 ,lastly1 moldy bread1 spoiled cheese1 putrid water1 and spoiled vegetables themselves1 are proper agents for determining attacks of botulic poisoning4 ,we have seen1 at the beginning of this volume1 that putrid meats contain ptomaines1 which are among the most toxic alkaloidal bases4 ,we have shown that ,brieger has isolated from them neuridine1 putrescine1 muscarine1 and guanidine2 that ,nencki has isolated hydrocollidine2 and that ,gautier and ,etard have obtained from them parvoline--only to mention a few of them4 ,lastly1 there may develop within the gastrointestinal tract dangerous putrefactions1 the products of which may enter the veins and arteries from the ileum 7a portion of the small intestine7 and be distributed throughout the organism4 ,although such poisonings occur1 they do not immediately follow the ingestion of the spoiled or toxic foods1 but they are always preceded by a period of incubation varying from several hours to several days4 ,these alimentary poisonings are recognized by a great physical depression1 accompanied by vomiting and paralysis of the lower extremities1 sweats1 and diarrheas4 ,in some cases there occur cutaneous eruptions2 and when death happens1 this occurs only several days later1 and generally without being preceded by any great pain4 ,urinary ,toxins4--,as we have already remarked several times1 it is by the renal way that the organism voids its principal waste products4 ,we have seen also that it is by the kidneys that the toxins are eliminated in all pathological conditions4 ,as a general rule1 the urines are always more or less toxic4 ,this toxicity of the urines must be attributed in the first place to the crystallizable organic principles 7ptomaines and leucomaines#ge7 which they contain2 secondly1 to the non-crystallizable#gf extractive matters not so well known2 and lastly1 to the saline substances1 among which the potassium salts are the most active4 ,we find these mineral salts particularly abundant under normal conditions in the urines of the herbivora4 ,according to ,bouchard1 #j4ah ,gm4 of potassium chloride are sufficient to prove fatal to #ajjj ,gm4 of living organism2 a man excretes on the average #b4e ,gm4 of this salt1 and a rabbit excretes about double this quantity1 weight for weight4 #ge ,,adduco3 ,arch4 ,ital4 de biolog41 #ahia4 #gf ,,pouchet3 ,thse de ,doctorat en ,mdecine1 ,paris1 #ahgh4 ,a very large number of hypotheses have been advanced regarding the toxicity of the urines4 ,wilson considers the urea as being responsible for it2 ,stadthagen#gg believes it to be due to the potassium salts1 etc4 ,bouchard#gh was the first to recognize that the toxicity of the urines is due to a number of causes4 ,we will not dwell further on these active principles which1 in the last analysis1 are no other than those that form in the various portions of the organism1 and which are eliminated by the urine4 #gg ,,stadthagen3 ,zeitschr4 f4 ,klin4 ,med41 ,,xv4 #gh ,,bouchard3 ,leons sur les ,autointoxications4 ,it is self-evident1 and it has already been shown1 that the toxicity of the urines varies greatly according to the malady1 in consequence of the elimination of toxins by the urines4 ,according to ,bouchard1 in infectious maladies the urines are twelve times more highly charged with toxins than is blood serum4 ,moreover1 the toxicity of the urines is considerably augmented the moment there is the least febrile condition1 no matter what the cause is4#gi #gi ,regarding this point see the excellent work by ,a4 ,,charrin3 ,poisons de l',organism4 ,masson1 publ4 ,even in the normal condition1 the urinary toxicity varies greatly2 and this is easily conceived since the physiological phenomena that control this secretion undergo incessant rise and fall4 ,thus1 for example1 the urines eliminated during sleep are less active than those produced during waking1 because during sleep the elimination of cellular poisons is at a minimum4 ,exercise1 walking1 physical and intellectual labor1 exert their portion of influence on these oscillations of toxicity2 and this variation of toxicity is due not to any one variation in the mineral extractive matters1 but rather more or less to the organic toxic products4 ,we will not dwell further on this subject1 but will simply refer to the work by ,charrin1 already mentioned1 for all supplementary details4 ,autointoxications4#hj--,the cells of the organism having1 as a whole1 a life very much like that of the microbes1 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 albuminoids4 ,experiment has demonstrated that this is so1 and ,armand ,gautier has irrefutably proven the existence of these principles4#ha ,bouchard was the first to demonstrate the toxic nature of muscle extract1#hb and ,roger#hc established the fact that the toxicity of this extract is due to ferment-toxins2 it has since been recognized that after death these toxins accumulate in the muscles4 #hj ,,ch4 ,,bouchard3 ,des ,autointoxications4 ,paris1 #ahhg4 #ha ,bull4 ,acad1 de ,mdecine 7#b71 ,x1 p4 #idg1 and ,,xx1 p4 #aae4 #hb ,,bouchard3 ,leons sur les ,autointoxications1 ,paris1 #ahhg4 #hc ,,roger3 ,toxicit des ,extraits des ,tissus ,normaux4 ,soc4 de ,biolog41 #ahia1 p4 #gbh4 ,the extract of kidney made rapidly by cold process by triturating the washed kidney with glycerin1 and precipitating the glycerinic solution with alcohol1 contains toxic ferments to which the name hystozymes has been given4#hd ,these ferments split up hippuric acid into benzoic acid and glycocoll4 ,lpine has likewise discovered in the kidney a very toxic pyrogenic substance4#he ,roger has given us evidence of the toxic properties of the liver1 washed and pulped1 and then sterilized by filtration through a porous diaphragm4 ,this scientist has shown that the toxic properties are due to albuminoids1 which lose their activity when heated to #ajj;,c4#hf #hd ,it is well to recall here that the kidneys contain both reducing and oxidizing ferments1 as has been demonstrated by de ,rey-,pailhade1 and later by ,abelous and ,grard4 #he ,l,,pine3 ,compt4 rend4 de l',acad4 des ,sciences1 ,may #ac1 #ahhi2 ,soc4 de ,biol41 #ahia1 p4 #gbd4 #hf ,,roger3 ,compt4 rend4 ,soc4 ,biol41 #ahia1 p4 #gbg4 ,it must be remarked that the organs we have studied are essentially reducers1 and that the more powerful reducers yield the most toxic extracts4 ,we find here a confirmation of ,armand ,gautier's views regarding the anaerobic origin of the toxic substances formed within the organism4#hg #hg ,,pozzi-,,escot3 ,compt4 rend4 de l',acad4 de ,mdecine 7#c71 ,,xlvii1 p4 #djj4 ,see also ,,pozzi-,,escot3 ,etat actuel de nos ,connaissances sur les ,oxydases et les ,rductases4 ,dunod1 publ41 ,paris4 #aijb4 ,blood serum precipitated by alcohol affords products which possess very marked toxic power4 ,it would appear that the toxic products we speak of here are thermogenic diastatic substances derived from the white blood corpuscles4 ,in certain diseases the blood serum may acquire a high degree of toxicity4 ,we will recur again presently to this property as a normal characteristic of the blood of various animal species1 and will study it in greater detail in a future volume of this collection1 devoted to the immunizing active principles4 ,glandular ,secretions4--,on studying the venoms we will see that a certain number of these products are the result of glandular secretion4 ,this is a general property of the glands2 and it was ,brown-,sequard who first drew attention to the rle played by these glands1 and to the importance of the products that they throw into the blood4#hh #hh ,compt4 rend4 de l',acad4 des ,sciences1 ,,cxiv1 pp4 #abcg1 #acah1 #acii1 and #aecd2 ,,cxv1 p4 #cge2 and ,,cxvi1 p4 #hef4 ,p4 ,noel showed later that the testicular juice possesses a high degree of activity1 which he attributed to an oxidizing ferment1 and which we have already mentioned1 spermine4 ,the greater number of the other glands contain proteid matters and various peptones1 more or less toxic1 with amides and alkaloids4 ,particular mention must be made of the thyroid gland1 the secretions of which exercise a powerful action on the nervous centers and on nutrition4#hi ,it appears reasonable to attribute to the secretions of this gland a very powerful antitoxic action1 and the first proof of this fact is that the organisms deprived of this gland become the seat of serious derangements2 the urines of such organisms become particularly toxic1 while1 on the other hand1 the hypodermic injections of the aqueous extract of the gland1 when the derangements spoken of exist1 cause the immediate disappearance of the derangements caused by the excision of the gland4#ij #hi ,,laulani3 ,compt4 rend4 ,soc4 de ,biol41 #ahid1 p4 #ahg4 #ij ,,gley3 ,compt4 rend4 ,soc4 de ,biol41 #ahia1 p4 #bej4 ,attempts have been made to isolate the active principle of the glands4 ,notkine isolated a tyroproteid1#ia which is not sensibly toxic to animals who still retain the gland1 but which becomes toxic when the gland is excised4 ,it seems probable1 however1 that this product is not the principal agent of the thyroid gland4 #ia ,semaine ,mdicale1 ,apr4 #c1 #ahie1 p4 #ach4 ,from the researches of ,schaeffer1 ,roos1 and ,sigmund ,fraenkel#ib it results that the active principle of the gland is not a toxin1 but a purely chemical substance1 a true leucomaine1 which has received the name thyroantitoxin4 #ib ,wiener ,med4 ,bltter1 ,no4 #dh2 and ,gesellsch4 d4 ,aerzte in ,wien1 ,nov4 #bb1 #ahie4 ,on the other hand1 ,baumann quite recently extracted from the thyroid gland an iodized substance1 which he named thyroiodine4#ic #ic ,zeitschr4 f4 ,physiol4 ,chem41 ,,xxi1 pp4 #cai and #dha2 and ,,xxii1 p4 #a4 ,,armand ,,gautier3 ,chimie ,biologique1 #b;d edit41 pp4 #ccj-ccb4 ,masson1 publ4 ,the suprarenal capsules also possess properties that have often attracted the attention of physiologists during the last few years4 ,they are considered as being1 just like the thyroid gland1 producers of antitoxins2 they destroy1 or seem to destroy1 toxins that are artificially introduced into the circulation4 ,albanse#id maintains that the function of the suprarenal capsules is to neutralize neurine1 the toxic product of the disassimilation of the nervous system2 this view1 however1 is opposed by ,boinet#ie and ,langlois4#if ,on the contrary1 it has been definitely proven that the suprarenal glands exert a specific action on the poisons of muscular origin4 ,abelous and ,langlois#ig have in fact demonstrated that the alcoholic extract of the muscle of a decapsulated animal has the same properties as the extract of tetanized muscle2 the decapsulated animal gives ergographic tracings analogous to those afforded by tetanized animals4 ,the removal of the suprarenal capsule from an animal brings results1 hence1 analogous to those of fatigue--that is to say1 that the toxic substances which accumulate as a result of the decapsulation resemble those that result from muscular exertion4 ,the suprarenal capsules exert their action furthermore on other toxic products as well1 as ,guieysse#ih has shown1 and particularly on the exogenous poisons4 ,in conclusion1 it may be said that the matter concerns a most important rle1 and we cannot do better in this respect than to refer the reader to the memoir presented by ,sergent and ,bernard to the ,acadmie de ,mdecine in #aijb and entitled l',insuffisance ,surrnale4#ii #id ,,alban,,se3 ,recherches sur les fonctions des capsules surrnales4 ,arch4 ,italiennes ,biol41 #ahib4 #ie ,,boinet3 ,compt4 rend4 ,soc4 de ,biol41 ,mch4 #ahif4 #if ,see ,compt4 rend4 de ,biol4 et ,arch4 ,physiologie1 #ahia-ahig4 #ig ,,langlois3 ,thse de doctorat en ,md41 ,paris1 #ahig4 #ih ,,guieysse3 ,les capsules surrnales du cobaye1 ,thse1 ,paris1 #aija4 #ii ,encyclopdie ,laut1 ,,cccxiv1 ,masson1 publ41 ,paris1 #aijd4 ,,chapter ,,iv4 ,,the ,,microbial ,,toxins4 ,there is but one way of characterizing the toxic poisons secreted by microbes1 and that is to apply to them the name of the microbes generating them2 thus the soluble and toxic poison of the tetanus bacilli has received the name tetanus toxin4 ,in toxic microbial cultures it is necessary to distinguish the toxins proper from the toxic alkaloids 7ptomaines7 which generally accompany them2 this is easily accomplished by evaporating the solution in a vacuum at about #cj;,c41 and then treating with alcohol and ether1 in which the alkaloids are soluble1 while the true toxins are insoluble4 ,by fractional precipitation with alcohol it is easy to isolate the peptones and true toxins4 ,the microbial toxins possess two essential properties2 one the pyogenic property1 thanks to which the toxins first attract1 then destroy the white blood corpuscles or leucocytes1 and transform them into pus1 and the other the pyretogenic property1 which appears to belong only quite indirectly to the pyogenic substance4 ,the toxins in general retard the heart action4 ,we will not speak of the distinctions it has been sought to establish between the substances which possess these different properties1 but will at once take up the discussion of several of the microbial toxins4 ,anthrax ,toxin#ajj 7from ,bacillus ,anthracis74--,we will describe the preparation of this toxin as a type4 #ajj ,,arloing1 ,,cornevin1 ,,thomas3 ,le ,charbon ,symptomatique1 #ast edit41 ,paris2 and ,,le ,,dantec3 ,la ,bactridie du ,charbon1 ,masson1 publ42 ,,straus3 ,le ,charbon des ,animaux et de l',homme1 ,paris1 #ahhg4 ,the cultures of the bacillus are made in ,liebig's bouillon1 to which has been added #j4a of fibrin1 the whole being carefully sterilized for a long time at #aaj ,c4 ,the cultures medium is inoculated with a drop of blood taken from the heart or spleen of an animal that has died of anthrax4 ,at the end of a week1 the culture is filtered1 and the filtrate acidulated with a little acetic acid and precipitated by adding powdered ammonium sulphate4 ,the flocculent precipitate is collected1 washed1 dissolved in distilled water1 and dialyzed4 ,the dialyzed solution is concentrated in vacuo at #dj-de ,c41 and precipitated by adding to it alcohol4 ,the precipitate formed is then collected and dried4#aja #aja ,,hankin3 ,british ,medical ,journal1 ,oct4 #ab1 #ahhi1 and ,july #ab1 #ahij4 ,in this manner there is obtained a grayish-white substance which is soluble in water1 and which is fatal in large doses1 but which1 given in repeated small doses1 confers immunity against anthrax4 ,according to ,hankin1 it seems that the toxic property of this toxin is due to an albumose4 ,marchoux#ajb has been able to confer immunity upon sheep by injecting first small quantities of the filtered culture of the anthrax bacilli1 and then the virulent anthrax itself4 #ajb ,annal4 ,instit4 ,pasteur1 ,,ix1 p4 #ghe4 ,the animals thus rendered immune yield a serum which may be used as a vaccin against anthrax1 and which even possesses curative properties under certain conditions4 ,in every case the acquired immunity is only temporary4 ,we will recall to recollection the method employed by ,pasteur for vaccinating against anthrax1 using attenuated cultures1 a method which is practiced daily at the present time4#ajc #ajc ,,chamberland3 ,le ,charbon et la ,vaccination ,charbonneuse1 ,paris1 #ahhg4 ,,petermann3 ,annal4 ,instit4 ,pasteur1 ,,vi1 p4 #cb4 ,from the cultures of symptomatic anthrax 7,bacillus ,chauv7 ,chauve extracted a very active toxin which can withstand without impairment a temperature of #aaj;,c4#ajd ,roux#aje has shown that the serum of animals that have succumbed to the symptomatic anthrax is capable of vaccinating against this disease2 we have here a new proof that the antitoxin is in fact a product of the defense of the cells of the organism1 and the author mentioned has been able to vaccinate guinea-pigs by injecting into the peritoneum culture bouillon sterilized by heating to #aae ,c4 or by filtering through porcelain4 #ajd ,,deutschmann3 ,annal4 ,instit4 ,pasteur1 ,,viii1 p4 #djc4 #aje ,annal4 ,inst4 ,pasteur1 ,feb4 #ahhh4 ,tubercular ,toxin4--,the culture bouillons of ,koch's bacillus contain one or more active substances which constitute1 and which is at the present designated as1 tuberculin4#ajf ,koch's therapeutic tuberculin is obtained by evaporating to one-tenth its volume a culture bouillon of ,koch's tubercle bacilli prepared from a #d-per cent4 glycerinic mutton bouillon1 and filtering through porcelain4 ,by fractional precipitation it is possible to obtain from the crude tuberculin so prepared a product which is considered as pure tuberculin1 and which possesses considerable activity4 #ajf ,,auclair3 ,thse de doctorat1 ,paris1 #ahig2 and ,arch4 de ,mdecine1 exp4 #ahih4 ,prolonged boiling on the water-bath completely destroys the activity of this tuberculin1 which moreover hardly ever keeps longer than three weeks4 ,it has been found possible to preserve it for an indefinite period1 however1 by adding to it #cj to #dj per cent4 of glycerin4 ,it possesses all the general reactions of albuminoids4 ,tuberculin is not toxic in the proper sense of the word4 ,injected in small quantities into the healthy human being#ajg and into healthy animals1 it exerts no effect2 on the other hand1 however1 in tubercular organisms1 even in incipient stages of the disease1 even where it is almost impossible to make a clinical diagnosis1 the injection of very small quantities develops a lively and characteristic reaction4#ajh #ajg ,,koch3 ,deutsch4 ,med4 ,woch41 ,nov4 #ac1 #ahij-ahig1 ,no4 #ad1 p4 #bji4 #ajh ,annal4 de l',instit4 ,pasteur1 ,v1 p4 #aia2 ,arch4 de la ,soc4 ,biol4 de ,saint-,ptersbourg1 ,i1 p4 #bac4 ,grasset and ,vedel consider the tuberculin as an excellent means of diagnosing tuberculosis in man1 but in such a case it is necessary to operate with the greatest caution1 with very small quantities of the tuberculin1 and to feel1 in some sort1 the sensitiveness of the patient1 particularly in the case of children4 ,it is chiefly for the diagnosis of tuberculosis in cattle1 however1 that tuberculin is valuable4 ,thanks to ,nocard1 the procedure has to-day become a common practice4 ,the injection of a fairly large dose1 #j4c to #j4d ,gm41 according to the size of the animal1 causes1 in about ten hours or so1 if the animal is tuberculous1 a strong febrile reaction with an elevation of temperature of #a4e to #c ,c41 whereas if the animal is not tuberculous no such reaction takes place4 ,cases in which tuberculosis is far advanced1 and in which the organism is impregnated with tuberculin1 do not react after the injection of tuberculin4#aji #aji ,,nocard and ,,leclainche3 ,les ,maladies ,microbiennes des ,animaux4 ,tuberculin does not confer immunity1 and the bacillus retains all its virulence1 even in injected tissues2 nevertheless1 the return to health of animals in which injections have been recently made may be due to the action of large doses of the serum2 and on the other hand the tuberculin1 in large quantities1 may render the location unsuitable for the development of the tubercle bacilli4 ,diphtheria ,toxin4--,the most characteristic property of the diphtheria bacillus is the production1 in culture media1 of a special toxic substance which has been named diphtheritic toxin2 this name1 however1 has come to be also extended to a liquid in which the bacilli have lived1 and which has been sterilized by filtration or by any other suitable process4 ,roux and ,yersin#aaj 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 develops4 ,in order to obtain this toxin#aaa a culture of the bacillus is first made in a mutton bouillon made strongly alkaline with sodium carbonate 7#aj grams per liter71 and with the addition of #b per cent4 of peptone4 ,at the end of about one month1 the culture being kept at about #cg ,c41 the liquid is filtered through porcelain4 ,it is indispensable to employ a very virulent bacillus2 it is hence frequently advantageous to increase the virulence and toxigenic power of the bacilli it is desired to use4 #aaj ,annal4 de l',instit4 ,pasteur1 ,,ii1 p4 #fcb1 and ,,viii1 p4 #faa4 #aaa ,see ,,spronk3 ,annal4 de l',instit4 ,pasteur1 ,,ix1 p4 #ghe2 ,ibid41 ,x1 p4 #ccc2 ,,martin1 ,ibid41 ,,xii1 p4 #bf2 ,,spronk1 ,ibid41 ,,xii1 p4 #gaa4 ,the toxic liquid obtained is exceedingly powerful3 #j4a ,cc4 kills a rabbit in forty-eight hours4 ,this toxin is very sensitive to the effects of heat4 ,when heated to #fe ,c4 it loses almost all its toxicity2 at #gj ,c4 it becomes innocuous2 and it only requires to be heated to #ajj ,c4 for fifteen minutes in order to lose all immediate activity even in large doses4 ,nevertheless toxins thus weakened are capable of proving fatal to an animal even after five or six months4 ,light1 oxygen1 ozone and all oxidizers destroy the active principle of the diphtheria toxin1 which is1 moreover1 rendered almost inactive by organic acids4 ,this toxin is capable of diffusing through animal membranes1 a fact that is in agreement with the toxic effect seen in a subject attacked with diphtheria1 and due to the toxin passing through the mucosa4 ,in spite of this property1 however1 the diphtheritic poison may be taken into the stomach without any pernicious results4 ,roux and ,yersin have shown that1 like all the diastases1 it may be precipitated from its solutions by the development1 within these1 of certain precipitates1 particularly calcium phosphate4 ,it is precipitated from its solutions by alcohol1 as has been observed also in the case of diastatic solutions4 ,all the toxic substance is contained in the albuminous precipitate thus obtained2 but the prolonged action of alcohol1 or repeated successive precipitations1 alter it finally4 ,diphtheria toxin is likewise precipitated by the reagents for albumoses1 particularly sodium sulphate in saturated solution4 ,this procedure has been utilized by ,brieger and ,fraenkel for preparing the pure toxin1 which they obtained in the form of very light1 brilliant white1 amorphous flocks1 affording all the principal reactions of the soluble albumoses 7biuret1 xanthoproteic1 ,millon's71 and which they characterized as a toxalbumin4 ,on injecting into healthy animals this diphtheria toxin attenuated by sufficiently heating at #gj ,c1 employing at first small doses1 and gradually increasing1 it is possible to immunize them against diphtheria1 as was first demonstrated by ,carl ,fraenkel4 ,roux and ,martin1 who have specially studied this procedure1#aab 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 solution1 and in successively increasing doses4 ,the initial dose is #j4be ,cc42 then1 after two days1 #j4e ,cc4 of the same toxin is injected1 and in like manner the dose is increased up to the eighteenth day1 when the pure toxin is injected1 at first in small doses1 which are gradually increased so that at the end of two or three months injections of #hj ,cc4 of the pure toxin may be given without danger2 the animal is then completely immunized4 #aab ,contribution l'tude de la ,diphtrie4 ,annal4 de l',instit4 ,pasteur1 ,,viii1 p4 #fji2 ,ibid41 p4 #fdj4 ,the serum of an animal rendered immune in this manner contains a diphtheria antitoxin which possesses high power4 ,a guinea-pig which has received an injection of #j4ja ,cc4 of the antitoxin is perfectly capable of withstanding a lethal dose of #j4e ,cc4 of the toxin4 ,the antidiphtheria serum thus obtained1 and in almost limitless quantities1 from an immunized animal1 is capable of saturating the therapeutic diphtheritic toxin1 and has to-day taken rank in therapeutics as the most efficacious remedy in diphtheria4 ,injected in varying doses1 it confers a temporary but immediate immunity4 ,nevertheless antidiphtheria serum must not be considered as an antidote2 and in pathological diphtheria1 the more serum is required the later it is used4#aac ,in certain cases1 if employed too late1 it may prove ineffective4 #aac ,,bayeux3 ,thse de ,doctorat1 ,paris1 #ahii4 ,the preventive action of the serum is remarkable4 ,in #aj #jjj inoculated cases ,behring and ,ehrlich have had but #aj cases of diphtheria1 and these were1 moreover1 of a benign character4 ,the duration of the immunizing action appears to be from three weeks to two months4 ,this diphtheria antitoxin was first prepared by ,gurin and ,mac#aad by adding to the antidiphtheria serum a large volume of alcohol1 washing the precipitate1 and drying it in a vacuum4 ,it is soluble in water1 and loses its activity when heated to #fe ,c4 ,wassermann#aae has proposed to extract it from the milk of immunized animals1 by first coagulating the milk by rennet in the presence of sodium chloride1 filtering1 and removing the fat from the clear liquid by means of chloroform4 ,after decanting1 the clear solution obtained is precipitated by adding to it #cj to #cc per cent4 of ammonium sulphate4 ,the precipitate is dried in a vacuum on a polished porcelain slab after having first been strongly expressed4 ,it is then dissolved in water4#aaf #aad ,compt4 rend4 de l',acad4 des ,sc41 ,apr4 #e1 #ahie4 #aae ,zeitschr4 fr ,hygiene1 ,,xviii1 p4 #bce4 #aaf ,,roux and ,,martin3 ,contribution l'tude de la ,diphtrie4 ,annal4 de l',instit4 ,pasteur1 ,,viii1 p4 #eab4 ,tetanus ,toxin4--,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 economy4 ,kuno ,faber was the first to fully recognize the fact that the culture bouillon of this bacillus1 fully sterilized by filtration through porcelain1 possesses an exceedingly high toxicity1 and exerts a toxic effect on #ej #jjj #jjj times its own weight of living organism4 ,brieger had previously1 however1 extracted three ptomaines from the cultures of the bacillus--tetanin1 tetanotoxin1 and spasmotoxin4#aag ,in order to obtain a highly active liquid1 the same culture medium is inoculated several times in succession1 but filtering each time before the new inoculation2 the microbes greatly increase in number after each fresh inoculation1 and the toxic substance developed by them accumulates4#aah #aag ,die ,pathogenese des ,tetanus4 ,berlin4 ,klin4 ,wochenschr41 #ahij1 ,no4 #ca4 #aah ,,naillard3 ,compt4 rend4 de l',acad4 des ,sciences1 ,,cxx1 p4 #aaha4 ,experiment has shown that the culture bouillon thus obtained contains two kinds of toxic substances#aai--;highly toxic alkaloidal bases 7ptomaines1 tetanin1 tetanotoxin1 etc471 and a true toxin1 possessing diastatic properties1 and of almost incredible toxic power4 #aai ,annal4 ,instit4 ,pasteur1 ,v1 #ae4 ,this toxin had already been isolated by ,kitasato4 ,it is a toxalbumin1 and is very sensitive to the action of heat4 ,a temperature of #fe ,c41 maintained for #cj minutes1 renders it quite inactive2 and it becomes oxidized and is destroyed by the action of the air in the presence of light4 ,brieger and ,boer1#abj by precipitating with zinc chloride the filtered culture bouillon1 obtained a pure1 amorphous tetanus toxin1 which they also considered as a toxalbumin1 and which possesses exceedingly toxic properties4 #abj ,deutsche ,med4 ,wochenschr41 ,no4 #di1 ,dec4 #c1 #ahif4 ,if a precipitate be caused to form in these toxic solutions1 as1 for instance1 a precipitate of calcium phosphate1 this carries down with it all the toxin present in the liquid4 #j4jjje ,gm4 of this precipitate is surely fatal to a guinea-pig4 ,dozon and ,cournemont have observed that even in doses of #cjj to #djj ,gm4 of the filtered culture liquid1 this toxin is not immediately toxic to a horse1 but kills the animal only after a period of incubation of at least twenty-four hours4 ,the blood of such an animal1 however1 is immediately and directly fatal to animals into which it is injected4#aba #aba ,compt4 rend4 ,soc4 ,biol41 #ahic1 p4 #bid2 ,ibid41 #ahid1 p4 #hgh4 ,experiment has shown that animals that have been cured of tetanus possess no immunity whatever against tetanus2 nevertheless ,behring and ,kitasato#abb first1 and ,wassermann and ,kitasato later on1 succeeded in preparing a tetanus antitoxin4 ,to obtain this1 the immunization of the animal1 horse or cow1 is effected by injecting increasing quantities of the toxin1 more or less attenuated by mixing it with ,gramm's iodine solution2 the immunization is easily and rapidly accomplished by the process devised by ,roux and ,vaillard4#abc #abb ,deutsch4 ,med4 ,wochenschr41 #ahij4 #abc ,annal4 ,instit4 ,pasteur1 ,,vii1 p4 #fd4 ,the immunized animals yield a serum which1 mixed with tetanus cultures1 renders these innocuous1 and which enjoys an antitoxic power that borders on the marvelous4#abd ,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 toxin4#abe #abd ,,nocard3 ,bull4 de l',acad4 de ,mdecine1 ,oct4 #bb1 #ahie4 #abe ,,naillard3 ,compt4 rend4 de l',acad4 de ,sciences1 ,,cxx1 p4 #aaha4 ,this serum is nevertheless powerless to preserve man in cases of acute tetanus2 it confers an immediate1 but only transitory1 immunity4 ,as to its mode of action1 it appears to cause a permanent condition of excitation or of nutritive reaction of the cells1 which makes these resistant to the poison4 ,as in the case of the other toxins1 the quantity of antitoxin necessary to protect an organism is so much greater the later the treatment is applied4 ,mallein 7,toxin of ,glanders74--,among the soluble products secreted in the culture media by the glanders bacilli1 there are found true toxins to which are ascribed certain symptoms of glanders infection4 ,these toxins have been isolated and designated by the name mallein4 ,first prepared by ,helman and ,kalmino1 mallein was later on specially studied by ,roux and ,nocard1 and1 in consequence of the researches of the last-mentioned scientist1 it has acquired great importance4#abf ,it is obtained by sterilizing at #aaj ,c4 cultures of the glanders bacillus made with mutton bouillon with the addition of salt1 glycerin1 and peptones4 ,to isolate the toxin the culture bouillon is first sterilized by heating for half an hour in an autoclave at #ajj ,c4 ,it is then filtered1 concentrated to one-tenth its volume on a water-bath1 and filtered through a ,chardin filter4 ,the mallein is thus obtained in the form of a brown syrupy liquid containing half its weight of glycerin4 #abf ,,nocard3 ,les ,maladies microbiennes des animaux1 ,paris4 ,this solution keeps well when kept from air1 light1 and heat4 ,in practice it is employed in #aj-per cent4 solution in phenolated water 7#e3ajjj74 ,the mallein may be precipitated from the crude solution by the addition of alcohol1 as recommended by ,foth4 ,foth's mallein occurs as a white1 light powder1 very easily soluble in water4 ,mallein enjoys a very important rle in veterinary therapeutics1 a rle analogous to that of tuberculin1 permitting the diagnosis of incipient glanders4#abg #abg ,,strauss3 ,arch4 de ,mdic4 expriment1 #ahhf4 ,experience has shown that in animals already attacked by glanders1 even if ever so slightly1 the thermic reaction never fails when #j4be ,cc4 of the mallein solution is injected4 ,in healthy animals1 however1 the injection of mallein1 even in much larger quantities1 causes no apparent effect4 ,in animals attacked by glanders the reaction attains its maximum in twelve hours1 and several days are required for the temperature to return to normal4#abh #abh ,,cadiot and ,,roger3 ,compt4 rend4 ,soc4 ,biol41 #ahie1 p4 #ggj2 ,,wladimirow3 ,arch4 des ,sciences ,biol4 de ,st4-,ptersbourg1 ,,iv1 p4 #cj2 ,,bourges and ,m,,ry3 ,soc4 de ,biol41 ,feb4 #e1 #ahgh4 ,according to ,nocard1 mallein possesses no immunizing properties whatever4#abi #abi ,,galtier3 ,compt4 rend4 de l',acad4 des ,sciences1 ,,xcii1 p4 #cjc2 ,,strauss3 ,arch4 de ,mdic4 expriment1 ,i1 p4 #dhi4 ,typhoid ,toxin4--,this is obtained1 like the other microbial toxins1 from a culture1 prepared with more or less difficulty1 from ,eberth's typhoid bacillus4 ,this toxin1 injected into guinea-pigs1 develops in them typhoid fever4 ,in the solution there occurs a ptomaine1 which has been isolated by ,brieger1 and which gives rise to almost all the phenomena of typhoid fever2 this ptomaine is called typhotoxin4#acj #acj ,,brieger3 ,microbes1 ,ptomanes et ,maladies1 ,doin1 publ41 ,paris1 #ahhg2 ,,luff3 ,brit4 ,med4 ,journ41 #ahhi4 ,the same author1 in collaboration with ,fraenkel1#aca later on isolated a toxalbumin from the culture bouillon of the typhoid bacillus4 ,sanarelli#acb obtained an active toxin by macerating for several days at #fj ,c4 a month-old culture of the typhoid bacillus made with a #b-per cent4 glycerin-bouillon4 ,chantemesse has also published a process which yields a highly virulent toxin4#acc #aca ,berlin4 ,klin4 ,wochenschr41 #ahij4 #acb ,annal4 de l',instit4 ,pasteur1 ,,viii1 p4 #ajc4 #acc ,compt4 rend4 ,soc4 de ,biol41 p4 #bcb1 ,jan4 #cj1 #ahig4 ,congrs d',hygine de ,madrid1 #ahih4 ,chantemesse and ,widal#acd have shown that on injecting into an organism increasing quantities of the sterilized cultures of ,eberth's ,bacillus1 it is possible to fully immunize an animal against the bacillus itself1 and even also against the ,bacillus coli communis4 ,the operation1 however1 is tedious and painful4 ,the serum of immunized animals possesses preventive and curative properties respecting the effects of typhoid bacilli4 #acd ,annal4 l',instit4 ,pasteur1 ,,vi1 p4 #gee2 ,,sanarelli3 ,ibid41 p4 #gba4 ,a dose of the filtered culture1 which is fatal to a guinea-pig1 becomes innocuous when mixed with #j4e ,cc4 of the serum of a vaccinated guinea-pig2 #f ,cc4 of the serum injected six hours after an injection of the virulent culture1 hence when this is in full action1 suffice to save the animal4#ace ,so far as the human being is concerned1 the results obtained have not been sufficiently satisfactory4 #ace ,,funck3 ,la ,srothrapie de la ,fivre ,typhode1 ,i1 ,brussels1 #ahif4 ,the culture bouillon of the ,bacillus coli communis1 which is closely allied to ,eberth's bacillus1 also contains soluble toxic substances which have been named coli-bacillus toxin4 ,this substance1 which is produced only in small quantity by the microbe1 is fatal only in very large doses4 ,cholera ,toxin4--,very little is known regarding the toxic products of the spirillium choler2 nevertheless1 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 microbe4 ,villiers#acf found in it a liquid ptomaine2 ,klebs#acg found another and crystallizable ptomaine2 while ,pitai discovered in it a toxin unalterable by heat1 and which he considered as a toxopeptone4 ,according to ,gamaleia#ach there is present a true toxin1 alterable by heat1 and the reactions of which entitle it to be considered as a nucleo-albumin2 he has also found in it a toxic nuclein4 #acf ,compt4 rend4 de l',acad4 des ,sciences1 ,jan4 #ab1 #ahhe4 #acg ,,klebs3 ,allgem4 ,wien4 ,med4 ,zeit41 #ahhg4 #ach ,arch4 de ,md4 ,exprim41 ,,iv1 p4 #agc4 ,these toxic substances are found1 according to ,gamaleia1 ,pfeiffer1 and ,sanarelli1#aci confined during the life of the microbe within its cellular envelope1 and does not diffuse through this4 ,metchnikoff and ,roux are of the contrary opinion1#adj however1 and they have prepared a toxin almost insensitive to a temperature of #ajj ,c41 and precipitable from its solutions by ammonium sulphate or strong alcohol2 the toxin is a toxalbumin4 ,this toxin is quite toxic2 one-third of a cubic centimeter suffices to kill #ajj ,gm4 of guinea-pig in #ah hours2 with larger doses1 death is almost immediate4 #aci ,annal4 de l',instit4 ,pasteur1 ,,ix1 p4 #abi4 #adj ,ibid41 ,x1 p4 #beg4 ,by immunizing guinea-pigs1 rabbits1 and horses with this cholera toxin1 ,metchnikoff and ,roux obtained a serum which is distinctly antitoxic for rabbits4 ,nothing absolutely certain has been found as to its action on man4#ada #ada ,,haffkine3 ,compt4 rend4 de l',acad4 des ,sciences1 #ahib2 ,,metchnikoff3 ,annal4 de l',instit4 ,pasteur1 ,,vii1 p4 #djc2 and ,,roux3 ,ibid41 ,x1 p4 #bec4 99 99 99 99 99 ,we will not dwell longer here on the toxins of microbial origin4 ,it appears evident1 however1 from what has been stated above1 that the great majority1 if not all1 of the virulent microbes manifest their virulence by means of toxic secretions4 ,almost every one of these toxins has been the subject of study4 ,they would otherwise not have interested us here1 where our main object was but to dwell upon the general properties4 ,,chapter ,v4 ,,the ,,venoms4 ,general ,nature of ,venoms4--,the venoms are more or less toxic products secreted by certain reptiles1 batrachians1 and fish2 by a large number of invertebrates2 by arachnids1 apids1 scorpionids1 araneids1 and a large number of other insects4 ,the venoms are toxic principles very closely allied to the microbial toxins2 like the latter1 they form two classes1 the one alkaloidal1 the other proteid1 possessing a true diastatic character4 ,they closely resemble the microbial toxins1 moreover1 by the fact that they are capable of being transformed into vaccins by attenuation of their virulence1 by the action of heat or chemical reagents1 and of leading to habituation of use and the conference of immunity4#adb ,moreover1 like the various viruses1 the serum of immunized animals is antivenomous1 so that if injected into the veins or beneath the skin of non-immunized animals1 the serum confers upon them an immunity against venom which lasts for some time4 #adb ,annal4 de l',instit4 ,pasteur1 ,,viii1 p4 #bha2 ,journ4 of ,physiol41 ,,viii1 p4 #bjc2 and ,soc4 de ,biol41 #ahid1 p4 #aaa4 ,these venoms1 like the microbial toxins1 possess but slight toxicity when absorbed via the stomach4 ,fraser1 utilizing a method previously advocated1 succeeded1 by following this method1 in vaccinating against serpent-venom by causing the absorption by animals of constantly increasing doses of venom4 ,it was thus possible to make the animals withstand doses a thousand times greater than the ordinary lethal dose2 the blood and serums of these animals at this point possessed immunizing properties1 and this property passed by heredity to the offspring1 to which it is transmitted by the blood itself1 and by the milk during feeding4 ,along with these resemblances between the venoms and toxins1 attention must be called to a very important difference4 ,as we have already seen1 the action of the toxins on the organism is always preceded by a certain period of incubation2 the action of the venoms1 on the contrary1 is almost instantaneous1 and in this respect they behave like chemical agents and alkaloidal toxins4 ,if the venoms are preserved in a moist condition1 they change because they undergo putrefaction1 which is generally the case with all diastatic substances1 and particularly the toxins4 ,it is interesting to note that animals which have been bitten by a venomous serpent1 but which1 for some reason or other1 have not succumbed to the venom1 never recover their former condition2 if they were young1 their functions cease to develop1 and they droop2 if they are adults1 their general condition remains that of stupefaction4 ,venomous ,serpents4--,among the venomous serpents1#adc the most important as well as the most dangerous are the following3 ,cobra di capello 7,naja tripudians1 the hooded cobra7 and its analogues1 the black ,naja1 ,naja hag1 etc42 the elops 7coral serpent72 the bungurus of ,bengal and ,burmah2 the ,platycercus proteroglyphia1 which is found chiefly in the waters of the ,indian ,ocean2 the crotalian solenoglyphs of the two ,americas1 and among which in particular are the rattlesnake1 the fer-de-lance 7the yellow viper7 of ,martinique2 the surucucu of ,guiana2 and the moccasins and copperheads of ,texas and ,florida4 ,lastly1 the entire group of viperian solenoglyphs1 among which are the ,echidn1 the bite of some of which1 for instance the daboia or echidna1 is dreadful2 the ,african vipers1 among which may be mentioned the horned viper1 the bite of which will kill a camel2 the springing viper of ,congo1 and the rhinoceros-viper of ,gabun2 the ,european vipers1 the most dangerous of which is certainly the asp of ,france1 which is exceedingly numerous in certain regions4 #adc ,,calmette3 ,le ,venin des ,serpents1 ,paris1 #ahif4 ,the effects of the bites of venomous serpents on man and animals are generally well known to the public2 it is well to recall them1 nevertheless4 ,from the moment the bite has been inflicted1 complete symptoms of poisoning develop1 attended by a condition of extreme and increasing weakness1 with vomiting1 hemorrhage1 and decomposition of the blood4 ,there are1 besides1 particular effects which vary with every venom4 ,the following table by ,calmette#add gives the comparative toxicity of various venoms1 taking as the standard of comparison the quantity sufficient to kill a rabbit in three or four hours3 ,naja tripudians #j4jjjdg ,naja hag #j4jjjc-j4jjjg ,acanthophis antarctica #j4jja ,ceraste #j4jjag-j4jjba ,haplocephalus variegatus #j4jjbe ,trigonocephalus #j4jjbe #add ,,calmette3 ,annal4 ,instit4 ,pasteur1 ,,viii1 p4 #bgf2 ,,ix1 p4 #bbi4 ,nature of ,serpent-venoms4--,these venoms are homogeneous liquids1 somewhat more dense than water1 in which they are soluble1 slightly colored green or yellow1 transparent1 and insoluble in alcohol2 they contain from #cj to #ce per cent4 of solid matter4 ,when fresh1 they have a slightly acid reaction4 ,towards chemical reagents1 and particularly acids1 they behave like albuminoids2 almost all the combinations they afford with the various albuminoid reagents are active1 despite their insolubility4 ,according to ,gautier1 they are decomposed by caustic potash4 ,according to numerous researches1 oxidizers like potassium permanganate1 the hypochlorites1 hydrogen peroxide1 and gold chloride 7in #a solution7 destroy the venoms2 in certain cases when immediately injected hypodermically in the poisoned region1 these substances are excellent antidotes in vivo4#ade #ade ,,winter and ,,blyth3 ,the ,analyst1 #ahgg1 p4 #bjd2 ,,lacerda3 ,compt4 rend4 de l',acad4 des ,sciences1 ,,xciii1 p4 #dff2 ,,calmette3 ,annal4 ,instit4 ,pasteur1 ,,vi1 p4 #age1 and ,,viii1 p4 #bgh4 ,we shall not here enter upon a detailed study of the toxic albuminoid principles of serpent-venoms2 moreover1 our knowledge is rather vague1 as it is1 on a number of points4 ,it will suffice us to know that1 taken altogether1 the active albuminoids of these venoms are numerous1 and that each venom has its own particular active constituents1 differing according to the species and variety of the snake4 ,each one of these substances acts more or less rapidly1 and may be associated with different principles which give rise to the variability of the action of these toxic agents4 ,among these toxic albuminoids1 the most virulent appear to be true albumins and globulins1 followed by the nucleo-albumins1 as we have already stated2 there are also found in venoms alkaloidal bases1 but these principles are present only in very slight quantity4 ,these bases are but very slightly toxic compared with the toxins that accompany them4 ,natural ,immunity towards ,serpent-venoms4--,certain animals exhibit a natural immunity toward snake-bites2 among them are the snakes themselves1 the hog1 the hedgehog1 and the mongoos 7an ,egyptian rat72 the blood of these animals contains apparently an antitoxin4#adf #adf ,compt4 rend4 de l',acad4 des ,sciences1 ,,cxxi1 p4 #gde2 ,,jacodot3 ,arch4 de ,mdecine ,navale1 ,,vii1 p4 #cij4 ,fontana#adg had remarked that snakes were quite unaffected by the bite of the viper1 even when inoculated with the venom hypodermically4 ,physalix and ,bertrand#adh confirmed these statements1 and showed that the snake perfectly resisted quantities of viper-venom capable of killing at least #bj guinea-pigs4 ,according to these scientists1 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 snake1 and pass into the blood and the fluids via the internal secretions4 ,these writers1 and also ,calmette1 have shown that the blood of venomous serpents becomes antitoxic when heated4 #adg ,trait sur le ,venin de la ,vipre1 ,florence1 #agha4 #adh ,archives de ,physiologie1 #ahid1 p4 #dbc4 ,it has been known for a long time that the hedgehog and the mongoos eat certain venomous reptiles1 and eagerly hunt for the vipers in particular4 ,when the hedgehog is bitten1 which happens quite often despite its dexterity1 it resists the viper-venom quite well4 ,physalix and ,bertrand#adi have experimentally demonstrated that the hedgehog withstands a dose of viper-venom capable of killing at least #dj guinea-pigs4 ,levin#aej has shown that young individuals are less resistant1 and it is concluded from this1 and perhaps incorrectly so1 that the immunity of the hedgehog is naturally acquired1 rather than inherent4 ,bertrand and ,physalix have nevertheless shown that on heating the blood of the hedgehog to #hh ,c4 it manifests an antitoxic power toward serpent-venom in vitro4 #adi ,bull4 ,musum ,histoire ,naturelle1 ,i1 p4 #bid2 ,compt4 rend4 ,soc4 de ,biol41 #ahii4 p4 #gg4 #aej ,deutsche med4 ,woch41 #ahih1 p4 #fbi4 ,artificial ,immunity toward ,serpent-venom4--,immunity may be conferred upon every individual by utilizing the method of habituation4 ,this fact was simultaneously elicited by ,calmette1 ,bertrand1 and ,physalix4 ,to effect the immunity these scientists prepare an antivenomous serum and inject it into animals1 giving at first very small quantities of the diluted venom1 and gradually increasing the doses1 and the periods intervening between the injections4 ,at the end of about two months of this treatment1 the immunity has reached its maximum4 ,certain rabbits1 thus slowly inoculated1 have been able to withstand #j4jd ,gm4 of the venom of the naja at a single injection2 such rabbits then yield a vaccinal serum4#aea #aea ,annal4 de l',instit4 ,pasteur1 #ahie1 p4 #bbi2 ,compt4 rend4 de l',acad4 des ,sciences1 ,,cxxii1 p4 #bjc4 ,at the ,institut ,pasteur at ,lille there is prepared in this manner an antivenomous serum from the horse2 it is capable of acting upon #bj #jjj times its own weight4 ,this has rendered great service in the treatment of snake-bites1 particularly in hot countries1 where the accidents are of daily occurrence4 ,in vitro it acts quite as well preventively as therapeutically4 ,it arrests the effects of the naja1 the horned ceraste1 the trigonocephalus1 the rattlesnake1 and of almost every one of the venomous serpents known4 ,the relatively considerable immunity possessed by certain snake-charmers1 and which passes for a magical gift1 is due to nothing else but a natural immunity1 acquired perhaps by heredity1 and it always appears to follow as a result of a nonfatal snake-bite4 ,venoms of ,batrachians and ,saurians4--,we observe here a fundamental difference between these poisons and those of snakes1 as we shall see4 ,these latter1 in fact1 appear to owe all their toxicity to true toxins which they contain1 while the poisons of batrachians and saurians are chiefly composed of alkaloidal bases4#aeb #aeb ,,cloez3 ,compt4 rend4 de l',acad4 des ,sciences1 ,,xxxiv1 p4 #eib4 ,the poison of toads and frogs 7studied by ,faust1 ,bertrand1 and ,physalix7 is chiefly secreted by the glands of the subcutaneous tissues of these animals2 it has but a very slight action on the unbroken skin1 but it rapidly inflames the nasal and buccal conjunctival mucosa4 ,the poison is a yellowish liquid1 milky and viscid1 with a waxy odor and an insupportably bitter taste4 ,it is strongly acid and caustic4 ,when dried1 the poison yields to ether a fatty matter which1 when absorbed by an animal1 plunges the latter into a coma that may end in death4 ,the residue insoluble in ether contains the non-toxic albuminoids1 and ptomaines1 such as methylcarbylamine1#aec and isocyanacetic acid1 resulting from the decomposition of a lecithin that appears to be soluble in ether4 #aec ,ibid41 ,,xcviii1 p4 #ech4 ,to obtain this venom1 ,physalix and ,bertrand#aed skin the toads1 first chloroformed1 and dry the skins in a vacuum over sulphuric acid2 the skins are then cleaned by treating with carbon disulphide to remove fatty matters1 and the toxic principles removed by means of #ie-per cent4 alcohol2 the poison so obtained1 however1 is impure4 ,a better procedure is to express the parotid glands which have been placed in distilled water4 ,faust found in this venom a principle which he named bufonin4 ,physalix and ,bertrand isolated from it also a resinoid substance soluble in alcohol and in a large excess of water2 this substance1 which they named bufotaline1 acts upon the heart4 ,these authors have also obtained another substance which has a paralyzing action1 and which they have named bufotenin4 #aed ,ibid41 ,,cxxviii1 pp4 #de-dh4 ,the poison of the common toad acts as a paralyzant upon the heart and on the spinal marrow#aee2 that of the common frog possesses similar properties4 ,the poison of the tritons is quite analogous to that of the toads2 it contains a lecithin hydrolyzable by water with the formation of alanin1 formic acid1 and alpha-isocyanopropionic acid4 #aee ,p4 ,,bert3 ,compt4 rend4 de la ,soc4 de ,biologie1 #ahhe1 p4 #ebd4 ,zalnosky#aef isolated from the glands of the skin of the salamander a white1 thick1 bitter and alkaline liquid poison1 containing a highly poisonous alkaloid1 salamandrine1 or samandarine1 which acts on the brain1 the medulla1 and the spinal cord1 and which has the formula ,c#ed;,h#fj,n#b,o#e2 it is a strong base and yields crystallizable salts4 #aef ,bull4 ,soc4 ,chim4 #b1 ,,vi1 p4 #cdd4 ,fish-poisons4#aeg--,very little accurate knowledge is extant regarding these4 ,many fish are poisonous1 and among them are the synanceia1 found in the ,indian ,ocean between the ,netherland ,isles and ,new ,caledonia2 considerable numbers are found in the neighborhood of the latter locality4 ,these fish are provided with spiny rays which are in direct communication with a poisonous system having its seat in the dorsal fin4 ,the prick of one of the spiny rays of this fish may under certain circumstances result fatally1 and in every case it causes a rapid and painful gangrene4 #aeg ,,bofford3 ,thse de doctorat en ,mdecine--,les ,poissons venimeux1 ,paris1 #ahhi2 ,o4 ,,arcos3 ,thse de doctorat--,essais sur les accidents causs par les poissons venimeux1 ,paris1 #ahhg4 ,from the reservoir the poison is conducted to the sharp extremity of the spines by a deep channel with which each spiny ray is provided2 the animal has #bf poison-sacs1 two for each ray1 and the sacs burst when the corresponding sting is in any manner compressed4 ,the poison is an odorless liquid having a slight styptic or acidulous taste1 and exhibiting a bluish fluorescence2 it rapidly becomes turbid4 ,the weevers1 which are numerous on the shores of the ,mediterranean ,sea1 and which are also met with in the northeastern portion of the ,atlantic ,ocean1 are likewise very dangerous1 which explains their popular names viper-weever1 spiderweever1 etc4 ,these fish are provided with a double set of poisonous apparatus1 the one opercular1 which is the more dangerous1 and the other dorsal4 ,the opercular spine has a double channel in connection with a conical cavity hollowed out in the base of the opercular bone4 ,the bottom of this cavity is provided with special cells which secrete the poison4 ,the dorsal glands have a similar structure4 ,the poison of the weever is a liquid1 limpid when the fish is alive1 and turbid when dead2 it has a slight bluish fluorescence1 is neutral in reaction1 and is coagulated by acids and bases4 ,it acts as a paralyzant1 its action being exerted on the medulla and spinal cord2 it retards the heart's action4 ,these examples will suffice2 and we will not dilate further on this subject1 because1 as already stated1 but little is accurately known regarding the subject1 and what is known may be summed up as follows3 ,fish-poisons always give rise to an intense pain1 frequently with motor paralysis1 followed by paralysis of sensation2 they affect the heart1 arresting it in diastole2 and they are more dangerous to fish and cold-blooded animals than to mammifers4 ,poisons of the ,hymenoptera4#aeh--,the poison system of the bee1 and of such insects as the wasps1 bumblebees1 etc41 is known to consist of a hollow sting consisting of two sharp needles communicating with two poison-bearing glands1 and forming a flexible tube4 ,one of these glands secretes an acid liquid 7formic acid72 the other secretes an alkaline fluid4 #aeh ,,philouze3 ,venin des ,abeilles4 ,annales de la ,socit ,linn4 du ,maine-et-,loire1 ,,iv4 ,the action of the bee-poison is very often benign1 but there have been cases where death followed the infliction of numerous stings4 ,our information regarding the poison of the cantharides and flies is very vague#aei2 the same is true of the poisons of various arachnids1 acarides1 and myriapoda4 ,so far as spiders are concerned1 it is known that their poison is an oily liquid having an acid and bitter taste1 and containing a toxalbumin derived from the skin of the insect4 ,the bite of the ordinary spider occasions simply a slight local pain1 with redness2 that of the large poisonous spider1 however1 may kill the larger animals1 and even man4 #aei ,,joyeux-,,laffri,e3 ,thse de doctorat en ,mdecine1 ,paris1 #ahhc2 ,p4 ,,bert3 ,compt4 rend4 de la ,soc4 de ,biol41 ,,ii #d1 p4 #acf4 ,poison of ,scorpions4#afj--,this poison is a colorless1 acid liquid1 having a higher specific gravity than water1 in which liquid it is soluble4 ,the famed legend of the suicide of scorpions is well known to all4 ,it is stated that when the insect finds itself in a position where its death is inevitable1 it stings itself1 and dies from the effects of its own poison4 ,a simple method has even been described of bringing this result about experimentally by surrounding the insect with a circle of fire4 ,bounne1 of ,madras1#afa who has studied the procedure1 has demonstrated its entire falsity by showing1 first of all1 that the insect dies from the effects of the excessive heat1 and further1 that the poison of the scorpion is harmless to individuals of the species that furnish it4 #afj ,,calmette3 ,annales de l',instit4 ,pasteur1 ,x1 p4 #bcb4 #afa ,proceedings of the ,royal ,society1 ,,xlii1 p4 #ag4 ,metchinkoff#afb has confirmed these facts1 and has moreover demonstrated that the blood of the scorpion possesses an undoubted antitoxic power against the poison of the insect4 #afb ,,metchnikoff3 ,l',immunit1 p4 #cdd4 ,the poison of the scorpion serves it to kill the insects which are its prey4 ,frogs and birds stung by the scorpion also generally die4 ,a dose of #j4jjje ,gm4 kills a guinea-pig in less than one hour2 and according to ,calmette#afc less than #j4jjje will kill a white mouse in two hours4 ,oxidizers destroy the toxicity of the poison4 ,guinea-pigs immunized against the poison of the scorpion resist perfectly very large doses of the poison4 #afc ,,calmette3 ,annal4 de l',instit4 ,pasteur1 ,x1 p4 #bcb4 ,poisonous ,blood and ,serums4--,it is an almost general fact that the blood and blood serum of batrachians1 eels1 lampreys1 snakes 7even non-poisonous ones71 and hedgehogs are very poisonous4 ,mosso has found in the blood serum of the lamprey a toxin possessing a strong hemolytic power1 and which he has named ichthyotoxin4 ,o4#e ,cc4 of this serum injected into a dog kills it in a few minutes4 ,he also observed1 in #ahhh1 that the blood of the eel1 in like dose1 kills a dog almost immediately1 and that the blood contains an ichthyotoxin analogous to that of the lamprey4 ,this substance1 which appears to be closely allied to the sero-albumin of the blood1 has a phosphorus-like1 sharp1 and burning taste4 ,by digestion it loses its toxicity1 as well as by heating at #fh to #gj ,c4 ,it is easily obtained by precipitating with ammonium sulphate the serum of eels1 and dialyzing the precipitate dissolved in water4 ,the power of this substance is almost as great as that of the cobra poison1 #j4jjb ,gm4 being instantly fatal per kilo of dog4 ,the blood of snakes is likewise very toxic2 the same is true of the blood of the viper1 as #j4jb ,cc4 will kill a guinea-pig in two hours4 ,all these bloods lose their toxicity when heated above #gj ,c4 ,the serum of the hedgehog is peculiar in this respect2 when heated at #ch ,c4 for fifteen minutes it loses its toxicity1 but it then possesses an immunizing power against the poisons4 ,the subject possesses great interest1 because it was in studying these immunizing properties that ,camus and ,gley1#afd and later on ,kossel#afe and ,tchistowitch1#aff discovered the first anticytotoxin1#afg which they obtained by treating the animals with increasing quantities of the serum of eels4 ,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 eels1 it is found that the blood-corpuscles kept quite well4 #afd ,archives internat4 de ,pharmacodynamie1 ,,iii and ,,iv4 #afe ,berliner ,klin4 ,wochenschr41 #ahie1 ,no4 #g4 #aff ,annal4 de l',instit4 ,pasteur1 ,,xiii1 p4 #djf4 #afg ,the name cytases or alexins has been given to hemolyzing diastatic substances which are found in certain serums4 ,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 species4 ,the chemical composition of these cytases or alexins is not yet definitely known1 but the substances rank among the albuminoids2 they are destroyed by a temperature of #ee to #ef ,c41 and act only in saline solutions 7,ehrlich and ,morgenroth1 ,berlin4 ,klin4 ,woch41 pp4 #f and #dha74 ,the cytases or alexins1 which will be studied in another volume of this collection1 and which will discuss the active principles of the immunizing serums1 constitute one of the numerous soluble intraleucocytary ferments1 and they pass into the serous liquids of the organism only as the result of a rupture of or injury to the phagocytes4 ,as to the blood of the hedgehog1 we have already seen that ,physalix and ,bertrand have shown that it may be a counter-poison towards serpent-venom under certain conditions4 ,in its normal condition it is highly toxic4 ,poisonous ,meats4--,it is particularly among the fish that we find these normally present1 and it is a singular fact that1 for a given species1 the toxicity frequently depends upon the period of the year4 ,thus1 at the period of spawning1 certain fish may be extremely poisonous1 or1 on the contrary1 may entirely cease to be so4 ,the anchovy ballassa from the shores of ,india occasions death even in very small quantity2 the poisonous meltite of the same seas causes violent vomiting2 the fugu of the ,japanese seas possesses an extreme poisonousness at the spawning period1 while1 on the contrary1 it is perfectly innocuous at all other periods4 ,numerous cases of poisoning have been chronicled every year by the journals1 due to the ingestion of mussels2 in the flesh of these crustace is found a dangerous toxin1 methylotoxin4 ,the flesh of oysters is also unwholesome at the spawning period4 ,the toxic symptoms caused by these animals become apparent in not less than twenty-four hours after ingestion4 ,the poisoning due to these fresh meats must not1 however1 be confounded with that caused by tainted or spoiled meats4 ,,works ,,of ,,alfred ,i4 ,,cohn ,,published ,,by ,,john ,,wiley ,,sons4 ,indicators and ,test-papers4 ,their ,source1 ,preparation1 ,application1 and ,tests for ,sensitiveness4 ,with ,tabular ,summary of the ,application of ,indicators4 ,second ,edition1 ,revised and ,enlarged4 #abmo1 ix #bfg pages4 ,cloth1 #b4jj4 ,tests and ,reagents4 ,chemical and ,microscopical1 known by their ,authors' ,names2 together with an ,index of ,subjects4 #hvo1 iii #chc pages4 ,cloth1 #c4jj4 ,,translations4 ,fresenius's ,quantitative ,chemical ,analysis4 ,new ,authorized ,translation of the latest ,german ,edition4 ,in two volumes4 ,by ,alfred ,i4 ,cohn1 ,phar4,d4 ,recalculated on the basis of the latest atomic weights1 and also greatly amplified by the translator4 #hvo1 #b vols41 upwards of #bjjj pages1 #bhj figures4 ,cloth1 #ab4ej4 ,techno-,chemical ,analysis4 ,by ,dr4 ,g4 ,,lunge1 ,professor at the ,eidgenssische ,polytechnische ,schule1 ,zurich4 ,authorized ,translation by ,alfred ,i4 ,cohn1 ,phar4,d4 #abmo1 vii #acf pages1 #af figures4 ,cloth1 #a4jj4 ,toxins and ,venoms and ,their ,antibodies4 ,by ,,em4 ,,pozzi-,,escot4 ,authorized ,translation by ,alfred ,i4 ,cohn1 ,phar4,d4 #abmo1 vii #aja pages4 ,cloth1 #a4jj1 net4 ,transcriber's ,notes ,obvious typographical errors have been silently corrected1 but all other variations in spelling1 punctuation and accents are as in the original1 with the exception of ,symptomatology 7in the contents list7 and symptomology 7in the text7 which has been corrected to symptomatology4 ,variations between the treatment and phrasing of headings in the table of contents and in the text have not been changed4 ,italics are represent thus italic and bold thus bold4 ,subscripts are represented thus #b ,the book begins with a page of adverts for works by the translator1 this has been moved to the end4