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Cytotoxins
3 86
ABSTRACTS AND REPORT.
some disturbance of innervation of the tongue. The spasm of the pharynx and resophagus and the reflex closure of the cardia might be referred, in the absence of anatomical lesions of th ese organs and of respiratory and cardiac disturbance, to some change in the pharyngeal and resophageal branches of the pneumo-gastric. The failure to detect brain disturbance forces one to reject the idea of any lesion in the cerebra I centres of the affected nerves. Injury at the point where the hypoglossal, pharyngeal, and the resophageal and pharyngeal branches of the pneumo-gastric have structural relations or come together could alone explain the symptoms observed, and this point is in the guttural pouch.-(Receuil de Meatcine Veterinaire, 15th April t903.)
CYTOTOXINS. By M.
KAUFMANN.
The blood is a liquid medium which bathes all the living elements of the organism, furnishing them with the materials necessary for their nutrition and function; receiving from them, on the other hand, various products, the result of wear, degeneration, and secretion. The greater part of the materials thus returned to the blood by the cells of the tissues play no particular part. They are only destined to be excreted, principally by the kidneys and lungs. Among these products, however, are some which play an important physiological part. The secretion of certain cells is necessary to the regular performance of function by other forms of cells, and when these products are absent disturbance at once occurs in the functions indicated. Thus, for example, the absence from the blood of the special material secreted by the pancreatic cells brings about that serious disturbance in nutrition known under the name of saccharine diabetes. Similarly, removal of the thyroid and parathyroid glands produces myxredema, cretinism, and other disturbances, varying according to the species of animal in which the operation is performed and various other conditions. We also know, according to Claud Bernard, that the hepatic cells continually furnish sugar to the blood passing through the liver, sugar which is indispensable for the nourishment of all the other cells of the organism. These examples are sufficient to show that in addition to the part the blood plays as a nutritive and as an excretory liquid it exercises that of exciting or sustaining certain functions or of regulating them by means of special secretions produced by certain cells. The organs of one and the same individual reciprocally act and react throu gh the medium of the nervous system and of the blood. The influence exerted at a dista nce by means of the blood stream is often more important than that transmitted by the nervous system, but most commonly the transmission is double, that is, it occurs through both the nervous and blood channels, a nd is in consequence more perfect. I. Even in the same animal or individual, the blood if comparatively examined in different tissues has not at all points the same properties. Each tissue communicates to it a particular quality. In any two individuals the constitution of the blood is different, and th e difference is greater the furth er apart the two individuals happen to be in the zoological scale. The blood draws its special qualities from the products secreted by the living cells which it bathes. Now, the different kinds of cells secrde products which are by no means identical, and which usually differ among themselves. It results from the preceding that the blood of a given animal may have
ABSTRACTS AND REPORT.
injurious and even toxic properties {or certain of its own cells, or, and still more frequently, for the cells of another animal. These products of cellular secretion which render the blood of an animal toxic for certain cells have been given the names of cellular poisons or cytotoxins. The cytotoxins, therefore, are poisons of animal origin, which are poured into the blood and communicate to it the power of killing certain cells. To clearly demonstrate the presence of cytotoxins in the blood a quantity of blood is allowed to coagulate, sheltered from germs, and the serum so obtained is caused to act either in vitro directly on isolated living cells like microbes or blood parasites, or is injected into the veins, under the skin, or into the peritoneum of an animal, and so allowed to act on the entire organism. Certain microbes have difficulty in developing, or fail altogether to develop, in blood serum; while others may even be killed by certain sera. These toxic sera are therefore termed microbicidal or bactericidal. This bacteri· cidal power of the serum assists the animal in defending itself against microbic infection, and plays an important part in natural or acquired immunity against infectious disorders. In order to study the cytotoxins in blood serum one usually uses as a reagent the red blood corpuscles, that is to say, the living normal elements of the blood. We know that in blood removed aseptically from the vessels of an animal the red blood corpuscles undergo no alteration; they preserve their form, colour, consistence, and all th eir normal characters. But if, instead of adding to this serum red blood discs from the animal which has furnished the blood, we add to it some obtained from another animal, particularly from a different species, the red blood discs may undergo change and be rapidly destroyed. There is, therefore, in the serum a substance capable of destroying certain red blood corpuscles, a h::emolysant substance, a special cytotoxin which dissolves certain red blood corpuscles derived from an outside source. The normal blood of an animal is not toxic for its own red blood corpuscles. Usually it does not injure the red blood corpuscles of individuals of th e same species, nor, it may be, of species distinctly different; but a blood which is normally not h::emolytic for the red blood corpuscles of any given animal may become so experimentally. Bordet has drawn attention to the artificial production of a cytotoxin in the guinea-pig's blood by the following experiment. Having discovered that the Se6um of a normal guinea-pig'S blood does not affect the red blood corpuscles of the rabbit, or scarcely so, he afterwards tested the effect on these same red blood corpuscles of the rabbit of serum obtained from a guinea-pig which had for some time previously been given subcutaneous injection s of rabbit's blood. He found that the serum of the prepared guinea-pig, that is to say, the guinea-pig which had undergone several injections of rabbit's bloo~, dissolved the red blood corpuscles of the rabbit with remarkable energy. Thus, under the influence of hypodermic injections of rabbit's blood, the cells of the guinea-pig's body had secreted and poured into its blood a h::emotoxin or h::emolysin destructive to the red blood corpuscles of the rabbit. Bordet has shown, moreover, that this special h::emotoxin produced by the guinea-pig's cells and poured into its blood is formed of two different substances, one of which, the alexin or cytase, is-destroyed by heating to 56° c., whilst. the other, the sensitising substance or the phytocytase, resists this temperature perfectly, and is not destroyed before 66' C. Neither of these two substances ha~ any manifest h::emolytic action when alone. A serum which only contains one of them, either alexin or phytocytase, is not h::emotoxic. Alexin or cytase exists in all normal serums, whilst the sensitising substance is not found in these serums, but always appears in animals pre-
ABSTRACTS AND REPORT.
viously treated by injections of blood. The serum, therefore, is active when it contains the two indispensable substances. The serum of a fresh subject which only contains alexin, and which is inactive as regards the red blood corpuscles, may become very h
II. Metchnikoff succeeded in producing a serum against leucocytes, and another against spermatozoa. Landsteiner, of Vienna, obtained about the same time a serum spermatoxic for the spermatozoa of the bull by injecting the semen of this animal into rabbits. The serum of the rabbit thus prepared rapidly paralysed the spermatozoa of the bull. Metchnikoff, by injecting rabbits with the pulp obtained by crushing the lymphatic ganglia of the same animal. obtained a serum which had the power of destroying the white mononuclear and polynuclear blood corpuscles of this rodent. Added in small quantities, this serum almost instantly immobilised the leucocytes of rabbits and brought about their destruction. This serum, therefore, might be termed leucotoxic. Von Bungern has likewise obtained a serum which stops the movements of vibrating cili
III. Cellular poisons, as has just been shown, can easily be produced by injecting animals with cells obtained from other species. But the question arises if the resorption of the blood or cells of the animal itself is capable of producing in its blood cytotoxins for the red blood corpuscles or for its own cells. We know that blood extravasations and pathological exudates are readily absorbed, and that in different diseases certain tissues become atrophied or disappear by resorption. Is there then in these cases a formation of cytotoxin?
ABSTRACTS AND REPORT.
Several experimenters have endeavoured to solve the question. Ehrlich and Morgenroth injected goats with goat's blood previously treated with water, in order to destroy a certain number of the red blood corpuscles. They thus obtained a serum which dissolved the red blood corpuscles of goats other than those which supplied the serum. In this case, therefore, there had been formed a cytotoxin which acted not merely on the red blood corpuscles of a strange species but even on the red blood The authors term this special form of corpuscles of the same species. cytotoxin, isotoxin. Nevertheless, it must be remembered that this isotoxin is not an autotoxin, for it has no solvent action on the red blood corpuscles of the goat which has undergone the injections. The serum of that goat is only toxic for the red blood corpuscles of other goats. Metalnikoff, under the direction of Metchnikoff, has endeavoured to produce not an autoh;emotoxin . but a n autospermatoxin by injecting male guineapigs with semen from the same species. At the end of a short time the serum of animals thus treated immobilizes the spermatozoa of guinea-pigs in a few minutes. This toxic action occurs not only in connection with the spermatozoa of strange guinea-pigs, but also in connection with those of the guinea-pigs submitted to the injection of semen. Here then is a case of a true auto-cytotoxin produced as a consequence of resorption of the cells of the same species. A very curious fact is that the spermatozoa of a guineapig whose blood serum is very spermatotoxic live without difficulty in the genital organs of the same animal, but are killed when mixed in 1,itro with a little of the same individual's serum. This difference of action is explained by the fact that spermatotoxin, like all the cytotoxins, appears to be formed of two substances, one of which circulates in the blood, the other existing in the bodies of the leucocytes, but not hecoming diffused in the plasma as long as the leucocytes undergo no change. Now, this change would occur after rem oval of the blood, the leucocytes would then pour their cytase into the serum in which the phytocytase already existed, and the cytotoxin would become complete and active. We see, therefore, that an organism may develop an autotoxin of which the two constituent parts remain separate and consequently inactive in the living animal. But it is possible to imagine that in consequence of some pathological change or other the leucocytes might undergo alteration and allow the cytase, which they had formerly contained, to escape; an active autotoxin would then be produced, for the two substances would be acting together, and a veritable auto-intoxication might result. To sum up, the preceding facts show that under the influence of certain conditions the animal body manufactures particular poisons which have a specific toxic action on certain cellular elel11ents. 1 hese poisons or cytotoxins, whether we are dealing with h;emotoxins, Jeucotoxins, nephrotoxins, hepatotoxins, spermatotoxins, neurotoxins, or others, are always formed by two different soostances, which may remain isolated and then have no action, or may become mixed and then acquire the specific toxic powers of the corresponding cytotoxin. One of these elementary substances, phytocytase, may circulate in the 'blood plasma, the otber, the cytase, remaining enclosed within the leucocytes. These two substances have the characters of true digestive ferments. The study of cytotoxins is extremely interesting and important both as regards general pathology and therapeutics. The results it has given explain a number of intoxications, the mech anism of which has hitherto appeared extremely mysterious; and the best examples of which perhap$ are Ulremia and eclampsia.-(Receuil de MMecillt Veterinaire, 15th May 1903.)
ABSTRACTS AND REPORT.
some disturbance of innervation of the tongue. The spasm of the pharynx and resophagus and the reflex closure of the cardia might be referred, in the absence of anatomical lesions of th ese organs and of respiratory and cardiac disturbance, to some change in the pharyngeal and resophageal branches of the pneumo-gastric. The failure to detect brain disturbance forces one to reject the idea of any lesion in the cerebra I centres of the affected nerves. Injury at the point where the hypoglossal, pharyngeal, and the resophageal and pharyngeal branches of the pneumo-gastric have structural relations or come together could alone explain the symptoms observed, and this point is in the guttural pouch.-(Receuil de Meatcine Veterinaire, 15th April t903.)
CYTOTOXINS. By M.
KAUFMANN.
The blood is a liquid medium which bathes all the living elements of the organism, furnishing them with the materials necessary for their nutrition and function; receiving from them, on the other hand, various products, the result of wear, degeneration, and secretion. The greater part of the materials thus returned to the blood by the cells of the tissues play no particular part. They are only destined to be excreted, principally by the kidneys and lungs. Among these products, however, are some which play an important physiological part. The secretion of certain cells is necessary to the regular performance of function by other forms of cells, and when these products are absent disturbance at once occurs in the functions indicated. Thus, for example, the absence from the blood of the special material secreted by the pancreatic cells brings about that serious disturbance in nutrition known under the name of saccharine diabetes. Similarly, removal of the thyroid and parathyroid glands produces myxredema, cretinism, and other disturbances, varying according to the species of animal in which the operation is performed and various other conditions. We also know, according to Claud Bernard, that the hepatic cells continually furnish sugar to the blood passing through the liver, sugar which is indispensable for the nourishment of all the other cells of the organism. These examples are sufficient to show that in addition to the part the blood plays as a nutritive and as an excretory liquid it exercises that of exciting or sustaining certain functions or of regulating them by means of special secretions produced by certain cells. The organs of one and the same individual reciprocally act and react throu gh the medium of the nervous system and of the blood. The influence exerted at a dista nce by means of the blood stream is often more important than that transmitted by the nervous system, but most commonly the transmission is double, that is, it occurs through both the nervous and blood channels, a nd is in consequence more perfect. I. Even in the same animal or individual, the blood if comparatively examined in different tissues has not at all points the same properties. Each tissue communicates to it a particular quality. In any two individuals the constitution of the blood is different, and th e difference is greater the furth er apart the two individuals happen to be in the zoological scale. The blood draws its special qualities from the products secreted by the living cells which it bathes. Now, the different kinds of cells secrde products which are by no means identical, and which usually differ among themselves. It results from the preceding that the blood of a given animal may have
ABSTRACTS AND REPORT.
injurious and even toxic properties {or certain of its own cells, or, and still more frequently, for the cells of another animal. These products of cellular secretion which render the blood of an animal toxic for certain cells have been given the names of cellular poisons or cytotoxins. The cytotoxins, therefore, are poisons of animal origin, which are poured into the blood and communicate to it the power of killing certain cells. To clearly demonstrate the presence of cytotoxins in the blood a quantity of blood is allowed to coagulate, sheltered from germs, and the serum so obtained is caused to act either in vitro directly on isolated living cells like microbes or blood parasites, or is injected into the veins, under the skin, or into the peritoneum of an animal, and so allowed to act on the entire organism. Certain microbes have difficulty in developing, or fail altogether to develop, in blood serum; while others may even be killed by certain sera. These toxic sera are therefore termed microbicidal or bactericidal. This bacteri· cidal power of the serum assists the animal in defending itself against microbic infection, and plays an important part in natural or acquired immunity against infectious disorders. In order to study the cytotoxins in blood serum one usually uses as a reagent the red blood corpuscles, that is to say, the living normal elements of the blood. We know that in blood removed aseptically from the vessels of an animal the red blood corpuscles undergo no alteration; they preserve their form, colour, consistence, and all th eir normal characters. But if, instead of adding to this serum red blood discs from the animal which has furnished the blood, we add to it some obtained from another animal, particularly from a different species, the red blood discs may undergo change and be rapidly destroyed. There is, therefore, in the serum a substance capable of destroying certain red blood corpuscles, a h::emolysant substance, a special cytotoxin which dissolves certain red blood corpuscles derived from an outside source. The normal blood of an animal is not toxic for its own red blood corpuscles. Usually it does not injure the red blood corpuscles of individuals of th e same species, nor, it may be, of species distinctly different; but a blood which is normally not h::emolytic for the red blood corpuscles of any given animal may become so experimentally. Bordet has drawn attention to the artificial production of a cytotoxin in the guinea-pig's blood by the following experiment. Having discovered that the Se6um of a normal guinea-pig'S blood does not affect the red blood corpuscles of the rabbit, or scarcely so, he afterwards tested the effect on these same red blood corpuscles of the rabbit of serum obtained from a guinea-pig which had for some time previously been given subcutaneous injection s of rabbit's blood. He found that the serum of the prepared guinea-pig, that is to say, the guinea-pig which had undergone several injections of rabbit's bloo~, dissolved the red blood corpuscles of the rabbit with remarkable energy. Thus, under the influence of hypodermic injections of rabbit's blood, the cells of the guinea-pig's body had secreted and poured into its blood a h::emotoxin or h::emolysin destructive to the red blood corpuscles of the rabbit. Bordet has shown, moreover, that this special h::emotoxin produced by the guinea-pig's cells and poured into its blood is formed of two different substances, one of which, the alexin or cytase, is-destroyed by heating to 56° c., whilst. the other, the sensitising substance or the phytocytase, resists this temperature perfectly, and is not destroyed before 66' C. Neither of these two substances ha~ any manifest h::emolytic action when alone. A serum which only contains one of them, either alexin or phytocytase, is not h::emotoxic. Alexin or cytase exists in all normal serums, whilst the sensitising substance is not found in these serums, but always appears in animals pre-
ABSTRACTS AND REPORT.
viously treated by injections of blood. The serum, therefore, is active when it contains the two indispensable substances. The serum of a fresh subject which only contains alexin, and which is inactive as regards the red blood corpuscles, may become very h
II. Metchnikoff succeeded in producing a serum against leucocytes, and another against spermatozoa. Landsteiner, of Vienna, obtained about the same time a serum spermatoxic for the spermatozoa of the bull by injecting the semen of this animal into rabbits. The serum of the rabbit thus prepared rapidly paralysed the spermatozoa of the bull. Metchnikoff, by injecting rabbits with the pulp obtained by crushing the lymphatic ganglia of the same animal. obtained a serum which had the power of destroying the white mononuclear and polynuclear blood corpuscles of this rodent. Added in small quantities, this serum almost instantly immobilised the leucocytes of rabbits and brought about their destruction. This serum, therefore, might be termed leucotoxic. Von Bungern has likewise obtained a serum which stops the movements of vibrating cili
III. Cellular poisons, as has just been shown, can easily be produced by injecting animals with cells obtained from other species. But the question arises if the resorption of the blood or cells of the animal itself is capable of producing in its blood cytotoxins for the red blood corpuscles or for its own cells. We know that blood extravasations and pathological exudates are readily absorbed, and that in different diseases certain tissues become atrophied or disappear by resorption. Is there then in these cases a formation of cytotoxin?
ABSTRACTS AND REPORT.
Several experimenters have endeavoured to solve the question. Ehrlich and Morgenroth injected goats with goat's blood previously treated with water, in order to destroy a certain number of the red blood corpuscles. They thus obtained a serum which dissolved the red blood corpuscles of goats other than those which supplied the serum. In this case, therefore, there had been formed a cytotoxin which acted not merely on the red blood corpuscles of a strange species but even on the red blood The authors term this special form of corpuscles of the same species. cytotoxin, isotoxin. Nevertheless, it must be remembered that this isotoxin is not an autotoxin, for it has no solvent action on the red blood corpuscles of the goat which has undergone the injections. The serum of that goat is only toxic for the red blood corpuscles of other goats. Metalnikoff, under the direction of Metchnikoff, has endeavoured to produce not an autoh;emotoxin . but a n autospermatoxin by injecting male guineapigs with semen from the same species. At the end of a short time the serum of animals thus treated immobilizes the spermatozoa of guinea-pigs in a few minutes. This toxic action occurs not only in connection with the spermatozoa of strange guinea-pigs, but also in connection with those of the guinea-pigs submitted to the injection of semen. Here then is a case of a true auto-cytotoxin produced as a consequence of resorption of the cells of the same species. A very curious fact is that the spermatozoa of a guineapig whose blood serum is very spermatotoxic live without difficulty in the genital organs of the same animal, but are killed when mixed in 1,itro with a little of the same individual's serum. This difference of action is explained by the fact that spermatotoxin, like all the cytotoxins, appears to be formed of two substances, one of which circulates in the blood, the other existing in the bodies of the leucocytes, but not hecoming diffused in the plasma as long as the leucocytes undergo no change. Now, this change would occur after rem oval of the blood, the leucocytes would then pour their cytase into the serum in which the phytocytase already existed, and the cytotoxin would become complete and active. We see, therefore, that an organism may develop an autotoxin of which the two constituent parts remain separate and consequently inactive in the living animal. But it is possible to imagine that in consequence of some pathological change or other the leucocytes might undergo alteration and allow the cytase, which they had formerly contained, to escape; an active autotoxin would then be produced, for the two substances would be acting together, and a veritable auto-intoxication might result. To sum up, the preceding facts show that under the influence of certain conditions the animal body manufactures particular poisons which have a specific toxic action on certain cellular elel11ents. 1 hese poisons or cytotoxins, whether we are dealing with h;emotoxins, Jeucotoxins, nephrotoxins, hepatotoxins, spermatotoxins, neurotoxins, or others, are always formed by two different soostances, which may remain isolated and then have no action, or may become mixed and then acquire the specific toxic powers of the corresponding cytotoxin. One of these elementary substances, phytocytase, may circulate in the 'blood plasma, the otber, the cytase, remaining enclosed within the leucocytes. These two substances have the characters of true digestive ferments. The study of cytotoxins is extremely interesting and important both as regards general pathology and therapeutics. The results it has given explain a number of intoxications, the mech anism of which has hitherto appeared extremely mysterious; and the best examples of which perhap$ are Ulremia and eclampsia.-(Receuil de MMecillt Veterinaire, 15th May 1903.)