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broad zone of colourless exudation, in which numerous blood corpuscles and a few nuclei appeared. This zone passed into tissue full of leucocytes, escaped blood corpuscles and nuclei in which ran full blood-vessels enormously dilated. In the follicles of the tonsils the epithelium was wanting, in its place was a fibrinous nuclear exudation but which contained no bacilli. In the trachea the exudation was in several layers, in the upper part of which there were bacilli of various kinds, whilst in the deeper parts as well as in the tissue no bacilli were found. In the sections of the lungs the capillaries were filled with blood corpuscles and colourless cells. In the interstitial tissue there were numerous leucocytes, in the alveola a fibrinous and cellular exudation but no bacteria. were also no bacteria in the spleen.

There

Thirty cases of diphtheria investigated by Oertel gave somewhat similar results. The general conclusions which may be fairly drawn from the observations of Oertel and of Loeffler is that the disease known under the term diphtheria, consists of at least three forms. In the one the septic infection predominates, and whether Klebs's bacillus was originally present or not, the sufferer is affected with a disease closely analogous, if not identical, with septicemia; in such a case there will be no membranous exudation, and the sequelæ of paralysis will not be observed. In a second class of cases there is a more or less copious exudation, and in this form Klebs's bacillus will be found, and paralysis may occur as a sequela, but it is not essential. A third form appears to be a mixture of septic and true diphtheritic infection.

(330) The Nature of the Diphtheritic Poison.

According to Roux and Yersin1 the diphtheritic poison resembles the diastases in some of its properties. A filtered liquid capable of killing guinea-pigs in subcutaneous doses of one-eighth of a c.c., when heated to 38° for two hours, only produces oedema at the seat of inoculation when injected in doses of a c.c. The same liquid, boiled for twenty minutes, may be introduced into the veins of a rabbit in a dose of 35 c.c. without causing immediate illness, whilst, before boiling, one-half c.c. would have produced certain death. Animals which receive in the veins or under the skin 1 Annales de l'Institut Pasteur, July, 1889; Public Health, vol. ii., p. 112.

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large quantities of liquids which have been thus heated, although at first presenting no symptoms, nearly always die after a longer or shorter time. They emaciate, although eating as usual, and show symptoms of paralysis, chiefly in the posterior limbs, a few days before death.

Roux and Yersin have sought to discover in the bodies of persons dead from diphtheria the same poison. The spleen of an infant dead from infectious diphtheria was macerated in sterilized water, and the liquid filtered through porcelain; 35 c.c. were injected into the veins of a rabbit, and 8 c.c. subcutaneously into a guinea-pig. The latter died five days after the injection. The rabbit survived for two months; at first well, it emaciated little by little, and died paralyzed in the hinder extremities.

In another case of diphtheria the urine was collected when the prostration was very marked, filtered fresh, and injected into the veins of a rabbit and under the skin of a guinea-pig. Eleven days after, the guinea-pig, much emaciated, was dead. The rabbit was paralyzed in the hind extremities on the 45th and died on the 51st day. If these animals be compared with those which have been treated with cultures boiled and filtered, the cause of death in both cases will be seen to be the same. Heat destroys a great part of the poison, or induces a modification similar to that which it undergoes in the organism.

Kept in close vessels, preserved from air and light, filtered cultures of diphtheria long preserve toxic properties. A filtered liquid was found after five months to be as poisonous as the day in which it was sealed up in tubes. Exposed to the air its toxic properties gradually diminish. This action of the air is slow in the dark, rapid in the solar light. After two hours of insolation 1 c.c. of a liquid exposed to the air killed guinea-pigs; the same dose after five hours caused only local oedema. But when not exposed to the air, ten hours of sunshine had but little effect.

Cultures of the diphtheritic bacillus have only energetic toxic properties when they become alkaline; when acid, large doses of the filtered liquid are required to affect animals.

Evaporated in a vacuum at 25°, a residue is left which, when dissolved in a little water, is very toxic, because it contains in small volume the active matter of a large quantity of the culture. An alcoholic extract is innocuous, therefore alcohol does not dissolve

the poison. The active matter may be precipitated by absolute alcohol in the form of white greyish flocculi, exactly in the same way as an aqueous solution of diastase is precipitated by alcohol.

When a diphtheritic culture is submitted to dialysis, the outer liquid is found to be lethal. Like the diastases, it also has the property of adhering to certain precipitates.

The best precipitate is phosphate of lime. By fractional precipitation with calcic chloride, and essaying after each precipitation the effect of the liquid, it was found that in general the second precipitate was the most active. The dried precipitate is not so active as the moist, but it retains its properties a long time. Even after being heated for twenty minutes in the water-bath at 100°, it will kill guinea-pigs. This is, therefore, a convenient method of preservation of the diphtheritic poison.

An attempt was made by Roux and Yersin to ascertain the quantity of the dry organic matter which must contain the toxic material requisite to cause death in guinea-pigs or rabbits. A c.c. of active liquid gives a centigramme of dry residue; on subtraction of the ash and the portion soluble in alcohol which have no toxic action, there remain two-fifths of a mgrm. of organic matter; but it is certain the greater part of these two-fifths are formed of other substances than the diphtheritic poison. This weak dose is yet sufficient to kill at least eight guinea-pigs weighing 410 grammes, or two rabbits of 3 kilos each; a dog weighing 9 kilos, should he receive these two-fifths of a mgrm. in his blood, if he does not die, will remain very ill for a long time.

Hence it follows that if the real poison could be separated in a state of absolute purity, it would be lethal to guinea-pigs in a less dose than 0.75 mgrm. per kilo ( gr. per lb.), to rabbits in a less dose than 0.13 mgrm. per kilo.

(331) Klein's1 later Researches on Diphtheria.

While these sheets were passing through the press Klein has published researches, which, if confirmed, throw considerable light on the etiology, and in some points modify the foregoing account. In the first place he found that cultures of Klebs's bacillus were

1 Report of Medical Officer in Supplement to Eighteenth Annual Report of Local Government Board, 1888-1890. Proceedings of the Royal Society, 1890.

virulent to guinea-pigs on subcutaneous injection, but that the disease thus produced could not be considered diphtheritic. The same cultures were inactive when tested on fowls, pigeons, and rabbits. He next experimented with human diphtheritic membrane and found that pigeons, fowls, and rabbits were resistant to its action, but that guinea-pigs when inoculated with the membrane died of a septic infection, and he could not consider that the reaction was of a diphtheritic nature.

The true bacillus of diphtheria according to Klein is not that discovered by Klebs, but one which is shorter, and its most striking difference to that of Klebs is that it grows on gelatin at 20° C., whereas the bacillus of Klebs does not grow at all below 22° and flourishes best at 35°-37°. The bacillus of Klein seems to be readily obtained in a state of purity by inoculation of a cat's cornea with human diphtheritic membrane, as in the experiments to be mentioned.

Experiments upon cats with human diphtheritic membrane gave some striking results. On various occasions during the last few years there have been observations of some relation between human diphtheria and a malady in cats; instances such as e.g., that a cat or cats were taken ill with a pulmonary disease, and when ill were nursed by children, and then these latter sickened with well marked diphtheria. Or reversely, children were taken ill with diphtheria and either at the same time or afterwards the cat or cats sickened. The disease in the cat was described as an acute lung trouble; the animals were quiet, did not feed and seemed unable to swallow. In some cases they recovered; in others they became emaciated, while the lung trouble increased, and they ultimately died. In one instance the cat malady occurring where children were soon after attacked by diphtheria was of a wide-spread nature; and post-mortem examination of the animals affected showed severe lung disease, broncho-pneumonia, and large white kidneys due to fatty degeneration of the entire cortex; a similar condition being also met with in the human subject as an effect of diphtheria.

Subcutaneous inoculations into cats were carried out with particles of fresh human diphtheritic membrane and with cultures of the diphtheritic bacillus, producing a local diphtheritic swelling at the seat of inoculation and general visceral disease. In the cases

in which death followed after a few days the lungs were found much congested, and when death followed after one or more weeks the lungs showed broncho-pneumonia, and the kidneys were enlarged and white, the cortex being in a state of fatty degeneration. If the disease lasted beyond from five or seven days, both kidneys were found uniformly white in the cortex; if of shorter duration, the fatty degeneration was sometimes only in patches, although in these experiments the bacillus was recoverable by cultivation from the swelling at the seat of inoculation. No bacilli were found in the lungs, the blood, or the kidneys, and hence the conclusion is justified that, as in human diphtheria and in that produced by the inoculation of guinea-pigs, so in these experimental facts the visceral disease was the result of the action of a chemical poison produced by the growth of the bacillus at the seat of inoculation. From this it is seen the similarity between the natural and the artificial disease in the cat is very great, and the question arises as to the manner in which the cat either receives or imparts the diphtheritic contagion in the natural disease. This natural disease is in its symptoms and pathology a lung disease, and it is reasonable to suppose from analogy that the lung. is the organ in which the diphtheritic process in the cat has its seat. The microscopic examination of the diseased lungs of a cat dying from the natural disease bears out this supposition, the correctness of which has also been proved by direct experiment. Broth culture of the special bacillus was introduced into the windpipe of cats without injury to the mucous membrane. The animals became ill with acute pneumonia, and on post-mortem examination from two to seven days later there was found extensive pneumonia and fatty degeneration of the kidneys. The air passages contained an exudation like that of human diphtheria and the bacilli were present in large numbers. During the last ten or twelve years several epidemics of diphtheria have been traced to milk, but the way in which the milk became contaminated with the diphtheritic virus was not ascertained, although the evidence was very strong. that it had not been from a case of disease in the human subject. The cows which yielded the milk were not reported to be unhealthy, except for having sores or chaps on their teats. Klein inoculated a broth culture of the diphtheritic bacillus into two cows. On the second or third day there was a soft tender swelling at the

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