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174
BACTERIOLOGY

work on this subject is highly suggestive, and opens up new possibilities with regard to the investigation of bacterial action within the body. Not only are the general symptoms of poisoning in bacterial disease due to toxic substances, but also the tissue changes, many of them of inflammatory nature, in the neighbourhood of the bacteria. Thus, to mention examples, diphtheria toxin produces inflammatory oedema which may be followed by necrosis; dead tubercle bacilli give rise to a tubercle-like nodule, &c. Furthermore, a bacillus may give rise to more than one toxic body, either as stages in one process of change or as distinct products. Thus paralysis following diphtheria is in all probability due to a different toxin from that which causes the acute symptoms of poisoning or possibly to a modification of it sometimes formed in specially large amount. It is interesting to note that in the case of the closely analogous example of snake venoms, there may be separated from a single venom a number of toxic bodies which have a selective action on different animal tissues.

Regarding the chemical nature of toxins less is known than regarding their physiological action. Though an enormous amount of work has been done on the subject, no important bacterial toxin has as yet been obtained in a Nature of toxins.pure condition, and, though many of them are probably of proteid nature, even this cannot be asserted with absolute certainty. Brieger, in his earlier work, found that alkaloids were formed by bacteria in a variety of conditions, and that some of them were poisonous. These alkaloids he called ptomaines. The methods used in the investigations were, however, open to objection, and it is now recognized that although organic bases may sometimes be formed, and may be toxic, the important toxins are not of that nature. A later research by Brieger along with Fraenkel pointed to the extracellular toxins of diphtheria, tetanus and other diseases being of proteid nature, and various other observers have arrived at a like conclusion. The general result of such research has been to show that the toxic bodies are, like proteids, precipitable by alcohol and various salts; they are soluble in water, are somewhat easily dialysable, and are relatively unstable both to light and heat. Attempts to get a pure toxin by repeated precipitation and solution have resulted in the production of a whitish amorphous powder with highly toxic properties. Such a powder gives a proteid reaction, and is no doubt largely composed of albumoses, hence the name toxalbumoses has been applied. The question has, however, been raised whether the toxin is really itself a proteid, or whether it is not merely carried down with the precipitate. Brieger and Boer, by precipitation with certain salts, notably of zinc, obtained a body which was toxic but gave no reaction of any form of proteid. There is of course the possibility in this case that the toxin was a proteid, but was in so small amount that it escaped detection. These facts show the great difficulty of the problem, which is probably insoluble by present methods of analysis; the only test, in fact, for the existence of a toxin is its physiological effect. It may also be mentioned that many toxins have now been obtained by growing the particular organism in a proteid-free medium, a fact which shows that if the toxin is a proteid it may be formed synthetically by the bacterium as well as by modification of proteid already present. With regard to the nature of intracellular toxins, there is even greater difficulty in the investigation and still less is known. Many of them, probably also of proteid nature, are much more resistant to heat; thus the intracellular toxins of the tubercle bacillus retain certain of their effects even after exposure to 100° C. Like the extracellular toxins they may be of remarkable potency; for example, fever is produced in the human subject by the injection into the blood of an extremely minute quantity of dead typhoid bacilli.

We cannot as yet speak definitely with regard to the part played by enzymes in these toxic processes. Certain toxins resemble enzymes as regards their conditions of precipitation and relative instability, and the fact that Enzymes.in most cases a considerable period intervenes between the time of injection and the occurrence of symptoms has been adduced in support of the view that enzymes are present. In the case of diphtheria Sidney Martin obtained toxic albumoses in the spleen, which he considered were due to the digestive action of an enzyme formed by the bacillus in the membrane and absorbed into the circulation. According to this view, then, a part at least of the directly toxic substance is produced in the living body by enzymes present in the so-called toxin obtained from the bacterial culture. Recent researches go to show that enzymes play a greater part in fermentation by living ferments than was formerly supposed, and by analogy it is likely that they are also concerned in the processes of disease. But this has not been proved, and hitherto no enzyme has been separated from a pathogenic bacterium capable of forming, by digestive or other action, the toxic bodies from proteids outside the body. It is also to be noted that, as in the case of poisons of known constitution, each toxin has a minimum lethal dose which is proportionate to the weight of the animal and which can be ascertained with a fair degree of accuracy.

The action of toxins is little understood. It consists in all probability of disturbance, by means of the chemical affinities of the toxin, of the highly complicated molecules of living cells. This disturbance results in disintegration to a varying degree, and may produce changes visible on microscopic examination. In other cases such changes cannot be detected, and the only evidence of their occurrence may be the associated symptoms. The very important work of Ehrlich on diphtheria toxin shows that in the molecule of toxin there are at least two chief atom groups—one, the “haptophorous,” by which the toxin molecule is attached to the cell protoplasm; and the other the “toxophorous,” which has a ferment-like action on the living molecule, producing a disturbance which results in the toxic symptoms. On this theory, susceptibility to a toxin will imply both a chemical affinity of certain tissues for the toxin molecule and also sensitiveness to its actions, and, furthermore, non-susceptibility may result from the absence of either of these two properties.

A bacterial infection when analysed is seen to be of the nature of an intoxication. There is, however, another all-important factor concerned, viz. the multiplication of the living organisms in the tissues; this is Bacterial infection.essential to, and regulates, the supply of toxins. It is important that these two essential factors should be kept clearly in view, since the means of defence against any disease may depend upon the power either of neutralizing toxins or of killing the organisms producing them. It is to be noted that there is no fixed relation between toxin production and bacterial multiplication in the body, some of the organisms most active as toxin producers having comparatively little power of invading the tissues.

We shall now consider how bacteria may behave when they have gained entrance to the body, what effects may be produced, and what circumstances may modify the disease in any particular case. The extreme instance of bacterial The production of disease.invasion is found in some of the septicaemias in the lower animals, e.g. anthrax septicaemia in guinea-pigs, pneumococcus septicaemia in rabbits. In such diseases the bacteria, when introduced into the subcutaneous tissue, rapidly gain entrance to the blood stream and multiply freely in it, and by means of their toxins cause symptoms of general poisoning. A widespread toxic action is indicated by the lesions found—cloudy swelling, which may be followed by fatty degeneration, in internal organs, capillary haemorrhages, &c. In septicaemia in the human subject, often due to streptococci, the process is similar, but the organisms are found especially in the capillaries of the internal organs and may not be detectable in the peripheral circulation during life. In another class of diseases, the organisms first produce some well-marked local lesion, from which secondary extension takes place by the lymph or blood stream to other parts of the body, where corresponding lesions are formed. In this way secondary abscesses, secondary tubercle glanders and nodules, &c., result; in typhoid fever there is secondary invasion of the mesenteric glands, and clumps of bacilli are also found in internal organs, especially the spleen, though there may be little tissue change around them. In all such cases there is seen a selective character in the distribution of the lesions, some organs being in any disease much more liable to infection than others. In still