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"I'etjer Spirillum dcsutphuricans, &c.," Cent./. Boll. Abt. II.Bd.i ^'&95)» P- I; Mftlisch. Die Pflante in ihrtn BcziehitnReit turn Eisen lIciM. 1893). Pigment Bacteria: Ewart, "On the Evolution of Oxygen from Coloured Bacteria." Linn. Joutn.. l£97. vol. xxxiii. p. 123; Mulisch, Die Purpurlakltrien (Jena. 1007). Oxydases and Enzymes: Green. The Soluble Ferments and Fermentation (Cambridge. 1899). Action of Light. &c.: Marshall Ward. " The Action o( Light on Bacteria," Pkil. Trans.. 1803, p. 961. and literature. Resistance to Cold, &c.: Kavcnel, If of. News, 1899. vol. Ixxiv.; Uachdyen and Rowland. Proc. R. Soc. vol. Ixvi. pp. 180. 330. and 486; Farmer, " Observations on the Effect of Desiccation of Albumin ufon its Coagulability," ibid. p. 329. Pathogenic Bacteria: fcaumganen. Pathotofiscrte Mykologte (1890): Koflc and Wasserfflann. Handbuth der fxithoienen Aiikrooreonilmtn (1002-1904); awl numerous special works in medical literature. Immunity: Ehrlich, " On Immunity with Special Reference to Cell-life," Proc. R. Sec. vol. Ixvi. p. 424; Calcar, Die Fortftchritte der Immunitatsutwi Spezirtzetatftlehre seit 1870," Protressus Rei Botanicae, Bd. I Heft 3(1907). Bacteriosis: Migula, u. p. 322, has collected the literature; sec also Sorauer, Handbuch der Pflanunkrankheiten, 1. t'9°5). pp. t8-93, for later literature. Symbiosis: Marshall Ward, "Symbiosis," Ann. of Bot. vol. xiii. p. 549, and literature.

(H. M. W.;V. H. B.)

II. Pathological Iiifoktancc

The action of bacteria as pathogenic agents is in great part merely an instance of their general action as producers of chemical ^ogf, yet bacteriology as a whole has become so extensive, wd has so important a bearing on subjects widely different from one another, that division of it has become essential. The »'tnce will accordingly be treated in this section from the pathokpcal standpoint only. It will be considered under the three following heads, viz. (i) the methods employed in the study; (') the modes of action of bacteria and the effects produced by them, and (3) the facts and theories with regard to immunity •gamst bacteria! disease.

The demonstration by Pasteur that definite diseases could °t produced by bacteria, proved a great stimulus to research in the etiology of infective conditions, and the result TM was a rapid advance in human knowledge. An allimportant factor in this remarkable progress was the introduction by Koch of solid culture media, of the "plate"Wthorl." 8:c., an account of which he published in 1881. By °*»nj of these the modes of cultivation, and especially of separa''°n, ol bacteria were greatly simplified. Various modifications

have since been made, but the routine methods in bacteriological procedure still employed are in great part those given by Koch. By 1876 the anthrax bacillus had been obtained in pure culture by Koch, and some other pathogenic bacteria had been observed in the tissues, but it was in the decade 1880-1890 that the most important discoveries were made in this field. Thus the organisms of suppuration, tubercle, glanders, diphtheria, typhoid fever, cholera, tetanus, and others were identified, and their relationship to the individual diseases established. In the last decade of the igth century the chief discoveries were of the bacillus of influenza (1897), of the bacillus of plague (1894) and of the bacillus of dysentery (1898). Immunity against disease* caused by bacteria has been the subject of systematic research from 1880 onwards. In producing active immunity by the attenuated virus, Duguid znd J. S. Burdon-Sandcrson and \V. S. Greenfield in Great Britain, and Pasteur, Toussaint and Chauveau in France, were pioneers. The work of Mctchnikoft, dating from about 1884, has proved of high importance, his theory of phagocytosis (vide infra) having given a great stimulus to research, and having also contributed to important advances. The modes by which bacteria produce their effects also became a subject of study, and attention was naturally turned to their toxic products. The earlier work, notably that of L. Brieger, chiefly concerned ptomaines (vid£ infra), but no great advance resulted. A new field of inquiry was, however, opened up when, by filtration a bacterium-free toxic fluid was obtained which produced the important symptoms of the disease—in the case of diphtheria by P. P. E. Roux and A. Yersin (1888), and in the case of tetanus a little later by various observers. Research was thus directed towards ascertaining the nature of the toxic bodies in such a fluid, and Brieger and Fraenkel (1890) found that they were proteids, to which they gave the name " toxalbumins." Though subsequent researches have on the whole confirmed these results, it is still a matter of dispute whether these proteids are the true toxins or merely contain the toxic bodies precipitated along with them. In the United Kingdom the work of Sidney Martin, in the separation of toxic substances from the bodies of those who have died from certain diseases, is also worthy of mention. Immunity against toxins also became a subject of investigation, and the result was the discovery of the antitoxic action of the serum of animals immunized against tetanus toxin by E. Behring and Kitazato (1890), and by Tizzoni and Cattani. A similar result was also obtained in the case of diphtheria. The facts with regard to passive immunity were thus established and were put to practical application by the introduction of diphtheria antitoxin as a therapeutic agent in 1894. The technique of scrum preparation has become since that time greatly elaborated and improved, the work of P. Ehrlich in this respect being specially noteworthy. The laws of passive immunity were shown to hold also in the case of immunity against living organisms by R. Pfeiffer (1894), and various anti-bacterial sera have been introduced. Of these the anti-streptococcic serum of A. Marmorek (1895) 's onc °f lnc best known. The principles of protective inoculation have been developed and practically applied on a large scale, notably by W. M. W. Haffkine in the case of cholera (1893) and plague (1896), and more recently by Wright and Semple in the case of typhoid fever. One other discovery of great importance may be mentioned, viz. the agglutinative action of the serum of a patient suffering from a bacterial disease, first described in the case of typhoid fever independently by Widal and by Grtinbaum in 1896, though led up to by the work of Pfeiffer, Graber and Durham and others. Thus a new aid was added tomedical science, viz. serum diagnosis of disease. The last decade of the ioth century will stand out in the history of medical science as the period in which serum therapeutics and serum diagnosis had their birth.

In recent years the relations of toxin and antitoxin, still obscure, have been the subject of much study and controversy. It was formerly supposed that the injection of attenuated cultures or dead organisms—vaccines in the widest sense— was only of service in producing immunity as a preventive measure against the corresponding organism, but the work of Sir Almrolh Wright has shown that the use of such vaccines may be of-scrvice even after infection has occurred, especially when the resulting disease is localized. In this case a general reaction is stimulated by the vaccine which may aid in the destruction of the invading organisms. In regulating the administration of such vaccines he has introduced the method o[ observing the opsonic index, to which reference is made below. Of the discoveries of new organisms the most important is that of the Spirochacte pallida in syphilis by Schaudinn and Hoffmann in 1905; and although proof that it is the cause of the disease is not absolute, the facts that have been established constitute very strong presumptive evidence in favour of this being the case. It may be noted, however, that it is still doubtful whether this organism is to be placed amongst the bacteria or amongst the protozoa.

The methods employed in studying the relation of bacteria to disease are in principle comparatively simple.but considerable

experience and great care are necessary in applying ofttuay. lnem an(**n interpreting results. In any given disease

there arc three chief steps, viz. (i) the discovery of a bacterium in the affected tissues by means of the microscope; (2) the obtaining of the bacterium in pure culture; and (3) the production of the disease by inoculation with a pure culture. By means of microscopic examination more than one organism may sometimes be observed in the t issues,but one single organism by its constant presence and special relations to the tissue changes can usually be selected as the probable cause of the disease, and attempts towards its cultivation can then be made. Such microscopic examination requires the use of the finest tenses and the application of various staining methods. In these latter the basic aniline dyes in solution are almost exclusively used, on account of their special affinity for the bacterial protoplasm. The methods vary much in detail, though in each case the endeavour is to colour the bacteria as deeply, and the tissues as faintly, as possible. Sometimes a simple watery solution of the dye is sufficient, but very often the best result is obtained by increasing the staining power, e.g. by addition of weak alkali, application of heat, &c., and by using some substance which acts as a mordant and tends to fix the stain to the bacteria. Excess of stain is afterwards removed from the tissues by the use of decolorizing agents, such as acids of varying strength and concentration, alcohol, &c. Different bacteria behave very differently to stains; some take them up rapidly, others slowly, some resist dccolorization, others are easily decolorized. In some instances the stain can be entirely removed from the tissues, leaving the bacteria alone coloured, and the tissues can then be stained by another colour. This is the case in the methods for staining the tubercle bacillus and also in Gram's method, the essential point in which latter is the treatment with a solution of iodine before decolorizing. In Gram's method, however, only some bacteria retain the stain, while others lose it. The tissues and fluids arc treated by various histological methods, but, to speak generally, examination is made cither in films smeared on thin cover-glasses and allowed to dry, or in thin, sections cut by the microtome after suitable fixation and hardening of the tissue. In the case of any bacterium discovered, observation must be made in a long scries of instances in order to determine its invariable presence.

In cultivating bacteria outside the body various media to serve as food material must be prepared and sterilized by heat. Caltlv The general principle in their preparation is to supply ttoa. *' l^e nutriment for bacterial growth in a form as nearly

similar as possible to that of the natural habitat of the organisms—in the case of pathogenic bacteria, the natural fluids of the body. The media are used either in a fluid or solid condition, the latter being obtained by a process of coagulation, or by the addition of a gelatinizing agent, and are placed in glass tubes or flasks plugged with cotton-wool. To mention examples, blood serum solidified at a suitable temperature is a highly suitable medium, and various media arc made with extract of meat as a basis, with the addition of gelatine or agar as solidifying agents and of ncm-coagulable proteids (commercial "pep

tone ") to make up for protrids lost by coagulation in the preparation. The reaction of the media must in every case be carefully attended to, a neutral or slishtly alkaline reaction being, as a rule, most suitable; for delicate work it may be necessary to standardize the reaction by titration methods, The media from the store-flasks are placed tn glass test-tubes or small flasks, protected from contamination by cotton-wool plugs, and arc sterilized by heat. For most purposes the solid media arc to be preferred, since bacterial growth appears as a discrete mass and accidental contamination can be readily recognized. Cultures arc made by transferring by means of a sterile platinum wire a little of the material containing the bacteria to the medium. The lubes, after being thus inoculated, arc kept at suitable temperatures, usually either at 37° C., the temperature of the body, or at about 20° C., a warm summer temperature, until growth appears. For maintaining a constant temperature incubators with regulating apparatus are used. Subsequent cultures or, as they are called, "subcultures," may be made by inoculating fresh tubes, and in this way growth may be maintained often for an indefinite period. The simplest case is that tn which only one variety of bacterium is present, and a " pure culture " may then be obtained at once. When, however, several species arc present together, means must be adopted for separating them. For this purpose various methods have been devised, the most important being the plate-method of Koch. In this method the bacteria arc distributed in a gelatine or agar medium liquefied by heat, and the medium is then poured out on sterile glass plates or in shallow glass dishes, and allowed to solidify. Each bacterium capable of growth gives rise to a colony visible to the naked eye, and if the colonies are sufficiently apart, an inoculation can be made from any one to a tube of culture-medium and a pure culture obtained. Of course, in applying the method means must be adopted for suitably diluting the bacterial mixture. Another important method consists in inoculating an animal with some fluid containing the various bacteria. A pathogenic bacterium present may invade the body, and may be obtained in pure culture from the internal organs. This method applies especially to pathogenic bacteria whose growth on culture media is slow, e.g. the tubercle bacillus.

The full description of a particular bacterium implies an account not only of its microscopical characters, but also of its growth characters in various culture media, its biological properties, and the effects produced in animals by inoculation. To demonstrate readily its action on various substances, certain media have been devised. For example, various sugars— lactose, glucose, saccharose, &c.—arc added lo lest the fermentative action of the bacterium on these substances; litmus is added to show changes in reaction, specially standardized media being used for estimating such changes; peptone solution is commonly employed for testing whether or not the baricrium forms indol; sterilized milk is used as a culture medium to determine whether or not it is curdled by the growth. Sometimes a bacterium can be readily recognized from one or two characters, but not infrequently a whole scries of tests must be made before the species is determined. As our knowledge has advanced it has become abundantly evident that the so called pathogenic bacteria arc not organisms with special features, but that each is a member of a group of organisms possessing closely allied characters. From the point of view of evolution we may suppose that certain races of a Rfoup of bacteria have gradually acquired the power of invading the tissues of the body and producing disease. In the acquisition of pathogenic properties some of their original characters have become changed, but in many instances this has taken place only to a slight degree, and, furthermore, some of these changes arc not of a permanent character. It t* to b? noted that in the case of bacteria we can only judge of organisms being of different species by the stability of (he characters which distinguish them, and numerous examples might be given where their characters become modified by comparatively slight change in their environment. The cultural as well as the microscopical characters of a pathogenic organism may be closely similar to other non-pathogenic members o{ the same group, and it thus comes to be a matter of extreme difficulty in certain cases to itate what criterion should be used in differentiating varieties. The tests which are applied for this purpose at present are chiefly of two kinds. In the first place, such organisms may be differentiated by the chemical change produced by them in various culture media, e.g. by their fermentative action on various sugar*, Sic., though in this case such properties may become modified in the course of time. And in the second place, the various scrum reactions to be described below have been called into requisition. It may be stated that the introduction of a particular bacterium into the tissues of the body leads to certain properties appearing in the serum, which are chiefly exerted towards this particular bacterium. Such a scrum may accordingly within certain limits be used for differentiating this organism from others closely allied to it (ride infra).

The modes of cultivation described apply only to organisms which grow in presence of oxygen. Some, however — the strictly anaerobic bacteria—grow only in the absence of oxygen; hence means must be adopted for excluding this gas. It is found that if the inoculation be made deep down in a solid medium, growth of da anaerobic organism will take place, especially if the medium contains some reducing agent such as glucose. Such cultures are called " deep cultures." To obtain growth of an anaerobic organism on the surface of a medium, in using the plate method, ifti also for cultures in fluids, the air is displaced by an indifferent |ai, usually hydrogen.

In testing the effects of bacteria by inoculation the smaller rodents, rabbits, guinea-pigs, and mice, arc usually employed. One great drawback in certain cases is that such animals arc not susceptible to a given bacterium, or that the disease is different in character from that in the human subject. Insornecases,e.|\Maltaicvcrandreiapsingfever, monkeys have been used with success, but in others, t.g. leprosy, none of the lower animals has been found to be susceptible. Discretion must therefore be exercised in interpreting negative results in the lower animals. For purposes of inoculation young vigorous cultures must be used. The bacteria are mixed with some indifferent fluid, or a fluid culture is employed. The injections are made by means of a hypodermic syringe into the lubcutancous tissue, into a vein, into one of the serous sacs, or more rarely into some special part of the body. The animal, after injection, must be kept in favourable surroundings, and any resulting symptoms noted. It may die, oc may be killed it any lime desired, and then a post-mortem examination is made, the conditions of the organs, &c., being observed and noted. The various tissues affected are examined microscopically ud cultures made from them; in this way the structural changes ud the relation of bacteria to them can be determined.

Though the causal relationship of a bacterium to a disease may be completely established by the methods given, another very important part of bacteriology is concerned with the poisons or toxins formed by bacteria. These toxins may become free in the culture fluid, and the living bacteria may then be got rid of by filtering the fluid through a filter of unglazed porcelain, 'hose pores are sufficiently small to retain them. The passage of the fluid is readily effected by negative pressure t* produced by an ordinary water exhaust-pump. The effects of the filtrate are then tested by the methods used in pharmacology. In other instances the toxins are retained to a large extent within the bacteria, and in this case 'be dead bacteria are injected as a suspension in fhiid. Methods lave been introduced for the purpose of breaking up the bodies °f bacteria and setting free the intraccllular toxins. For this Purpose Koch ground up tubercle bacilli in an agate mortar and trrattd them with distilled water until practically no deposit Kmamed. Rowland and Macfadyen for the same purpose introduced the method of grinding the bacilli in liquid air. At this temperature the bacterial bodies are extremely brittle, and are tatttreadily broken up. The study of the nature of toxins requires, *l wursc, the various methods of organic chemistry. Attempts

to obtain them in an absolutely pure condition have, however, failed in important cases. So that when a " toxin " is spoken of, a mixture with other organic substances is usually implied. Or the toxin may be precipitated with other organic substances, purified toacertain ex tentby re-solution, re-precipitation, &c., and desiccated. A " dry toxin 'is thus obtained, though still in an impure condition. Toxic substances have also been separated by corresponding methods from the bodies of those who have died of certain diseases, and the action of such substances on animals is in some cases an important point in the pathology of the disease. Another auxiliary method has been applied in this department, viz. the separation of organic substances by filtration under high pressure through a colloid membrane, gelatine supported in the pores of a porcelain filter being usually employed. It has been found, for example, that a toxin may pass through such a filter while an antitoxin may not. The methods of producing immunity are dealt with below.

The fact that in anthrax, one of the first diseases to be fully studied, numerous bacilli are present in the blood of infected animals, gave origin to the idea that the organisms might produce their effect by using up the oxygen asa~ata of the blood. Such action is now known to be quite a otaiscas*. subsidiary matter. And although effects may sometimes be produced in a mechanical manner by bacteria plugging capillaries of important organs, e.g. brain and kidneys, it may now be stated as an accepted fact that all the important results of bacteria in the tissues are due to poisonous bodies or toxins formed by them. Here, just as in the general subject of fermentation, we must inquire whether the bacteria form the substances in question directly or by means of non-living ferments or enzymes. With regard to toxin formation the; following general statements may be made. In certain instances, e.g. in the case of the tetanus and diphtheria bacilli, the production of soluble toxins can be readily demonstrated by filtering a culture in bouillon germ-free by means of a porcelain filter, and then injecting some of the nitrate into an animal. In this way the characteristic features of the disease can be reproduced. Such toxins being set free in the culture medium are often known as cxtroctllul r. In many cases, however, the filtrate, when injected, produces comparatively little effect, whilst toxic action is observed when the bacteria in a dead condition are used; .this is the case with the organisms of tubercle, cholera, typhoid and many others. The toxins arc here manifestly contained within the bodies of the bacteria, i.e. are intraccllular, though they may become free on disintegration of the bacteria. The action of these intracellular toxins has in many instances nothing characteristic, but is merely in the direction of producing fever and interfering with the vital processes of the body generally, these disturbances often going on to a fatal result. In other words, the. toxins of different bacteria are closely similar in their results on the body and the features of the corresponding diseases are largely regulated by the vital properties of the bacteria, their distribution in the tissues, &c. The distinction between the two varieties of toxins, though convenient, must not be pushed too far, as we know little regarding their mode of formation. Although the formation of toxins with characteristic action can be shown by the above methods, yet in some cases little or no toxic action can be demonstrated. This, for example, is the case with the anthrax bacillus; although the effect of this organism in the living body indicates the production of toxins which diffuse for a distance around the bacteria. This and similar facts have suggested that some toxins are only produced in the living body. A considerable amount of work has been done in connexion with this subject, and many observers have found that fluids taken from the living body in which the organisms have been growing, contain toxic substances, to which the name of aggressins has been applied. Fluid containing these aggrcssins greatly increases the toxic effect of the corresponding bacteria, and may produce death at an earlier stage than ever occurs with the bacteria alone. They also appear to have in certain cases a paralysing action on the cells which act as phagocytes. The 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 fox/as. important bacterial toxin has as yet been obtained in a pure condition, and, though many of them are probably of proteid nature, even this cannot be asserted with absolute certainty. Bricgcr, 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 ptotttaittfs. 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 Fracnkel 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, precipitablc by alcohol and various salts; they are soluble in water, arc somewhat cosily dialyaablc, 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 /«alkumosrs 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-frcc medium, a fact which shows that if the toxin is a proleid 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 invesli* gation and still less is known. Many of them, probably also of proteid nature, are much more resistant to heat; thus the intraccllular 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 Enxymts. resemble enzymes as regards their conditions of precipitation and relative instability, and the fact that 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 arc 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 tie noted th.it, 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 cliangcs cannot be delected, 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 "toxo* phorous," 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 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 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 arc 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 mesenterie 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 case3 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 another class of diseases the bacteria are restricted to some particular part of the body, and the symptom) arc due to toxins which are absorbed from it. Thus in cholera the bacteria are practically confined to the intestine, in diphtheria to the region of the falsa membrane, in tetanus to some wound. In the lastmentioned disease even the local multiplication depends upon the presence of other bacteria, as the tetanus bacillus has practically Do power of multiplying in the healthy tissues when introduced alone.

The effects produced by bacteria may be considered under the following heads: (i) tissue changes produced in the vicinity nim of the bacteria, either at the primary or secondary .-..'<i- foci; ()) tissue changes produced at a distance by absorption of their toxins; (3) symptoms. The changes in the vicinity .of bacteria are to be regarded partly as the direct fault of the action of toxins on Jiving cells, and partly as indicating a reaction on the part of the tissues. (Many iuch changes are usually grouped together under the heading of "inflammation" of varying degree—acute, subacutc and chronic.) Degeneration and death of celts, haemorrhages, serous and fibrinous exudations, leucocyte emigration, proliferation of connective tissue and other cells, may be mentioned as some of the fundamental changes. Acute inflammation of various types, luppucalion, granulation-tissue formation, &c., represent some of the complex resulting processes. The changes produced at a distance by distribution of toxins may be very manifold— cloudy swelling and fatty degeneration, serous effusions, capillary haemorrhages, various degenerations of muscle, hyaline degeneration of small blood-vessels, and, in certain chronic diseases, waxy degeneration, all of which may be widespread, are examples oi the effects of toxins, rapid or slow in action. Again, in certain uses the toxin has a special affinity for certain tissues. Thus in diphtheria changes in both nerve cells and nerve fibres have been found, and in tetanus minute alterations in the nucleus and protoplasm of nerve cells.

The lesions mentioned arc in many instances necessarily accompanied by functional disturbances or clinical symptoms, 3sMoa>». varying according to site, and to the nature and degree of the affection. In addition, however, there occur in bacterial diseases symptoms to which the correlated structural changes have not yet been demonstrated. Amongst these the ttost important is fever with increased protein metabolism, attended with disturbances of the circulatory and respiratory systems. Nervous symptoms, somnolence, coma, spasms, convulsions and paralysis arc of common occurrence. All such phenomena, however, arc likewise due to the disturbance of the nolecular constitution of living cells. Alterations in metabolism are found to be associated with some of these, but with others no corresponding physical change can be demonstrated. The action o( toxins on various gbnds, producing diminished or increased functional activity, has a close analogy to that of certain drugs. In short, if we place aside the outstanding exception of tumour growth, we may say that practically *U the important phenomena met with in disease may be ttperimenully produced by the injection of bacteria or of their tuxins.

The result of the entrance of a virulent bacterium into the tissues of an animal is not a disease \viUi hard and fast characters, but varies greatly with circumstances. With regard to the subject of infection the chief factor is susceptibility; with regard to the bacterium virulence is allimportant. Susceptibility, as is well recognized, varies much "nder natural conditions in different specie*, in different races «f the same species, and amongst individuals of the same race. It alio varies with the period of life, young subjects being more wiiceptible to certain diseases, e.g. diphtheria, than adults, ruitttcr, there is the very important factor of acquired susceptibility. It }, r, Ijcen experimentally shown that conditions such tt fatigue, starvation, exposure to cold, &c., lower the general powers and increase the susceptibility to bacterial So also the local powers of resistance may be lowered or depressed vitality. In this way conditions formerly

believed to be the causes of disease are now recognized as playing their part in predisposing to the action of the true causal agent, viz. the bacterium. In health the blood and internal tissues arc bacterium-free; after death they offer a most suitable pabulum for various bacteria; but between these two extremes lie states of varying liability to infection. It is also probable that in a state of health organisms do gain entrance to the blood from time to time and are rapidly killed off. The circumstances which alter the virulence of bacteria will be referred to again in connexion with immunity, but it may be stated here that, as a general rule, the virulence of an organism towards an animal is increased by sojourn in the tissues of that animal. The increase of virulence becomes especially marked when the organism is inoculated from animal to animal in series, the method of passage. This is chiefly to be regarded as an adaptation to surroundings, though the fact that the less virulent members of the bacterial species will be liable to be killed off also plays a part. Conversely, the virulence tends to diminish on cultivation on artificial media outside the body, especially in circumstances little favourable to growth.

By immunity is meant non-susceptibility to a given disease, or to experimental inoculation with a given bacterium or toxin. The terra must be used in a relative sense, and account must always be taken of the conditions present. An animal may be readily susceptible to a disease on experimental inoculation, and yet rarely or never suffer from it naturally, because the necessary conditions of infection are not supplied in nature. That an animal possesses natural immunity can only be shown on exposing it to such conditions, this being usually most satisfactorily done in direct experiment. Further, there arc various degrees of immunity, and in this connexion conditions of local or general diminished vitality play an important part in increasing the susceptibility. Animals naturally susceptible may acquire immunity, on the one hand by successfully passing through an attack of the disease, or, on the other hand, by various methods of inoculation. Two chief varieties of artificial immunity are now generally recognized, differing chiefly according to the mode of production. In the first—active immunity— a reaction or scries of reactions is produced in the body of the animal, usually by injections of bacteria or their products. The second—passive immunity—is produced by the transference of a quantity of the serum of an animal actively immunized to a fresh animal; the term is applied because there is brought into play no active change in the tissues of the second animal. The methods of active immunity have been practically applied in preventive inoculation against disease; those of passive immunity have given us serum therapeutics. The chief facts with regard to each may now be stated.

I. Active Immunity.—The key to the artificial establishment of active immunity is given by the fact long established that recovery from an attack of certain infective diseases is accompanied by protection for varying periods of time against a subsequent attack. Hence follows the idea of producing a modified attack of the disease as a means of prevention— a principle which had been previously applied in inoculation against smallpox. Immunity, however, probably results from certain substances introduced into the system during the disease rather than from the disease itself; for by properly adjusted doses of the poison (in the widest sense), immunity may result without any symptoms of the disease occurring. Of the chief methods used in producing active immunity the first is by inoculation with bacteria whose virulence has been diminished, i.e. with an " attenuated virus." Many of the earlier methods of attenuation were devised in the case of the anthrax bacillus, an organism which is, however, somewhat exceptional as regards the relative stability of its virulence.. Many such methods consist, to speak generally, in growing the organism outside the body under somewhat unsuitable conditions, e.g. at higher temperatures than the optimum, in the presence of weak antiseptics, &c. The virulence of many organisms, however, becomes diminished when they are grown on the ordinary artificial media, and the diminution is sometimes accelerated by passing a current

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