shown by the fact, established experimentally, that the larger the number of bacteria introduced, the more speedily does the death of the animal take place.

With regard to the purity of the infecting material, the question especially of mixed infection-that is, infection with a mixture of bacteria-arises. In a number of diseases in man several varieties of bacteria may almost always be found in the disease-focus; thus, for instance, in diphtheria streptococci as well as diphtheria-bacilli, and in advanced. tuberculosis pyogenic cocci as well as tubercle-bacilli. The presence of one variety of bacteria may facilitate the entrance and the activity of others, whose virulence is increased by the symbiosis; in other words, infection with the one variety of bacteria is rendered possible through the agency of the other. Attenuated pyogenic cocci may be rendered again virulent by the simultaneous introduction of bacterium coli, of proteus, and even of saprophytes, such as prodigiosus, or hay-bacillus. Streptococci are said to restore the toxicity of attenuated diphtheria-bacilli when injected simultaneously into guinea-pigs. The causative agents of typhoid fever and of cholera regain their infectiousness when they are introduced into animals in association with streptococci, coli commune, or with metabolic products of proteus. Tetanusbacilli or tetanus-spores alone, without their toxins, do not give rise to disease, as has been demonstrated experimentally by Vaillard; but if with them are injected other bacteria in themselves indifferent (as takes place in natural infection through earth and splinters of wood), germination takes place, with toxin-production and the development of tetanus. For other anaerobic bacteria similar conditions. appear to prevail; at least, it is possible to favor materially infection with malignant edema and symptomatic anthrax by simultaneous inoculation with pyogenic cocci, proteus, or prodigiosus, or their metabolic products. With such mixed infection, the clinical picture-the infection-may be a mixed one, as the result of the activity of the various bacteria. Thus, in the clinical picture of septic diphtheria the distinctively septic symptoms are to be attributed to streptococci; the intermittent fever of tuberculous patients, to pyogenic cocci. In other cases, however, the effect of the activity of the specific bacterium only may make itself manifest in the clinical picture (as with tetanus), and the rôle of the second is exhausted with the rendering possible of infection.

Finally, it is also possible, as Nencki has shown, that two microbes may produce an entirely new substance through their influence upon the culture-medium, and which neither of the two bacteria was alone capable of producing. Also, the observation of Nencki's, so characteristic for the significance of mixed infection, is to be borne in mind, that "sterile solutions of grape-sugar, simultaneously injected with two given bacteria, are much more rapidly and more energetically decomposed than by either of the two germs alone."

(c) The Portals of Infection.-Natural portals of infection are constituted by all those parts already named that communicate with the external world (p. 36). The most important infectious agents are taken up with the inspired air and with the nourishment or through the skin. The uninjured skin forms an insuperable barrier that can be overcome only by vigorous inunction of bacteria in an ointment-basis. It is possible, in this way, to produce furuncles by the rubbing in of staphylococci, and general infection by the rubbing in of anthrax-bacilli or of glandersbacilli. If, however, a breach in the continuity of the skin takes place, then the chances for the invasion of bacteria are rendered much more favorable. Superficial cutaneous fissures suffice to permit the bacteria of anthrax and of septicemia to gain entrance into the organism. Deeper subcutaneous wounds are more dangerous, because the lax tissues permit absorption in much greater degree. Contused and lacerated wounds, to which access of the oxygen of the air is not unobstructed, favor the development of anaerobic bacteria, especially that of tetanus. The absence of oxygen appears, further, to constitute a favoring influence for the activity of the ordinary pyogenic cocci. Recent wounds take up microorganisms with remarkable rapidity through the opened blood-vessels. Within as short a time as thirty or forty minutes, bacteria, even saprophytes, placed upon a fresh wound may be found within the internal organs. In the case of old suppurating wounds, on the other hand, absorption of microorganisms takes place only in quite limited degree.

The mucous membranes also, in an uninjured state, prove not especially susceptible to bacterial invasion. If, however, a breach in the continuity of the epithelial covering takes place, then opportunity is afforded for the entrance and the absorption of the germs present. Exceptions to

theria.

the rules just cited are furnished by a number of mucous membranes in relation to certain microorganisms. The normal conjunctiva is, for instance, susceptible to invasion by the gonococcus and also by the bacillus of intestinal diphUpon the mucous membrane of the urethra likewise, only the causative agent of gonorrhea thrives. In the mouth, according to the investigations of Sanarelli, only two microorganisms develop properly: the diplococcus of pneumonia and the bacillus of diphtheria. The tonsils, however, with their markedly irregular surface, and with their richly developed lymphatic structure, do not share in the protection of the remainder of the mucous membrane of the mouth, but, on the contrary, constitute a frequent portal of entry for numerous infections.

The gastric juice, by reason of the hydrochloric acid it contains, is disinfectant and bactericidal, but this gastricjuice hydrochloric-acid barrier has for a long time been greatly overestimated. The permanent forms-the spores -are not at all affected by the gastric juice, and the resistant tubercle-bacilli in no greater degree; and even less resistant germs pass the pylorus so rapidly, especially after the ingestion of large amounts of fluid, that the gastric juice is not afforded sufficient opportunity to cause the death of the microorganisms. The mucous membrane of the intestine is far more markedly predisposed to infection. The cause for this difference, as in the case of the tonsils, must be looked for in the abundance of glands, of lymphatic elements, and of the absorptive apparatus generally.

Bacteria are, under certain conditions, absorbed from the mucous membrane of the air-passages, and are then intercepted by the bronchial lymphatic glands. Only in this way is to be explained the not uncommon discovery of the presence of tuberculosis of these glands, with complete. immunity of the lungs. The uterine mucous membrane is, as may be readily understood, a most suitable surface for the absorption of infectious agents during parturition and also during menstruation.

In animal experimentation subcutaneous, intravenous, and intraperitoneal injections are especially employed. Other methods of inoculation, such as the cutaneous, the intraocular, the intracranial (subdural), etc., are employed less commonly, and only for special purposes. In animal experimentation the same amount of a culture exerts differ

ent effects in the same animal in accordance with the site of introduction. An amount of pneumococci that, injected subcutaneously, would cause death in a dog, will, when given by intraabdominal injection, cause no disturbance. Conversely, cholera-bacilli act more energetically in guineapigs when introduced into the peritoneal cavity than by subcutaneous inoculation. Cattle tolerate without ill result the bacilli of symptomatic anthrax when injected into a vein, whereas the same material introduced subcutaneously invariably gives rise to disease. In the same way also in human pathology the point of entrance of the bacteria into the body is of importance for the occurrence of an infection. Thus, cholera-infection occurs, as a rule, only through the intestine, pneumonic infection only through the upper air-passages-at least, it has been demonstrated that the subcutaneous injection of not too large amounts of cholera-bacilli or of pneumococci is without injurious effect upon human beings.

(d) The Susceptibility of the Infected Organism (Predisposition).—The susceptibility of different species of animals to an infectious disease varies widely. To tetanus, for instance, the guinea-pig and the white mouse are highly susceptible, the rabbit far less so, and fowl so little susceptible that it is only with difficulty that tetanus can be induced in these animals. To no variety of bacteria are all animals equally susceptible. Thus, while cattle, mice, and guinea-pigs are highly susceptible to anthrax, rats, dogs, and birds are almost entirely insusceptible, and coldblooded animals tolerate the pathogenic microorganisms almost universally without injury.

Also in the same animal species differences in susceptibility exist toward the same bacterium. Thus, field-mice suffer from glanders, while white mice do not. Older animals are, in general, less readily infected—that is, they are less susceptible than young animals. Congenital susceptibility is designated natural predisposition. This predisposition is, however, not constant in degree even in the same animal. It may be intensified or diminished. Thus, insusceptible animals may be rendered temporarily susceptible to certain diseases by protracted hunger, great muscular exercise, and similar influences. Such a temporary predisposition can, for instance, be induced in frogs to anthrax by exposure to heat, in fowl to the same disease

by exposure to cold, in pigeons by hunger or long-continued withholding of water, and in white mice to glanders by the production of phloridzin-diabetes. In the same way, intoxication with alcohol or with various substances, especially such as are destructive of the blood-corpuscles, gives rise, temporarily, to especial susceptibility. The predisposition of diabetics to certain infections (suppuration, gangrene, tuberculosis) may also be mentioned. Likewise, a temporary predisposition is established, according to the well-known theory of Pettenkofer, through telluric (groundwater elevation) and temporal influences (summer's heat) when an epidemic of cholera occurs.

In addition to the general predisposition a local predisposition may be distinguished, depending upon the varying susceptibility of the different tissues of the body. Hermann undertook the establishment of a scale of susceptibility for the staphylococcus. The anterior chamber of the eye proved most susceptible; then followed the circulatory apparatus of the rabbit; next the subcutaneous connective tissue of the dog; then the pleura, the cerebral meninges, the subcutaneous tissue, and the peritoneum again of the rabbit. Little is known with regard to the actual conditions upon which the degree of predisposition or susceptibility of a body for a given species of bacteria is dependent. The word predisposition is only an expression for the sum of resistances that the body offers to infection. What the nature of these resistances is will be fully discussed in the next section in a consideration of the subject of immunity.

A certain measure of resistive influences against infection must be present in every animal tissue; at least, there appears to be no absolute susceptibility. The weapons of the bacteria against these resistances are most probably their toxins; in this way the significance of the virulence and of the amount of the infectious agents introduced is rendered comprehensible. On the other hand, it must be assumed that the devices mentioned that are capable of increasing the susceptibility (inanition, overexertion, overcooling and overheating, anemia, glycemia, etc.) diminish these resistances of the organism.

With regard to the susceptibility of human beings to bacterial diseases, this is comparatively slight for most infectious diseases for the suppurations, pneumonia, cholera,