times causes its death. Opposed to the original opinion of Koch is the fact that the action of tuberculin upon tuberculous tissues is, however, not specific, and not confined to it alone. As Römer was the first to show, the products derived from other microorganisms by boiling (proteins) induce precisely the same reaction.

The influence of tuberculin upon healthy and diseased human beings has been tested from both a diagnostic and a therapeutic standpoint in so large a number of cases that a definite opinion can now be expressed. Diagnostically, tuberculin has proved an exceedingly delicate reagent for the detection of tuberculous lesions. Subcutaneous injection of five milligrams is followed by no appreciable effect in healthy persons. In tuberculous individuals, however, this dose gives rise to fever of moderate degree, lasting for several hours, while at the same time a local reaction, manifested by redness and swelling, takes place in the tuberculous lesions in so far as these are accessible to examination. Initial doses of ten milligrams cause in tuberculous subjects greater and more protracted elevation of temperature, together with headache, nausea, and vomiting. Similar doses cause also in healthy persons febrile disturbance and general manifestations.

The undoubted diagnostic utility of minimal doses of tuberculin is rendered practically unavailable from the fact that the injection is followed by febrile movement in all persons who harbor tubercle-bacilli, even when these are latent and encapsulated—as, for instance, in lymphatic or. bronchial glands. It has been found, in numerous cases, that apparently healthy persons develop fever after injections of tuberculin in the same way as tuberculous patients. From what has been said with regard to the frequent occurrence of tubercle-bacilli in healthy persons, this manifestation should not occasion surprise; but a diagnosis of tuberculosis is not, in a clinical sense, justifiable when merely the presence of tubercle-bacilli within the organism has been demonstrated. The conditions are quite different in the diagnosis of tuberculosis than in that of diphtheria or of cholera. It is of the greatest sanitary importance to recognize the existence of diphtheria or of cholera in persons in whom, though apparently in perfect health, the exciting agents of those diseases are present in the saliva or in the dejections, because further cases of infection may

arise through them. In the case of tuberculosis, however, only those individuals are dangerous who present actual symptoms of disease-that is, those who throw off tuberclebacilli with the sputum or other excretions. In the case of tuberculosis thus the diagnostic requirements on the part of both physician and sanitarian are identical; whereas in the case of cholera and of diphtheria these diverge. From the foregoing considerations the employment of injections of tuberculin for diagnostic purposes should be restricted to cases of actual disease of obscure etiology. Frequently, however, under such conditions also this test has been abstained from because experience in some cases has demonstrated the possibility of the bacilli being disseminated from a previously circumscribed focus throughout the entire body as the result of an injection of tuberculin.

The therapeutic employment of tuberculin in tuberculous. individuals has yielded the following results: Lupus is at times favorably influenced by tuberculin. Extensive areas of lupus undergo necrosis and are exfoliated, so that complete recovery may take place; but no case is yet known in which recurrence has not taken place. Ulcers of the larynx clear in a most remarkable manner after injections of tuberculin, and undergo healing; but in these cases also recurrence generally takes place. Intestinal and peritoneal tuberculosis appears to pursue a relatively favorable course when treated with injections of tuberculin. Under all of these conditions, however, the fact stands out that the results are not final, because tuberculin lacks immunizing properties. Tuberculous disease of bones and joints is not at all influenced by the treatment. With relation to pulmonary tuberculosis, it may be stated with certainty that in the presence of advanced infiltration, of cavity-formation, and of mixed infection success can not be attained with tuberculin-treatment; and it is questionable, further, whether even incipient tuberculosis can be cured by the original method of Koch. A large number of unfavorable results are opposed to a small number of undoubted cases of incipient tuberculosis treated with favorable results. The objection may be raised that the results obtained in these cases are not attributable to the specific agent, but to the nutritive and general therapeutic measures employed simultaneously. Tuberculin has been almost entirely abandoned by physicians. In veterinary medicine, especially in France,

it is still employed on a large scale for diagnostic purposes, and, it appears, with great success.

The New Tuberculin-preparations, TO and TR.-After the failure of the original tuberculin, Koch applied himself unremittingly to the improvement of tuberculin-preparations. He found that immunity could not be conferred upon animals by subcutaneous injection of unchanged tubercle-bacilli. He, therefore, undertook to disintegrate the tubercle-bacilli mechanically, in order to render them the more easily absorbable. The cultures were dried in a vacuum and rubbed up in an agate mortar without addition until only a small number of bacilli were visible microscopically. The powder was mixed with distilled water, and centrifugated for from a half to three-quarters of an hour. In this way Koch effected a separation into two layers—an upper transparent, opalescent layer, which contained no bacilli, and a densely adherent lower layer. The latter was again dried, rubbed up, and centrifugated in the manner described, and the entire process was repeated until all the bacilli had practically been reduced to solution. Koch then determined that the solutions thus obtained were readily absorbable, and that they did not give rise to the formation of abscesses. It was found, however, that the fluid obtained from the first centrifugation exhibited reactions different from that obtained from the second and from subsequent centrifugations. Koch designated the first tuberculin O (obere, upper-TO); and all of the others, which were alike in their reaction, tuberculin R (residueTR). TO contains the constituents of the tubercle-bacilli soluble, and TR those insoluble, in glycerin. It can be readily understood that the properties of TO are comparable, on the whole, with those of the original tuberculin. TR, however, according to Koch, exhibits distinct immunizing properties, and gives rise to reaction in tuberculous subjects only when used in large doses. Its action is entirely independent of the reactions that played so important a part when the original tuberculin was used. Koch states that in conferring immunity with TR the reactions. may be entirely avoided, and, by carefully increasing the dose, tuberculous subjects may be habituated quite rapidly, without any reaction, to considerable amounts of the new remedy. When this has been accomplished, the organism may be considered as immune to the original

tuberculin and to TO-that is, to all of the bodily constituents of the tubercle-bacilli.

The new preparations are put upon the market by the Höchst Works. For purposes of preservation 20 per cent. of glycerin is added. One cubic centimeter of the new tuberculin TR contains 10 mg. of solid substance. After appropriate dilution with sterile, physiologic solution of sodium chlorid (if the daughter-solution is to be preserved for some time, 20 per cent. of glycerin is added), the treatment is begun by injecting 50 mg. The next higher dose is to be administered on the second day, and it should be of such an amount that temperature-elevations of more than 1⁄2 do not take place. Should these occur, the next injection must be deferred until the temperature has again become normal. As a rule, the treatment is suspended when the dose reaches 20 mg., and, if no reaction follows, the same amount is repeated at considerable intervals.

If it is desired to immunize healthy animals, as large a quantity is injected at first as is well borne by them-for instance, in the case of guinea-pigs, 2 or 3 mg. In this way Koch was able to immunize a considerable number of guinea-pigs to highly virulent tubercle-bacilli. The height of the immunity is attained two or three weeks after administration of the large dose. From this it appears that in therapeutic experiments on artificially infected guineapigs, which rapidly succumb to the disease, the treatment must be instituted quite early-not later than two weeks after the introduction of the virus.

Koch recommends that this new remedy be employed only in recent, pure cases of tuberculosis, uncomplicated by mixed infection. Patients who exhibit a temperature above 38° C. (100.4° F.) are not adapted to the new method of treatment. In cases of lupus Koch obtained considerable improvement without noteworthy local reaction. At the conclusion of his communication Koch emphasizes the fact that perhaps combinations of TO and TR with serum-preparations made from TO and TR may more quickly lead to the desired results. The clinical reports that have thus far been made with regard to the treatment of tuberculosis with TR show the freedom from danger that attends the use of the remedy, but little as to its therapeutic utility. Personally, no noteworthy results have been obtained in fifteen cases of pulmonary tubercu

losis thus treated. Behring is of the opinion that tuberculin R is less well adapted for therapeutic employment in the case of human beings than for the fundamental inoculation of animals for the purpose of further immunization. His own experiments, in connection with von Lingelsheim, in the preparation of a serum for tuberculosis, according to his statement read before the Fifteenth Congress for Internal Medicine, appear promising. Behring and von Lingelsheim in their experiments employed dry, highly virulent, pure cultures of tubercle-bacilli. According to Behring, the tubercle-bacilli contain various substances, but only one of the tuberculosis-toxins appears to possess immunizing properties. With the aid of this toxin it may be hoped that a curative serum or an antitoxin will be produced, as in the case of diphtheria and of tetanus; but according to Behring, years may elapse before this serum will prove sufficiently powerful to be introduced into general practice.

FOWL-TUBERCULOSIS.

The bacillus of fowl-tuberculosis is closely related to the bacillus of human and mammalian tuberculosis. It is somewhat longer and thinner, and exhibits more frequently bulbous and branched variations. It is more easily stained, but it retains the stain with similar tenacity. It is not so fastidious with regard to culture-media, and it develops upon ordinary agar and upon ordinary bouillon. The addition of glycerin, however, materially favors its growth, which, on the whole, is more rapid than that of the bacillus of mammalian tuberculosis. The cultures are not so dry, but more moist, and on solid media they form a coherent coating that bridges over the water of condensation. All cultures constantly exhibit a yellowish discoloration. At temperatures of 42° C. (107.6° F.), 43° C (109.4° F.) or 45° C. (113° F.) the bacilli of fowl-tuberculosis thrive as luxuriantly as at a temperature of 37° C. (98.6° F.). This is their most radical distinguishing feature as compared with the bacilli of human tuberculosis, which will not develop at this temperature. If the two varieties are considered identical, this difference must be explained by the fact that by reason of their residence in the body of birds, which naturally have a higher temperature (41° C.—105.8° F., or 42o C.-107.6° F.), the bacilli have adapted themselves to a higher temperature. The bacilli of fowl-tuberculosis are even more resistant to heat than those of human tuberculosis, being destroyed by exposure for fifteen minutes to a temperature of 70° C. (158° F.).