THE LIBRARY OF THE UNIVERSITY OF CALIFORNIA PRESENTED BY PROF. CHARLES A. KOFOID AND MRS. PRUDENCE W. KOFOID ipf • District case (E) Puerperal fever well Puerperal fever Hospital nurse (C) Scarlet fever The original case of scarlet fever infected two other people, one with scarlet fever and the other with puerperal fever ; this case of puerperal fever also infected two other people, one with puerperal fever and the other with scarlet fever. An even more remarkable instance is recorded by Dunn CH. vn] VARIATIONS IN PATHOGENICITY 99 and Gordon (1905). They describe an epidemic in Hertford- shire characterised by an extraordinary diversity of symptoms in different patients. In some cases there were sneezing, coryza, and the ordinary symptoms of a common cold. In other cases patients had "aches and pains all over," stiff neck and suffered subsequently from great debility ; such cases had all the appearances of influenza. In others, again, the illness closely simulated scarlet fever ; it began with sore throat, rigors, vomiting, headache, fever and rapid pulse, and was accompanied by a punctate rash at the end of the first 24 hours (followed later by desquamation), the " strawberry " tongue, circumoral pallor, enlarged cervical glands which in some cases suppurated, and, in some patients, complications such as nephritis, arthritis and otorrhoea. A fourth type resembled diphtheria and exhibited a suspicious membrane on the tonsil. A fifth type was notified in some cases as typhoid fever and was characterised by epistaxis, melaena, prostra- tion and, in some cases it is stated, a positive Widal reaction. Finally, a number of cases, particularly amongst children, resembled cerebrospinal fever and were so diagnosed ; these were characterised by profuse nasal discharge, pain in the back of the neck, headache, photophobia and irritability, dilatation of one or both pupils, persistent vomiting, drowsi- ness, head retraction, paralysis, coma and, sometimes, con- vulsions and death. Sometimes these widely divergent types were exhibited by the different members of a single family or household struck down by the disease, either simultaneously or con- secutively. After a thorough investigation these observers were convinced that the outbreak of these various types of illness was due to the prevalence and spread of only one disease and not a number of different diseases, and a bacterio- logical examination of a large number of cases by Gordon showed that the disease was due to infection by an organism closely resembling, if not identical with, M . catarrhalis. 4. In the fourth place, the same species of organism may give rise in different epidemics to widely different types of disease. For example, strains of B. influenzae may give rise 7—2 100 VARIATIONS IN PATHOGENICITY [CH. vn to epidemics of "influenza" characterised by symptoms resembling in one epidemic a simple coryza, in another rheumatic fever, in a third typhoid fever, and in a fourth cerebrospinal meningitis. 5. In the fifth place, the train of symptoms characteristic of infection by one organism may develop as a result of infection by a totally different organism. A striking instance of this is recorded by Head and Wilson (1899) who proved that a supposed case of rabies was actually due to infection by the diphtheria bacillus. The diagnosis of rabies was founded on the history and clinical symptoms. " The well authenticated history of a bite on the cheek by an unknown animal, the two months' incubation period, the onset with extreme pain and numbness in the region of the scar, the development of the characteristic laryngeal and respiratory spasms on attempting to take liquids, the spasm at first being slight but later more pro- nounced and towards the close again feeble or absent, the insomnia, the absence in the beginning of fever which later in the illness became pronounced, the rapid pulse at all stages, the attacks of violent delirium interspersed with periods of calm and complete rationality, the absence of all symptoms pointing towards any other simulating disease and the fatal termination — all serve to make an almost complete picture of rabies." The Klebs-Loeffler bacillus was isolated from the ventricular fluid and detected in the nerve cells of the medulla. The recognition of this organism was complete and beyond doubt. " Not less suggestive of rabies than the clinical history were the results of subdural inoculations of rabbits with emulsions prepared from the medulla of the patient. There occurred the long period of incubation (20 and 21 days) followed by phenomena similar to those in experimental rabies of rabbits, and other rabbits inoculated subdurally with the medulla of the first rabbits behaved in a similar manner." B. diphtheriae was demonstrated after death in the medulla of the rabbits. By a thorough investiga- tion, full details of which are given, infection by the virus of rabies was definitely excluded. CH. vii] VARIATIONS IN PATHOGENICITY 101 Dunn and Gordon (1905, vide supra p. 99) have described almost typical cases of scarlet fever, of cerebrospinal fever and of influenza, which proved to be due to infec- tion by the micrococcus catarrhalis. Gordon has described elsewhere typical cases of cerebrospinal fever due to B. typliosm. Nash has recorded a remarkable case of malignant en- docarditis characterised by fever, constipation, headache, drowsiness and delirium, photophobia, strabismus, head re- traction and the appearance of a petechial rash. The illness, in fact, presented all the clinical features of cerebrospinal fever. A copious growth of a pure culture of the Klebs- Loeffler bacillus was obtained post mortem from the spinal fluid and a similar growth from the heart's blood. There was a history of a discharge from the ear at the beginning of the illness but no history of sore throat. Thomson (1911) has recorded his own experience of an acute inflammation of the throat simulating diphtheria in producing, in the fourth week of the illness, temporary para- lysis of the tongue, arms and legs, but proved to be due to pneumococcal infection. Colman and Hastings (1909) state their conviction that some strains of B. coli are capable of causing a disease clini- cally identical with typhoid fever. III. The pathogenicity of bacteria presents yet another aspect, namely the character of the lesions produced by them in the living tissues. This can be studied in two ways. Firstly, by observing the lesions produced in the body at various stages in the course of an infective disease ; and secondly, by observing the lesions produced by the artificial inoculation of organisms into animals, both at the site of inoculation and elsewhere. 1. The lesions produced in the course of disease and ob- served post mortem not infrequently enable one to identify the infecting organism. For example, tuberculous ulceration of the intestine, tuberculous consolidation of the lungs, and tuberculous invasion of the skin, present altogether different features from typhoid ulceration of the intestine, pneumococcal 102 VARIATIONS IN PATHOGENICITY [OH. vn consolidation of the lung and streptococcal invasion of the skin, respectively. It is however common experience that even in the post mortem room a certain diagnosis of the nature of the infec- tion cannot always be made. Sydney Martin, in speaking of tuberculosis, says "There is, with the exception of the presence of the tubercle bacillus, no element in the structure of the tu- berculous lesion which is diagnostic of the disease." In other words the lesions regarded as characteristic of infection by one species of organism may be produced by infection by a totally different species. Such departures from what experience has taught us to regard as the normal or characteristic lesion in the case of a given organism may be accounted for by the influence of other factors beside the nature of the organism itself— such factors, for example, as the age of the patient, the route of invasion, the presence of a secondary infection, the effect of treatment, and many others. The question arises, how far, if it were possible to exclude such disturbing influences, would the lesions retain their specific character ? 2. This leads us to a consideration of the second method of studying the question — by observing the lesions produced by artificial inoculation of animals, both at the site of inocu- lation and elsewhere. Such a method enables one to, so to speak, "standardise" the lesion. A healthy animal of the same species, age and weight can be utilised at each experi- ment, the inoculation made in the same manner, at the same site, with the same number of organisms and these of the same degree of virulence, and the animal can be killed after the same interval of time. Many investigators maintain that under such conditions the lesions produced by a certain species of organism are constant in their appearance — that, however much the other characters of an organism may vary, this character at any rate is invariable and will establish beyond dispute to which of two species a doubtful organism actually belongs. Thus, Klein as long ago as 1899 in describing the "bacillus of pseudo-tuberculosis " stated that in cultural and morpho- CH. vn] VARIATIONS IN PATHOGENICITY 103 logical characters this organism showed certain resemblances to B. coli. The two organisms could be distinguished from each other most certainly by animal inoculation. Subcutaneous inoculation of the first named into the guineapig gave rise to typical nodular, necrotic, purulent changes in the lymphatic glands, omen turn, pancreas, liver, spleen, and lung, an effect which B. coli and its varieties did not produce. Again, Shattock (and others, 1907) regards the avian tu- bercle bacillus and the human tubercle bacillus as two distinct species on the ground that, whereas the former when inoculated into guineapigs produces merely a local or a local and glandu- lar disease, the latter produces visceral disease as well. Savage (1908-9) has recorded some interesting experiments illustrating the value of animal inoculation in revealing differ- ences in pathogenicity. He found that streptococcus mastitidis, which causes mastitis in the cow, was non-virulent to mice and other rodents but possessed to a marked degree the power to produce mastitis in goats when inoculated into the mammary ducts, and was thereby differentiated from streptococcus an- ginosa (isolated from human sore throat) which, though virulent to mice, did not possess the power to produce mastitis in goats. Continuing his experiments with pyogenic streptococci derived from many sources, he found that, although in their cultural properties and their virulence to mice they displayed wide differences, they all resembled each other in their inability to produce mastitis in goats. One streptococcus, for example, isolated from a fatal lymphadenitis in a boy, after it was in- oculated into the teat of a goat survived for seven months as a harmless saprophyte in the milk passages. One other example will suffice. We recognise clinically two types of pneumonia, lobar or croupous pneumonia and lobular, catarrhal or broncho-pneumonia. Both types may result from infection of the lung by the pneumococcus. The invading organism is apparently identical in the two cases, judged by the ordinary cultural and morphological tests, and the difference in the results produced are therefore attributed to differences in the age and vitality of the patient and the route of infection. 104 VARIATIONS IN PATHOGENICITY [CH. vn Eyre, Leatham and Washbourne (1906) endeavoured by the method of animal inoculation to ascertain whether the difference in the lesions caused depended upon specific differ- ences in the pathogenicity of the infecting strains. They found that strains of the pneumococcus isolated from cases of lobar pneumonia when inoculated subcutaneously into the guineapig almost invariably gave rise to a local inflammatory exudation of a fibrinous type, whereas strains isolated from cases of broncho-pneumonia, when similarly inoculated, almost invariably gave rise to a local inflammatory exudation of a celMar type, easily distinguished from the other. A number of strains of pneumococci obtained from a " neutral " source, such as the mouth, likewise showed differences in the nature of the inflammatory reaction they provoked at the site of in- oculation, some belonging to the "fibrinous" type and others to the " cellular " type. They further showed that this feature was not associated with any other differences between the strains as regards morphology or cultural characters or fer- menting properties and was quite independent of their degree of virulence. They therefore regarded it as a specific character. If the lesions produced in the body during the course of an infective disease are subject to variation, are those which result from the artificial inoculation of animals any more constant? The materials from which to form an opinion on this point are somewhat scanty. That the feature in some cases is very constant was shown by Shattock (and others, 1907) by means of the following experiment. They grew a strain of human tubercle bacilli for eight weeks in the spleen of a pigeon. The subsequent inoculation of the organisms into a guineapig gave rise, not as might have been expected to the lesions charac- teristic of avian tubercle, but to those characteristic of the human type. Baldwin (1910) likewise grew the human type of tubercle bacillus for 19 months continuously in the bovine tissues without in any way affecting its pathogenic powers to- wards rabbits and guineapigs. On the other hand, we have quoted in an earlier paragraph an instance of a certain strain of the diphtheria bacillus which CH. vn] VARIATIONS IN PATHOGENICITY 105 not only gave rise to atypical symptoms and lesions (namely those of rabies) in the human body in the course of disease but produced no less atypical lesions when inoculated into a rabbit (vide p. 100). Again, Savage (1908-9) found in further experiments that a virulent strain of the streptococcus mastitidis from the udder secretion in a case of bovine mastitis, under certain conditions (namely 3 days' residence in the human pharynx), was almost deprived of its characteristic power to produce mastitis in goats. Again, Mohler and Washburn (1906) claim that the various types of tubercle bacilli — human, bovine, avian — can be readily converted one into another, by prolonged residence in a suitable animal host, so as to be indistinguishable by the ordinary in- oculation tests. Rosenow (1914) obtained a strain of haemolysing strepto- cocci from the throat in a case of scarlet fever. A culture on blood agar yielded two distinct kinds of colonies, (a) non-ad- herent colonies of a haemolysing organism which fermented mannite but failed to ferment maltose and saccharose, (6) adherent, green-producing colonies of a non-haemolysing organism which would not ferment mannite but fermented maltose and saccharose. When injected into a rabbit, the former attacked primarily the joints while the latter showed a predilection for the heart valves. In other words, the original strain on artificial cultivation gave rise to two strains which differed in their pathogenicity. Finally, may be mentioned Foa's experiments (1890). He inoculated a rabbit with the diplococcus lanceolatus capsulatus with a fatal result. From this dead rabbit he inoculated two others, the first by injecting organisms derived from some of the fresh fibrinous pneumonic exudate in the lung, and the second by injecting organisms derived from the cerebrospinal fluid. He found that the disease set up in these two rabbits differed. The first rabbit showed, for example, an inflammatory oedema of the skin ; the second did not show this. He found, however, that if the strain isolated from the lung were grown anaerobically and then injected into a rabbit the effects it 106 VARIATIONS EST PATHOGENICITY [OH. vn produced were indistinguishable from those produced by the strain isolated from the spinal fluid. Whatever aspect of pathogenicity, therefore, we study, the same feature becomes apparent — namely, that this property of bacteria is, like others, subject to variation. VARIATION IN OTHER CHARACTERS OF BACTERIA. In the foregoing pages variations in morphology, ferment- ing power, virulence and pathogenesis have been discussed in detail. There remain many more characters of bacteria to be considered — such as their viability, their staining properties, their power to produce indol and to liquefy gelatin, their ag- glutination reactions and many others. It would be easy to illustrate the variations these characters also undergo under different conditions. Many examples will be found in Chapter II. CHAPTER VIII THE POSSIBLE OCCURRENCE OF TRANSMUTATION IN THE LIVING BODY THE significance of the variations recorded in the foregoing sections, with reference to the question whether actual trans- mutation of bacteria can be brought about artificially or not, will be dealt with later. It is proposed, at this point, to consider another aspect of the problem, namely the possibility of transmutation occurring in the tissues of the living body. In certain regions of the body one finds growing side by side two strains of organisms closely resembling each other in every respect save one — namely their pathogenicity. One strain is capable of causing a definite train of lesions and symptoms ; the other, as a rule, does not give rise to any signs of disease. The suggestion that one strain may be in some way a derivative of the other offers a tempting hypothesis to explain both their resemblance and their proximity to each other. An illustration will, perhaps, make this clearer. In the hides of cattle may sometimes be found non-virulent bacilli closely resembling B. anthracis. Such an organism was discovered by Andre wes and described by Bainbridge (1903) under the name B. anthracoides (vide p. 92). The organism was stated to differ from B. anthracis in the appearance of its colonies, in its rate of growth, in possessing slight motility and in being non-virulent. By slightly modifying the conditions of growth, colonies on agar could be made to assume the typical appearance of anthrax colonies, while its virulence proved capable of increase by "passage." The differences in character between this organism and B. anthracis were deemed sufficient by these observers to justify them in classifying it as a distinct species, but it is difficult to resist the conclusion either that 108 THE POSSIBLE OCCURRENCE OF [OH. vm the non-virulent organism was a direct derivative of the true anthrax bacillus or that it would be capable of giving rise to the latter under suitable conditions. Such a supposition is favoured, firstly, by the admission that the bundle of horse hair from which the B. anthracoides was isolated contained also the spores of true anthrax, and, secondly, by the discovery of Hueppe and Wood some years before (1889) of a similar non- virulent saprophytic anthrax-like organism in earth, which however on injection into a mouse rendered the animal immune to anthrax. Similar examples of association between non-virulent and virulent organisms, otherwise closely resembling each other, may be found in the human body — in the intestine B. coli and B. typhosus, in the throat Hofmann's bacillus and the Klebs- Loeffler bacillus, in the skin the Staphylococcus epidermidis albus and the Staphylococcus pyogenes aureus, in the naso- pharynx the micrococcus catarrhalis and the meningococcus. The exact relationship in each case has never been satis- factorily determined. Over twenty years ago Adami (quoted by Arloing, 1891) put forward the suggestion that B. coli might give rise in the presence of fermenting faecal matter to B. typhosus, a theory which has been recently revived by Tarchette (1904) and others (quoted by Hamer, 1909). The precise relationship between the virulent Klebs-Loeffler bacillus and Hofmanns bacillus is still a matter of controversy. The latter is a harmless saprophyte not infrequently found in the pharynx of healthy persons. It is distinguished from the true diphtheria bacillus by the somewhat different appearance of its colonies on artificial media, by slight and, according to some observers, inconstant differences in its morphology and staining, by its inability to ferment glucose and other sugars, and by being non-pathogenic to man and to the guineapig. It has not been found possible to produce immunity against true diphtheria by inoculation with Hofmann's bacillus, and the injection of a filtered broth culture of the latter does not give rise to antitoxin formation in the horse (Petrie, 1905) though the filtrate in the case of even avirulent Klebs-Loeffler bacilli will do so (Arkwright, 1909). Nevertheless many in- CH. vin] TRANSMUTATION IN THE LIVING BODY 109 vestigators claim to have converted the Klebs-Loeffler type of organism into the Hofmann type — by prolonged cultivation (Lesieur, 1901), by growth at a high temperature (Hewlett and Knight, 1897), by growth in the subcutaneous tissues of an immune rat (Ohlmacher, 1902) and other methods — and main- tain that the reverse change can be brought about by "passage" (Lesieur, 1901, Hewlett and Knight, 1897, Ohlmacher, 1902, etc.). Salter (1899) has stated that, by five successive passages through goldfinches, he was able to convert four strains of typical Hofmann's bacilli into no less typical Klebs-Loeffler bacilli, the transformation being complete as regards virulence, morphology and acid production, and in the power to form a toxin neutralised by diphtheria antitoxin. Thiele and Embleton claim to have converted Hofmann's bacillus into a bacillus morphologically indistinguishable from the diphtheria bacillus and capable of secreting an exotoxin which can be neutralised by diphtheria antitoxin. This was accomplished by inoculating a succession of guineapigs with an emulsion of Hofmann's bacillus containing a certain pro- portion of gelatin, the organism being recovered from the peritoneal cavity after each passage. As regards the fermenting properties of the two organisms, Clark (1910) has shown that Hofmann's bacillus does produce slight acidity in dextrose broth; while Goodman (1908), by a process of selection, obtained strains of the true diphtheria bacillus which exhibited differences in fermenting power as wide as those naturally existing between this organism and Hofmann's ; and he concluded that the fermenting power was a poor guide in determining whether an organism was a pathogenic one or a harmless saprophyte. Finally, Boycott's statistics demonstrate (Muir and Ritchie) that the period of maximal seasonal prevalence of Hofmann's bacillus immediately precedes that of true diphtheria, and Hewlett and Knight (1897) have offered evidence in support of the opinion that Hofmann's bacillus is present in increasing numbers in the throats of diphtheria patients during recovery from the disease. Recent work by Graham Smith and others, and the inability 110 THE POSSIBLE OCCURRENCE OF [CH. vin of these observers, on repeating the experiments of earlier investigators, to obtain the same results, somewhat invalidates the conclusions of the latter, so that the question of the possi- bility of a mutation between the two species remains sub judice. Several species of staphylococci are recognised, — £ epidermidis albus, S. pyogenes albus, S. pyogenes aureus. The distinction between these three rests on their inequality in virulence, on their different powers of fermenting carbo- hydrates, and, as their names imply, on their dissimilarity in the production of pigment. As regards virulence, the first-named organism is normally present in the skin of healthy persons and is non-pathogenic ; the second possesses slight virulence, producing mild local inflammatory conditions ; while the third is a virulent organism found in pathological conditions such as suppurative cutaneous and subcutaneous lesions, acute bone infection and septicaemia. Staphylococcus epidermidis albus may however assume a certain degree of virulence and give rise to a stitch abscess or mild inflammation (Dudgeon and Sargent, 1907) and plays an important role in peritonitis (ibid.). Andre wes and Gordon (1905-6) isolated it in pure culture in one case of otitis media and also from a boil. The Staphylococcus pyogenes albus can be made much more virulent by artificial passage. It has been known to become parasitic, invading the human body and circulating in the blood stream (Panichi, 1906, Southard, 1910). In the second place, as regards their fermenting properties, Gordon (1904-5) has shown that strains of Staphylococcus albus isolated from the skin of healthy persons show very great diversity in their fermenting power. In an earlier paper (1903-4) he describes two strains, one a Staph. albus derived from the skin and the other a Staph. pyogeiiies aureus derived from pus — which, when "put through" no less than 20 carbo- hydrate substances, revealed different fermenting power in one only, namely mannite. In the third place, as regards pigment formation, it has been proved by many investigators (Neumann, Dudgeon, 1908, Andrewes and Gordon, 1905-6) that non-pigmented cocci can CH. vin] TRANSMUTATION IN THE LIVING BODY 111 be obtained on culture from pigmented ones, and that cocci which fail to produce pigment under certain conditions will ) "Studies in Bacterial Variation." Journal of Hygiene, April 8th, 1911, vol. xi, No. 1, p. 30. (c] "Bacterial Variation." Reports to Science Committee Brit. Med. Association. Brit. Med. Journ. supplement, vol. u, 1911, p. 363. "Discussion on Variability among Bacteria and its bearing on Diag- nosis." Brit. Med. Journ., 1914, vol. n, p. 710. PETRIE, G. F. Quoted Arkwright, 1909. Journal of Hygiene, 1905, vol. v, p. 134. PETRUSCHKY. Quoted by J. Lorrain Smith, Clifford Allbutt and Rolleston's Syst. of Medicine, vol. I, p. 1091. (Article "Enteric Fever.") PREBLE. "Pneumococcic and Meningococcic Infections." Trans. ofAssoc. of American Physicians, vol. xxiv, p. 203. PRESCOTT, S. C. and BAKER, S. K. " On some Cultural Relations and Antago- nisms of Bacillus coli and Houston's Sewage Streptococci." Journal of Infectious Diseases, 1904, p. 193. RETTGER, L. F. and SHERRICK, J. L. "Studies in Bacterial Variation." Journal of Medical Research, Boston, vol. xxiv(N.S. xix), 1911, p. 265. REVIS, Cecil. "Milk and the Physiological Properties of Coliform Organisms." Journal of Pathology and Bacteriology, 1908, vol. xn, p. 228. RITCHIE, J. "On Meningitis associated with an Influenza-like Bacillus." Journal of Pathology and Bacteriology, 1910, vol. xxiv, p. 615. ROBERTS, E. H. and FORD, A. P. "A Case of Cerebro-spinal Fever simulat- ing Acute Nephritis with Uraemic Convulsions." Brit. Med. Journ., 1915, vol. i, p. 998. ROSENOW, E. C. "On the Nature of the Toxic Substance from Pneumococci." Journal of Infectious Diseases, 1912-13, vol. xi-xn, p. 235. "A Study of Streptococci from milk and from epidemic sore throat and the Effect of Milk on Streptococci." Journal of Infectious Diseases, 1912-13, vol. xi-xn, p. 338. "Transmutation within the Streptococcus-Pneumococcus group." Journal of Infectious Diseases, 1914, vol. xiv, p. 1. Roux, E. "Bacteridie Charbonneuse Asporog&ne." Annales de Vlnstitut Pasteur, 1890, iv, p. 25. Roux and YERSIN. "Mutation of Diphtheria and Hofmann's bacillus." Annales de I'Institut Pasteur, 1890, iv, p. 385. Russ, C. "Changes Produced in Coli bacilli after Electrolysis." Proc. ofJRoy. Soc. of Medicine, 1914, vol. vm, p. 54. SALTER. Quoted by Clark, 1910. Transactions ofJenner Inst., 2nd series, 1899, p. 113. SANARELLI. "Etudes sur la fievre typhoide experimentale." Annales de Ulnstitut Pasteur, 1894, vin, p. 193. SAVAGE, W. G. " Report on the Differentiation of the Streptococci by the Goat test." Reports to Local Gov. Board, 1908-9, vol. xxxvui, p. 295. 178 APPENDIX SAVAGE, W. G. "Gelatin surface colonies of Bacillus colicommunis." Journal of Pathology and Bacteriology, 1904, vol. ix, p. 347. Further Report upon the Presence of the Gaertner group of Organisms in the Animal Intestine. Reports to Local Gov. Board, vol xxxvn, 1907-8. "The coagulation of milk by Bacillus coli communis." Journal of Pathology and Bacteriology, 1905, vol. x, p. 90. SCHMITT, F. M. "Zur Variabilitat der Enteritis-bakterien." Zeitschrift f. Infektionskrankheiten, par asi tare Krankheiten und Hygiene der Haustiere, 1911, vol. 9, p. 188. SCHOTMULLER. See Muir and Ritchie, p. 207. SCHULTZ, O. T. "The Proportion of Granular and Barred forms of Bacillus diphtheriae in Throat Cultures." Journal of Infectious Diseases, 1909, vol. vi, p. 610. SHATTOCK, S. G., SELIGMANN, C. G., DUDGEON, L. S. and PANTON, P. N. "A Contribution to the Study of the Relationship between Avian and Human Tubercle." Proc. of Royal Soc. of Medicine, Pathological Section, Nov. 1907, p. 17. SMIRNOW, M. R. "Some Symbiotic Relations of the Bacillus diphtheriae." Journal of Medical Research, 1908, vol. xvm, p. 257. SMITH, Graham. Journal of Hygiene, 1906, vol. vi, p. 286. SMITH, Theobald. "The Relation of Dextrose to the production of Toxin in Bouillon Cultures of the Diphtheria bacillus." Journal of Experimental Medicine, 1899, vol. iv, p. 373. SOBERNHEIM and SELIGMANN. Zeitschrift fur Immunitdts-Forschung, 1910, vol. 6, p. 401 (Originale). SOUTHARD. Boston Med. and Surg. Journal, 1910, vol. 162, p. 452. STELWAGON, H. W. Diseases of the Skin, 1910, p. 710. SYMMERS, W. St. C. and WILSON, W. J. "Some points bearing on the Bac- teriology of Cerebro-spinal Meningitis." Journal of Hygiene, 1909, vol. ix, p. 10. TARCHETTI. Quoted Hamer, 1909. Centralblatt fur Bakteriologie, 1904, vol. xxxvi, p. 307, Referate. THIELE, F. H. and EMBLETON, D. "The Pathogenicity and Virulence of Bacteria." Journal of State Medicine, 1914, May, p. 270. THOMSON, W. H. "Vagaries of the Pneumococcus." The Medical Record, New York, 1911, vol. LXXIX, p. 565. TORREY, J. C. "A Comparative Study of Dysentery and Dysentery-like Or- ganisms." Journal of Experimental Medicine, 1905, vol. vn,No. 4, p. 365. TWORT, F. W. "The Fermentation of Glucosides by Bacteria of the Typhoid Coli group and the Acquisition of new Fermenting powers by Bac. dysen- teriae and other Micro-organisms." Proc. of Royal Society, 1907, Series B, vol. LXXIX, p. 32.9. WALKER, E. W. Ainley. "On Variation and Adaption in Bacteria. Illustrated by observations upon Streptococci with special reference to the value APPENDIX 179 of Fermentation Tests as applied to these." Proc. of Royal Society, 1911, Series B. vol. LXXXIII, p. 541. WALKER, E. W. Ainley. "Immunisation against Immune Serum." Journal of Pathology and Bacteriology, 1903, vol. vm, p. 34. and MURRAY, W. "The effect of certain Dyes upen the Cultural Characters of the Bac. typhosus and some other Organisms." Brit. Med. Journ., 1904, vol. n, p. 16. WASSERZUG, E. "Variations de forme chez les bacteries." Annales de rinstitut Pasteur, 1888, n, p. 75. WARD, Marshall, and BLACKMAN. Encyclopedia Britannica, xith Edition, 1910. (Article "Bacteriology.") WESBROOK, F. S., WILSON, F. B., MCDANIEL, 0. "Varieties of B. diphtheriae." Trans, of Assoc. of American Physicians, 1900, vol. xv, p. 198. WHIPPLE, G. C. and MAYER, A. "On the Relation between Oxygen in Water and the Longevity of the Typhoid bacillus." Journal of Infectious Diseases, 1906, supp. No. 2, p. 76. WILLIAMS, Anne W. "Persistence of Varieties of the Bacillus Diphtheriae and of Diphtheria-like bacilli." Journal of Medical Research, 1902, vol. vm, p. 83. WILSON, W. J. "Variation among Bacteria." Brit. Med. Journ., 1910, Dec. 17th. "Bacteriological Observations on Colon Bacilli of the 'Anaerogenes class'." Journal of Hygiene, vol. viii, No. 4, Sept. 1908. "Pleomorphism as exhibited by Bacteria grown on Media containing Urea." Journal of Pathology and Bacteriology, 1906, vol. xi, p. 394. WINSLOW, C. E. A. "The Systematic Relationship of the Coccaceae." WOOD, G. E. Cartwright. "Enzyme Action in Lower Organisms." Proc. of Royal Soc. Edinburgh, 1889, vol. xvi, p. 27. ZURCH and WEICHEL. Arbeiten aus dem Kaiserlichen Gesundheitsamte, 1910, vol. xxxni, p. 250. CAMBRIDGE : PRINTED BY J. B. PEACE, M.A., AT THE UNIVERSITY PRESS. 178 APPENDIX SAVAGE, W. G. "Gelatin surface colonies of Bacillus colicommunis." Journal of Pathology and Bacteriology, 1904, vol. ix, p. 347. Further Report upon the Presence of the Gaertner group of Organisms in the Animal Intestine. Reports to Local Gov. Board, vol xxxvn, 1907-8. "The coagulation of milk by Bacillus coli communis." Journal of Pathology and Bacteriology, 1905, vol. x, p. 90. SCHMITT, F. M. "Zur Variabilitat der Enteritis-bakterien." Zeitschrift f, Infektionskrankheiten, parasitare Krankheiten und Hygiene der Haustiere, 1911, vol. 9, p. 188. SCHOTMULLER. See Muir and Ritchie, p. 207. SCHULTZ, 0. T. "The Proportion of Granular and Barred forms of Bacillus diphtheriae in Throat Cultures." Journal of Infectious Diseases, 1909, vol. vi, p. 610. SHATTOCK, S. G., SELIGMANN, C. G., DUDGEON, L. S. and PANTON, P. N. "A Contribution to the Study of the Relationship between Avian and Human Tubercle." Proc. of Royal Soc. of Medicine, Pathological Section, Nov. 1907, p. 17. SMIRNOW, M. R. "Some Symbiotic Relations of the Bacillus diphtheriae." Journal of Medical Research, 1908, vol. xvm, p. 257. SMITH, Graham. Journal of Hygiene, 1906, vol. vi, p. 286. SMITH, Theobald. "The Relation of Dextrose to the production of Toxin in Bouillon Cultures of the Diphtheria bacillus." Journal of Experimental Medicine, 1899, vol. iv, p. 373. SOBERNHEIM and SELIGMANN. Zeitschrift far Immunitdts-Forschung, 1910, vol. 6, p. 401 (Originate). SOUTHARD. Boston Med. and Surg. Journal, 1910, vol. 162, p. 452. STELWAGON, H. W. Diseases of the Skin, 1910, p. 710. SYMMERS, W. St. C. and WILSON, W. J. "Some points bearing on the Bac- teriology of Cerebro-spinal Meningitis." Journal of Hygiene, 1909, vol. ix, p. 10. TARCHETTI. Quoted Hamer, 1909. Centralblatt fur Bakteriologie, 1904, vol. xxxvi, p. 307, Referate. THIELE, F. H. and EMBLETON, D. "The Pathogenicity and Virulence of Bacteria." Journal of State Medicine, 1914, May, p. 270. THOMSON, W. H. "Vagaries of the Pneumococcus." The Medical Record, New York, 1911, vol. LXXIX, p. 565. TORREY, J. C. "A Comparative Study of Dysentery and Dysentery-like Or- ganisms." Journal of Experimental Medicine, 1905, vol. vn,No. 4, p. 365. TWORT, F. W. "The Fermentation of Glucosides by Bacteria of the Typhoid Coli group and the Acquisition of new Fermenting powers by Bac. dysen- teriae and other Micro-organisms." Proc. of Royal Society, 1907, Series B, vol. LXXIX, p. 329. WALKER, E. W. Ainley. "On Variation and Adaption in Bacteria. Illustrated by observations upon Streptococci with special reference to the value APPENDIX 179 of Fermentation Tests as applied to these." Proc. of Royal Society, 1911, Series B. vol. LXXXIII, p. 541. WALKER, E. W. Ainley. "Immunisation against Immune Serum." Journal of Pathology and Bacteriology, 1903, vol. vm, p. 34. and MURRAY, W. "The effect of certain Dyes upen the Cultural Characters of the Bac. typhosus and some other Organisms." Brit. Med. Journ., 1904, vol. n, p. 16. WASSERZUG, E. "Variations de forme chez les bacteries." Annales de VInstitut Pasteur, 1888, u, p. 75. WARD, Marshall, and BLACKMAN. Encyclopedia Britannica, xith Edition, 1910. (Article "Bacteriology.") WESBROOK, F. S., WILSON, F. B., MCDANIEL, 0. "Varieties of B. diphtheriae." Trans, of Assoc. of American Physicians, 1900, vol. xv, p. 198. WHIPPLE, G. C. and MAYER, A. "On the Relation between Oxygen in Water and the Longevity of the Typhoid bacillus." Journal of Infectious Diseases, 1906, supp. No. 2, p. 76. WILLIAMS, Anne W. "Persistence of Varieties of the Bacillus Diphtheriae and of Diphtheria-like bacilli." Journal of Medical Research, 1902, vol. vm, p. 83. WILSON, W. J. "Variation among Bacteria." Brit. Med. Journ., 1910, Dec. 17th. "Bacteriological Observations on Colon Bacilli of the 'Anaerogenes class'." Journal of Hygiene, vol. vm, No. 4, Sept. 1908. "Pleomorphism as exhibited by Bacteria grown on Media containing Urea." Journal of Pathology and Bacteriology, 1906, vol. xi, p. 394. WINSLOW, C. E. A. "The Systematic Relationship of the Coccaceae." WOOD, G. E. Cartwright. "Enzyme Action in Lower Organisms." Proc. of Royal Soc. Edinburgh, 1889, vol. xvi, p. 27. ZURCH and WEICHEL. Arbeiten aus dem Kaiserlichen Gesundheitsamte, 1910, vol. xxxm, p. 250. CAMBRIDGE : PRINTED BY J. B. 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