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The present study of the action of tryparsamide in human trypanosomiasis concludes a series of chemical and biological investigations in a particular problem of chemotherapy and thus represents the final step in a logical method of approach to such a problem. It has been shown that tryparsamide, the sodium salt of N-phenylglycineamide-p-arsonic acid, possesses a marked trypanocidal activity in human trypanosomiasis caused by Tr. gambiense. Single doses of from 0.5 to 5.0 gm. produced a peripheral sterilization of lymph glands and blood in an average of 6 to 12 hours. The duration of the peripheral sterilization following single doses of 17 to 83 mg. per kilo ranged from 17 to 58 days in patients who ultimately showed a return of trypanosomes to the peripheral blood. In a number of patients, however, treated with single doses of 9 to 68 mg. per kilo, no such relapse was detected during an observation period of from 40 to 111 days. The drug is extremely soluble in water and may be administered intramuscularly as well as intravenously. The immediate trypanocidal action after intramuscular administration was as rapid as that following the intravenous route while the duration of peripheral sterilization was appreciably longer. Relatively few repeated doses produced in advanced cases a marked and rapid diminution of the cells of the spinal fluid and were associated with definite improvement of mental and nervous symptoms. The occurrence of visual disturbances in certain advanced cases was the only untoward effect detected during the course of the work, and was apparently related to a too frequent administration of the drug. The condition was transitory in the majority of instances and resumption of treatment was not followed by a recurrence of this symptom. The general beneficial effect of the drug was a noticeable feature of its action in both early and advanced cases as shown by the disappearance of subjective symptoms, by the return of the pulse and temperature to normal limits, by the pronounced improvement of the blood picture, and by well marked gains in weight.

The results of serum neutralizing tests with the viruses of pox, vaccinia, and virus III disease herewith reported generally agree and supplement the results of reinoculation experiments on immune rabbits reported in the previous paper (1). The finding that pox virus is neutralized by pox immune serum indicates that the refractory state of recovered pox rabbits to reinoculation with pox virus and the failure of recovered pox rabbits to contract a second pox infection after adequate exposure is to be explained upon the basis of the development of an active immunity. The failure of virus III immune serum to neutralize pox virus is in agreement with the previous conclusion drawn from the positive results of reinoculation and exposure experiments that there is no specific relationship between pox virus and virus III. Rabbits which had recovered from a pox infection were completely refractory to inoculation with dermo-(culture) vaccine, while rabbits which had recovered from vaccinia were partially refractory to inoculation with pox virus. Vaccine immune adult rabbits did not show any clinical evidence of pox upon exposure to florid cases, but young recently weaned vaccine immunes developed definite although comparatively mild pox infections. The serum neutralization tests showed that pox immune serum neutralized vaccine virus although the action was not complete as shown by the positive results obtained with high dilutions of serum; vaccine immune serum possessed some but comparatively slight neutralizing properties against pox virus. The results of the crossed inoculation and serum neutralizing experiments with pox and neurovaccine viruses resembled those obtained with pox and dermo-(culture) vaccine but the differences were less pronounced. The differences in virus neutralizing ability on the part of the three immune sera paralleled the differences in virus potency as indicated by the character of the local lesions at the site of injection and by the general character of the clinical manifestations of the infection. The potency or virulence of pox virus was much greater than that of neurovaccine and vastly greater than that of dermo-(culture) vaccine. The complete identity of pox and vaccine virus could not be established, but a definite relationship between them was demonstrated and this was shown to have an immunological basis. From a practical standpoint vaccination with vaccine virus as a prophylactic measure against rabbit pox was clearly indicated.

The white mouse, the guinea pig, the calf, and probably the rat, were found to be susceptible to infection with the virus of rabbit pox. Serial transmission of the virus in mice by brain to brain passage was characterized by a fatal outcome usually on the 5th or 6th day after inoculation. Infection of the guinea pig was accomplished by intratesticular injection and the virus was continued to the 2nd passage in this species. Guinea pigs developed a well marked cutaneous reaction from the intradermal injection of both rabbit and guinea pig tissue virus. Active virus was demonstrated in the testicles of rats 8 days after intratesticular injection by rabbit subinoculation. In the calf inoculation of the scarified skin was followed by the development of large papular lesions with marked hemorrhage and necrosis. The results of the investigations on the etiology of rabbit pox and of the experimentally induced infection reported in this and the four preceding papers (1–4) are discussed with special reference to the relation of pox virus to other viruses and of rabbit pox to other pock diseases.

Experiments are reported in which it was shown that rabbits which had recovered from experimental or spontaneous rabbit pox were refractory to inoculation of pox virus injected by various routes, and in addition did not develop clinical manifestations of the disease under conditions of exposure to florid cases of pox. It was found that pox recovered rabbits were susceptible to inoculation with the virus of virus III disease of rabbits and that virus III recovered rabbits could be successfully inoculated with pox virus. Furthermore, virus III recovered rabbits developed pox when subjected to room exposure in the same manner as did normal rabbits. It thus appears that there is no specific relationship between the two viruses. Rabbits which had recovered from experimental or spontaneous pox were found to be just as susceptible to inoculation with the virus of infectious myxoma of rabbits as were normal rabbits, a result which demonstrates that there is no specific relationship between these viruses. Rabbits which had recovered from experimental or spontaneous pox were refractory to inoculation with culture dermovaccine virus, but vaccine recovered rabbits were not completely refractory to inoculation with pox virus. Under conditions of exposure to clinical cases of pox, adult vaccine immune rabbits did not develop clinical manifestations of pox, but young, recently weaned vaccinated rabbits did contract mild but definite clinical pox. Experimental pox recovered rabbits were partially refractory to inoculation with neurovaccine virus and neurovaccine recovered rabbits were partially refractory to inoculation with pox virus. The refractory condition of the pox immune rabbits appeared to be more pronounced than that of the neurovaccine immunes. The cutaneous lesions which developed from the intradermal injection of pox, neurovaccine, and culture vaccine viruses showed definite differences with respect to the rate and persistence of active growth, amount of edema, hemorrhage, and necrosis, and the degree of tissue destructiveness. These features were most pronounced in the lesions of pox virus and were least marked in the lesions of culture vaccine virus. The differences were particularly apparent in normal rabbits, but they were also present in the lesions which developed in immune animals. It was found that the calf was susceptible to inoculation with pox virus applied to a scarified skin area. There were many similarities in the appearance and course of the pox lesions to those resulting from culture vaccine virus, the New York Board of Health vaccine, and neurovaccine virus similarly inoculated. But the pox lesions were most numerous, much the largest and most destructive, and by far the most persistent while next in order were those of the Board of Health dermovaccine. The results of these various experiments showed that a close relationship obtains between pox virus, on the one hand, and vaccine virus and neurovaccine virus, on the other, but it cannot be said that pox virus is identical in all respects with either one of these viruses. The findings indicated that the relationship between pox and neurovaccine viruses is closer than that between pox and culture vaccine viruses. Upon the basis of the results observed in culture (dermo) vaccine immune rabbits inoculated with or exposed to pox, it appeared that vaccination with vaccine virus offered a method of protection against rabbit pox.

Experiments are reported in which was studied the effect of a concomitant infection, vaccinia, upon the syphilitic reaction of rabbits. Vaccine virus was inoculated intracutaneously on the side of the body at the time of intratesticular inoculation with Treponema pallidum. The results showed clearly that the vaccination caused a profound disturbance in the syphilitic reaction, the ensuing syphilis being extremely severe. From an analysis of various features of the reaction, it appeared that the factor of host resistance was primarily concerned in the effects observed.

Experiments are reported in which were studied the course and character of a transplantable malignant neoplasm in normal rabbits and in rabbits immunized with a filterable virus, Virus III. The disease which developed in immunized rabbits was extremely mild and much less severe than in normal animals. The effect upon the tumor process displayed by Virus III immune rabbits in the direction of diminished malignancy is considered to be entirely non-specific in character, and the suggestion is made that it is accomplished through a more effective resistance of the host.

A study of a malignant disease in rabbits has been made with reference to the presence or absence of a filterable virus, Virus III, in the tumor. The results are analyzed from the standpoint of certain characteristic features of the tumor process in order to determine any differences in degrees of malignancy. It was found that a more severe disease developed in the series in which the virus-bearing tumor was used than in the series in which the tumor was free of the virus, although the differences were not very marked and were not entirely constant. The influence of Virus III as a factor affecting malignancy has been discussed from the standpoint of its possible effect upon (α) the tumor cells and (b) the host reaction. It has been suggested that the greater malignancy of the pathological process usually induced by the virus-bearing tumor is attributable to a change in the response of the host to the tumor, which change is of the nature of a decreased resistance associated with the reaction of the host to the virus infection.

It has not been possible to propagate a malignant neoplasm of the rabbit with cell-free filtrates, or desiccated tumor tissue or by the use of fluid media kept in contact with tumor tissue. These findings confirm the results of previous experiments carried out with early generations of the tumor. The existence of an agent distinct from the tumor cell which could initiate growth has not been demonstrated. The experiments bring out an essential biological difference between this mammalian neoplasm which is considered to be of epithelial origin and certain filtrable tumors of fowls which have been classified as sarcomata.

A series of experiments was carried out for the purpose of determining whether the reaction of rabbits inoculated with Treponema pallidum might be influenced by their light environment. The conditions compared were (1) diffuse sunlight filtered through window glass and subject to variations due to natural causes, (2) constant and continuous exposure to artificial light with a wave-length of from 3022 to 5790 Ångström units (Cooper Hewitt), and (3) complete exclusion of light. The results showed clearly that each of these conditions produced a distinctive effect and that the effect tended to conform to the nature of the environmental condition. In general, the efficiency of the reaction to infection increased with the amount of light received and with the constancy of the exposure.

An experiment is reported in which an environment of constant and continuous light excluding the shorter ultra-violet rays, and one of constant darkness, have influenced the course and character of a malignant disease of rabbits induced by a transplantable neoplasm. Under the influence of constant light the level of malignancy was observed to be low; under the influence of constant darkness the level of malignancy was somewhat lower than in the control animals living under ordinary indoor light conditions, but the level was not as low as among the animals constantly illuminated. These observations furnish experimental evidence in support of the idea that there is a correlation between the external factor of light on the one hand and the manifestations of an experimental malignant disease on the other.

Data from 645 normal rabbits were used as the basis of an investigation of the relation existing between body and organ weights. Actual and relative weights were correlated with both gross and net body weight. The results obtained varied with different classes of organs but it was found that, in general, there was an agreement between the form and degree of the correlation shown and the structural and functional properties of the organs concerned.

Records of organ weights of normal rabbits covering a period of 3½ years were analyzed with a view to determining first, whether any significant variations of an orderly character could be demonstrated and, second, the general trend of the variations that occurred. It was found that many organs showed decided variations in weight which assumed the form of definite annual cycles. In addition, there was some evidence of a second cycle covering a period of years. These changes were most marked in the case of the endocrine glands (including the testicles), the lymphoid organs, and the liver.

A study of organ weights was made on a group of 295 normal rabbits for the purpose of determining whether any relation could be detected between the weights of organs and the extent and activity of the lesions found post mortem. The results obtained seemed to indicate that disease, even in its mildest form, is capable of affecting the weights of organs that are not directly involved by the disease process and that the effect produced bears a relation to both the extent and the activity of the lesions present. There was also some evidence that the converse might be true; namely, that the occurrence and subsequent course of disease may be influenced in some measure by the state of organ balance and the ability of the animal organism to adjust itself to meet the demands of disease-producing agencies.

A melanotic tumor developed in a defective eye of a syphilitic rabbit following repeated genital inoculations with Treponema pallidum. The appearance of the tumor coincided with the development of a syphilitic lesion in the same eye, suggesting a relation between the occurrence of the two lesions.

The results of a second series of organ weight determinations on normal rabbits are reported and the values obtained are compared with those for the first series. Figures are also given which represent the results obtained by combining the two series of animals or from weight determinations made on 645 apparently normal rabbits selected from stocks used for various experimental purposes.

Experiments are described in which the thyroid or thymus gland of rabbits was removed prior to inoculation of the animals with Tr. pallidum. The effect of these procedures is described from the standpoint of the manifestations of the disease. After complete thyroidectomy, the disease was considerably more severe than in the controls and very markedly so in certain instances. Partial tyroidectomy, on the other hand, resulted in a milder disease than that of the controls. The effect of complete thymectomy was less pronounced than that of either complete or partial thyroidectomy, but, in general, the syphilis resembled that in partially thyroidectomized animals. These effects are discussed in relation to the host's reaction and resistance to experimental syphilis and the conclusion was reached that the integrity and balance of the glands of internal secretion play an important rôle in the mechanism of defense against this infection.

We have found in the kidneys of twelve supposedly normal guinea pigs, coming from Pennsylvania and New Jersey, a parasite that closely resembles in some of its phases Klossiella muris, described by Smith and Johnson, and the renal parasite of two West African guinea pigs, described by Seidelin. The forms most commonly found by us and described as the sporoblast cycle, are evidently similar to those described by Smith and Johnson and by Seidelin. There are certain discrepancies of measurement between the parasite described by Seidelin and the one here described, but the most important difference between the two is the different number of sporozoites resulting from a final division of the daughter sporoblasts. Seidelin has found thirty sporozoites; we have found from eight to twelve, while the usual number is eight. Further, we have found a ring form which is unlike any of the stages in either the sporoblast or schizogonic cycle, and which we interpret tentatively as the male element or microgamete. In addition, we have found a tubular form which resembles the glomerular body of Klossiella muris and which we think is the schizogonic phase of this parasite.

1. The processes of repair in the kidneys of guinea pigs after sublethal doses of certain arsenical compounds indicate that all arsenicals do not produce a purely vascular type of renal injury. 2. While some arsenicals produce a predominantly vascular injury and others produce a predominantly tubular injury, both these tissue elements are undoubtedly always affected, although in varying proportion. In addition, the interstitial connective tissue is probably always affected. The diffuse proliferation of this tissue may be relatively conspicuous in the processes of repair after arsenicals that cause but slight vascular injury. 3. All red kidneys do not necessarily show identical pictures during the processes of repair; the same is true of pale kidneys. 4. The mode of action of an arsenical compound as a renal toxic agent is bound up with the chemical constitution of the compound.

1. We have shown that the type of renal lesion produced by compounds of arsenic varies widely: while some arsenicals produce changes in which vascular injury predominates, others produce an equally dominant tubular injury. 2. In either of these groups the character and degree of the vascular or tubular injury produced by different compounds shows further variation, such that the lesions of different arsenicals of the same group are not identical. Each compound of arsenic that we have tested, therefore, produces a lesion-complex in the kidney that is relatively characteristic for that compound. 3. The mode and character of the action of arsenicals are dependent upon the chemical constitution of the compound.

1. Toxic doses of all arsenicals of which we have any knowledge produce definite pathological changes in the adrenals of guinea pigs. These changes include congestion, hemorrhage, disturbances in the lipoid content, cellular degenerations and necroses, and reduction in the chromaffin content. 2. The character and severity of the injury produced by different arsenicals varies with the chemical constitution of the compounds. 3. From these facts, we believe that adrenal injury is an important factor in arsenical intoxication and suggest that therapeutic doses of some arsenicals may produce adrenal stimulation.

1. Two principal types of gonococci may be recognized by suitable immunological tests; e. g., agglutination and complement fixation. These two types correspond to the adult and infant types of infection with the gonococcus, seen clinically. 2. On the basis of the immunological reactions of agglutination and complement fixation the strains of gonococci isolated from three cases of ophthalmia are classed with the adult type. 3. A polyvalent antigen for the serological diagnosis of a gonococcus infection should represent strains of the infant type of organism in order that both types of infection, infant as well as adult, may be recognized.

N-PhenyIglycineamide-p-arsonic acid is an agent of marked therapeutic action in the treatment of experimental trypanosomiasis of mice, rats, and guinea pigs. It possesses an average curative range of from 0.2 to 0.3 gm. per kilo of body weight of the sodium salt against a 24 hour infection in mice and rats produced by several species of pathogenic trypanosomes. Since the lethal dose for mice is from 2 to 2.25 gm. and for rats 0.75 gm. per kilo of body weight, we have curative ratios of 1:8 and 1:3 respectively. The curative dose for guinea pigs is 0.15 gm. per kilo of body weight, thus giving a curative ratio of 1:10. The trypanocidal activity of this compound is relatively rapid in all three animal species, for the peripheral blood is cleared of organisms within 24 hours after its administration, and in addition, the lower limits of the curative range are comparatively sharply defined. Intraperitoneal, intravenous, and subcutaneous routes of administration for all practical purposes may be considered equally efficacious in Tr. brucei infections of mice both as regards the speed of action of the drug and the average curative range. The administration of the drug in therapeutic amounts in all three animal species is not followed by manifestations of organic or functional injury, but, on the contrary, the genera] physical condition of the treated animals shows an immediate and continued marked improvement. The therapeutic activity in trypanosomiasis of mice, rats, and guinea pigs as evidenced by the relative speed and sharpness of action, together with the curative ratio as expressed in fractions of the minimum lethal dose, and the absence of organic injury or functional disturbance following therapeutic doses are significant and characteristic features of the amide of N-phenylglycine-p-arsonic acid.

Gross and microscopic observations on the skeleton of rabbits with hereditary osteopetrosis have been described. All the bones were invariably and similarly affected. The outstanding abnormalities included the persistence of spongy bone and the presence of fibrous tissue together with the failure of development of a marrow cavity and medullary marrow. The amount of hemopoietic tissue, which was present only in comparatively small foci, was greatly reduced. The character of the lesions and their development as determined by examination of material at various stages of the disease suggested that the essential defect concerned the mesenchymal cell. The pathologic features observed generally resembled those of human osteopetrosis as did the manifestations of the disease during life (1, 2).

A study of the blood cytology of normal male rabbits was carried out from October 20, 1927 to November 22, 1928 in connection with an investigation of constitutional and environmental factors related to the occurrence and course of disease. In 1110 observations on 174 animals, total red and white cells counts, differential white cell counts by the supravital method, and hemoglobin estimations were made. A statistical analysis of the results obtained is presented. Attention is directed to the occurrence of wide variations in the numbers of the various white cells as contrasted with comparatively small variations in the numbers of red cells and of hemoglobin content. The results recorded are regarded as representing approximate rather than fixed values of normality.

Virus III and vaccine virus multiply in a transplantable rabbit tumor of epithelial origin; are carried along with the tumor through an indefinite number of transplants; and despite an immunity developed by the rabbit host survive longer in the tumor than when injected into the testicles of normal rabbits.

The effect of the removal of the complete cervical sympathetic nervous system, of both superior and of both inferior cervical ganglia, and of a small portion of the cervical sympathetic nerve in the rabbit was studied in relation to the character of a malignant disease induced by a transplantable neoplasm. It was found that the general character of the disease which developed in the operated groups of animals was more severe than that of a similar sized control group. Comparisons of the mortality rate in the several groups, of the animal inddence of metastases, the number of metastatic foci, and the distribution of these secondary growths all showed this to be the case. There appeared, furthermore, to be differences in malignancy among the operated groups themselves. The most severe disease occurred in the group in which a portion of the sympathetic nerve only was removed (sympathotomy); that in the complete sympathectomy and superior sympathectomy groups was slightly less malignant; and that in the inferior group was much less so. These results have been interpreted as due to a less effective animal resistance, the mechanism of which has been interfered with in some way by the interference with the sympathetic nerves. The reasons for the difference in malignancy exhibited by the several operated groups are undetermined. A tentative explanation is suggested upon the basis of coordinating, favorable or deleterious functions subserved by the cervical sympathetic nervous system.

A group of 350 normal rabbits was studied with reference to the occurrence of obscure lesions of various kinds and the probable or possible effect of such lesions or disease processes on organ weights. The results of the investigation are presented in the form of comparative tabulations. It was found that so long as the animals remained in apparently good health the values obtained for organ weights of animals with lesions did not differ materially from those for animals that were entirely free from lesions. There were, however, slight deviations from the normal which appeared to be significant in that they suggested a functional response similar in character to the more marked changes in mass and mass relationships that occur in rabbits presenting clinical symptoms of disease due to the same causes.

From a study of rabbits inoculated intratesticularly with two strains of treponemata derived from patients suffering from clinical yaws, it was found that a characteristic feature of the reaction to the infection was a well marked periorchitis of a granular or finely nodular type with or without a diffuse involvement of the tunic. While lesions of the testicular parenchyma also occurred they were relatively inconspicuous and consisted either of a minor diffuse orchitis which was usually followed by atrophy and fibrosis of the organ, or of small nodules; or there might be a combination of diffuse and nodular lesions. The granular periorchitis could be recognized clinically almost as soon as any change could be detected in the testicle, that is, about 3 weeks after inoculation; in the following month the covering of the testicle became studded with numerous tiny indurated nodules. Subsequently regression and healing took place and in the majority of animals no lesions were found 3 months after inoculation. In some animals residual lesions persisted for as long as 6 months. The granular periorchitis was a practically constant feature of the infection and was unlike any lesion of the tunic observed in experimental syphilis of the rabbit. Treponemata were numerous in the lesions of the tunic and somewhat less so in the testicle itself. Dissemination of organisms to the uninoculated testicle and to the inguinal lymph nodes was demonstrated by animal inoculation although the clinical signs of a metastatic orchitis and periorchitis were slight and a lymph adenitis was an inconstant feature of the infection. Generalized lesions in remote parts of the body, similar to those occurring in experimental syphilis of the rabbit, were not observed.

In November, 1921, a systematic study of normal rabbits was undertaken as a part of a more general investigation dealing with the subject of the animal organism in relation to disease. The present paper on organ weights is based on results obtained from a study of 350 male rabbits killed and examined between January 1, 1922, and July 1, 1924. Methods of conducting the experiments are described and the results are summarized in the form of a table and a series of text-figures. The organs studied were the heart, liver, kidneys, spleen, thymus, testicles, brain, thyroid, parathyroids, suprarenals, hypophysis, pineal gland, and representative groups of lymph nodes. The results recorded include maximum, minimum, and average weights, the median, the mode, the standard deviation, the probable error, the coefficient of variation, and the percentage distribution of organs of different weights. No final conclusions are drawn but it is pointed out that the results obtained are comparable to those that have been reported from similar studies of organ weight in man. Attention is also directed to the tendency to the occurrence of wide variations in the weights of nearly all organs, and to an apparent difference in the degree of correlation that exists between organ weight and body weight in the case of certain organs. In this connection it is pointed out that within certain limits the weight of the brain, in particular, and of other organs to a lesser degree appears to be independent of body weight. The results recorded in this paper are regarded as representing approximate values which are affected by numerous conditions for which correction should be made. These conditions will be considered in subsequent papers.

The results of transplantation, as recorded in the first section of the paper, are analyzed from the standpoint of the influence of the factors of serial passage, the material used for inoculation, the age and breed of the animals, and the time or season at which the experiments were carried out. The material used for the inoculation of different groups of animals appeared to have comparatively little effect on the ultimate results. The character of the animals used was found to be a factor of more importance in that the tumor displayed definite peculiarities of growth and malignancy referable to age and to breed or color markings. Still, it seemed unlikely that any of these factors would account for the variations in growth and malignancy that had been observed. After considering the various possibilities presented, it appeared that the principal factors concerned in determining the results of transplantation were adaptation to passage and variations in the conditions of season and weather that prevailed during the time the experiments were being carried out—the one affecting the energy of cell growth and the other affecting animal economy.

A report is given of the results obtained by intratesticular inoculation of a malignant tumor of the rabbit based on a study of the first twenty generations. The subject is presented from the standpoint of variations in growth and malignancy as they occurred with continued transplantation. Essential features of the experimental conditions and of clinical and postmortem observations are condensed and recorded graphically. On analyzing the results of these experiments, it was found that many changes had occurred in the behavior of the tumor during transplantation, but that the changes were of a very irregular character and as a rule did not proceed constantly in any given direction. Moreover, the evidence as to the effect of transplantation on the growth and malignancy of the tumor was contradictory in that there was a great deal of evidence to show that there had been a decided increase in the activity and capacity for growth on the part of the tumor cells. But, with the exception of a few generations, there was an apparent reduction in the incidence and percentage distribution of secondary tumors, while the death rate was unaltered or actually diminished. It was believed that this paradoxical situation afforded a basis for an explanation of the results that had been obtained by transplantation.

Experiments were carried out with three strains of Treponema pallidum to determine whether infection could be produced by applying an emulsion, rich in spirochetes, to normal mucous membranes of rabbits and whether an infection produced in this manner differed in any respect from one produced by other methods of inoculation. It was found that a simple instillation of a spirochete emulsion into the conjunctival sac or the sheath was all that was necessary to obtain an infection. Still, the infection produced in this manner differed from that produced by intracutaneous or testicular inoculations in that it tended to pursue a mild or asymptomatic course and frequently without the development of a characteristic chancre. It is pointed out that these experiments may have a bearing on problems pertaining to obscure and atypical cases of human syphilis as well as the more immediate question of the infectivity of Treponema pallidum.

Data bearing on the occurrence and distribution of metastases, as recorded in the preceding papers of the series, are analyzed with reference to the parts played by the tumor cell and by conditions which influence cell distribution and cell growth. It is shown that, while the tumor cell is an essential element in the production of metastases, its influence is relatively constant, and that the prime factors responsible for variations in the occurrence and distribution of metastatic growths are conditions that influence cell distribution or that affect the viability of the cell during transport, and conditions that affect the nutrition of the cell wherever it may become lodged. It is further shown that both the presence and the absence of metastases, as well as peculiarities of distribution and of growth, are susceptible of a comparatively simple explanation upon the basis of well recognized principles of pathological action. In brief, it was found that, while the tumor cells might be distributed by either the blood stream or the lymphatics, the mode of distribution and the fate of the cells were determined in accordance with the same general principles that are applicable to the distribution and disposal of foreign cells introduced into the animal body. It was pointed out, however, that in applying these principles to tumor metastasis, it was necessary to recognize the fact that tumor cells bear a definite relation to the tissues of the host and that they are living and agressive agents. Hence, the reaction that they arouse differs in some respects from that produced by inert or unorganized foreign material or by living cells of a foreign species.

As a part of a general investigation of a malignant tumor of the rabbit, the phenomena of metastasis were studied in a group of 191 animals. The results of this investigation are presented from the standpoint of the relation of metastasis to animal resistance. The incidence and distribution of different classes of lesions are given and the peculiarities of the growth in different organs and tissues are described with especial reference to the time and circumstances of their occurrence and the relation of metastases in one organ or tissue to those of another. It was found that while the picture presented by different animals varied greatly, there was a remarkable degree of uniformity in the character of the lesions in a given organ or tissue and in the circumstances under which metastases occurred in a given location. It was thus possible to establish a relationship between the distribution of metastases and the function of animal resistance. In brief, the conclusion was reached that the peculiarities of metastatic involvement displayed by individual animals were not entirely attributable to chance distribution of tumor cells but that they were founded very largely upon constitutional differences and that the picture presented in any given instance represented an expression of the interaction between tumor and host, the character and force of which were indicated by the nature and distribution of the lesions or by the organs and tissues affected.