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Objective Digital health interventions have potential to enhance rehabilitation services by increasing accessibility, affordability and scalability. However, implementation of digital interventions in rehabilitation is poorly understood. This scoping review aims to map current strategies, research designs, frameworks, outcomes and determinants used to support and evaluate the implementation of digital interventions in rehabilitation. Data sources Comprehensive searches from inception until October 2022 of MEDLINE, CINAHL, PsycINFO, PEDro, SpeechBITE, NeuroBITE, REHABDATA, WHO International Clinical Trial Registry and the Cochrane Library. Methods Two reviewers screened studies against the eligibility criteria. Implementation science taxonomies and methods, including Powell et al.'s compilation of implementation strategies, were used to guide analysis and synthesis of findings. Results The search retrieved 13,833 papers and 23 studies were included. Only 4 studies were randomised controlled trials and 9 studies (39%) were feasibility studies. Thirty-seven discrete implementation strategies were reported across studies. Strategies related to training and educating clinicians (91%), providing interactive assistance (61%), and developing stakeholder interrelationships (43%) were most frequently reported. Few studies adequately described implementation strategies and methods for selecting strategies. Almost all studies measured implementation outcomes and determinants; most commonly, acceptability, compatibility and dose delivered of digital interventions. Conclusion The rigour of implementation methods in the field is currently poor. Digital interventions require carefully planned and tailored implementation to facilitate successful adoption into rehabilitation practice. To keep pace with rapidly advancing technology, future rehabilitation research should prioritise using implementation science methods to explore and evaluate implementation while testing effectiveness of digital interventions.

Objective To test the hypothesis that people taking anxiolytic and hypnotic drugs are at increased risk of premature mortality, using primary care prescription records and after adjusting for a wide range of potential confounders.\ud \ud Design Retrospective cohort study.\ud \ud Setting 273 UK primary care practices contributing data to the General Practice Research Database.\ud \ud Participants 34 727 patients aged 16 years and older first prescribed anxiolytic or hypnotic drugs, or both, between 1998 and 2001, and 69 418 patients with no prescriptions for such drugs (controls) matched by age, sex, and practice. Patients were followed-up for a mean of 7.6 years (range 0.1-13.4 years).\ud \ud Main outcome All cause mortality ascertained from practice records.\ud \ud Results Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs). After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription.\ud \ud Conclusions In this large cohort of patients attending UK primary care, anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a seven year period, after adjusting for a range of potential confounders. As with all observational findings, however, these results are prone to bias arising from unmeasured and residual confounding.

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.

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.

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 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.

Experiments carried out on rabbits infected with Treponema pallidum showed that there was a constant invasion and localization of the organisms in the superficial lymph nodes, that the infection persisted indefinitely, and that organisms could be recovered at any time from such nodes as the popliteals. Based upon these observations, a method is proposed for the preservation or recovery of stock strains of Treponema pallidum and for the demonstration of infection in rabbits.

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.

Experiments are reported in which an environment of constant and continuous light with a wave-length of from 3022 to 5790 Ångström units, supplied by mercury arcs in crown glass, and 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 lower than in control animals living under ordinary conditions of diffused sunlight. Under the influence of constant darkness the level of malignancy was somewhat lower than in control animals but the effect of this environment was modified by the special character of the disease prevailing at this time. The incidence of bone metastases was unusually high, but it was greatly increased in the rabbits kept in constant darkness. These observations furnish experimental evidence in support of the belief that there is a correlation between the external factor of light and the manifestations of an experimental malignant disease.

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.

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.

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.

A group of 127 rabbits presenting clinical manifestations of disease of spontaneous origin was studied with a view to determining whether any relation could be detected between physical constitution as represented by organ weights and functional activity as measured by the efficiency of the reaction to disease. The results of the investigation are presented in tabular form and the values obtained are compared, by means of graphs, with corresponding values for normal rabbits. It was found that animals that were the subjects of disease showed decided changes in the weights of nearly all organs, changes which appeared to be of functional origin in that the values obtained for organ weights and coefficients of variation tended to conform, in general, with the efficiency of the reaction displayed by the various groups of animals into which the entire series was divided.

Consecutive weekly observations on the lymphocyte and monocyte counts of the peripheral blood were made on 5 groups of normal rabbits, a total of 45 animals, during a period of 20 months from October, 1927 to July, 1929. Individual groups were examined 8 to 35 weeks. The results are analyzed on the basis of the mean group values of each week. In the case of the 4 groups followed 13 to 35 weeks, there was a general tendency for the lymphocyte mean values to become increased; with the group observed 8 weeks, the level of mean values showed little change. The general trend of the monocyte mean values was also in the direction of higher levels but it was less pronounced than that of the lymphocytes. The period of greatest irregularity in the mean values of the lymphocytes was in the late winter and spring months of both years. With the monocytes, periods of fluctuating values occurred in the fall of 1927, the spring and early summer of 1928, and in the late winter, spring, and early summer of 1929. There was a certain degree of parallelism in the case of two groups examined during the same months with respect to the direction and time of occurrence of a change in the level of lymphocyte and monocyte mean values. The general levels of lymphocyte and monocyte mean values in the groups examined during 1927–28 were higher than in the groups of 1928–29. The results based upon the trends of mean group values obtained from consecutive weekly observations showed no evidence of a consistent numerical relationship between lymphocytes and monocytes.

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 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.

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.

The report is concerned with the occurrence of stigmata of syphilis in the progeny of syphilitic rabbits and the probable cause for such conditions in cases where no infection can be demonstrated. The history of a group of animals presenting these conditions is given and possible causes are discussed in the light of evidence derived from a study of these animals. In this instance, it appeared that the lesions suggesting syphilis were of functional rather than of infectious origin and that heredity was an important factor in determining their occurrence.

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. The blood cytology of 41 pairs of virgin rabbits was studied, each pair consisting of a buck and a litter mate sister. A comparison of the values for each blood factor of the two groups was made by obtaining the mean difference and the standard error of the mean difference. In addition, correlation coefficients, both zero order and first order eliminating age, and regression equations were calculated for each of the blood cell elements of the bucks and does. 2. It was found that the male values for both the red cell count and the hemoglobin content were higher than the corresponding female values, and these differences were of statistical significance. No differences were observed between the two groups with respect to other cells. Significant positive correlations were obtained between the two sexes for the following blood constituents: Red blood cell count, white blood cell count, hemoglobin content, lymphocytes in both absolute and relative numbers, and neutrophils, basophils, and monocytes in relative numbers. 3. Since all known variables had been held constant, it was concluded that the higher red cell count and hemoglobin value for the male group were the results of constitutional differences between the sexes. Moreover, the significant correlations between the blood cells of male and female litter mates were ascribed to hereditary influences, and thus the female as well as the male rabbit is available for studies on the mechanism involved in the inheritance of the blood formula. In addition, since high correlations were obtained for cells which have been found to be the most reliable indices of the natural immunity of the male host to subsequent inoculation with tumor or syphilis, it was concluded that these cells should give dependable information concerning the natural resistance of the female host to these two diseases.

A study of the red blood cells, hemoglobin, blood platelets, and the total and individual white blood cells was made on 180 male rabbits of known age and representing fifteen standard breeds. An attempt was made to eliminate or bold constant such variables as age, sex, season, time of examination, technical errors, food, housing, and disease. The mean, variance of the mean, and standard deviation were calculated for each breed sample and for the group as a whole. An analysis of the variance showed that the variation between the breed samples was significantly greater than the variation within the breed samples for the red blood cells, hemoglobin, blood platelets, total white blood cells, basophiles, eosinophiles, and lymphocytes per cubic millimeter and in per cent and the neutrophiles in per cent. No significant variations were detected in the monocytes except when the breeds were divided into heavy and light breeds. No variation in the neutrophiles per cubic millimeter was detected; a large number of the breeds had exactly the same mean neutrophile level. Characteristic blood formulae were found for the various breed samples having an adequate numerical representation. It was concluded that the varying blood formulae could not be explained on any other, except an hereditary (genetic) basis.

The results of postmortem examination of cases of hereditary osteopetrosis of the rabbit together with histologic observations on organs and tissues other than the skeleton have been described. The principal findings were, first, those associated with the characteristic progressive anemia of the disease, such as extramedullary foci of hemopoietic tissue, lymphoid hyperplasia, and the occurrence of hemosiderin in the liver, spleen, and lymph nodes. There was a widespread tissue distribution of intense phosphatase staining and of fine calcium deposition, as would be expected in the circumstances of the profound skeletal abnormality (3). In advanced cases with established growth retardation, malnutrition, and deterioration, the tissues generally showed a decreased glycogen content. The large amount of parathyroid tissue found in both early and late cases suggested a state of hyperparathyroidism. Low serum calcium, high serum phosphorus and phosphatase levels (2), and a predominately osteoblastic reaction (3) were suggestive of hypoparathyroidism. The possibility that an involvement of the parathyroid glands was a basic or primary condition of the disease is discussed. Evidence of a disturbance of other endocrine glands was shown by the predominately acidophilic staining reaction of the colloid of the thyroid, an enlargement of the adrenals in which both cortex and medulla participated, and the tendency toward a basophilia of the anterior lobe of the pituitary. It was pointed out that before an explanation of the part played by the parathyroid glands in this disease could be made, other data, including particularly embryological studies, must be available. Similarly, an interpretation of other endocrine gland changes must await additional information.

A group of 50 normal male rabbits kept under conditions of constant light that had none of the shorter ultra-violet rays and another group kept in constant darkness for 2 to 12 weeks were observed clinically and subjected to postmortem examination for the purpose of determining the effect of these environmental conditions upon general body health and the weights of organs. A similar group of 50 rabbits caged in an ordinary animal room for the same period, and two groups of 40 and 20 rabbits respectively, which had recently been brought into the laboratory, served as controls. It was found that the general health of the rabbits was not impaired by the artificial light or the exclusion of light. The gain in body weight which occurred in all groups was especially marked in the case of those kept under conditions of constant light. The incidence of spontaneous disease recognizable clinically during the experiment was extremely low and of a mild character and did not obviously disturb the health of the animal. It was found at postmortem examination, on the other hand, that 59.3 per cent of the rabbits caged indoors, that is in the light, dark, or unaltered rooms, and 58.3 per cent of those recently brought to the laboratory had visible lesions of some kind. The great majority of these lesions, however, were of a slight grade, and none appeared to have any deleterious effects upon the general physical state of the animals.

1. The blood cytology of 91 rabbits was studied prior to inoculation with a transplantable malignant neoplasm. The following statements refer in each instance to the mean values of the pre-inoculation counts. 2. The animals which were most resistant to the malignant disease had, before inoculation, normal red and white cell counts, normal hemoglobin percentages, high eosinophile counts, and low counts of monocytes and lymphocytes. The relations of the neutrophile and basophile counts were irregular, but normal values also appeared to be associated with greater resistance. 3. The most susceptible animals were those which had, before inoculation, red cell counts above 5,500,000 or below 5,000,000 per c.mm.; hemoglobin above 70 per cent or below 60 per cent (Newcomer); white cell counts below 6,000 or above 8,500 per c.mm.; low eosinophile, high monocyte, or high lymphocyte counts. 4. No animal with any of the following findings prior to inoculation recovered completely from the tumor as determined by autopsy examination: red cells above 5,500,000 per c.mm. of blood; hemoglobin above 70 per cent; total white cells above 10,000 per c.mm.; eosinophiles below 120 per c.mm., or below the relative value of 1.5 per cent; basophiles below 400 per c.mm., or below the relative value of 6 per cent; lymphocytes above 3,600 per c.mm.; monocytes above 1,500 per c.mm.; neutrophiles above 5,000 per c.mm.; and total granular cells above 5,700 per c.mm. In the case of each of the following pre-inoculation values, only 1 animal was completely free from tumor at autopsy: hemoglobin below 60 per cent; red cells below 4,800,000 per c.mm.; total granular cells below 3,300 per c.mm.; total non-granular cells below 2,300 per c.mm.; total non-granular cells above 3,700 per c.mm. No animal with pre-inoculation eosinophiles above 3.9 per cent, or basophiles above 16 per cent died from the tumor. 5. The blood findings before inoculation could be related to the character and outcome of the malignant disease, from the standpoint of animal groups as well as in the case of individual rabbits. 6. From the results of the experiments here reported, it seems possible to predict with an accuracy of between 80 and 90 per cent the individual resistance or susceptibility of rabbits to the tumor by a study of their blood cells before inoculation.

Two oriental strains of T. pallidum of Chinese origin were compared with two well known occidental strains, the Nichols and the Zinsser-Hopkins, on the basis of the clinical reaction to infection in the rabbit. Four experiments were carried out, two each in Peiping and New York. Animals from American and Chinese sources were represented in each experiment. The results obtained showed that the reaction to both Chinese strains was generally comparable to that of the American strains. But with both Chinese strains, lesions of the eyes were more frequent, the time relations of certain phases of the reaction were shortened, and there was a higher incidence of complete recovery (latency) within the observation period. In view of the well known variability of the syphilitic reaction, however, it was not felt that these qualitative differences in clinical response could be ascribed to inherent or biologically fixed properties of the strains.

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.

The manifestations and course of an hereditary disease of the rabbit are reported. The condition is present at birth and is invariably fatal, generally in the 4th and 5th weeks of age. Retardation and eventual cessation of growth with marked reduction in size are conspicuous characteristic symptoms. The condition, which first occurred in the backcross progeny of a pure bred Dutch male rabbit, is inherited. It is determined by the expression of a simple recessive unit factor, affected individuals being homozygous for the factor. Rabbits heterozygous for the factor are identified only by appropriate breeding tests. The condition is not sex-linked. The disease has a remarkable resemblance to osteopetrosis or marble bone disease of infants and children with respect to signs and general course and also, as may be stated in anticipation of later discussions (5, 6), to the characteristic abnormal condition of the skeleton.

In the course of routine postmortem examinations of rabbits infected with Treponema pallidum, six cases of pronounced granulomatous myocarditis were encountered. Treponemata were not demonstrated in the lesions, but the clinical history, and the gross and microscopic appearance of the lesions seemed to warrant a diagnosis of syphilitic myocarditis. The lesions measured 1.0 cm. or more in diameter and histologically were practically identical with those described by Warthin in cases of syphilitic myocarditis in man. These are the first cases of syphilitic myocarditis or of visceral syphilis in the rabbit that have been reported.

Pathological observations on hereditary achondroplasia in the rabbit have been described. At autopsy, the chief features of interest are: reduced size with disproportionately shortened extremities and large head, cutaneous and subcutaneous edema of variable degree and distribution, small shortened bones with a cartilaginous appearance and texture, immature teeth, and cleft palate in one-fourth the cases; blood-stained fluid in the thoracic and abdominal cavities; a comparatively small heart pointing to the right of the midline, a very large firm thymus, a large pale soft spleen, a large swollen liver with red mottling, and a stomach distended with thin greenish mucus but no milk. The mean relative weights of all organs in terms of the net body weight were larger than those of normal new-born litter mates. The mean actual weights of the kidneys, the brain, and especially the spleen and the thymus were also larger than their respective normal values, those of the heart, liver, and adrenals were slightly smaller, while that of the pituitary was the same. Histologically, all endochondral cartilages show marked abnormalities of differentiation with pronounced deficiency of ossification. Calcification of membranous bones is likewise deficient. The histological abnormalities of the long bones are very similar to, if not identical with, those characteristic of human fetal chondrodystrophy, the creeper fowl condition, the "bull-dog" calf, and achondroplasia of the dog. No histological evidence was found in any organ which would suggest a basis for a responsible causal agent of the abnormality. Minor to marked vascular dilatation and congestion and edema is a variable feature but is fairly widely distributed. The changes in the thyroid indicate an active gland. The cellular pattern of the pituitary is characterized by some increase in basophilic cells. The lymphoid elements of the spleen are more or less depleted. The hemopoietic tissue in the spleen and liver is reduced in amount. In blood obtained from the heart, there is a reduction in the numbers of red and white cells and platelets and in the hemoglobin content as well; immature cells and particularly normoblasts are comparatively numerous.

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.

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.

Periodic variations in the malignancy of a transplantable neoplasm of the rabbit, which have been studied during the last four years, have been correlated with certain meteorological conditions and especially with the actual hours of sunshine. It has been found, that periods of maximum and minimum sunlight corresponding with summer and winter were periods of relatively low malignancy; while the periods of greatest malignancy occurred at times of abrupt and rapid changes in the hours of sunshine corresponding roughly with spring and autumn.1, 2 The influence of these factors has been interpreted as operating upon or affecting animal economy, while susceptibility or resistance to disease is considered as a function of the animal organism. This conception is supported by analogous variations in experimental syphilis of the rabbit, and the observation that in normal rabbits rhythmic changes in the mass relationship of practically all organs of the body have been found which have a definite relationship to sea...

Summary and Conclusions Vaccination with vaccine virus of a rabbit colony of approximately 1500 animals was carried out as a prophylactic measure against rabbit pox. The observations made on the adult population are discussed in the present paper. Of 233 presumably susceptible animals, 195 or 83.7 per cent gave a positive local reaction to vaccination. Generalized lesions, comprising in particular cutaneous and mucocutaneous papules, adenopathy, and in males an orchitis, developed in 78 animals, an incidence of 33.5 per cent. Nine of these cases had had a negative vaccination. Clinical evidence of susceptibility to vaccinal infection was thus demonstrated in 204 presumably susceptible rabbits, an incidence of 87.6 per cent. Of 310 rabbits which had recovered from rabbit pox ten months previously and were, therefore, presumably refractory to vaccination with vaccine virus, 294 or 92.3 per cent gave completely negative results. A positive reaction to vaccination developed in 21 animals, however, and there were 3 cases of generalized lesions in animals with a negative local vaccination site, a result which shows that the refractory state induced by rabbit pox may eventually disappear. An outstanding feature of the results concerned the different character of the reaction of female as compared with male rabbits. A slight, even a negative, local reaction to vaccination was often observed in females and there were comparatively few cases of generalized lesions. This type of reaction was especially striking in the case of pregnant animals. The differences between the lower incidence of both local and generalized lesions in pregnant rabbits as compared with males were found to be statistically significant.

An experiment is reported in which was studied the effects of a concomitant vaccinal infection and of vaccinal immunity upon the reaction to syphilis in rabbits induced by intracutaneous inoculation. The results obtained showed that the reaction was modified by both conditions. A vaccinal infection initiated at the time of syphilitic inoculation was associated with a defensive reaction of lessened efficiency, the ensuing syphilis being more severe than in control animals. A state of vaccinal immunity present at the time of syphilitic inoculation was associated with a reaction of heightened efficiency, the ensuing syphilis being very mild. These results are in harmony with those obtained in other experiments in which the intratesticular route of syphilitic inoculation was employed.

From the study of a large number of rabbits with generalized cutaneous syphilis following local inoculation with Treponema pallidum, lesions were found most often about the hind feet and legs, the head, the front feet and legs, and the tail. There was further evidence of a selective distribution of cutaneous lesions in the fact that, on a given part of the body, the lesions were usually confined to a few restricted areas. About the head, they occurred almost exclusively on the sides and bridge of the nose, the lids, the brows, the lips, and the base and free portions of the ears. On the front feet and legs, the seat of predilection was the extensor and lateral surfaces of the fore arm, the carpus, and the feet, while on the posterior extremities they were situated upon the dorsum and lateral surfaces of the feet and ankles from the level of the tendo achillis to the base of the fifth toe. The positions of greatest frequency were the region of the tarsus and external malleolus, the base of the fifth metatarsal, the lateral and posterior surfaces of the heel and tendo achillis, and the base of the fifth toe. In many instances, the positions of predilection were exposed positions or areas of skin covering bony or tendinous prominences. It was also found that the character of the lesions differed somewhat in the various locations. The lesions of the head were mostly small circumscribed papules or processes of diffuse infiltration; on the fore arms and feet, affections of this type were about equally divided with larger granulomatous masses of a chancre-like character, while on the hind feet and legs, granulomatous lesions were far more numerous than those of any other type and frequently reached a very large size. The cutaneous eruption usually consisted of only a few lesions confined to some one part of the body, but occasionally they were more numerous and more widely distributed. In this connection, it was noted that when multiple lesions appeared in a given area at about the same time, the growth of most of them was abortive, and, as a rule, only one or two developed to any considerable size. Especial emphasis was placed upon this phenomenon of inhibition as a factor of fundamental importance in the experimental infection. From clinical observation, it was found that, as a rule, the first cutaneous eruption occurred at from 2 to 4 months after inoculation but might occur either earlier or later, depending upon the circumstances in the individual case. The earliest eruptions appeared 3 weeks after inoculation and the latest 2 years and 8 months, but, as a rule, the time between inoculation and the appearance of the first eruption did not exceed 4 to 6 months. Successive crops of cutaneous lesions appeared in a number of animals usually within the first 6 months after inoculation. In a few instances, however, there were repeated eruptions extending over a period of 2 years or more, the longest recorded period being 3 years and 7 months. The duration of individual lesions was found to be extremely variable, ranging from a few days in the case of a macular erythema to more than 2 years in the case of a few granulomatous lesions. The average duration of the lesions appeared to vary somewhat with the nature of the lesion but on the whole was not more than 2 to 4 months. No limits could be fixed, however, for the duration of an active skin infection as a whole. Again, it was found that the cutaneous infection tended to pursue a periodic or relapsing course. This was seen in the mode of growth and resolution of individual lesions, the occurrence of successive periods of eruption, and the recurrence of completely healed lesions, all of which was interpreted as evidence of the essential relapsing nature of syphilitic infections.

Summary and Conclusions The results of the vaccination with vaccine virus of 1185 nurslings in a rabbit breeding colony are reported. Failure to develop a local reaction to vaccination was of frequent occurrence, especially in very young rabbits. A characteristic finding in many animals was the occurrence of generalized manifestations, the most striking of which was a cutaneous papular eruption. Vaccination was carried out in three successive experiments on December 19, 1933, January 24, and March 21, 1934. The general character of the resulting vaccinia underwent a progressive decline in severity, and in the last experiment there was little clinical evidence of infection. The results are discussed from the standpoint of the reaction of the host and particularly with reference to such factors as the nature of the local response to vaccination, the age of the animal, the condition of fostering, and the immune or susceptible state of the nursing female.

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.

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.

Experiments were carried out on rabbits for the purpose of determining the effects of subcurative doses of arsphenamine and of neo-arsphenamine upon the resistance of infected animals to reinoculation with Treponema pallidum and hence the possibilities of the occurrence of a second infection in treated but uncured cases of infection. All the animals used were inoculated with the same virus, and the experimental tests were carried out when the first cycle of testicular reaction was nearing its height. The animals with the most marked testicular lesions were used for the basic experiment of treatment and reinoculation. The results of this experiment were controlled from four different standpoints: (1) the effect of the treatment employed upon the existing infection; (2) the immunity present at the time of treatment; (3) the virulence of the organisms used for reinoculation as compared with those causing the existing infection; (4) the comparative susceptibility of normal animals to the virus used for reinoculation. The results obtained showed (1) that the treatment employed was insufficient to cure any of the therapeutic controls; (2) that the infected controls were highly refractory to a second inoculation; (3) that the treated animals were highly susceptible to a second inoculation and although not cured of their original infection, reacted to the second inoculation with the formation of lesions indistinguishable from those of a first infection; (4) that in certain instances the treatment given had rendered infected animals more susceptible to infection than the normal controls.

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.

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.

In the treatment of experimental trypanosomiasis of rabbits with subsequent appraisal of the value of the therapeutic agent used, there are certain experimental factors including uniform infecting strains of trypanosomes and the observation of general procedures of method and time of inoculation conditioned by the infection itself which must be taken into account. The conspicuous and characteristic clinical signs and symptoms seen in rabbit trypanosomiasis serve as criteria of the severity and duration of the disease, and it is obvious that the infection should be well established before treatment is instituted. For the same reason, before the question of a permanent cure can be established, treated rabbits should be kept under observation for a sufficient period of time, which with the species of organisms that we have used is at least 3 months. The therapeutic results with the amide of N-phenylglycine-p-arsonic acid were obtained in rabbits which showed well marked clinical signs of a definitely established disease, and in many instances the infection was extremely advanced and of prolonged duration. The five species which we have employed, Tr. brucei, Tr.gambiense, Tr. equinum, Tr. equiperdum, and Tr. evansi, are uniformly fatal in rabbits. With the usual acute, actively progressing infection of from I to 2 weeks duration produced by our strain of Tr. brucei, the drug has a curative range of from 0.2 to 0.35 gm. per kilo of body weight, when administered intravenously in single doses, or from one-third to one-half the minimal lethal dose. Of the twenty-nine rabbits treated with doses falling within this range, twenty-five, or 86 per cent, were permanently cured and there were no relapses observed with doses above 0.3 gm. The infection produced by our strain of Tr. gambiense is controlled by a slightly lower dose, since there were no relapses with single doses of 0.3 gm. and a single dose of 0.15 gm. effected a cure in one of three rabbits so treated. The therapeutic experiments with Tr. equinum, Tr. equiperdum, and Tr. evansi are too few to admit of final conclusions, but apparently from the evidence at hand, much the same curative range is operative in Tr. evansi infections, while larger doses or a different system of treatment should have been employed in the treatment of rabbits infected with our strains of Tr. equinum and Tr. equiperdum. In addition to the ultimate curative results obtained with single doses within the curative range, it is important to consider the marked therapeutic action with smaller single doses, as shown by the rapid regression and healing of the clinical lesions of the acute infections produced by all five species of trypanosomes together with a marked improvement in the general physical state of the animal. Moreover, large single doses, above those of the so called curative range, caused no disturbance of a toxic nature and were apparently well borne. A system of repeated dose therapy may be employed with advantage in the treatment of both initial and relapsed infections in rabbits, especially in those instances in which there is induration or even necrosis of tissues with weakness and emaciation of the animal host. The factor of time of repetition or the spacing of doses is in our experience as important as that of size of the dose employed and depends upon the rate, degree, and duration of action of the particular dose of the drug in question. Since the amide of N-phenylglycine-p-arsonic add apparently possesses the power of tissue penetration to a marked degree, it is desirable to give the second dose within a short time after the first in order that it may have a full opportunity for the immediate and complete development of its action. The repetition of small doses such as 0.15 gm. per kilo of body weight on successive or alternate days has given successful results as regards both the immediate regression and healing of lesions and ultimate permanent cures in severe, chronic infections. It is possible, however, to administer increasingly large doses, if this is necessary, since infected as well as normal rabbits exhibit a remarkable tolerance to repeated large doses of the drug. The therapeutic activity of small doses administered intramuscularly is quite comparable with that observed after similar doses given intravenously, as indicated by the rate of regression and healing of clinical lesions, while such effects proceed somewhat more slowly after subcutaneous injections. Permanent cures have been obtained in Tr. brucei infection with intramuscular and subcutaneous administration of single doses of from 0.2 to 0.5 gm. of the drug per kilo of body weight and in other instances with three repeated doses of 0.1 gm. per kilo given intramuscularly. One severely infected rabbit which received 0.75 gm. per kilo per os immediately following a small dose of sodium bicarbonate was also cured. The therapeutic experiments here reported represent only a portion of those carried out with N-phenylglycineamide-p-arsonic acid and the scope of the present paper does not permit a detailed description of the many phases of the experiments or a full discussion of the various factors involved and the results obtained, all of which we hope to publish at some future time.

The occurrence of hereditary premature senescence in a family of pure bred Belgian hares belonging to a rabbit-breeding colony organized for the investigation of constitutional problems, has been described. Representatives of 20 generations of the complex have been studied. The condition was a degeneration of variable degrees of severity and two principal forms were recognized, the acute and the chronic, the chronic being the more frequent. The chronic form has now been described in terms of the principal local or external manifestations; that is, degeneration of the coat and skin, lesions of the eyes and feet, and reproductive abnormalities, and of the general deterioration which in severe cases pursued a progressive course characterized by muscle wasting, fat reduction, emaciation, weakness, and death. The acute form will be described in the next paper (2).

A widespread dissemination of Treponema pallidum from a local focus of inoculation in the rabbit constantly occurs by way of the lymphatics. Spirochetes were regularly recovered from the satellite lymph nodes by animal inoculation after scrotal inoculation; they were present as early as 2 days, when no specific primary reaction was detected, and at later periods of from 5 to 61 days after inoculation. Other superficial nodes at remote sites such as the popliteals and with no syphilitic lesions in the drainage area have also been shown to harbor active organisms. Although spirochetes were found in relatively few of the lymph node emulsions, the orchitis resulting from their injection was of a rapidly progressive type with an incubation period but slightly longer than that produced by a testicular or skin nodule emulsion rich in spirochetes. It has further been shown that a syphilitic infection is sufficiently established in the rabbit body within 48 hours after scrotal inoculation so that the primary lesion is no longer essential for its maintenance. Active treponemata survive in the popliteal lymph nodes for long periods of time and have been regularly recovered from them in cases of true latency. The lymph nodes, therefore, function as reservoirs of the organisms. The ability to recover the spirochetes from lymphoid tissue through successive generations is seen in the serial passage of lymph node emulsion to testicle during an 18 months period. The persistence of spirochetes in lymphoid tissue irrespective of the presence or absence of syphilitic lesions is a characteristic and fundamental feature of syphilis of the rabbit. The existence of infection, therefore, may be demonstrated at any time by the recovery of spirochetes from the popliteal lymph nodes by animal inoculation. This fact is of great practical importance in the therapy of the infection and may be profitably utilized in determining the ultimate effect of a therapeutic agent. These experiments demonstrate that the disease is not confined to the site of local inoculation but that lymphogenous dissemination of treponemata regularly takes place, and that during the course of this process organisms become localized in the lymph nodes and exist there indefinitely irrespective of the occurrence of manifestations of disease. The intimate relation of Treponema pallidum to lymphoid tissue is an essential concept of syphilis of the rabbit, and from this point of view, the infection is primarily one of lymphoid tissue.

From a study of a series of rabbits inoculated with two old strains of Treponema pallidum, it was found that localized infection of bones and tendons was of frequent occurrence and led to the formation of a variety of lesions. The bones usually involved were those of the face and the feet and legs. Most often the lesions arose from the periosteum but developed also within the bone or marrow cavities and at lines of epiphyseal union. Grossly, the periosteal lesions were of two types—one being a circumscribed, indurated, and nodular mass and the other a process of a more diffuse character. Histologically, the lesions presented the typical appearance of syphilitic granulomata composed of more or less distinct layers which corresponded roughly with structural divisions of the periosteum. The composition of lesions of membrane and of cartilage bones differed somewhat in this respect, especially in the development of an osteoclastic layer. Invasion of the bone with absorption and necrosis were constant features of periosteal affections and were most marked in the case of the facial bones and the small bones of the feet. Lesions in the bone and marrow cavities were detected chiefly by radiographs or by the occurrence of bone destruction in the absence of periosteal involvement. They were characterized by a loss of structural detail in the bone, rarefication, increased fragility, necrosis, pathological fracture, and epiphyseal separation associated with more or less granulomatous reaction. Histologically, the bone lesions presented essentially the same picture as those of the periosteum, while the lesions which arose from the marrow cavities were composed chiefly of polyblastic infiltrations. In this group of affections, the most important were those which developed at the epiphyses. The destructive effects produced by all classes of lesions varied from a slight surface erosion or rarefication to extensive necrosis resulting in the formation of bony defects or in disintegration or fracture of the bone. These conditions differed very decidedly with the particular bones involved. Of especial importance in this connection was the occurrence of a peculiar form of mass necrosis which at times resulted in the destruction of considerable areas of bone even in parts where the granulomatous type of lesion was comparatively slight. The most characteristic injuries were the saddle-nose deformities and the epiphyseal separation in the small bones of the tarsus and hind feet. The marks of permanent injury were, on the whole, comparatively slight, but they also differed both with the degree of the original injury and with the bone affected. Granulomatous lesions of tendons or tendon sheaths were occasionally seen, and in a few instances, lesions of synovial cavities were demonstrated microscopically.

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.