The Journal of Experimental Medicine

Niles, Walter L.; Wiggers, Carl J.

doi: 10.1084/jem.25.1.1pmid: 19868071

While auricular fibrillation is easily recognized by arterial and jugular tracings or by electrocardiograms, it is not possible to interpret all the waves found in these records. The venous tracings may in general be placed in one of two classes: ( a ) those in which prominent systolic waves predominate or occur alone; and ( b ) those in which large or small diastolic waves occur occasionally, in groups, or in a continued series averaging 250 to 500 per minute. The prominent systolic waves have generally been attributed to tricuspid regurgitation, the inference being that tricuspid regurgitation is a common state in auricular fibrillation. The diastolic waves are so numerous and so many electrocardiograms show diastolic waves that it is impossible to account for them on the assumption that the auricle is in a dilated and finely fibrillating state. It has been suggested that in these instances a condition of coarse fibrillation, which is closely allied to auricular flutter, obtains. The systolic and diastolic waves of the venous pulse of twenty-five clinical cases of auricular fibrillation, recorded by photographic methods, were studied. Six types of systolic waves (Text-Fig. 1) were found: (1) an intensified impact wave, the most common and often the only characteristic feature, indicating vigorous ventricular action; (2) a peaked impact followed by a rapid systolic drop due to light pressure of the tambour; (3) the intra-auricular type of systolic variation, so called from its resemblance to intra-auricular pressure curves found in animals, occurring in clinical cases only when ventricular systole is weak; (4) double systolic waves, attributed to a systolic tug of the ventricle on the auricles and large veins; (5) a systolic impact followed by a stasis wave, present when intravenous pressure is high; (6) a regurgitation wave composed of a steep rise continued into a systolic plateau with murmur vibrations superimposed. Our study showed (1) that tricuspid regurgitation, as indicated by the presence of regurgitation waves, is a rare accompaniment of auricular fibrillation; and (2) that the contrary opinion, arrived at by the frequent presence in polygraph tracings of ventricular types of waves, is due to the fact that the contour of intensified impact waves is distorted by polygraph levers so that they simulate regurgitation waves. Recurrent diastolic waves were frequently present in our records. Their relative size depended, to a considerable extent, on the pressure of the tambour. There was no constant relation to similar waves in the recorded electrocardiogram, nor is it proven that they are indicative of a coarse type of fibrillation or an associated flutter. Footnotes Submitted: 15 September 1916

Wiggers, Carl J.; Niles, Walter L.

doi: 10.1084/jem.25.1.21pmid: 19868076

With the clinical recognition, that different degrees of fibrillation occur and that these in turn are closely related to a coordinated type of auricular tachyrhythmia (flutter); further, that one type may lapse into another or into a perfectly normal rhythm, the conviction has grown that finer and coarser types of auricular movement may be recognized by the amplitude of the diastolic waves of the electrocardiogram and venous pulse. The present investigation into the cause of these waves has shown that this is not possible. There is no theoretical or experimental reason for the assumption that any fixed relation exists between the amplitude of the electrical variations of the electrocardiogram, which are the resultant of variations accompanying the irregularly spreading excitation wave, and the degree of mass contraction following. The large recurrent waves of the venous pulse, which may with more reason be regarded as related to the size of the auricular mechanical contractions on theoretical grounds, are also shown to be without differential value. The reasons for this may be briefly summarized. In the first place, the presence of diastolic waves is contingent upon a slow heart rate and long ventricular diastoles. With rapid heart rate their occurrence is prevented by the closely placed systolic variations. It is therefore conceivable that both coarse and fine fibrillation as well as flutter will be without diastolic waves as long as the heart is rapid. Even in the cases with long beats present their significance must remain doubtful. It is true that in the experiments the waves accompanying coarse fibrillation are as a rule somewhat larger than those occurring during fine fibrillation; waves of considerable size may, however, be present in fine fibrillation. Hence, as long as no calibrated method of recording is possible, it is difficult to draw any inference. It is possible from the same patient to record with the same apparatus diastolic waves of varying amplitude by merely changing the pressure of the receiving tambour. The chief reason that the amplitude of these waves cannot be regarded as of differential value is found in their origin. Fine fibrillating movements of the auricle do not in themselves produce waves in the jugular. They produce neither pressure variations in the auricle, nor exert any traction upon the veins. The only factor capable of producing jugular waves during fine fibrillation seems to be the traction exerted by the position changes of the ventricle on the auricle and large veins. This may, in a measure, explain why the diastolic waves recorded from the apex and second left interspace of patients often closely correspond with those simultaneously recorded from the jugular. The term "fibrillary waves" commonly applied to the smaller of these variations is evidently poorly chosen when their etiology is considered. The coarser contractions of the auricle during coarse fibrillation also produce no pressure changes within the auricle. They are vigorous enough at times, however, to exert a traction upon the venous walls. Hence, the waves during coarse fibrillation may be regarded as partly of ventricular and partly of auricular origin, or, as is frequently the case, as due to an interference of the two tractions. It is owing to their dual origin that they are more numerous and distinct when recorded from the same animal without changing the position or pressure of the receiving apparatus. Footnotes Submitted: 15 September 1916

Futaki, Kenzo; Takaki, Itsuma; Taniguchi, Tenji; Osumi, Shimpachi

doi: 10.1084/jem.25.1.33pmid: 19868077

1. Since our first report on the discovery of the cause of rat-bite fever, we have been able to prove the existence of the same spirochete in five out of six more cases which have come under our observation. 2. The clinical symptoms of rat-bite fever are inflammation of the bitten parts, paroxysms of fever of the relapsing type, swelling of the lymph glands, and eruption of the skin, all occurring after an incubation period usually of from 10 to 22 days, or longer. 3. Our spirochete is present in the swollen local lesion of the skin and the enlarged lymph glands. But as the spirochetes are so few in number it is exceedingly difficult to discover them directly in material taken from patients. It is therefore better to inoculate the material into a mouse. In some cases the organism is found in the blood of the inoculated animal after a lapse of 5 to 14 days, or at the latest 4 weeks. 4. Generally speaking, the spirochetes present thick and short forms of about 2 to 5 µ and have flagella at both ends. Including the flagella, they measure 6 to 10 µ in length. Some forms in the cultures reach 12 to 19 µ excluding the flagella. The curves are regular, and the majority have one curve in 1 µ. Smaller ones are found in the blood and larger ones in the tissues. 5. The spirochetes stain easily. With Giemsa's stain they take a deep violet-red; they also stain with ordinary aniline dyes. The flagella, too, take Giemsa's stain. 6. The movements of our spirochetes are very rapid, resembling those of a vibrio, and distinguish them from all other kinds of spirochetes. When, however, the movements become a little sluggish, they begin to present movements characteristic of ordinary spirochetes. 7. For experimental purposes, mice, house rats, white rats, and monkeys are the most suitable animals. Monkeys have intermittent fever after infection, and spirochetes can be found in their blood, but they are not so numerous as in the blood of mice. Mice are the most suitable animals for these experiments, and they appear, as a rule, to escape fatal consequences. 8. The spirochete is markedly affected by salvarsan. 9. The organism is not present in the blood of all rats, and there is no relation between the species of the rat and the ratio of infection. We have never found the spirochete in healthy guinea pigs or mice. By permitting a rat infected with the spirochete to bite a guinea pig, the latter develops the disease. 10. We have succeeded in cultivating the spirochete in Shimamine's medium. 11. Among the spirochetes described in the literature or discovered in the blood of rats and mice, there may be some resembling our spirochete, but none of the descriptions agree with it fully. Hence we have named our organism Spirochæta morsus muris and regard it as belonging to the Spironemacea (Gross) of the nature of treponema. 12. The spirochete can be detected in the bodies of patients. In seven cases out of eight, it disappears on recovery, only to reappear during the relapse. 13. The spirochete can be detected in about 3 per cent of house rats. These facts enable us to identify the cause of the disease. 14. There may be other causes than the spirochete for diseases following the bite of a rat. The cause, however, of rat-bite fever in the form most common in Japan is, we believe, the spirochete which we have described. Footnotes Submitted: 2 August 1916

Ishiwara, Kikutaro; Ohtawara, Toyoitsiro; Tamura, Kotaro

doi: 10.1084/jem.25.1.45pmid: 19868078

1. We have confirmed Ogata's results in experimental rat-bite fever caused by the bite of rats. 2. In our experiments with guinea pigs, swelling and congestion of the bitten parts, swelling of the subcutaneous lymph nodes, fever, and loss of weight were the typical symptoms. The progress of the fever was not so regular as in human cases, but we find records in the literature of patients who showed irregular fever types or were afebrile. The chief points that we noted in the anatomical view of the guinea pigs were swelling and congestion of the lymph gland system and acute changes in the adrenals and kidneys. 3. If an emulsion made from the lymph glands, cerebral substance, or the adrenals, or the heart's blood of a guinea pig of the original generation is inoculated subcutaneously or intraperitoneally into a fresh guinea pig, the animal invariably dies with the usual symptoms of fever and swelling of the lymph glands. The anatomical changes in this case were the same as those of the original guinea pig, except that the course was shorter and more regular. The same result was observed in further generations. No change was observed in pathogenicity, and in the guinea pigs of the original and further generations a species of spirochete as the causative agent was always observed. The incubation period in the original generation was from 1 to 2 weeks, and in further generations about 1 week. 4. When a mouse or white rat was inoculated, spirochetes always appeared in the peripheral blood, but no other symptoms developed. When peripheral blood drawn from a mouse thus treated was inoculated into a fresh mouse or a fresh white rat and peripheral blood drawn from the mouse and rat was inoculated into a fresh guinea pig, they all became infected and the guinea pigs always died. Thus we found that rats and mice are media but not victims of the disease, while guinea pigs are both media and victims of it. 5. In the rhesus monkey on which we made our experiment we witnessed a process similar to that of human rat-bite fever, and our spirochotes were observed in other animals into which blood drawn from the monkey was inoculated. 6. In the original animals spirochetes were seen chiefly toward the end of the process and the conditions as to the period previous to it are not yet clearly known. In further generations of all the animals we used, spirochetes were found in the peripheral blood 4 or 5 days after inoculation, and gradually multiplied until the greates number was reached about the 10th day after inoculation. They then began to decrease; yet spirochetes could be observed over 2 months later. 7. We have found spirochetes chiefly in the adrenals of the animals by Levaditi's method, but have not yet ascertained their distribution in other organs. 8. Our spirochete is short, round, and highly motile; it stains readily, and has few spirals. We have not yet observed an undulating membrane, but have seen what we believe to be flagellum at each end. 9. The identification of our spirochete with other species must be left for further study. The spirochete which Futaki, Takaki, Taniguchi, and Osumi found in two patients with rat-bite fever, seems to differ from ours in form. 10. Spirochetes disappear from the blood of the animals as a result of the injection of salvarsan, thus indicating that the spirochete is arsentropic. Footnotes Submitted: 7 August 1916

Cohn, Alfred E.; Jamieson, Ross A.

doi: 10.1084/jem.25.1.65pmid: 19868079

We have shown in a series of 105 cases of pneumonia, 95 of which we have selected as available for statistical study, that digitalis given by mouth has an action on the heart. We have judged this action to be present because changes occurred in the auriculoventricular conduction time and in the form of the T wave of the electrocardiogram, just as they do in the non-febrile heart. This conclusion is strengthened by finding that the pulse rate in fibrillating and fluttering cases fell in the presence of fever, exactly as it does in non-febrile cases. The dose and the time required to produce these effects are given and are the same as in the non-febrile cases. When there was a difference in the amount necessary to produce one or the other of the changes, it was found that the T wave is more often and more readily affected than the conduction interval. We have shown that the intoxication due to pneumonia is probably not responsible for the changes found, both from a study of the statistics and because in the control cases reverse tendencies were often found (that is, decrease in conduction time and increase in the size of the T wave). We have shown that the method of selection in consequence of which we treated a large number of severe cases did not prejudice our results, because it could be demonstrated that the proximity of death, whether in control or treated cases, was not necessarily associated with the changes we are describing. We have also, by referring to the literature of the subject, brought evidence to show that heart muscle does not undergo those changes in pneumonia, as it does in other infectious diseases, which would lead one to expect changes in conduction found in other diseases. The changes in conduction which have been reported by others were almost entirely associated with the giving of digitalis. Footnotes Submitted: 17 October 1916

Cutler, Elliott C.; Alton, Benjamin H.

doi: 10.1084/jem.25.1.83pmid: 19868080

We feel that the results obtained in the human case and in our animal experiments justify the supposition that magnesium sulphate may be of use in controlling cases of poisoning by strychnine. It is a method easily available not only in large hospitals but in private practice, and requires no elaborate technique. The amount of magnesium sulphate to be used should follow the advice of Meltzer (19) in tetanus cases: intraspinally 1 cc. of a 25 per cent solution to each 20 pounds of body weight in adults, and one-half the dose in young children. Should this not control the convulsions a small amount of ether may be used. In order to hasten the excretion of strychnine, 200 to 300 cc. of salt solution should be given intravenously. 6 In the event of the return of the convulsions, the intraspinal dose may be repeated, always taking precautions to keep the head elevated. Meltzer's apparatus for intrapharyngeal insufflation and a 2.5 per cent solution of calcium chloride should always be on hand in case of respiratory failure following an overdose of the magnesium salts (Meltzer (19)). Footnotes Submitted: 11 October 1916

Burrows, Montrose T.; Neymann, Clarence A.

doi: 10.1084/jem.25.1.93pmid: 19868081

Summing up these results, we found that all the ten α-amino-acids used inhibited the growth of the cells and finally killed the cultures. This inhibition is preceded by a short period of activity. The typical effect on the cells is shown in Figs. 1 and 2. The first (Fig. 1) is a control culture showing the usual growth of cells and their typical spindle shape form. The second (Fig. 2) is a culture in plasma plus asparagine showing the cells rounded off and beginning to undergo dissolution. We do not wish to draw too extensive conclusions from these experiments, but we believe that toxicity of α-amino-acids towards growing cells has been shown beyond a reasonable doubt; while we have found that compounds of higher molecular weight, namely, the peptones of egg yolk and proteins, are non-toxic. This toxicity depends upon the concentration and the time that the cells are exposed to their action. As these factors are reduced, the toxicity is decreased. In this respect, these substances are similar to all cell poisons. Applying these results to the work done on the intravenous injection of digestion mixtures, we believe that we have found a reason for the death of the experimental animals when the hydrolyzed proteins were injected too rapidly. Buglia found that large amounts of α-amino-acids could be injected into the circulation without causing deep-seated changes in the renal and intestinal functions, provided they were injected slowly enough; in fact, that enough of these mixtures could be injected in this way to cover the nitrogen consumption of the body. This injection, however, was always accompanied by an α-amino excretion through the urine and an increase of the peristalsis, of the intestine, with resultant liquid stools. As is well known, a sudden great concentration of these substances in the blood of an animal causes death. These results agree with our findings Folin and Denis demonstrated the fact that α-amino-acids probably pass into the circulation through the intestines. Van Slyke and Meyer, by means of Van Slyke's nitrogen method, have practically proven this, and Abel, Rowntree, and Turner, and Abderhalden have lately succeeded in obtaining α-amino-acids in crystalline form from the blood. Van Slyke and Meyer have shown that the tissues take up α-amino-acids to a certain point, but that after this the limit of saturation is reached. This is not so in the liver, which continually desaturates itself by metabolizing the α-amino-acids that it has absorbed, and consequently maintains indefinitely its power of removing them from the circulation, as long as they enter it no faster than the liver can metabolize them. Marshall and Rowntree have shown that there is an increase of the α-amino-acid concentration in the blood after injuries to the liver, which have caused deep-seated anatomical changes. Our experiments prove that tissue cells in general are unable to live in the presence of any great concentration of these acids. At the present time we do not feel able to give an explanation of the significance of this evident toxicity. However, the fact in itself seems to indicate that we should expect stimulation from a certain increase of the α-amino-acid concentration in the body, or the concentration of any one of the acids, while a greater increase would lead to marked disturbances of the metabolism. Footnotes Submitted: 25 October 1916

Bailey, C. H.

doi: 10.1084/jem.25.1.109pmid: 19868072

There may be produced in rabbits by the intravenous injection of large doses of diphtheria toxin a vascular degeneration involving the entire aorta, the carotids to the base of the skull, the subclavians, and iliacs, and, for a varying distance distally, the brachials, femorals, and large abdominal vessels. The first part of the pulmonary artery is sometimes affected. The lesion is practically diffuse throughout the aorta and vessels mentioned, consisting of a fatty degeneration and necrosis of the smooth muscle in a wide zone of the media and a crowding together of the elastic fibers in the region affected, resulting in an irregular thinning of the vessel walls and many small aneurysmal pouchings. In rabbits which received pituitrin with the diphtheria toxin extensive calcification occurred throughout this degenerated zone, both in the aorta and other large vessels. It is believed, however, that pituitrin is not essential to the calcification and that if it is of any importance it is because an extreme fatty degeneration is produced more quickly in the media of the vessels when it is administered simultaneously with the toxin. Diphtheria toxin, given in large doses intravenously, produces in the kidneys of the rabbit a pronounced vascular and parenchymatous degeneration. The former consists of a swelling and desquamation of the endothelial cells of the arterioles and small veins with the formation of fibrinous thrombi, a necrosis and thrombosis of the capillaries of the tufts with hemorrhage and the formation of fibrinous and hyaline masses, and in some of the affected glomeruli considerable collections of polymorphonuclear leukocytes. Footnotes Submitted: 2 October 1916

Park, Edwards A.

doi: 10.1084/jem.25.1.129pmid: 19868073

1. Accessory lobes of thymus, derived from the third pharyngeal pouch, occurring in close association with the parathyroids from the third pouch, were found in serial section of the cervical tissues of eleven out of fourteen guinea pigs, and probably would have been found in all fourteen but for a technical error. 2. It is probable, therefore, that accessory lobes of thymus having this situation and origin are usually, if not always, present in the guinea pig. 3. Additional accessory lobes of thymus belonging to, but at some distance from the main lobe were also present in several of the animals. 4. The discovery of these accessory lobes makes it certain that the guinea pig is unsuitable material for complete thymectomy, and probably complete extirpation of the thymus in this animal is rarely, if ever accomplished. 5. The extirpation experiments of previous investigators in the guinea pig must now be regarded as partial extirpations, and their results interpreted in that light. 6. Extirpation of the thymus in the guinea pig produced no changes in the writer's experiments. 7. The study of the serial sections of the cervical tissues of the guinea pig indicates that Ruben's statements regarding the parathyroid derived from the fourth pharyngeal pouch in the guinea pig are correct,—that it is much smaller than parathyroid III, may be rudimentary, and is sometimes absent at least on one side. 8. No accessory lobe of thymus was found accompanying the parathyroid from the fourth pouch, a finding also bearing out Ruben's statement that no thymus anlarge springs from the fourth pouch in the guinea pig. Footnotes Submitted: 2 October 1916

Motzfeldt, Ketil

doi: 10.1084/jem.25.1.153pmid: 19868074

1. The inconstant results of past observations on the relation of pituitary extracts to renal activity have been due chiefly to unsuitable methods. 2. A standard curve of artificially induced polyuria may be plotted for rabbits, giving 200 cc. of water by mouth. 3. Extracts of the pars intermedia and posterior lobe of the hypophysis, given by mouth, subcutaneously, or intravenously, are able definitely to check polyuria thus induced. Extracts of the anterior lobe show a similar effect, but only to a slight degree. 4. This antidiuretic effect is constant, and is independent of ( a ) changes in blood pressure, ( b ) intestinal absorption, and ( c ) the vagi. The effect is apparently prevented or delayed by division of the splanchnics, and is diminished by division of the renal nerves near the hilus. 5. A similar antidiuretic property is possessed: ( a ) by ß-imidazolylethylamine, ( b ) by p -oxyphenylethylamine, ( c ) by a preparation from Secale cornutum , ( d ) by small doses of nicotine, ( e ) by large doses of caffeine, and ( f ) by extracts of the adrenal cortex. 6. No effect on the polyuria is produced: ( a ) by strychnine ( b ) by morphine, ( c ) by adrenalin, or by extracts of ( d ) thyroid, ( e ) thymus, ( f ) pineal, ( g ) pancreas, or ( h ) corpora lutea. 7. In animals under chloral or paraldehyde anesthesia a short and inconstant initial increase in flow of urine is seen. 8. The antidiuretic effect is absent or only slightly marked in checking the so called salt diuresis. Footnotes Submitted: 29 September 1916