PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING OP THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION HELD IN ATLANTIC CITY, N. J., MAY 3, 1937 READ BEFORE THE SCIENTIFIC SESSION

The Etiological Relationship of the Eosinophile to the titer of serum antibodies, are not resistant to infection Gordon Test for Hodgkin's Disease. By JOSEPH C. with vaccinia. TURNER (by invitation) and HENRY JACKSON, JR., Boston, Mass. Estimation of Thyrotropic Hormone in Human Urine In 1932 Gordon reported that broth suspensions of and Blood in Health and Disease by the Micrometric lymphadenomatous (Hodgkin's) tissues upon inocula- Analysis of the Response of the Guinea Pig Thyroid. tion into the brains of rabbits or guinea pigs produce a By PAUL STARR and (by invitation) RULON W. RAW- characteristic paralysis (Gordon test). Subsequent in- SON, Chicago, Ill. vestigation has established that approximately 75 per cent of cases of Hodgkin's disease exhibit this phenomenon. A method of approximating the amount of thyrotropic Friedemann (1933) discovered that a paralysis in the hormone present in a solution by the micrometric analysis same animals, indistinguishable from that of Gordon, is of the response of the guinea pig thyroid has been de- produced with extracts of normal human bone marrow, scribed. A frequency curve of the heights of the acinar spleen, or leukocytes. cells measured with an ocular micrometer was plotted The nature and significance of the paralysis-producing and subjected to statistical analysis. Increasing doses of agents of Gordon and of Friedemann remain obscure. a known thyrotropic preparation (Parke, Davis and Com- Their identity has not been proved. pany) gave a series of curves shifting increasingly to We have performed the Gordon test in ten cases of the right. Hodgkin's disease. The test was positive in six and in The urine itself, or the acetone precipitate from small these six only could eosinophiles be found. Moreover, amounts, or the isoelectric precipitate from large amounts, the potency of the material used varied directly with the injected into the animal, produces characteristic shift of number of eosinophiles present. such a curve. In the case of a normal person with a In order to test the significance of this observation, normal metabolic rate and no evidence of thyroid in- suspensions were made of the bloods of normal and dis- activity, there is slight shift to the right. Patients with eased individuals, some of whom had a high degree of moderately low metabolic rates, "relative hypothyroid- eosinophilia. Animal inoculations showed that a paraly- ism," have more of this material in the urine. This sug- sis-producing factor was present in titers which paralleled gests that the procedure may be used to detect the need precisely the number of eosinophiles in suspension. Sus- for thyroid hormone when general metabolic measure- pensions containing few, or no, eosinophiles gave nega- ments are inconclusive. Following total thyroidectomy tive results. the urine contains excessive amounts. It appears that the Gordon test is positive in Hodgkin's In hyperthyroidism there is less thyrotropic hormone disease only because of the presence of eosinophiles. It present than in the normal urine. This is true whether is tentatively proposed that the paralysis-producing agent or not exophthalmos is present. This raises the possi- present in the tissues of certain cases of Hodgkin's dis- bility of the use of the procedure as a diagnostic aid in ease and that present in normal leukocytes are both de- hyperthyroidism. Patients with various types of pitui- rived specifically from the eosinophile and are therefore tary tumors and goiters have different amounts of the identical. material in the urine. The possibility that lack of response to the hyper- Studies of a Stable Antigen of Vaccine Virus. By thyroid urine is due to excess iodine present has been ROBERT F. PARKER (introduced by J. T. Wearn), covered by the addition of amounts of iodine of like Cleveland, Ohio. order to specimens giving marked stimulation. The pos- The isolation of a serologically active heat stable sub- sibility that the response is not specifically due to thyro- stance from tissues infected with vaccine virus has al- tropic hormone has been met by heating the specimen, ready been reported, and the chemical characteristics of since the pituitary thyrotropic hormone is heat labile. the substance have been described. On inoculation into Furthermore, the hyperthyroid urine containing similar rabbits, it elicits the formation of antibodies, demon- amounts of foreign material fails to give a response. strated by precipitation and complement fixation tests. Blood serum from these groups of patients may be The serum agglutinates heated and unheated elementary classified in the same way. bodies of vaccinia but apparently neutralizes only very Conclusion. The method affords a convenient and spe- small amounts of vaccine virus. Rabbits subjected to re- cific means of assaying the appearance of thyrotropic peated inoculation with the substance and having a high hormone in clinical material. 657 658 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING Influence of the Thyroid Gland on Intestinal Absorption without serious trophic disturbance of a permanent na- of Dextrose, Galactose, and Xylose. By T. L. AL- ture. Arteriograms in such cases often show direct THAUSEN, with the technical assistance of M. STOCK- anastomosis by means of smaller arteries between the HOLM, San Francisco, Calif. segments of the artery above and below the area of oc- Normal rats, rats treated with thyroxin, and thyroid- clusion. In such cases the roentgenograms show that the ectomized rats were given measured amounts of sugar by artery below the obturated portion is still functioning, stomach tube. The amount of sugar absorbed in one the blood having been shunted around the occluded por- hour was calculated from the unabsorbed residue in the tion. Arteriograms and drawings of the extremities of digestive tract. In hyperthyroidism, intestinal absorp- patients illustrating this mechanism of readjustment of tion of dextrose and of galactose was markedly increased. the circulation are shown. Various types of anastomoses In hypothyroidism, intestinal absorption of dextrose was are demonstrated. reduced considerably. The Effects on the Cardiovascular System of Fluids Ad- Depletion of carbohydrates, raised basal metabolism, mnittistered Intravenously. By MARK D. ALTSCHULE increased velocity of the blood flow, intestinal hyper- and DOROTHY R. GILLIGAN (introduced by Herrman L. peristalsis, and rate of gastric discharge appear to play Blumgart), Boston, Mass. no part in the observed changes of intestinal absorption. Therefore, a specific action of thyroid hormone on the The effect on the cardiovascular system of the injec- intestinal mucosa is suggested as a possible explanation. tion of fluids intravenously, such as is employed routinely Increased phosphorylation appears to be the chief in postoperative treatment, has been studied in a large mechanism by which thyroxin increases absorption of group of patients with no evidence of heart disease. The dextrose because phlorizin which inhibits this mechanism fluids employed were physiological saline solution or 5 greatly decreases the absorption of dextrose in experi- per cent glucose in distilled water, or 5 per cent glucose mental hyperthyroidism. But simple diffusion also seems in physiological saline; the volumes injected varied from to play a part since absorption of xylose is likewise in- 500 to 1500 cc. and the rates of injection from 6 to 80 cc. creased by thyroxin. per minute. Clinically, altered intestinal absorption may be an im- Immediately after the injection of fluids intravenously, portant factor in producing abnormally high dextrose the minute volume output of the heart and the blood vol- tolerance curves often seen in patients with hyperthyroid- ume were increased, and the velocity of blood flow was ism and unusually low curves observed in patients with accelerated. When the more rapid rates of injection myxedema. The same mechanism may play a major were employed or the larger volumes of fluid adminis- part in the impairment of "tolerance" to galactose ob- tered, significant and even marked increases in venous served in hyperthyroidism in man. pressure were observed; a return to the control level of venous pressure was again observed within approxi- Pressor Effects of Renal Extracts of Nornad Dogs and mately twenty minutes after the end of injection in these of Dogs with Experimental Renal Hypertension. By patients with no evidence of heart disease. Slight in- T. R. HARRISON, ALFRED BLALOCK and (by invitation) creases in pulse rate and in systolic blood pressure and M. F. MASON and J. R. WILLIAMS, JR., Nashville, pulse pressure were observed in approximately 40 per Tenn. cent of our studies. Electrocardiographic studies re- vealed in some instances appreciable increases in the Hypertension has been produced in dogs by the method height of the P and variable changes in the T-waves. of Goldblatt (partial occlusion of the renal arteries). The magnitude and duration of the above effects were Saline extracts of the kidneys of such animals have been influenced by the composition of the fluid injected. injected into rats and the changes in blood pressure com- These studies have demonstrated that the administra- pared with those produced by extracts of the kidneys of tion of fluids intravenously under conditions frequently normal dogs. The former extracts were found to have employed routinely subject the heart to increased work, greater pressor effects. which amounts to about 50 per cent above basal levels. In a second series of experiments preparations from The implications of these findings in the management of the two kidneys of a dog rendered hypertensive by the patients with cardiovascular disease is clear. application of a clamp to one renal artery were studied. Here again the extract of the ischemic kidney caused a The Estimation of the Subcutaneous Tissue Pressure by greater rise in blood pressure than did that of the normal a Direct Method. By G. E. BURCH and W. A. SODE- kidney. MAN (introduced by J. H. Musser), New Orleans, La. Direct determinations of tissue pressure have not been Maintenance of the Functional Integrity of the Occluded reported in this country. Wide variations reported in Large Arteries as Demnonstrated by Thorotrast Arteri- the German literature have prompted us to determine di- ography. By WALLACE M. YATER, Washington, D. C. rectly the tissue pressure by the simple manometric Arteriography is teaching us many things about the method employed by Yandell Henderson for the deter- mechanism of the circulation of vascular disease which mination of muscle tone. A 26-gauge needle was used in are not demonstrable otherwise. Large arteries may be- place of a 20. In each determination three readings come completely occluded in some part of their course were taken which agreed within ± 1 mm. of water. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 659 In 10 normal adults the mean values at heart level tity of extract, injected twice daily, but the same quantity varied from 17.9 to 37.1 mm. of water in the subcutane- of extract consistently produces the same change in a ous tissue of the dorsum of hand and foot, volar surface given animal. of the forearm and the pretibial area. The tissue pres- A method for the extraction of the "salt and water" sure in the dorsum of the foot was increased in the erect hormone from urine has been employed, based on extrac- position and further increased by weight bearing. Six tion of urine with ethylene dichloride and subsequent dis- normal subjects stood for one hour against a table in- tillation at a temperature of 400 C. under reduced pres- clined at 75°. The mean tissue pressure reading in the sure. An alcoholic extraction of the residue was distilled dorsum of the foot at the beginning of the hour was 53.5 at the same temperature, the final residue being taken up mm. of water, and at the end 65.2. In all cases there in normal saline solution and sterilized by passage was a rise on standing for one hour not to exceed 31 mm. through a Berkefeld filter. Extracts of urine to which of water. The effect of venous pressure on tissue pres- hormone had been added yielded a 40 per cent recovery sure readings was determined by inflating a blood pres- when tested by the above method of assay. Acid hy- sure cuff around the arm in steps of 135 mm. of water drolysis of the urine, to which adrenal cortical extract (10 mm. Hg) up to 810 mm. of water (60 mm. Hg) at had been added, almost completely destroyed the activity two minute intervals. In no case was the diastolic of the "salt and water" hormone. Intravenous injec- arterial blood pressure exceeded. Increase in venous tions of large quantities of adrenal cortical hormone pressure over short intervals of time had relatively (3000 dogs units) into normal dogs were followed by slight effect upon the tissue pressure readings. In 10 only 10 per cent recovery from the urine. Two liter patients with increasing cardiac edema the tissue pres- portions of urine obtained from normal male, female, sure was greatly increased. In receding cardiac edema pregnant dog and man, and pregnant mare have been the values were lowered, even below normal, to return extracted and tested for the presence of the salt and finally to a normal level. water hormone. No appreciable amount could be demon- These findings indicate: (a) Normal tissue pressure is strated from this volume of urine. less than the accepted values for capillary and venule Studies reported elsewhere have indicated that in the pressures; (b) tissue pressure is an important factor in intact dog a sodium sparing effect is common to several the control of the movement of fluid between blood ves- crystalline sex hormones and closely related compounds. sels and tissue spaces; (c) the full effect of venous pres- It is apparent that substances other than the adrenal cor- sure on tissue pressure is not immediate; up to one hour tical hormone exert a sodium sparing effect in the intact the effect of venous pressure upon tissue pressure is animal. For this reason, the method of assay which has slight but in congestive heart failure with prolonged high been described is limited to the determination of the rela- venous pressure the tissue pressure is greatly elevated; tive " salt and water hormone " content, of adrenal corti- (d) the tissue pressure in patients with cardiac edema cal extracts. varies with the state of the edema, and (e) factors other than venous pressure are important in the regulation of Chloride Depletion in Conditions Other Than Addison's tissue pressure. Disease. By ALEXANDER W. WINKLER and OmRN F. CRANKSHAW (introduced by John P. Peters), New Studies of the Salt and Water Hormone of the Adrenal Haven, Conn. Cortex. By GEORGE A. HARROP and (by invitation) Extensive studies of salt metabolism in two cases not GEORGE W. THORN, Baltimore, Md. having Addison's disease showed persistent urinary Cl Injections of adrenal cortical hormone have been excretion at abnormally low Na and Cl concentration in shown to produce a marked effect on the renal excretion the serum. One was a case of pulmonary tuberculosis, of sodium and potassium in normal male dogs, maintained the other a case of primary carcinoma of the lung. In a under uniform conditions with a constant fluid and min- series of other cases of tuberculosis without Addison's eral intake. A subcutaneous injection resulted in an disease, including three cases which subsequently came to immediate marked reduction in renal sodium excretion autopsy, determinations of Na and Cl in the serum were accompanied by an increased potassium excretion. Sub- made. Consistently subnormal values were noted. The cutaneous injections produced a much more prolonged difficulties in differentiating such cases from true Addi- action than the intravenous injection of a similar quantity son's disease by a characteristic chemical test are noted. of hormone. Subcutaneous injections twice daily ef- fected a marked reduction in sodium excretion during the Heat Stroke: A Clinical Study. By M. A. BLANKEN- twenty-four hour period, followed by a " rebound " effect HORN and E. B. FEmRs, JR., and (by invitation) G. E. during the second twenty-four hours in which the in- CULLEN and H. W. RoBINsoN, Cincinnati, Ohio. creased excretion of sodium approximated the initial During two successive heat waves in 1936 studies of retention. It has been demonstrated that this response patients suffering from heat stroke were made in the is proportional to the quantity of hormone given, and that Cincinnati General Hospital and the Children's Hospital the normal dog can thus be used for assay of the " salt Research Foundation of the University of Cincinnati. and water hormone " effect of adrenal cortical extracts. Forty-three patients with high temperatures were re- Individual animals vary in their response to a given quan- ceived, of whom sixteen died and thirteen were autopsied. 660 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING Routine clinical studies were made on thirty-nine patients. A diagnosis of heat prostration was made in 12 patients On seventeen patients studies of the circulation, including who either collapsed at work or who believed that col- venous pressures, were augmented by analysis of carbon lapse was impending. On admission to the hospital the dioxide content and oxygen content of arterial and patients in this group had no characteristic physical find- venous blood to demonstrate the state of circulation. ings, and the chemical studies of the blood and urine were Further chemical studies of the blood were carried out, essentially normal. There was no gain in body weight including determinations of protein concentration, hemo- during the hospital stay, and it was presumed that the globin concentration, acid base balance and cell volume. etiological mechanism was not associated with a loss of The results of these studies demonstrated adequate cir- water and salt from the body. culation, a moderate but definite hemoconcentration, and Three patients were sent to the hospital because of a moderate acidosis. There was no striking change in unexplained fever. The pyrexia lasted 1, 3 and 21 days the sodium chloride content of the serum in the seventeen respectively. Except for the elevation of temperature, patients who were adequately studied, which indicates that the clinical observations were negative and the chemical these cramps are distinctly different from the condition studies were normal. All of the patients lost weight in of " heat cramps." Absence of sweating was a constant the hospital. finding on admission and most patients noted a diminution This study was an attempt to differentiate clinically or absence of sweat preceding the onset of heat stroke. and chemically the several syndromes associated with the No cause for the cessation of sweating is suggested by breakdown of physiological processes in healthy persons. any of these studies. It is, however, apparent that It was believed that more satisfactory data would be ob- peripheral or congestive failure, deficient chlorides, and tained with this objective than would be possible in dehydration were not primary factors in the retention of groups of aged or infirm suffering from exposure to heat heat nor in the symptomatology. in large cities during the summer. The changes in the Of the several methods tried the most successful for concentration of constituents of the body fluids in pa- the rapid cooling of the patients was that of submerging tients with heat cramps were characteristic of a depletion them in tubs of ice water. of body water and mineral salts. The pathogenesis of An important question raised by these studies is why heat prostration is thought to be associated with transient the patients cease to sweat and thereby fail to regulate circulatory collapse rather than an alteration of the their body temperature. chemical equilibrium of the body. The pathogenesis of heat pyrexia is assumed to be related to failure of the Clinical and Chemical Observations on Forty-eight Men heat regulating mechanism. Suffering from Exposure to High Environmental Tem- perature. By JOHN H. TALBorr and (by invitation) On the Mechanism of Migraine Headache and the Action D. B. DILL, Boston, Mass. of Ergotamine Tartrate. By J. R. GRAHAM (by in- vitation) and H. G. WOLFF, New York, N. Y. is a of the data obtained This communication summary mechanism of migraine on off exposure New light is thrown on the workmen who reported duty following 1 of the action of ergota- The men in the headache through the analysis to high temperatures. were employed mine tartrate. Investigation has been carried out as fol- steel mills at Youngstown, Ohio, and previous to the normal and lows. The amplitude of pulsations in branches of the onset of symptoms were considered healthy external and internal carotid as well as other arteries has persons. After admission to the hospital one or more each for the been ascertained by means of optical levers and photogra- samples of blood were drawn from patient phy. In 14 patients with migraine headache, ergotamine following analyses; oxygen capacity, oxygen content, cell lactic red and tartrate (Sandoz) (0.3 to 0.5 mgm. intravenously) pro- carbon dioxide content, volume, acid, duced a decrease of as much as 80 per cent and an av- white cell count, sodium, potassium, calcium, chloride, 50 cent in amplitude of the temporal phosphate, hydrogen ion concentration, total protein, os- erage of per the motic pressure and nonprotein nitrogen. In urine samples artery pulsations. This effect persisted for an indefinite acetone period (90 minutes or more). In persons suffering head- the following were determined; albumin, sugar, ache there was a simultaneous decrease in the intensity of bodies, character of sediment, sodium, chloride, creatine, the headache with the progressive decrease in the ampli- creatinine, and total nitrogen. if the decreased slowly, The clinical syndromes observed were placed in one of tude of the pulsations: amplitude are heat heat the intensity of the headache decreased slowly; if the three categories. These cramps, prostra- amplitude decreased rapidly, the headache rapidly dis- tion and heat pyrexia. A diagnosis of heat cramps was appeared. Direct photography of the temporal artery made in 33 patients who complained of skeletal muscle taken before and after ergotamine injection showed ac- pain. Analysis of the concentration of the constituents tual constriction of the vessel. The middle meningeal of the blood showed, among other changes, a diminished artery also constricts. concentration of sodium and chloride, an increased con- On the other hand, ergotamine has little effect, if any, centration of hemoglobin and serum protein, and a nor- on the internal carotid and its branches, as indicated by mal osmotic pressure. In the urine there was a dimin- ished concentration of chloride. During the hospital stay 1 For definition see Wolff, H. G., Arch. Neurol. and the gain in body weight was as great as 4 kgm. Psychiat., 1937, 37, 895. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 661 the following data. The amplitude of the intracranial muscle is capable of responding to sympathetic impulses pulsations was measured through a needle in the lumbar and adrenaline. subarachnoid space in 5 patients with migraine headaches, It has also been shown, by placing a cannula in the and in 28 controls without headache. Ergotamine some- temporal artery of a migraine patient, that increased in- times produced a transitory decline followed by an actual travascular pressure with distension of the artery was increase in the amplitude of pulsations, but usually the accompanied by pain. These data, and those described effects were inconstant, of varying magnitude, and bore above, coupling the vasoconstrictor action of ergotamine no relationship to the state of the headache. Photo- tartrate with the relief from pain, lend support to the graphs of the retinal arteries (branches of the internal thesis that migraine headache is an expression of dys- carotid) before and after ergotamine revealed no change, function of the cranial vascular bed, probably dilatation though slight constriction in the veins was observed. of certain branches of the external carotid artery. To show further that headache was associated with in- creased amplitude of cranial artery pulsations and relief Antipneumococcus Rabbit Serum as a Therapeutic Agent associated with decreased amplitude, the following ex- in Lobar Pneumoitia. By F. L. HORSFALL, JR., K. periments were performed. GOODNER, C. M. MAcLEoD and A. H. HARRUs, 2d (in- (a) Histamine phosphate (0.1 mgm.) was given intra- troduced by Qswald T. Avery), New York, N. Y. venously to 3 patients just after the migraine headache Antipneumococcus rabbit serum has been found to pos- had been abolished by ergotamine. The amplitude of sess numerous characteristics which make it theoretically temporal pulsations then rose to more than 250 per cent a more advantageous therapeutic agent in lobar pneu- of the post-ergotamine level. With this increase in monia than is immune horse serum, Of these the more amplitude there was a return of severe headache. significant are: (1) higher protective titer per milligram (b) In one instance, histamine (0.05 mgm.) happened of specifically precipitable protein, (2) smaller size of to produce hemicrania indistinguishable from the pre- antibody as determined by ultrafiltration and ultracentrif- viously abolished migraine headache. Here the increase ugation, (3) absence of prozone phenomenon when more in amplitude of temporal artery pulsations was unilateral than optimum amounts are used in protection test, (4) and on the affected side. In all instances, with the de- failure of lipids to inhibit protective action, (5) ease and cline in the amplitude of the pulsations to the post- certainty of immunization, and (6) high potency of un- ergotamine level, the headache again disappeared. concentrated serum. (c) Similarly, in 11 subjects without headache, ergota- Because of these indications, unconcentrated type spe- mine tartrate given 15 minutes previously did not prevent cific antipneumococcus rabbit serum has been used in the the incidence of severe headache after histamine injection. treatment of 22 patients with pneumococcus pneumonia, The amplitude of intra- and extra-cranial pulsations in- 10 with Type I, 4 with Type II, 3 with Type VII, and creased 250 per cent during the period of most severe 5 with Type VIII. Bacteremia was present in 12 of the headache. These experiments show also that the action 22, consolidation of two or more lobes in 7, bilateral con- of ergotamine tartrate is not analgesic. solidation in 3 and pleural exudate containing large num- (d) In 6 subjects, pressure applied to the carotid or bers of pneumococci in 3. temporal arteries during the course of migraine headache The results of the clinical use of antipneumococcus decreased the amplitude of pulsations, and relieved the rabbit serum have been characterized by: 1, a strikingly headache while pressure was applied. low mortality rate; 2, early occurrence of crisis; 3, ab- (e) The administration of adrenaline (subcutaneous sence of anaphylactoid reactions; 4, sterilization of in- 0.012 cc. 1/1000 per kilo) during migraine headaches re- fected pleural exudates; and 5, mildness of serum sick- duced the amplitude of temporal pulsations 30 per cent. ness. These results together with the ease and rapidity This was accompanied by short-lived relief of the head- with which the serum can be administered, as well as the ache. With the return of pulsations to their original ability of rabbits to produce antisera against each of the level within 8 minutes, the headache also returned to its various types of pneumococci suggest that antipneumo- initial severity. It was then abolished by ergotamine coccus rabbit serum is a therapeutic agent of considerable which caused a long lasting reduction of 75 per cent in merit. the amplitude of temporal pulsations. Despite the above described vasoconstriction after ergotamine tartrate, the peripheral circulation in the skin Allergy and Desensitization in Tuberculosis. By H. S. of the ear, cheek and hand (by radiometric determina- WILLIs and (by invitation) C. E. WOODRUFF, Detroit, tions) showed inconsequential change, presumably due to Mich. the accompanying rise in blood pressure. When guinea pigs are infected with tubercle bacilli and During maximum vasoconstriction of the temporal ar- become allergic, their allergic phenomena are associated tery and at the onset and during the height of the head- with a demonstrable degree of immunity. It has recently ache relieving effect, reflex dilatation of the pupils on been claimed that, when such animals are densensitized painful stimulation of the neck, as well as pilomotor re- by the introduction of repeated doses of tuberculin, all flexes were unimpaired. Moreover, the pressor responses allergic phenomena disappear but immunity remains. In to adrenaline were unchanged. These data indicate that these experiments groups of normal, allergic and de- after the given amount of ergotamine tartrate, smooth sensitized guinea pigs were inoculated with virulent tu- 662 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING bercle bacilli and were sacrificed at varying intervals fed different isocaloric diets. Each diet contained 27 per thereafter. From the spleens of these animals tubercle cent fat, 4 per cent salt mixture, and vitamins. They dif- bacilli have been removed and their numbers determined. fered as follows: Diet 1, 64 per cent carbohydrate and 5 The work indicates definitely that tubercle bacilli spread per cent protein; Diet 2, 51 per cent carbohydrate and 18 over the body of the desensitized animal with distinctly per cent protein; Diet 3, 29 per cent carbohydrate and 40 more facility than they do over the allergic body and that per cent protein. Diet 2 was used during the control pe- the desensitized animal is actually not the same immune riod. Observations made during the control period were animal that it was during the days of its allergy. continued at three-week intervals for eleven months fol- Histological study of the spleen indicates development lowing injection. of widespread fibrosis as a result of the desensitization The course of the nephritis in all three groups was par- process. allel for one month following injection. During the sec- ond month evidences of nephritis markedly diminished or Studies on Anaphylaxis in the Isolated Heart. By HER- disappeared in all but two animals on Diet 1. These two BERT B. WiLcox, JR. (by invitation), and E. CowLEs died in the fifth month without renal failure. All other ANDRUS, Baltimore, Md. animals in this group survived, and at the end of the ex- If the hearts of guinea pigs are isolated and perfused periment all but three had normal urine. Every animal with Ringer-Locke solution, the introduction of horse fed Diet 3 showed progressive nephritis, and thirteen died serum into the normal heart via the perfusate produces of apparent renal failure during the experiment; the re- no significant effect. In the heart removed from an ani- maining three were in the terminal phases of the disease mal previously sensitized to horse serum the introduction when sacrificed. Of the animals fed Diet 2, one recov- of antigen (0.005 cc.) provokes obvious, though evanes- ered in the second month, nine died of apparent renal cent, alterations in function: (a) Changes in cardiac failure during the experiment, and the remaining six had rate; (b) Alterations in auriculoventricular conduction; abnormal urine findings throughout. It is concluded (c) The development of ectopic rhythms; (d) Variations that: 1. Chronic progressive nephritis follows a single in the form of the electrocardiographic complexes; (e) insult to the kidney, under certain conditions. 2. The Pronounced diminution in the rate of coronary flow. course of nephrotoxic nephritis in rats can be markedly The degree of reduction of the rate of coronary flow influenced by diet. which always accompanies the other phenomena of car- diac anaphylaxis, and the fact that often it is the first Hemoglobin Nephropathy; A Pathological Study in Man change to appear, suggests that it may be of primary im- and the Dog. By ELMER L. DEGOWIN and EMERY D. portance. WARNER (introduced by Horace M. Korns), Iowa The effects of small amounts of histamine on such City, Iowa. perfused hearts include: (a) Changes in cardiac rate; The tissues of 8 humans dying of transfusion anuria (b) The development of ectopic rhythms; (c) Variations and one dying from quinine hemoglobinuria were studied. in the form of the electrocardiographic complexes; (d) It is evident from a study of these and a comparison of Pronounced diminution in the rate of coronary flow. other cases reported in the literature that two distinct The presence of atropine in the perfusate in a con- types of nephropathy occur. In one, there is little evi- centration of 1: 100,000 inhibits all the manifestations of dence of tubular obstruction but there are varying de- cardiac anaphylaxis; but only the coronary-flow-diminish- grees of necrosis, particularly in the epithelium of the ing power of histamine. The possibility of a functional proximal convoluted tubules. In the other type, epithelial inter-dependence existing between cardiac anaphylaxis, degeneration is minimal while the distal portions of Hen- the coronary vascular bed, and perhaps the production of le's loops are plugged with hemoglobin precipitate and an histamine-like substance is suggested. crystals while the proximal lumina are dilated. The glomeruli are not damaged in either case. The Influence of Diet on the Course of Nephrotoxic Dogs were transfused with hemoglobin solutions. Nephritis in Rats. By LEE E. FARR and JOSEPH E. When the urine was alkaline the kidneys were not af- SMADEL (introduced by Homer F. Swift), New York, fected. When the urine was acid, however, they devel- N. Y. oped uremia and died. The recurring portions of Hen- The renal injury, induced in rats by anti-kidney serum, le's loops were plugged with hemoglobin pigment and provides a tool for testing the r6le of diet in nephritis, a crystals while the proximal lumina were dilated. The question that has been long under discussion in the treat- tubular epithelium showed little necrosis. In one dog ment of Bright's Disease. subjected to the same procedure, however, there was Forty-eight young rats were fed a purified diet for a tubular necrosis but no pigment obstruction. period of one month, while renal function studies, plasma We conclude that most of the dogs and some of the protein and hemoglobin determinations and urinalyses humans developed renal insufficiency because of the pre- were made. Then severe nephritis was induced uni- cipitation of hemoglobin in an acid medium producing formly in all the animals by intravenous injections of obstruction of the tubules. This explanation does not ac- nephrotoxic serum given on three successive days. The count for some of the human cases although the clinical animals were divided into three comparable groups and course is similar in all. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 663 The Urinary Excretion of Androgenic and Estrogenic One patient was given orally the extract for parenteral Substances in Normal Men and Women and in Hypo- use derived from 700 grams of liver daily for 6 days gonadism, Gynecomastia and Virilism. By T. F. GAL- without improvement. LAGHER, A. T. KENYON, D. H. PETERSON, R. I. DORF- The liver residue discarded in the process of manufac- MAN and F. C. KOCH (introduced by 0. H. Robert- turing the parenteral extract was ineffective in 5 patients son), Chicago, Ill. who received total doses derived from 7,680 to 9,600 Benzene extracts of hydrolyzed urine were assayed for grams of liver. A dose derived from 28,800 grams was androgenic properties upon the capon's comb and for effective in one case of pellagra but this same massive estrogenic properties upon adult spayed rats. The dose was also effective in 3 cases of pernicious anemia values given below are based on the two hour hydrolysis. and one of sprue. Four normal young men, studied for six weeks, ex- The combination of the partially effective dose of the creted an average of 40 international androgen units per parenteral extract (derived from 700 grams) and the in- day (range 13 to 79), and an average of the equivalent effective dose of residue (derived from 9,600 grams) pro- of 10 gamma of theelin per day (range 2 to 29), with no duced an immediate and dramatic remission in 4 cases of conclusive evidence of cyclic variation. pellagra. Four normal young women, studied for four weeks, Black tongue was produced in dogs by feeding a modi- excreted an average of 28 international androgen units fication of Goldberger's black-tongue producing diet num- per day (range 13 to 51), and an average of the equiva- ber 123. The treatment was limited to a ten day period. lent of 25 gamma of theelin per day (range 4 to 60). The criteria for a good result were (1) cure of the The cyclic increase in the estrogen output during the in- mouth lesion, (2) restoration of the appetite, and (3) a termenstruum was unaccompanied by alteration in the prompt gain in weight which must be maintained for 10 androgen output. days after the treatment is stopped. Eight male hypogonads excreted about a third of the An aqueous extract of whole liver, " solution liver ex- normal androgenic and estrogenic material. Four men tract-Valentine (N. N. R.)," was effective in 3 dogs with gynecomastia showed no conclusive changes in the receiving a total dose derived from 3,670 grams of liver. amount of excreted hormones. Twenty women with In 5 dogs parenteral injection of pernicious anemia virilism showed normal values as a rule, slightly high liver extract derived from 300 grams of liver improved values for the androgenic material on occasion, and in the mouth temporarily but had no other effect. one instance (adrenal cortical carcinoma) the high value Five dogs received 3,000 grams of the parenteral liver of 480 international androgen units. The urine with the with marked improvement in the mouth but unsatisfac- high values showed spectrographic properties unlike tory weight gain and a relapse of black tongue after 22 androsterone and like certain adrenal cortical derivatives. days. Eleven dogs received the residue derived from 1,000 Evidence for the Existence of Two Factors Necessary grams of liver without improvement. One dog made a for the Successful Treatment of Pellagra or Experi- slow improvement after receiving the residue derived mental Canine Black Tongue. By JULIAN M. RUFFIN, from 2,000 grams and 3 dogs made a satisfactory re- ELBERT L. PERSONS and H. I. HARVEY (by invitation), covery when the dose was raised to 3,000 grams. Even and DAVID T. SMITH, Durham, N. C. better results were obtained in 14 dogs when the 3,000 Patients with acute pellagra were hospitalized and fed gram dose was supplemented with 300 of the parenteral. a diet adequate in all respects except the pellagra preven- When the ineffective dose of parenteral extract (de- tive factor of Goldberger. The tests were limited to rived from 300 grams) was given with the ineffective those patients who showed increasing symptoms while dose of the residue (derived from 1,000 grams) to four subsisting on the basic diet and those whose symptoms dogs, dramatic improvement resulted which differed from were reactivated by exposure to graded doses of sun- our best results only in the shorter length of time which light. The criteria of a successful remission were (1) intervened before the next attack of black tongue. prompt disappearance of all symptoms, (2) marked in- From these observations it would seem that there are crease in appetite, and (3) failure of maximum doses of two factors in liver which are necessary for the success- sunlight to reactivate the disease. ful treatment of pellagra in man and experimental black Rapid and complete recovery was noted in 20 of 22 pa- tongue in dogs. tients receiving an aqueous extract of 675 grams of liver daily. " Solution liver extract-Valentine (N. N. R.)." Twenty-three patients were treated by parenteral injec- The Relation of Vitamin B to Serum Proteins and to tions of various liver extracts potent for pernicious Edema. By HENRY FIELD, JR., Ann Arbor, Mich. anemia. Total doses derived from 400 to 6,750 grams Nutritional edema has been commonly considered to be of liver gave prompt improvement in the mouth and the result of deficiency in protein intake. In 1935 Elsom tongue symptoms, but there was no improvement in ap- reported studies on two patients with decreased serum petite, no constant effect on the diarrhea and in most in- protein and edema while on a diet adequate in protein stances relapse occurred after exposure to sunlight. but deficient in vitamin B. 664 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING

We have observed cases with edema and lowered The Deposition of Radium Salts in Bones, and Their serum proteins despite diets apparently adequate in both Relation to Calcium Metabolism. By J. ALFRED CAL- protein and vitamin who had no apparent cardiac or HOUN and JOSEPH C. AUB, Boston, Mass. renal cause therefor. Relief has followed supplements Radioactive lead, a disintegration product of the gas of vitamin B complex. These include cases of cirrhosis Radon, was used to demonstrate the effects of acute poi- of the liver, one of whom has been maintained edema soning. A small amount of this substance, given intra- free and with nearly normal serum proteins for one year venously to three dogs, caused death in from ten to despite increasing impairment of liver function by other twelve days. Because of the presence of a radioactive evidence. In another, who has recently developed evi- salt, the bones were self-photographic, and it was shown dence of hepatic insufficiency after two years of treat- that most of the radioactive lead had been deposited in ment, edema and lowered plasma proteins have recurred the trabeculae. Analyses, done by very delicate physico- three times when the vitamin supplement has been ne- chemical methods (sensitive to 0.0001 mgm.), showed glected and have been relieved each time by its resump- that the trabeculae contained an average of eleven times tion. as much radioactive lead as the cortical bones. One case of amyloidosis developed edema four weeks Bones and teeth from two patients demonstrate the after urine specimens were known to be normal and at a chronic effects of radioactive materials. A self-photo- time when he had mild proteinuria. Edema disappeared graph of a tooth from a living patient, who has been a and serum proteins increased despite greatly increased radium dial painter for fourteen years, shows radium de- proteinuria. Another patient had had a partial gastrec- posited deeply in the tooth. Thus, the area of inorganic tomy for duodenal ulcer and a jejunostomy for in- salt deposit in teeth has been established. Self-photo- testinal obstruction. In three of these patients edema graphs of bones secured at autopsy from a patient who has disappeared before the serum proteins reached the received " Radium water " and who died of a neoplasm " critical level." One case of nutritional edema with nor- of the bones of the knee, demonstrate the position of mal serum proteins has been promptly relieved by vitamin heavy metals in bones long after exposure has ceased. B supplements. Analyses of these bones show practically an even distri- It is suggested that vitamin B complex is a factor in bution of radium between the trabeculae and cortex. the maintenance of serum proteins and that an increased Therefore, it is clear that therapy should be more intake may be beneficial when they are lowered in or- effective early, for at that time heavy metals are local- ganic disease. It is also suggested that it is a factor in ized in regions where they can be more readily mobilized. production of edema aside from its relation to serum proteins. The Use of the Cathode-ray Oscillograph in the Study of the Monocardiogram. By FRANK N. WILSON, Positive Pressure Respiration and its Application to the FRANKLIN D. JOHNSTON and PAUL S. BARKER, Ann Treatment of Acute Pulmonary Edema and Respirae- Arbor, Mich. tory Obstruction. By ALVAN L. BARACH and (by in- The concept of a single figure which represents the di- vitation) JOHN MARTIN and MORRIS ECKMAN, New rection of the electrical axis and the magnitude of the York, N. Y. cardiac potential at every instant during the cardiac cycle Evidence is presented which supports the concept that is not new. Mann has referred to this figure as the obstructive dyspnea produces pulmonary congestion, monocardiogram. Such curves can be constructed from edema and emphysema because of the pathologically in- measurements made on any two of the three standard creased negative pressure within the chest during inspira- leads recorded simultaneously, but the process is too tion. The application of moderate positive pressures to laborious for use in the analysis of a large number of inhalation therapy reduces the negative intrapleural pres- electrocardiograms. When conventional Lead I and the sure, relieves the dyspnea and tends to prevent pathologi- potential variations of the left leg (VF) are amplified to cal changes in the lungs. the required degree and impressed upon the plates of a In various types of experimental and clinical acute pul- cathode-ray tube, the former upon the horizontal and monary edema the most important causal factor appears the latter upon the vertical plates, the monocardiogram to be the negative pressure in the lungs during the in- is inscribed on the end of the tube by the luminous spot spiratory phase of respiration, since a suction action is produced by the electron beam and may be easily photo- exerted on pulmonary capillaries which may already have graphed. a tendency to ooze serum either because of engorgement We have taken a considerable number of monocardio- or increased capillary permeability. Inhalation of air, grams in this way, using both normal individuals and pa- oxygen or helium mixtures is followed by a clearance of tients with various electrocardiographic abnormalities as pulmonary edema, the mechanism of which appears to be subjects. the lowering of the pathologically increased negative The figures obtained are closed loops of varying size pressure within the chest. and shape. The spot may traverse the loop in a clock- The effects of positive pressure respiration on circu- wise or counterclockwise direction. Irregularities in its latory function in normals, patients with cardiac insuffi- movement, or a reversal in the direction of its motion, ciency and patients with asthma were presented. occurs in cases in which conspicuous notching of the AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 665

QRS group is present. The orientation of the loop with contents. The capacity of the diluting mechanism has reference to the zero position of the spot depends on the been tested and, excluding the bile and pancreatic juice, position of the mean electrical axis. the fluid derived from the duodenal mucosa alone has It is hoped that the monocardiogram may give in- been found sufficient to double the volume of a 25 cc. formation of value in the analysis of the electrocardio- sample of a 15 per cent solution in four minutes. The gram by making it possible to distinguish between curves response of the duodenum to glucose has been compared which have a similar appearance but are fundamentally to that of the jejunum and ileum, and the changes in the different with respect to the origin of their components. electrolyte concentration and the osmotic pressure of The method makes it possible to convert the three curves the intestinal contents have been determined. of the standard leads into a single curve and this greatly simplifies the analysis of the form of the electrocardio- Photometric Studies of Visual Adaptation in Relation to graphic deflections. Mild Vitamin A Deficiency in Adults. By JOHN B. YOUMANS and (by invitation) MARVIN B. CoRLEmE, Metabolic Studies on Idiopathic Steatorrhea. By SAMUEL HELEN FRANK and MILDRED G. CORLETTE, Nashville, H. BASSETT and E. HENRY KEUTMANN (introduced by Tenn. Wm. S. N. Y. McCann), Rochester, Using an improved type of visual photometer we have Lipid, nitrogen, calcium and phosphorus balances have studied the dark adaptations of a group of 54 presum- been determined in three cases of idiopathic steatorrhea ably healthy adults and a group of 50 adult outpatients in an attempt to evaluate various therapeutic procedures. of our clinic. Eighty-three per cent of the former had Prolonged administration of large doses of liver extract initial recovery readings, after blanching, of 0.7 milli- intramuscularly was found ineffective in all cases. Re- foot candles or less, while 50 per cent of the patient placing starches and sucrose in the diet by addition of group showed poorer readings than this. Practically all equivalent amounts of dextrose and ripe banana, while subjects in both groups who had relatively poor dark the quantity and source of fat remained constant, did not adaptations and who were given large amounts of vita- cause improvement in the steatorrhea. Absorption of min A for 4 to 6 weeks showed definite improvement and fatty acids was not improved by glycerophosphate or ox came within the limit of 0.7 millifoot candles. These bile given orally. findings have led us to propose 0.7 millifoot candles in Two patients showed the expected decrease in steator- the initial recovery reading as a tentative limit of normal rhea when the intake of fat was sharply restricted. In dark adaptation in adults. Normal subjects with good one of these, defective absorption of calcium was not im- adaptations were improved only very slightly after simi- proved by practically complete removal of fat from the lar treatment showing that they were already at their diet. In a third patient with a relatively mild steator- optimum levels of dark adaptation, and vitamin A nu- rhea, the fatty acids of the feces could be reduced fifty trition. per cent by shifting from normal to a low calcium in- take. It is believed that the steatorrhea in this last pa- Clinical Results with the Elsberg Olfactory Test. By tient was caused in part at least by defective absorption ALEXANDRA ADLER and KNOX H. FINLEY (introduced of calcium, failure to absorb fatty acids with the usual by Tracy J. Putman), Boston, Mass. completeness being due to formation of insoluble calcium soaps in the small intestine. Elsberg's investigations have opened a wide field for physiological and clinical studies on olfaction. READ BY TITLE For clinical purposes his most important methods are: Factors Controlling the Behavior of Glucose in the Hu- 1. The " M. I. O." (minimal identifiable odor) express- man Stomach and Small Intestine. By W. OSLER AB- ing the minimum amount of air saturated with odor BOTT, WALTER G. KARR (by invitation) and T. GRIER necessary for recognition. MILLER, Philadelphia, Pa. 2. "Olfactory fatigue," which is the interval of rest The factors governing the behavior of glucose in the after an odor fails to be perceived before it can be normal human digestive tract have been studied. Evi- perceived again. dence has been secured to show that a glucose solution, Elsberg found an increased M. I. 0. in cases of brain even of 50 per cent concentration, begins to leave the tumor producing direct pressure on the olfactory tract stomach within two minutes, but that the concentration and an increased olfactory fatigue with tumors within of the solution as it enters the duodenum may be re- the brain substance. duced to 15 per cent or less. The glucose may in turn In 7 verified pituitary tumors with signs and supra- enter the jejunum within two minutes but when its con- orbital tumors respectively we found the M. I. 0. nor- centration usually is only 3 to 5 per cent. The rapid re- mal in 4 and increased in 3. The olfactory fatigue was duction in the sugar content of the ingested solution normal in all 7. In 16 verified cerebral tumors without from 50 per cent to 5 per cent within less than five direct pressure on the olfactory tract we found the minutes and during its passage along a scant two feet of M. I. 0. increased in 3 and normal in 13. Olfactory alimentary canal is accomplished by dilution and by selec- fatigue was increased in one, undeterminable in one be- tive absorption of glucose from the fluid of the duodenal cause of the high M. I. 0. and normal in 14. 666 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING

In conclusion the Elsberg olfactory test enables us to Studies in Pernicious Anemia. Extirpation of " Intrisic determine quantitatively the olfactory function. In a Factor" Sources. By ARTHUR GEIGER, LouIs GOOD- few of our cases with direct pressure on the olfactory MAN and LoUIE N. CLAIBORN (introduced by Francis tract the M. I. 0. was increased suggesting that this part G. Blake), New Haven, Conn. of the test may be of diagnostic help in such cases. In Experiments on swine designed to elucidate further the respect to intracerebral growths the occurrence of in- r6le of gastro-intestinal factors in pernicious anemia creased olfactory fatigue seems to be too rare (1 out of have been carried into the third year. The main sources 16) to be of practical clinical value. of the "intrinsic factor" have been eliminated by total Hematopoietic Principle in the Diseased Human Liver. gastrectomy, isolation of the pylorus, duodenectomy, and By LEON SCHIFF and (by invitation) MumRY L. RICH gastrectomy plus duodenectomy. and STANLEY D. SIMON, Cincinnati, Ohio. Thirty-six young swine were used. Growth and de- velopment were normal in all animals In an attempt to elucidate the mechanism of macrocytic surviving simple anemia in liver disease, extracts made of livers obtained gastrectomy. Only a mild hypochromic anemia resulted during the first postoperative year despite repeated from two cases of hepatic cirrhosis with associated preg- nancies. One sow, now 30 months agastric, has in the macrocytic anemia were administered intramuscularly to patients with pernicious anemia in relapse. Positive past 6 months developed a striking and steadily progress- ing macrocytic and hyperchromic red cell morphology. hematopoietic responses were obtained. Similarly pre- Bone marrow studies are in preparation. Spinal cord le- pared extracts made from cases of acute yellow atrophy, toxic hepatitis, chronic passive congestion and malignant sions have thus far appeared in only one animal. Clini- cal assay of the livers from agastric animals revealed neoplasm of the liver also yielded positive responses. The results indicate that the severely diseased liver appreciable loss of reticulocytogenic power in 2 months, marked depletion in 6 months, and complete absence of may store the antianemic principle and that the macro- cytic anemia of liver disease cannot necessarily be antianemic potency in 18 months. Gastrectomy plus ascribed to failure of such storage. duodenectomy, and duodenectomy alone resulted in con- siderable disappearance of liver potency within several The Production of Signs and Symptoms of Toxemia of months. The differentiation between a hormonal and Pregnancy by the Administration of Sodium Salts to enzymatic nature of the antianemic principle is being Pregnant Women with Hypoproteinemia. By MAURICE sought by assay of livers of newborn pigs obtained from B. STRAUSs, Boston, Mass. agastric and from normal sows. Twenty-four women have been studied in the last trimester of pregnancy. Eight women with known pre- Medical Treatment of Hyperthyroidism with a High Fat existing arterial hypertension without exacerbation in Diet. By S. SOSKIN and (by invitation) I. A. MIRSKY, pregnancy and with essentially normal plasma proteins Chicago, Ill. were given daily 6.3 grams of sodium (either as 16 The present adequacy of surgery in hyperthyroidism grams of the chloride or 23 grams of the bicarbonate) has left little opportunity for the observation of medical for one week. Water was allowed ad libitum. Slight treatment in severe cases. A patient who absolutely re- increments of weight unassociated with blood pressure fused operation offered us such an opportunity. The re- changes or other signs or symptoms occurred. sults are recorded in order that others may be able to Ten women with hypoproteinemia and arterial hyper- compare their observations as occasion arises. tension in the last trimester of pregnancy were given The rationale of our treatment was based on several similar amounts of sodium daily. Eight of these women reports that diet may influence the hyperthyroid state or had no pre-existing arterial or renal disease. Weight the action of administered thyroxin. More specifically, gains of from 3.3 to 7.7 per cent together with gross Loumos and also Scoz have shown that the feeding of edema occurred. The arterial blood pressure, particu- certain fats may inhibit the activity of thyroxin in ex- larly the diastolic, rose significantly. In 5 women in- perimental animals. It seemed possible that the hypo- creasing albuminuria was noted, and in 3 symptoms of lipemia in hyperthyroidism might be playing a primary pre-eclampsia became so alarming that the administration rather than a secondary r6le. of sodium had to be discontinued within 4 days. Six A woman, age 36, was admitted to the Max Pam Unit, women with hypoproteinemia were observed under identi- Michael Reese Hospital, on June 10, 1935, four months cal conditions, but without the administration of sodium after the advent of an acute hyperthyroidism. She com- salts, as a control of the above observations. No gain plained of nervousness, palpitations, loss of weight and in weight, edema, elevation of the blood pressure, or oligomenorrhea. She showed thyroid enlargement, lid other symptoms occurred. The administration of a high lag, tremor, pulse rate of 116, blood pressure 140/74, protein diet to these women resulted in weight losses of basal metabolic rate plus 62.9, blood cholesterol from 147 from 2.9 to 4.1 per cent and the subsidence of symptoms. to 176, and she weighed 110 pounds. On a diet of P. 90 The conclusion is drawn that the signs and symptoms F. 230 CHO. 90, with 3 grams of cholesterol per day of toxemia of pregnancy in the patients studied resulted added to the butter ration for about 3 weeks, she soon from water retention induced by sodium salts in the pres- showed remarkable improvement. No iodine was given ence of hypoproteinemia. at any time. She was discharged on October 15, 1935, AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 667 on the above diet, and has been observed at weekly inter- upon 8 patients with Addisonian pernicious anemia while vals to date. At present there are no signs or symptoms on controlled dietary regimes. of hyperthyroidism. Pulse rate is 70 to 80, blood pres- The daily administration of mixtures of beef muscle sure 120/70, basal metabolic rate minus 6 to plus 13, and gastric juice incubated for 6 hours and administered blood cholesterol over 200 mgm. per cent and weight 140 at an acid reaction (pH 1.8 or 2.5) produced negative pounds. results. However, positive effects upon blood formation were observed if, after such incubation, the mixture was Studies of Blood Formation in the Fetus and Newborn. administered at a reaction of pH 5 to 7. Control ob- IV.' By M. M. WINTROBE and (by invitation) DEAN servations showed that a mixture of beef muscle and A. CLARK, Baltimore, Md., WILLIAM TRAGER, Prince- gastric juice incubated with pepsin for 12 hours at pH ton, N. J., and LEWIs DANZIGER, Baltimore, Md. 1.8 was effective upon administration after neutraliza- Whereas extracts for parenteral injection made from tion. The failure of the unneutralized mixtures was the livers of pig fetuses showed no antianemic potency in therefore apparently not due merely to the prolongation cases of pernicious anemia, desiccated liver of the last during an in vivo period of a destructive process begun third of the gestation period, administered orally, caused during the in vitro acid incubation. Thus, the strongly a slight reticulocyte response in two out of three cases. acid reaction seemingly provided an environment unsuit- However, the erythrocyte count did not rise and desic- able for the essential interaction of the beef muscle and cated adult liver caused a much more striking response. gastric juice. This unfavorable effect must have oc- Desiccated placenta showed no potency whatever. In curred in vitro or within the intestinal tract rather than assays for the growth promoting factor needed by mos- parenterally. quito larvae, the desiccated fetal livers were found to be The activity of mixtures of beef muscle and gastric about half as potent as desiccated adult liver. This fac- juice, with or without the serial addition of normal hu- tor was present in desiccated placenta but the quantity man duodenal contents or hogs' duodenal and small in- was small as compared with that found in adult liver. testinal mucosa after 2-hour incubation at pH 7, was Desiccated fetal stomach, on the other hand, appears to destroyed by temperatures (400 to 1000 C.) not destruc- contain significant amounts of the antianemic substance tive of the activity of aqueous solutions of the liver frac- effective in pernicious anemia, although the quantity may tion "G" of Cohn, Minot and their associates. There- be less than in desiccated adult stomach. A concentrate fore, contrary to the assertion of Klein and Wilkinson,1 of milk vitamins has been shown to contain "extrinsic the formation of the thermostable active principle of liver factor." Extracts of the livers of stillborn pigs admin- could not be demonstrated in zitra under the above condi- istered parenterally, have shown no potency but the lim- tions. ited observations made to date indicate that antianemic As shown above, the active principle of liver is ap- substance is found in increasingly greater concentration parently not formed from beef muscle in vitro by serial in the liver as age advances. contact with gastric, duodenal or intestinal secretions. It is therefore probable that, although an essential inter- The Site of the Interaction of Extrinsic and Intrinsic action between beef muscle and normal human gastric Factors in Pernicious Anemia. By WILLIAM B. juice occurs within the alimentary tract, it involves only CASTLE and (by invitation) R. W. HEINLE, Boston, a preliminary step in the formation of the active prin- Mass. ciple of liver. Convincing evidence is lacking for any specific action in vitro of normal human gastric juice (intrinsic factor) Observations on the Action of Aminophyllin on the Intra- upon beef muscle (extrinsic factor) responsible for the thecal and Venous Pressures and on the Bronchi as a observed increased blood production and clinical improve- Possible Mechanism for Its Beneficial Effect on ment in pernicious anemia. Indeed, since neutral mix- Cheyne-Stokes Breathing, Dyspnea, and Paroxysmal tures are effective, the essential interaction between these Dyspnea. By JAMES A. GREENE, and (by invitation) factors may take place only after their absorption from W. D. PAUL and A. E. FELLER, Iowa City, Iowa. the alimentary tract. The purpose of the present ob- The mechanism by which theophylin-ethylene-diamine servations was therefore to discover whether any essen- ameliorates cardiac dyspnea and converts Cheyne-Stokes tial interaction between beef muscle and gastric juice oc- breathing to a regular rhythm is not known and has been curs within the alimentary tract, and, if so, whether such the object of this investigation. These effects of the interaction results in the production of the active prin- drug are attributed to an improvement in cerebral circula- ciple of the normal mammalian liver. During successive tion. 10-day periods of the daily administration of test mix- The effect of intravenous administration of the drug tures reticulocyte and red blood cell counts were made upon the intrathecal and venous pressures measured both separately and simultaneously has been observed. The 1 This investigation has been made with the assistance intrathecal and venous pressures decrease almost simul- of grants from The National Research Council and The Committee on Therapeutic Research, Council on Phar- 1 Klein, L., and Wilkinson, J. F., Biochem. J., 1934, macy and Chemistry, American Medical Association. 28, 1684. 668 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING

taneously with the improvement of respiratory distress or studies were carried out upon the blood. Plasma vol- change of periodic breathing to a regular rhythm. Amyl umes were estimated by the dye method of Gregersen. nitrite and nitroglycerine, on the other hand, increase the Estimations of the alcohol content of the blood were intrathecal and venous pressures and do not alter the made to see if any correlation could be demonstrated be- respirations. tween alcohol content and changes in the electrolytes. Bronchial obstruction tnay be relieved, if it is present, It was found that during the period of intoxication as evidenced by the increase in vital capacity and sub- there was a marked retention of the urine potassium, jective relief when the drug is administered to patients which was reflected in an increase of the plasma potas- during an acute attack of bronchial asthma of allergic sium concentration. To a lesser degree there was a re- etiology. tention of sodium chloride and water. An increase in plasma volume and in body weight was also noted. No Studies on the Anemia of Chronic Glomerulonephritis constant change was found in the blood sugar; there was, and Its Relationship to Gastric Acidity. By S. R. however, a slight decrease in the carbon dioxide content TOwNSEND, E. MASSIE and R. H. LYONS (introduced and an increase in lactic acid. by J. P. O'Hare), Boston, Mass. From these data it is concluded that in acute alcoholism Forty-eight cases of chronic glomerulonephritis were in man there is an increase in the circulating blood vol- studied in relation to the anemia, degree of nitrogen re- ume. Since the increase in the plasma potassium concen- tention and gastric acidity. In addition, histological stud- tration is not great enough to explain the total potassium ies were made of rib marrow and sections of stomach in retained, it would appear that the intracellular fluid is thirty-one cases of glomerulonephritis. also increased. It is suggested that some of the sequellae The result of our observations indicate that the anemia of alcoholic intoxication are due to an excess of potas- was of the normocytic type, the red cell being normal in sium. size with the hemoglobin content of the cell slightly de- creased. The anemia became manifest with the develop- The Effect of Certain Specific Dietary Factors on the ment of renal insufficiency and increased with the degree Circulation in Patients with Heart Disease. By SAM- of nitrogen retention. As the anemia, renal insufficiency uEL H. PROGER and (by invitation) HEINZ MAGEN- and retention of nitrogen became more marked, gastric DANTZ, Boston, Mass. acidity was found diminished. Absolute achlorhydria was discovered when acidosis became evident and the In the past we have reported the results of observa- blood CO2 content fell below thirty volumes per cent. tions on the effects of general dietary restriction on the Our investigations, along with those of others, lead us circulation in patients with heart failure. On such a to feel that the diminished to absent gastric acidity plays regime there is a disturbance of balance in sodium, nitro- an important r6le in the improper digestion and absorp- gen and water. This report deals with an attempt to tion of ingested food and iron and can account, in part at isolate the effects of these three factors. The results in least, for the persistence of the anemia and its lack of general have been as follows: response to therapy. (1) There is under certain circumstances a definite re- Studies of the bone marrow do not support the common lationship between water and oxygen metabolism, the theory of lack of active blood-forming tissue as the eti- basal metabolic rate falling as the 24-hour level of water ological factor in the production of the anemia since the exchange is decreased and vice versa. While there is at postmortem rib marrow is in a normal or hyperplastic times evidence that fluid restriction may have beneficial state. Studies of sections of stomach did not reveal any effects on the circulation, large quantities do not appear histopa-thological explanation for a diminution of the to alter significantly the dynamics of the circulation. gastric acidity, although many cases died in acidosis and (2) When other factors are controlled, a reduction of uremia. protein intake with the development of a negative nitro- gen balance is associated with a lowering of the basal The Effect of Alcohol on the Water and Electrolyte Bal- metabolic rate. This is not constant, and changes in ances in Man. By WILLIAM M. NICHOLSON and HAY- nitrogen balance produce relatively little effect on the wooD M. TAYLOR (introduced by D. T. Smith), Dur- state of the circulation of patients with cardiac insuffi- ham, N. C. ciency. The effects of alcohol on the electrolytes and water (3) After heart failure seems well overcome and a balances have been studied in normal, healthy, adult male steady state established, a total of 16 grams of sodium volunteers. The subjects were placed on a constant diet, chloride in the diet with a retention of 4 to 6 grams aliquots of which were analyzed for their sodium, potas- daily will, in two to four days, produce striking evidence sium, chloride, nitrogen and water contents. The day of heart failure as manifested by increased venous pres- was divided into eight hour periods. Urine and stool col- sure, diminished vital capacity, increased heart rate, ele- lections were made for these periods. At the end of vated blood pressure, enlargement of the liver and edema. three days on the diet the subjects were given alcohol in The effect upon the liver appears disproportionately great. sufficient quantities to produce intoxication. The sodium retention in these experiments is of about The sodium, potassium, chloride, and nitrogen content the same magnitude as in the acute infections and may of the urine was determined, and complete electrolyte act in the latter state as an important contributing factor AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 669 in the precipitation of heart failure in patients with or- gram at the end of the expiration phase. During the ganic disease. period of unpleasant ideas in fourteen of these patients there was an increase in the respiratory rate, an increase The Development of Pellagra in Certain Persons Eating in total ventilation, and a marked tendency to the forma- a Well-Balanced Diet. By TOM D. SPIES, Cincinnati, tion of more acute angles on the spirogram at the end of Ohio, and (by invitation) AUSTiN B. CHINN, Wash- the expiration. During the relaxed period the type of ington, D. C. respiratory curve approximated that of the pleasant Three selected recurrent pellagrins were admitted to period. There was no marked change in oxygen con- the Tennessee Coal, Iron and Railway Hospital of sumption during any of the periods. Ensley, Alabama, and given a diet rich in pellagra-pre- In five of the patients no changes were observed. In ventive foods and calculated to meet basal energy re- three of these patients, the report during the interview quirements. Despite the fact that each patient was in was an inability to " let pleasant ideas come into mind." good health at the time of admission and was observed Four of the control cases showed similar changes in the to have eaten the required amount of the prescribed diet same general direction as that of the psychoneurotic pa- at each meal, he developed symptoms of pellagra within tients, but not nearly so marked. a month. These symptoms disappeared after the diet was increased in amount and supplemented with large Arteritis of the Temporal Vessels. By BAYARD T. HOR- amounts of powdered brewers' yeast. TON and (by invitation) THOMAS B. MAGATH, Ro- The findings of this study in no way contradict the chester, Minn. statement that pellagra is a dietary deficiency disease, but This report presents a new clinical syndrome, the eti- do point out that an occasional person at least, probably ology of which is still obscure. Arteritis of the tempo- because he is unable to utilize properly the essential sub- ral vessels is a nonfatal disease which is characterized stances present in food, is not protected by a diet which by periarteritis and arteritis of the temporal vessels, with prevents other people from developing pellagra. painful tender areas over the scalp. It is accompanied by headache, general malaise and lassitude, weakness, Effect of Pleasant and Unpleasant Mental Content upon fever, night sweats, anorexia, loss of weight, anemia, the Respiratory Tracing (Spirogram) in Psychoneu- and mild leukocytosis. Seven patients, aged fifty-five, rotic Patients. By JACOB E. FINESINGER (by invita- sixty-eight, sixty-nine, seventy-five, seventy-two, sixty- tion) and STANLEY COBB, Boston, Mass. five, and sixty-eight years respectively were studied. Respiratory records were made by means of a Bene- Segments of the temporal arteries of five of the seven dict-Roth metabolic apparatus on a series of nineteen patients were resected for microscopic study, cultures, psychoneurotic patients of various types, and upon a con- and inoculation into animals. Each patient made a satis- trol series of six subjects, all of whom were under basal factory recovery. The microscopic appearance of the conditions. The patients were interviewed and were arteries and bacteriological studies will be reported in asked to express any ideas that came up in mind when detail. Reports of similar cases have not been noted in they were told to think about pleasant and about un- the literature. pleasant ideas. After the initial interview a six minute record of the respiration was made during which time no The Effect of the Administration of Bile on the Be- suggestions were made (the so-called control period). havior of Peptic Ulcer. By EDWARD S. EMERY, JR., This was followed by a six minute period during which and (by invitation) MAURICE A. SCHNITKER, Boston, time the patient was told "think of pleasant ideas," or Mass. " let pleasant ideas come into your head." This was fol- The successful production of experimental ulcers in lowed by a six minute period during which the patient dogs by the Mann-Williamson type of operation was was told to think unpleasant ideas. The "unpleasant originally explained by a resulting lack of sufficient period" was followed by another six minute period of gastric neutralization. However, numerous facts justify pleasant ideas. The second period of pleasant ideas was some skepticism about this explanation, and suggest the followed by a six mninute period during which the pa- possibility of a deficiency being the real cause. Recently tient was told "just relax." The suggestions were given Ivy has succeeded in preventing the development of ulcers at intervals of from thirty to sixty seconds. After the in his animals by a special diet which includes the feed- experiment the patient was interviewed in an attempt to ing of pancreas. We chose to study the effect of giving find out precisely what ideas were present during the bile to patients with ulcer because many observers have various periods. reported a higher incidence of ulcers in animals deprived The respiratory rate, depth of inspiration and expira- of bile than of pancreatic juice. A specially prepared tion, total ventilation per minute, oxygen consumption dessicated bile was given to 40 patients over periods as and the type of breathing, all were noted. In fourteen long as two years. of the psychoneurotic patients, pleasant ideas were as- The results were such as to exclude bile as a specific sociated with a decrease in rate of respiration, a decrease treatment for the disease. However, many of the pa- in amplitude, a decrease in the total minute ventilation, tients obtained definite relief, and of 27 who had sea- and a marked tendency toward rounding of the spiro- sonal attacks 18 were kept symptomless. Observations 670 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING on these patients suggest that bile has a beneficial effect two years, four major variant forms of the original which does not seem readily explicable by a lowering of " White " form were isolated. The variant colonies gastric acidity. were characterized by distinctive pigments and were called pink, yellow, pink-yellow and brown. Since each The Use of Ergonovine in Migraine. By WILLIAM G. of the variants were immunologically specific, and since LENNOX, Boston, Mass. the component M, S and R culture phases of each of Ergonovine is the recently isolated alkaloid of ergot. these variants were subsequently isolated, they were re- Its effect in aborting headaches of the migraine type has garded as specific types. Spontaneous transformation been tested in a large group of patients. Injection of from one type into another in broth, on agar or in vivo ergonovine is less effective than ergotamine tartrate in in mice was frequently noted. stopping individual headaches, but is preferred by some Further studies of the characteristics of differential patients because its use is followed by less nausea and growth of the five types indicated that the S form of vomiting. The action of the two drugs on blood pres- the white type, originally isolated from the patient, was sure, pulse and blood gases has been studied and com- peculiarly fitted to survive in vivo as regards optimal pared. growth in certain ranges of temperature and pH con- centration in vitro. This observation suggested that in A Study of the Bactericidal Properties of the Synovial the process of bacterial variation of certain so-called Fluid and Blood of Patients with Gonococcal Arthritis. saprophytes, variant types which are especially endowed By WESLEY W. SPINK (by invitation) and CHESTER with capabilities to exist in tivo under certain condi- S. KEEFER, Boston, Mass. tions, may appear spontaneously. Such variant types For several years we have been studying the various may be regarded as possessing potential " virulence." properties of the synovial fluid obtained from patients Further observations and evidence that a similar phe- with gonococcal arthritis. It was pointed out several nomenon occurs among other bacteria will throw con- years ago that bacteriological study of samples of syn- siderable light on certain obscure problems of the origin ovial fluid from patients with this type of arthritis failed of epidemic diseases and on the problem of virulence. to demonstrate the presence of gonococci in all cases. To Further Observations on Anti-Neutrophilic Serum. By determine whether this might be explained in part by JOHN S. LAWRENCE and (by invitation) WILLIAM B. differences in the bactericidal activity of the synovial CHEW, Rochester, N. Y. fluid, the following investigation was carried out. Guinea pigs injected with antineutrophilic serum have Bactericidal tests were done on the blood and synovial been treated, while the action of the antiseum was at its fluid of a group of patients with gonococcal arthritis; height, with substances which, under normal conditions, 4 had infected fluids and 10 were uninfected. Four produce distinct changes in the white blood cell picture. other specimens of synovial fluid which were obtained Adrenalin subcutaneously, sodium bicarbonate solution from other types of arthritis were studied and used as intraperitoneally and a broth culture of B. coli intra- controls. peritoneally have been used. Adrenalin given to normal It was found that when the fluids were infected there guinea pigs produced at 2 to 3 hours a neutrophilic leuko- was a wide difference in the bactericidal power of the cytosis with little or no change in the lymphocytes. synovial fluid and whole blood. When the fluid was Sodium bicarbonate resulted in a neutrophilic leukocyto- sterile the bactericidal content of the blood and synovial sis with lymphopenia at 6 hours; and the broth culture fluid was the same. of B. coli produced at 6 hours lymphopenia without The complement titer of the synovial fluid was found neutrophilic leukocytosis, but at 12 hours neutrophilic to be the same or slightly lower than that of the blood, leukocytosis with lymphopenia, and at 24 hours neutro- and the bactericidal action was abolished by heating at philic leukocytosis with a normal lymphocyte level. 560 C. for 2 hours. The bactericidal action of synovial The results obtained with animals in whom the neutro- fluid could be enhanced by the addition of antigonococcal phils were absent from the blood due to antiserum show immune serum. that exactly the same response to these substances is ob- The evidence so far indicates that the difference be- tained on the part of the lymphocytes as in normal ani- tween infected and sterile samples of synovial fluid from mals. In other words, the curve for the lymphocytes, patients with gonococcal arthritis is due in part to the under the condition of these experiments, is independent presence of antibodies in those which are sterile and of the response on the part of the neutrophils. Our their absence in those which are infected. An investiga- data, also, indicate a similar response on the part of the tion of other factors is being pursued at present. other white blood cells. Bacteril Type Transformation. By HOBART A. REI- On the Prolonged Coagulation Time Subsequent to Ana- MANN, Philadelphia, Pa. phylactic Shock. By HARRY EAGLE, Baltimore, Md., A strain of M. tetragenus isolated from the blood of a and (by invitation) C. G. JOHNSTON and I. S. RAVDIN, patient with purulent arthritis and meningitis produced Philadelphia, Pa. typical white colonies on agar. In a study of the The retarded coagulation observed in rabbits and dogs microbic dissociation of the organism over a period of immediately after anaphylactic shock is regularly asso- AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 671 ciated with the presence of increased amounts of anti- gurgitated and p is mean systolic intraventricular pres- thrombin in the blood. The increased antithrombic ac- sure. X bears a fairly direct relationship to the duration tivity may be as much as one hundred times the normal of diastole in a given insufficiency. Doubling the net level. output per minute requires a relatively small increase in The fibrinogen content of the plasma is unaffected; for the work of the left ventricle and may require less than the reasons cited in the text, there is reason to believe with a normal output when the increased output is ob- that even the plasmas completely non-coagulable by cal- tained by doubling the rate. cium and tissue extract nevertheless contain sufficient These calculations may give a clue to the reason for prothrombin to effect coagulation; and although the the clinical impression that patients with mitral stenosis platelet count is usually decreased after anaphylactic recover more readily from myocardial insufficiency than shock, the amount remaining would ordinarily suffice to do patients with aortic insufficiency. They do not permit cause coagulation within approximately normal time an estimate of the cost of the work required. limits. The increased antithrombic activity of the blood after Venous Pressures, Cardiac Output and Blood Volume in anaphylactic shock is apparently the primary cause of Arteriovenous Fistula. By C. SIDNEY BURWELL and the observed retardation of coagulation. (by invitation) J. ALLEN KENNEDY, Boston, Mass. Scarlet Fever Immunization by Intracutaneous Injection This report deals with the dynamics of the circulation of Scarlatinal Streptococcus Toxin. By RICHARD A. in a young man with an arteriovenous fistula in his fore- KERN, and (by invitation) JEAN CRUMP and RUDOLPH arm. It deals particularly with the venous blood pres- L. RODDY, Philadelphia, Pa. sures, the total blood volume and the cardiac output: aspects of the circulation concerning which little is In brief, the work grew out of some earlier work in known relating to human subjects. our clinic with diphtheria immunization by the intra- The venous pressure was increased near the fistula and cutaneous route. Subcutaneous immunization against at all points measured between the fistula and the heart. scarlet fever has been attended by severe local and con- The venous pressure in the other limbs was not elevated. stitutional reactions in many instances. This has been It was necessary to test the validity in this patient of particularly true among allergic individuals, so that the the method used for the determination of the cardiac prophylactic treatment may be worse than the disease. output. To this end measurement was made of the The intracutaneous injection of immunizing material in "recirculation time," i.e., the period required for blood one-tenth of the subcutaneous dose results in a negative to travel from the pulmonary capillaries to the fistula in Dick test, as a rule, after four or five injections. There the forearm, pass through the abnormal connection and is never a severe local reaction and we have never seen return by way of the veins and right heart to the lung. a single constitutional reaction with fever. We have The period was divided into the " vein-to-lung time " and given over 500 injections to over 100 patients. the " lung-to-vein time." The former was determined Mitral by the ether method of Hitzig, the latter was estimated The Effect of Increased Cardiac Output in the time for inhaled carbon monoxide to Stenosis and Aortic Insufficiency. By EMMET B. BAY by required (introduced by C. Phillip Miller), Chicago, Ill. reach the vein adjacent to the fistula. Carbon monoxide hemoglobin was recognized by means of a specific light Formulas for the calculation of the work of the ap- filter and a photo-electric cell. It was possible to get propriate part of the heart in the presence of the valvular checks with the three sample acetylene method within the lesions noted were tested on a model of the circulation. time limits thus established. In mitral stenosis: The cardiac outputs thus determined were elevated. Vv VT? Left auricular work = Vp + - + n -, When the fistula was closed by a blood pressure cuff on 2g 2g the arm, the output was within the usual limits; after operation it gradually approached the same level. where V is output per beat, p is diastolic intraventricular The total blood volume was determined by the method pressure, v is velocity, g is the force of gravity, and n is of Gregersen, Gibson and Stead,1 using the blue azo dye, a constant for a given stenosis. Doubling the cardiac T-1824, and spectrophotometric analysis. The volume output per minute requires a relatively large increase in was elevated when the fistula was widely open, and ap- the work of the left auricle since it results in a greater proached the calculated normal after surgical treatment velocity, a factor which is squared in the formula. The in Doubling the heart rate requires more work to overcome of the arteriovenous connection. variations the stenosis than doubling the output per beat. cardiac output occurred at the same time and in the same In aortic insufficiency: direction as those in total blood volume. Left ventricular work = (V + X)p, 1 Gregersen, Magnus I., Gibson, J. J., and Stead, E. A., where V is net output per beat, X is the amount re- Am. J. Physiol., 1935, 113, 54. 672 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING Vasoconstriction as a Response to Increased Venous A Rare Form of Pararrhythmia wuith " Exit" Block Oc- Pressure.' By WILLIAM A. SODEMAN and GEORGE E. curring in a Patient with Multiple Ectopic Pacemakers. BURCH (by invitation), and Roy H. TURNER, New By L. N. KATZ and (by invitation) J. L. ESCHEL- Orleans, La. BACHER, S. STRAUSS, S. H. ROBERTSON and H. BINS- WANGER, Chicago, Ill. Volumetric changes in the finger tip were studied with use of a sensitive Im- This patient has shown multiple ventricular and auricu- the syphygmoplethysmograph. lar premature systoles for years, together with attacks of mediately proximal to a plethysmographic cup an occlud- paroxysmal supraventricular and ventricular tachycardia ing air cuff was loosely wrapped so as not to produce any and periods of bradycardia. A large number of electro- constriction when deflated. The cuff was connected to a cardiograms had been taken. On three occasions electro- pressure reservoir and manometer so that any desired cardiograms were obtained sufficiently long for analysis, pressure might be suddenly applied and the resulting vol- and on analysis it could be shown that each of the various ume changes in the finger tip noted. Thirteen normal ectopic pacemakers was discharging at time intervals subjects, 10 patients with diastolic hypertension and one which were multiples of a common divisor distinct for patient with acrocyanosis were studied under controlled each pacemaker. It is therefore possible that they repre- atmospheric conditions. They were seated comfortably sented instances of pararrhythmia not only with inter- with the arm resting passively upon a support with the ference dissociation and " entrance " block, but also with finger tip at heart level, 30 minutes being allowed to reach " exit" block. On one occasion a record was obtained a steady metabolic state. Reactions were then noted for with only one active auricular ectopic pacemaker compet- obstructing pressures varying from 5 mm. Hg to diastolic ing with the sinus node for control of the heart. The " " for 15 to 120 an inter- exit block was marked. The sinus node was kept dis- pressure and maintained seconds, charged whenever the ectopic rhythm was active, and the val exceeding the time of obstruction being allowed for sinus node took control only when the " exit " block in- recovery between each observation. creased and prevented the ectopic pacemaker from main- In the normal subjects, for cuff pressures up to a defi- taining control. We have not seen such a mechanism nite critical level, varying in different individuals from reported in the literature. It offers unusually convincing 15 to 40 mm. Hg, there was a sudden increase in finger proof of the theory of pararrhythmia with " exit " block tip volume, reaching a maximum within 5 to 10 seconds first postulated by Rothberger and Kaufmann. after occlusion and followed by a gradual diminution in The Effect of Digitalis on the Anesthetized Dog. By L. volume reaching to or below the original level within one N. KATZ and (by invitation) S. RODBARD, M. FRIEND minute (Response A). Release of cuff pressure at that and W. ROTrERSMAN, Chicago, Ill. time always resulted in a further diminution in volume, In a series of acute experiments on anesthetized dogs usually greater than the reduction occurring before pres- with arterial blood pressure within normal limits, digitalis sure release. But when cuff pressures above this critical given intravenously in therapeutic doses (0.34 cat unit per level were applied only swelling occurred, that is until kgm. as Digifoline, Ciba) elevates the arterial and portal pressure was released (Response B). pressures, lowers the venous pressure, and decreases the In the 10 patients with diastolic hypertension the re- venous return flow to the heart. Our experiments indi- sponses were similar, and the levels at which the reaction cate that these digitalis actions are due in part to periphe- changed varied from 7.5 to 60 mm. Hg. No differences ral vasoconstriction and in part to a constrictor action were noted between the red and pale hypertension of on the blood vessels of the liver. The result is a reduc- Volhard. In a patient with acrocyanosis with arteriolar tion in venous return and therefore in the minute volume constriction and dilatation of the non-arterial vessels, a output of the heart. These effects persist but are less in response only of Type B was observed. degree when the portal blood is shunted directly to the The in vena cava without passing through the liver. gain volume of the finger tip immediately fol- In anesthetized dogs with arterial blood pressures at lowing application of pressure in the obstructing cuff is shock level, results are the same as above except that the probably due mainly to distension of small veins, venules venous return flow to the heart is increased. These ef- and capillaries, and loss of volume which followed under fects also persist when the portal blood is diverted from proper conditions is probably due to active constriction of the liver. The major effect of digitalis at low blood these same vessels. The critical pressure at which the pressure appears to be the result of vasoconstriction im- type of response changes is an index of tone of the ves- proving the deficient coronary circulation by elevating sels responsible for the volume change. The mechanism the arterial blood pressure. In this way the heart action of the response is not known, but it is likely that it is is benefited and the minute volume output of the heart is initiated by intravascular tension. increased. The reduction in venous pressure load on the right heart would enhance this action. While the experiments reported by us have not ruled 1 Aided by grants from the Josiah Macy, Jr., Founda- out an action of digitalis directly on the heart muscle, tion, the David Trautman Schwartz Research Fund and they show that such a possible action need not be in- the American Medical Association. voked to explain our observations. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 673

The Electrocardiogram in Air and Fat Embolism. By previous investigators that, first, systolic clicks usually THOMAS M. DURANT (introduced by Charles L. occur in individuals who show no evidence of organic Brown), Philadelphia, Pa. heart disease and that they therefore have no unfavorable A series of experiments was carried out, using the dog prognostic significance, and second, that their sole clinical as the experimental animal, to determine the type and importance lies in the possibility that they may be mis- origin of electrocardiographic changes associated with taken for the more common diastolic gallop sounds. air and fat embolism originating in the systemic venous Measurements made from a fixed point of the accom- circulation. The electrocardiographic changes obtained panying electrocardiogram show that, with few excep- were of an extreme type and were remarkable for their tions, the position of the extra sound from cycle to cycle constancy in all experiments regardless of whether air is much more variable than is the onset of the second or fat was the embolic substance. These changes con- heart sound. sisted in very marked lowering of the S-T segment in Although the exact cause for systolic clicks remains Leads II and III, without appreciable change in Lead I, obscure we believe that their clinical characteristics and and not associated with alteration of the QRS complex, the results of the measurements indicate that while they corresponding with changes often seen in infarction of are intimately associated with movements of the heart the myocardium. That these changes were not, how- within the chest they are not intracardiac in the sense ever, due to coronary artery embolism was proven by that they are due to pressure changes within the cavities pathological study. They occurred in association with a of the heart or the aorta. marked, sudden rise in venous pressure, and, in animals with the thorax open, appeared synchronously with the The Sedimentation Rate in Angina Pectoris and Coro- onset of right ventricular dilatation. It is concluded nary Throm:bosis. By JOSEPH E. F. RISEMAN and from the evidence made available by these experiments MORTON G. BROWN (introduced by Samuel L. Gargill), that the electrocardiographic changes observed were those Boston, Mass. of acute right heart dilatation secondary to obstruction of The corrected sedimentation index was studied in the pulmonary circulation by the embolic substance. The thirty-seven cases of coronary thrombosis, fifty-five pa- similarity to S-T changes observed in cases of human tients with angina pectoris, and twenty-one apparently pulmonary embolism is discussed. normal persons of similar age. It was evident that individuals between the ages of 45 Factors Which Affect the Prognosis of Bundle Branch and 70, without any evidence of disease, may have a cor- Block. By A. CARLTON ERNSTENE, Cleveland, Ohio. rected sedimentation index slightly higher (up to 0.70) That bundle branch block usually is associated with than the accepted normal for young adults. serious organic heart disease is a matter of common Over half of the patients with angina pectoris had a knowledge. It is not so generally recognized, however, moderate elevation of the sedimentation index (0.73 to that the prognosis in patients with this type of electro- 1.38). There is reason to believe that attacks of angina cardiographic abnormality is determined by the cardio- pectoris occasionally result in myocardial damage. vascular symptoms and signs, which are so often present, Two-thirds of the cases of coronary thrombosis had rather than by the bundle branch block itself. In the ab- rates considerably greater than that seen in any patients sence of congestive failure or of the anginal syndrome, with angina pectoris; in the remaining third, the values bundle branch block ip not incompatible with several were above 0.1 mm. The fastest rates were observed be- years of life. tween the fourth and twelfth days after the onset of In a series of 66 consecutive cases of bundle branch symptoms of coronary occlusion. Measurement of the block, there were 7 patients in whom the abnormality is sedimentation rate is of value in differentiating between known to have been present for two to ten years and in angina pectoris and coronary occlusion. The sedimenta- whom significant symptoms referable to the heart have tion rate is of little or no aid in predicting the immediate not developed. Six other patients have had bundle outcome of the acute attack. The mortality of patients branch block for at least one year and have remained free discharged from the hospital with fast rates, however, from symptoms. The case records of these patients have was twice as great during the first year after discharge been analyzed, and a comparison has been made with the as that of patients discharged with low or normal rates. clinical findings in the patients who have died or who Since the sedimentation rate signifies tissue damage, it is are still living but are experiencing cardiovascular symp- advisable to continue bed rest until the rate either returns toms. to normal or shows no further progression towards nor- mal. Systolic Gallop Rhythm. By FRANKLIN D. JOHNSTON, Ann Arbor, Mich. A Clinical Study of the Action of Commonly Used Twenty-one patients displaying on auscultation extra Drugs on the Heart and Circulation. By C. J. GAMBLE, sounds in cardiac systole have been studied by the com- ISAAC STARR and (by invitation) A. MARGOLIES, J. S. monly used clinical methods and by means of sound trac- DONAL, JR., N. JOSEPH and E. EAGLE, Philadelphia, Pa. ings taken simultaneously with the electrocardiogram. The subjects consisted of about 100 patients suffering The clinical data obtained confirms the opinions of chiefly from cardiac or circulatory disease, but not from 674 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING congestive heart failure. As far as possible we studied from congestive heart failure were studied by means of the action of drugs given under the conditions in which the dye method of determining the blood volume de- physicians are accustomed to employ them. The num- scribed by Gibson and Evans (J. Clin. Invest., 1937, 16, ber of patients receiving a single drug varied from 4 to 301). 14. The change from the compensated to the decompen- The drugs investigated included digitalis, epinephrine, sated state is characterized by a progressive increase in ephedrine, caffeine, theophylline, carbaminoylcholine, the volume of plasma and red blood cells. This increase sodium nitrite, nitroglycerine, pitressin, quinidine, mor- is shared to a less extent by the plasma than by the red phine, and strychnine. cells resulting in a slight concentration of the blood, as The study consisted of a group of estimations made evidenced by an increase above normal levels in hemato- before, during, and sometimes after, the drugs' action. crits. The degree of elevation of blood volume above This group consisted of duplicate determinations of the average normal level, as determined in 90 individuals, cardiac output and metabolic rate, and repeated estima- parallels the degree of elevation of venous pressure and tions of pulse rate, blood pressure, respiratory rate and increase in circulation time above average normal values. volume. Orthodiagrams and electrocardiograms were During clinical recovery from congestive heart failure secured also. there is a diminution in both plasma and red cell volume, A statistical analysis of the data affords a basis for the decrease in plasma volume being at first more rapid describing the action to be expected after the administra- than that of the red cell volume, resulting in still further tion of these drugs in clinical conditions. Almost with- concentration of the blood. With continued improvement out exception the results support the conceptions of drug the proportion of red cells to plasma tends to return to action derived from animal experiments. normal levels. The diminution in total volume is com- mensurate with the degree of clinical improvement. The Effect of Epinephrin in Circulatory Collapse. By An increase in blood volume over levels obtaining dur- ROBERT W. WILKINS (by invitation) and SOMA WEISS, ing failure was not observed in any case studied during Boston, Mass. recovery from chronic congestive heart failure. Re- Nitrite collapse induced in normal subjects was used lapses to more severe degrees of circulatory failure are to test the therapeutic efficacy of epinephrin. Epinephrin accompanied by maintained elevation of or further in- produces elevation of the arterial pressure with essen- crease in blood volume. tially unchanged venous pressure both in the horizontal and in the upright position. As indicated by the be- The Influence of Theophylline upon the Absorption of havior of the vessels of the hand studied by plethysmo- Mercurial Diuretics from the Site of Injecton. By graphic methods, the arteries and arterioles become ARTHUR C. DEGRAFF and (by invitation) ROBERT A. sharply constricted and the blood flow decreases. The LEHMAN and ROBERT C. BATTERMAN, New York, N. Y. venous tone, however, remains unaltered or only moder- It has previously been shown that a mercurial diuretic ately increased. When epinephrin, in doses which pro- containing theophylline (mercupurin) is capable of pro- duce therapeutic or slightly toxic effects, is given soon ducing a greater diuresis than a simple mercurial after the administration of nitrites but before the ap- (salyrgan). Furthermore, tissue destruction noted at pearance of symptoms, all the manifestations of col- the site of injection with a mercurial diuretic was for the lapse and syncope develop just as soon as, if not sooner most part prevented by the presence of theophylline in than in the controls, in spite of the fact that the fall of sufficient concentration in the injected solution (DeGraff, arterial pressure associated with nitrite collapse may be Nadler, and Batterman). partially or completely prevented. In the presence of In the light of these results it was thought to be of collapse, epinephrin augments the already existing ar- interest to determine quantitatively the rates of absorp- terial and arteriolar constriction with decreased blood tion of mercurials from muscle with and without the ad- flow but fails to produce significant constriction of the dition of theophylline. Experimentally, this was carried capillary and venous reservoirs. The venous return of out by giving a series of rabbits intramuscular injections blood to the right side of the heart is not enhanced. of mercupurin and salyrgan. The animals were killed at These observations indicate that the level of the arterial definite time intervals and the amount of mercury re- pressure is not necessarily a criterion of circulatory col- maining at the site of injection determined by chemical lapse. It is concluded that in spite of its arteriopressor analysis of the muscle used. By this procedure we have effect, epinephrin may be harmful in certain types of come to the following conclusions: (1) that a mercurial collapse as it may further enhance tissue anoxia. diuretic containing theophyllin is completely absorbed one hour after intramuscular injection whereas a mercurial Changes in Blood Volhme in Congestive Heart Failure. diuretic without theophyllin is only 25 per cent absorbed By WILLIAM A. EVANS, JR., and JOHN G. GIBSON, 2D after the same interval; (2) that a mercurial diuretic (introduced by Henry A. Christian), Boston, Mass. without theophyllin is still only 80 per cent absorbed Changes in plasma and total blood volume occurring in after 48 hours; and (3) that this marked difference in chronic heart disease during the transition from com- the rates of absorption of the two drugs is entirely due pensation to decompensation, and during clinical recovery to theophyllin. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 675

Prostigmin in the Diagnosis and Treatment of Myas- aminations of the synovial fluid are of diagnostic and thenia Gravtis. By GEO. D. GAMMON and (by invita- prognostic significance. tion) E. A. SCHEIE, Philadelphia, Pa. Relief of myasthenia gravis by eserine and prostigmin Calcium and Phosphorus Metabolism Studies in Rheuma- suggests the mechanism involved is a failure of the toid and Degenerative Arthritis. By MARIAN RoPEs motor nerve impulse to activate the muscle fiber; de- (by invitation), CHARLES L. SHORT and ELSIE Ross- ficiency of neurohumoral transmission may be involved. MEISL (by invitation), and WALTER BAUER, Boston, The possibility of utilizing the response to prostigmin as Mass. a diagnostic test of myasthenia is not widely appreciated. The marked decalcification observed in rheumatoid Schwab and Viets have shown cases of upper and lower arthritis and the osteophyte formation seen in hyper- motor neurone paralysis are not relieved by the drug. trophic arthritis suggest the possibility of an altered cal- In this study we found that various muscular diseases cium and phosphorus metabolism in these two diseases. likewise failed to respond. The cases include progres- The fasting serum calcium, phosphorus and phos- sive muscular dystrophy, myotonic atrophy, family peri- phatase values in such individuals were found to be odic paralysis, and amyotonia congenita. Thus the only within normal limits. Therefore, complete calcium, condition so far examined which is relieved by prostig- phosphorus and nitrogen metabolism studies were car- min is myasthenia gravis; hence the drug can be used to ried out on eight rheumatoid and three hypertrophic ar- diagnose the disease. In the treatment of myasthenia, thritics. When studied on a low calcium intake, the ob- symptomatic relief may be obtained; it appears likely served negative calcium balances in both groups were the natural course of the disease is uninfluenced. essentially the same as in the controls. The four pa- tients with rheumatoid arthritis exhibiting the most The Interpretation of Pathological Joint Effusions. By marked decalcification had the highest negative calcium H. C. COGGESHALL, MARIAN ROPES and ELSIE Ross- balances. That marked restriction of activity is an ade- MEISL (by invitation), and quate explanation for the observed increased calcium WALTRm BAUE, Boston, excretion is suggested by the fact that immobilization Mass. of a normal individual in a cast will result in an in- The cytological, physical and chemical characteristics creased calcium excretion of 0.95 gram per three-day of normal bovine and human synovial fluid have been period. Four rheumatoid arthritic patients studied on a established. Normal human synovial fluid is more high calcium diet showed no abnormalities. The actual viscous and the concentration of serum proteins and phosphorus balances were in all cases in close agreement mucin are greater. Both fluids are relatively acellular. with the theoretical phosphorus balances. The predominant cells are monocytes. These results indicate that an altered calcium and Having defined normal synovial fluid, we are in a phosphorus metabolism is not a primary feature of either better position to interpret the variations that we have rheumatoid or hypertrophic arthritis. encountered in pathological fluids obtained from patients with various types of joint disease. The Mechanism of Human Diabetes Insipidus. By Edema from any cause results in a lowering of the HENRY L. SCHMITZ, Chicago, Ill. total cell count, mucin and protein. Most of the pro- The nature of the disturbance in water metabolism in tein is albumin. diabetes insipidus has been studied in four patients with The total cell count is increased in hypertrophic ar- this disease. The following observations were made. thritis. Both total and polymorphonuclear cell counts The withdrawal of water for periods of four to six hours are increased in traumatic effusions. The total cell and had no significant effect upon the urine output although polymorphonuclear cell counts increase progressively the patients complained of thirst. When water was then with increasing inflammation of the synovial membrane. allowed ad libitum the output was influenced but little, There is no absolute relationship between sugar con- and the enormously excessive intake approximately made tent and cell counts. Some of the lowest sugar values up the deficit created during the period of abstinence. have been observed in rheumatoid arthritis. The total Analysis of renal function by the creatinine clearance and method of Rehberg indicated that the polyuria was due protein globulin content increases with increasing to a deficient reabsorption of water in the renal tubules. inflammation of the synovial membrane, the highest Glomerular filtration was within normal limits. The ad- values being encountered in long standing effusions of ministration of pituitrin decreased the urine volume by rheumatoid arthritis. Mucin increases are seen only in increasing tubular reabsorption. As the effect of pitui- non-inflammatory joint diseases. trin wore off tubular reabsorption decreased and urine These and similar data from rheumatoid arthritics volume increased. Increase in the fluid intake lagged with regularly recurring knee joint effusions show that behind the return of the polyuria. the cytological and chemical variations depend on the These results are interpreted as meaning that the essen- severity and duration of the inflammation of the syn- tial defect in diabetes insipidus is renal, specifically a ovial membrane as well as on the etiology. If these failure in tubular reabsorption of water and that pi- facts and the clinical history are taken into account, ex- tuitrin corrects this defect. 676 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING Effect on Tumor Growth of Treatment with Coichicine sium was studied in a patient with periodic family paraly- and X-rays. By AUSTIN M. BRUES and BEULA B. sis. The patient was a 15 year old male who had peri- MARBLE (introduced by Joseph C. Aub), Boston, Mass. odic attacks of paralysis involving most of the voluntary The alkaloid colchicine is a specific poison for cell muscles, lasting for about 24 hours. Following the oc- division, blocking mitosis in the visible metaphase stage. currence of a few of these attacks, the urinary and fecal It is also known to have a specific metabolic effect on output of calcium, phosphorus, and magnesium was deter- tissues, consisting in marked reduction in vitamin C con- mined for 8 periods of 6 days each during which care- tent. The present experiments have been performed on fully weighed diets were given. The mineral content of rats and mice bearing experimental tumors, and indicate the diet was kept constant from day to day during each that the administration of repeated large doses of colchi- period, but varied for the different periods. The calcium cine retards the growth of these tumors very markedly, balance was normal. The patient was in balance on a although regression of tumors rarely occurs. This diet containing 1.0 gram of calcium daily. On a daily seems to be due in part to the effect of the drug on cell intake of 2.0 grams of calcium, 0.550 gram were retained division, and in part to vascular injury such as occurs daily; on a daily intake of 0.100 gram there was a nega- after administration of bacterial filtrates. Retardation tive balance of 0.260 gram. Likewise, the output of occurs only with toxic or near-toxic doses, and many of magnesium was normal. The amounts of magnesium these animals died of colchicine poisoning. A series of eliminated daily were similar to those in the diet on in- animals receiving smaller doses, in amounts that could takes varying from 0.162 gram to 0.306 gram. On the safely be administered daily, showed no tendency to other hand, there was a negative balance of phosphorus retardation of growth and no lowering of tissue or tu- during all the periods of investigation. During the pe- mor ascorbic acid, although some arrest of mitosis was riods when 1.6 grams of phosphorus was contained in the seen. The smaller doses of colchicine, when combined daily diet, the average daily negative balance was 0.362 with x-ray treatment (300 r daily for ten days) caused gram. On an intake of 2.0 grams the average daily no further regression of tumors than did x-rays alone. negative balance was 0.147 gram and when 0.60 gram of phosphorus was given daily the amounts eliminated ex- Insensible Water Loss in Disease. By ALEXANDER W. ceeded the intake by 0.358 gram. By the use of similar WINKLER (introduced by John P. Peters), New Haven, methods and diets the mineral balance of 2 patients with Conn. progressive muscular dystrophy and 2 patients with myo- The daily insensible loss of weight over considerable tonia atrophica was determined. In these 4 patients with- periods of time was determined in a group of some out periodic family paralysis the metabolism of calcium, twenty patients presenting various metabolic disturbances. phosphorus, and magnesium was normal. In 6 edematous nephritic subjects the insensible loss did The data suggest that in periodic family paralysis there not vary significantly with urine flow, fluid intake, or is a disturbance in the metabolism of phosphorus without change in body water and salt content during diuresis. any involvement of the metabolism of calcium or mag- In both edematous and non-edematous subjects the aver- nesium. These observations were made after the occur- age insensible loss was definitely correlated with the basal rence of a few attacks of paralysis. Whether a similar metabolism. The daily insensible loss varied more in loss of phosphorus precedes an attack of paralysis or individual subjects than did the basal metabolism. In whether phosphorus is retained at that time has not yet certain cases of renal and vascular disease the average been determined. insensible loss over prolonged periods was found to be related to the total metabolism by the following approxi- Further Experiments on Experimental Hyposthenuria. mate equation: By PAUL DUMKE (by invitation) and J. M. HAY- Calories burned 2.0 X I. L. (grams). MAN, JR., Cleveland, Ohio. Evidence, however, is presented suggesting that the fac- This is a continuation of experiments reported last tor may be greater than 2.0 in certain of the edematous spring by Shumway and Hayman. At that time, it was and less than 2.0 in the hyperthyroid cases. In one case shown that dogs subjected to subtotal nephrectomy ex- of recovered acute nephritis with malnutrition, there was creted an increased volume of dilute urine, but could be a definite discrepancy between the total metabolism cal- made to put out a concentrated urine under certain ex- culated from the insensible loss by this equation, and the perimental conditions (intravenous sodium sulphate, in- insensible loss as estimated from indirect calorimetry. creased plasma colloids, low blood pressure). Dogs poi- It is concluded that while insensible loss is closely de- soned by uranium, on the other hand, could not be made pendent on total metabolism in disease as well as in to excrete a concentrated urine under any circumstances. health, under some circumstances the quantitative rela- In the present experiments, the effects of ureteral ob- tionship may be different. struction have been studied. Dogs subjected to adequate ureteral obstruction excrete a dilute urine, and cannot be The Metabolism of Phosphorus in Periodic Family Pa- made to concentrate by withholding food and water, nor ralysis. By A. T. MILHORAT (introduced by Eugene by any methods tried. The daily urine volume is usually F. DuBois), New York, N. Y. increased. Creatinine and urea clearances are markedly The metabolism of calcium, phosphorus, and magne- reduced. Blood pressure is not significantly elevated. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 677

These changes in renal function are apparent as early as The Treatment of Diabetes Mellitus with PYrotamine Zinc five days after obstructing the ureters. Histologically, Insulin. By S. SOSKIN, and (by invitation) R. LEVINE such animals show tubular degeneration. This damage, and M. D. ALLWEiss, Chicago, Ill. however, is reversible, for if the ureteral obstruction is There can be no doubt as to the greater efficacy and removed the animal recovers its ability to excrete a urine convenience of protamine zinc insulin, in the treatment of of high gravity. diabetes mellitus, as evidenced by a number of recent clinical reports. However, further experience has tem- Successful Management of Addisons Disease with Adre- pered our initial enthusiasm with certain practical con- nal Cortex Extract. By W. 0. THOMPSON and (by siderations. Treatment with protamine zinc insulin was invitation) P. K. THOMPSON, S. G. TAYLOR, III, and instituted under carefully controlled conditions in the W. S. Hoffman, Chicago, Ill. Max Pam Metabolism Unit of the Michael Reese Hos- pital. After several weeks of hospital observation, these We have been able to rehabilitate patients with typical same cases were followed for many months in the out- Addison's disease and maintain them in good health for patient dispensary. Our observations on these and other long periods by the administration of large doses of an patients have led us to the following conclusions: (a) A adrenal cortex extract (10 to 20 cc. daily) without any single dose of protamine insulin may show some effect other form of therapy. When typical symptoms of adre- for as long as 48 hours in a fasting individual, but its nal insufficiency develop during the administration of an clinically significant period of activity under the ordinary inadequate dose of the extract, or following its omission, conditions of feeding is probably 16 to 20 hours. (b) the patient may be revived by large doses of the extract Diabetes of the adult type can usually be well controlled alone, provided the insufficiency has not been allowed to with one dose of protamine insulin per day. (c) Dia- develop too far. When a crisis is well marked the ad- betes of the juvenile type can be well controlled but ministration of sodium salts must be added to the treat- usually requires two doses of protamine insulin per day. ment until nausea and vomiting disappear. While pa- (d) Occasional severe juvenile diabetics cannot be well tients may be maintained for periods of several months controlled throughout the 24 hours of the day by either by the administration of sodium salts alone or by com- protamine or ordinary insulin. (e) Because of its lesser bining this form of therapy with small doses of extract, effect on alimentary hyperglycemia, protamine insulin the most desirable clinical condition is not produced un- may be less effective than ordinary insulin in the treat- less an adequate dose of extract is given, and then supple- ment of the uncooperative or unintelligent patient. menting with sodium salts is unnecessary. If the dose of Indirect Calorimetric Study of the Oxidation of Glucose extract is adequate, the potassium content of the diet may in Controlled and Uncontrolled Diabetic Men. By J. be ignored. While changes in the composition of the M. SHEIDON (by invitation) and L. H. NEWBURGH, blood are important in diagnosis and as an index of the Ann Arbor, Mich. efficacy of treatment, the data show that, early in a crisis, The study consisted of a continuous four hour meas- there may be some discrepancy between the concentration urement by means of a respiration chamber of the of various substances in the blood and the clinical condi- amount of carbohydrate oxidized by normal men and by tion of the patient. When the crisis is well marked, the diabetics when they were controlled and uncontrolled. blood findings usually coincide with the clinical condition. Standard, open circuit, indirect calorimetry was em- ployed. All subjects were first studied while subsisting The Role in Growth and Development of Certain Potent on a low carbohydrate, high fat type of diet. Insulin Chemical Agents Found in Thymus Extract. By L. G. was not employed. The diets for all subjects were ad- ROwNTRE, and (by invitation) ARTHUR STEINBERG, N. justed so that the blood sugars of the diabetics remained H. EINHORN, N. K. SCHAFFER and WILLAM ZIEGLER, within the normal range. The energy of the diet was Philadelphia, Pa. approximately maintenance. Subsequently, the oxidation With freshly prepared solutions of glutathione, ascor- of glucose by the same diabetics was studied while they were and due to the bic acid and cysteine administered to parent rats, we have constantly hyperglycemic glycosuric, produced definite acceleration in the rate of growth and addition of sufficient carbohydrate to the diet (calories development of the offspring, in the second generation. were kept constant by an isocaloric reduction of fat). The controls received the same diet. A typical example These may be used singly or in combination. They are follows: now being tried by way of substitution therapy in the retardation in growth and development incident to thy- Carbohydrate Glucose at mectomy, through successive generations of rats. Ergo- of beginning of preparatory indirect Glucose thioniene, another iodine-reducing agent, is not present in diet calorimetry oxidized the thymus extract. The effects of glutamic acid and grams grams grams are glycine under investigation. Normals ...... 50 50 22

The possibility of obtaining thymus effects from a syn- Diabetic controlled..... 50 50 18 thetic extract containing glutathione, ascorbic acid and Normals...... 130 100 42 cysteine is being tried at present. Diabetic uncontrolled ... 130 100 20 678 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING

The data indicate that the diabetic is unable to oxidize indicate that in this case the thyroxine iodine is the better as much glucose as the normal control. A considerable determinant. This result agrees with data obtained in increase in the dietary carbohydrate causes the normal to normal guinea pigs by other investigators. In hyper- oxidize much more glucose but has no measurable effect thyroidism, artificially induced, the total thyroxine stored upon the diabetic. and the daily thyroxine need increase in roughly loga- rithmic fashion with the basal metabolic rate. 'Such The Corpus Luteum Hormone in Pregnancy. By J. S. L. data are illuminating in considering spontaneous hyper- BROWNE, and (by invitation) J. S. HENRY and ELEA- thyroidism. When thyroid medication is administered to NOR M. VENNING, Montreal, Canada. man, the better index of its effectiveness is (a) the total Using a gravimetric method, the excretion of sodium iodine for the athyreotic individual and (b) the thyroxine pregnandiol glucuronidate in the urine has been followed iodine for the thyreotic individual. in nine apparently normal cases at various periods of pregnancy. This compound has been shown to be ex- The Progtnostic Use of Iodine in Thyrotoxicosis. By S. creted during the luteal phase of the menstrual cycle and HERTZ (by invitation) and J. H. MEANS, Boston, Mass. the authors regard it as an excretion product of corpus In previous papers we have discussed the therapeutic luteum hormone (progesterone) in human urine. The and diagnostic use of the response to iodine in thyro- values are expressed as milligrams of pregnandiol ex- toxicosis. Evidence can now be presented which indi- creted in 24 hours, and days are counted from the first cates that the character of the response also gives in- day of the last menstrual period. formation of value in prognosis. Up to the 60th day the values found in four cases have A follow-up study on patients treated in our clinic in been from 4 to 10 mgm.; these are approximately the 1930 by Thompson revealed that the patients who did same as those found during the menstrual cycle. The well on prolonged iodine medication with but few ex- rate of excretion began to rise from this level, in the cases ceptions showed a substandard basal metabolic rate at studied, between the 80th and 100th day. By the 150th one time or other during their course of treatment. Pa- day in four cases it had reached a level of 40 mgm. The tients who did not exhibit this type of response to iodine rate continued to rise and a peak was reached in the came to operation. eighth month; in two cases 80 and 73 mgm. were ex- The animal experiments of Friedgood on the behavior creted at this period. Within 24 hours of delivery the of the basal metabolic rate of guinea pigs with anterior compound disappeared, practically completely from the pituitary induced hyperthyroidism showed a similar be- urine. In one case after removal of the ovary containing havior of the basal metabolic rate when the animals the corpus luteum at the fourth month, the compound reached the refractory or remissive stage and iodides continued to be excreted. were administered coincidentally. There are variations in the rate of excretion; but it is Upon the basis of such evidence we have taken the de- impossible to say at present whether or not these are of velopment of a substandard level of metabolism on iodine a cyclic nature or what are the limits of normal variabil- to indicate that the patient exhibiting it is approaching a ity. The efficiency of the glucuronide synthesizing mech- spontaneous remission of his disease and therefore does anism as well as the amount of progesterone produced is not require operation. In an impressive number of cases probably a factor in determining the rate of excretion of this reasoning has proved sound. the glucuronidate. The requirements of the body for corpus luteum hormone throughout pregnancy and the Observations in Chronic Hypoparathyroidism. By WIL- r6le of the placenta as a site of its production in the LIAM T. SALTER and (by invitation) DOROTHY M. TIB- later months are discussed. BETTS, Boston, Mass. The treatment of chronic hypoparathyroidism, whether The Calorigenic Activity of Thyroid Iodine at Different idiopathic or postoperative, often presents a complicated Levels of Metabolism. By JACOB LERMAN and WIL- therapeutic problem. In order to study the effect of LIAM T. SALTER, Boston, Mass. various therapeutic agents, the calcium and phosphate Several questions with regard to thyroid medication are metabolism was studied in four dogs whose thyroids and in dispute. Does myxedematous (athyreotic) man re- parathyroids had been removed. The observations ex- spond to the whole thyroid iodine or only to thyroxine tended, after operation, continuously over periods of 2, iodine? Does the athyreotic organism with normal or 14, 17, and 60 weeks, respectively: they comprised the hypernormal metabolism respond in accordance with to- effects of low and high calcium diets, of parathyroid ex- tal thyroid iodine or with the thyroxine iodine only? tract in varied dosage, of thyroid hormone, and of vita- As the normal organism becomes hyperthyroid in re- min D in various combinations. Similar observations sponse to medication, does it respond in accordance with were obtained also in two cats. total thyroid iodine or with the thyroxine iodine only? Among the results noted were the following: (1) Our investigations in human myxedema have shown During the continuous administration of minimal doses that the caloric response can be predicted more accurately of parathyroid extract, thyroxine was ineffective unless in terms of the total thyroid iodine. In the artificial pro- high calcium was available in the diet, when the blood duction of hyperthyroidism in man, however, our studies calcium rose. On a low calcium intake, thyroxine ag- AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 679 gravated tetany. (2) Parathyroid extract became pro- tinued despite progressive reduction in insulin dosage. gressively less effective as the animals' calcium reserves In October 1935 on 8 units a day she was constantly were depleted, as indicated by the calcium balance, but aglycosuric while following her diet. "Breaking diet" its effectiveness returned with high calcium intake. (3) caused only slight glycosuria. No menstrual period oc- Vitamin D with high calcium intake alone might preserve curred between June and November 1935. During a the normal status for long periods, but vitamin D with- hospital stay in February 1936 it was found that with no out dietary calcium was ineffective even in tremendous insulin whatever, hypoglycemic attacks occurred despite -dosage. However, after a recent repletion of calcium a liberal diet. She reentered the hospital in March 1936 stores, vitamin D continued to be effective for several for special studies. These showed a curious combination weeks after calcium was largely withdrawn from the diet. of mild diabetes and spontaneous attacks of hypo- (4) " Withdrawal " tetany occurred after excessive doses glycemia. No insulin was administered and yet no acido- of parathyroid extract were suddenly omitted. Indeed, sis developed despite a diet which at times included as with a rapidly dropping serum calcium, the onset of much as carbohydrate 300 grams, protein 130 grams and tetany was noted at levels of 14 to 12 mgm. per cent. fat 120 grams a day. Ergotamine brought about in one Conclusion. The thyroid hormone may elevate the hour severe hypoglycemia with a transient right hemi- serum calcium to normal levels if abundant calcium be plegia. Pure carbohydrate seemed to provoke rather supplied in the diet while parathyroid extract also is in- than to prevent hypoglycemia (after a period of transient jected in small amounts. In other words, in relieving hyperglycemia) whereas a mixed meal was more effec- hypoparathyroidism, thyroxine does not act upon the tive in preventing "reactions." residual parathyroid glandules, but upon some other At home between April 1936 and February 1937, she mechanism of calcium mobilization. The beneficial effect was entirely without insulin. Attempts were made to of vitamin D is likewise dependent upon readily available keep her on a diet relatively low in carbohydrate but be- calcium either from the diet or from recent storage as cause of the easy tendency to hypoglycemia the diet as demonstrated by positive calcium balances. actually taken at home was high in all three food com- ponents. Consequently she gained 20 pounds in weight Idiopathic Hypoparathyroidism. By FULLER ALBRIGHT, in the 10 months. and WALTER BAUER, and (by invitation) BENJAMIN Further studies under controlled conditions were car- CASTLEMAN and TRUMAN G. DRAKE, Boston, Mass. ried out in the hospital in February 1937. A blood sugar This report is based on five cases of hypoparathyroid- curve over a 24 hour period revealed a marked tendency ism occurring spontaneously, and includes the autopsy to the development of low values when 2 or 3 hours had findings on one of these cases. It is not so much con- elapsed after the taking of food. After 100 grams of cerned with the metabolic disorder resulting from the glucose there was an immediate rise to a level con- hypoparathyroidism as with the underlying cause of the sistent with mild diabetes and then a precipitous fall to hypoparathyroidism itself. It is pointed out that the a hypoglycemic level with attendant symptoms. disease usually starts in adolescence and that the time of These diagnoses have been thought most worthy of onset can be approximately determined by certain changes consideration: (1) Pancreatic islet cell adenoma; (2) seen in roentgenograms of the teeth. To the knowledge Hypofunctioning of the pituitary; (3) Some disturbance of the authors the autopsied case here reported is the of glycogen storage in the liver. Studies designed to first one in which the underlying pathology in the para- demonstrate a pituitary tumor have been negative and thyroid glands in this rare condition has been studied. although the liver is definitely enlarged, functional tests The disease is contrasted with hyperparathyroidism due have given values within normal limits. The patient and to idiopathic hyperplasia. The possible r6le of the her family have refused abdominal exploration. pituitary gland and of infection in the etiology is dis- cussed. The Reticulocyte Response to Liver Extract in Experi- mentally Induced Anemia. By B. E. HALL, G. R. HIG- Chronic (Spontaneous) Hypoglycemia in a Juvenile Dia- GINS and C. H. WATKINS (introduced by H. Z. Gif- betic with AMIarked Amelioration of the Diabetes. By fin), Rochester, Minn. PRISCILLA WHITE (by invitation) and ALEXANDER Macrocytic anemia, associated with hepatic cirrhosis, MARBLE, Boston, Mass. was induced in adult white rats by exposing the animals Studies are reported on a young woman now 21 years to inhalations of carbon tetrachloride for short daily old with onset of typical juvenile diabetes of marked periods over a span of two to three months, according severity at the age of 7.8 years. The patient has been to the method of Higgins and Stasney. Data with ref- under close medical observation from the date of onset erence to erythrocyte and reticulocyte counts in normal until the present. Symptoms, blood and urine findings and anemic rats were established and were compared with and course during this period leave no doubt even in the data of the aforementioned workers. A group of retrospect that the patient had true diabetes mellitus of normal rats were injected intraperitoneally with com- severe grade. In the summer of 1934 it was noted that mercial liver extract. Separate groups of anemic rats her insulin requirement (previously 40 to 65 units daily) were injected with: (1) single doses of liver extract was becoming less and that hypoglycemic attacks con- intraperitoneally, (2) single doses of physiologic saline 680 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING solution intraperitoneally, and (3) repeated daily doses turn in red cell volume to normal values is closely re- of liver extract intramuscularly for one week. In each flected by the degree of return to normal values of red instance the amount injected was arbitrarily chosen: 0.5 cell counts, hemoglobin determinations and hematocrit cc. per 100 grams of body weight. The normal rats re- values. ceiving liver extract and the anemic rats which were Certain evidence has been obtained which indicates that given saline solution failed to show reticulocyte reac- the response, in terms of percentage return to normal in tions. However, significant responses were observed in red cell volume is slower following multiple small doses the anemic animals which received either one injection or of liver extract than that which follows single large repeated daily injections of fresh commercial liver ex- doses, even though a satisfactory reticulocyte response tract. An attempt was made to control these experi- occurs in both instances. ments by eliminating other factors known to cause reticulocyte reactions. The Maturation of Transfused Reticulocytes in the Rat. By A. J. CRESKOFF (by invitation) and THOMAS FITZ- The Etiology of Idiopathic Hypochromic Anemia. By HUGH, JR., Philadelphia, Pa. W. M. FOWLER and (by invitation) ADELAIDE P. BARER, Our previous study 1 of the reticulocytosis of fetal and Iowa City, Iowa. nursling rats indicated the probability of peripheral re- During the course of studies of iron metabolism on pa- ticulocyte maturation. tients with hypochromic anemia certain observations per- In the present experiments litters of young rats with taining to the etiology of " idiopathic hypochromic high reticulocyte counts were used to supply donor-blood anemia " were made. to a recipient group of adult rats with low reticulocyte Determinations of iron balance show that patients with counts. Just before transfusion, recipients were bled an achlorhydria retain less iron from a normal dietary iron amount equal to the volume to be transfused (average intake than do patients with a normal gastric acidity. 5 cc.). In another group, anemic adult animals, with Although the patients with idiopathic hypochromic high reticulocyte counts induced by repeated bleedings, anemia denied excessive menstrual blood loss, it was were used as donors. In both groups the donor blood found that the average loss for these individuals was con- was concentrated to an 8,000,000 erythrocyte count be- siderably larger than the average for 100 normal women. fore transfusion. Control bleeding and transfusion ex- It was also found that the amount of iron which these periments were made with normal adult animals. patients retained from a normal dietary intake was not In all of our experiments the transfused reticulocytes sufficient to replace that lost by menstruation. disappeared progressively over a period of 48 to 96 A daily iron intake of approximately 12 mgm. is ap- hours, at the end of which time the recipient's reticulo- parently necessary to naintain a positive balance. cyte count had declined to pre-transfusion level without The patients with idiopathic hypochromic anemia re- any concomitant change in the recipient's elevated post- tained as much iron and regenerated hemoglobin as transfusion erythrocyte counts. This we believe indi- rapidly while receiving medicinal iron as did patients cates peripheral reticulocyte maturation and suggests with chronic hemorrhagic anemia, so that no evidence that the youngest reticulocytes (rat) require almost 4 of faulty iron metabolism was apparent. days to "mature" in the peripheral blood. Our data suggest also that transfused erythrocytes survive for 5 Blood Volume Changes in Pernicious Anemia. By J. G. to 8 days. Wistar-strain albino rats have no demon- GIBSON, 2D (by invitation) and WILLIAM P. MURPHY, strable intra-group hemagglutinins. Boston, Mass. Changes in plasma and red blood cell volume occurring The Questionable Relationship of Staphylococcus Infec- in patients with pernicious anemia treated by parenteral tion to Leukemia. By FRANKLIN R. MILLER, Cleve- liver extract were studied by the method described by land, Ohio. Gibson and Evans (J. Clin. Invest., 1937, 16, 301). Infection has been considered frequently as an eti- In severe anemia the total blood volume is reduced, ological agent in the leukemia group. In the past three averaging 17.5 per cent below normal in six patients with years I have studied five leukemias, each of whom had red cell counts around 1,500,000. The dimiaution in red at sometime one or more foci of infection caused by cell volume is offset to some extent by an increase in the hemolytic staphylococcus aureus. Three of these cases plasma volume. The individual cell volume is high. were studied to see if the white cell count and the num- With clinical improvement there is a progressive in- ber of immature cells bore any relationship to the infec- crease in the total blood volume, the plasma volume tend- tions. Two of these cases were given antigen made ing to diminish as the red cell volume rises. With com- from staphylococcus aureus, in the one case autogenous plete clinical recovery the red cell and total blood volume vaccine and in the other commercial staphylococcus returns to normal limits. Changes in individual cell vol- toxoid. In each case the white cell counts were low at ume vary with individuals but the general trend is to- the start and as the doses of antigen increased, the level ward smaller cells as red cell volume rises. During recovery, the relationship between changes in 1 Fitz-Hugh, T., Jr., Creskoff, A. J., and Taylor, H. B., plasma and red cell volume is such that the degree of re- J. Clin. Invest., 1936, 15, 468. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 681

of the white blood cell count increased, and the increase here for defibrinated blood, could be used as an accurate was chiefly made up of immature cells. Following the or specific method of estimating the concentration of any use of toxoid in the one case, diphtheria toxoid was given one blood constituent, such as plasma fibrinogen, serum in an immunizing dose with little or no increase in white globulin or lipoids, because of the influence of variations blood cell level. The third case had a leukemic count at in any one of these substances on the suspension stability. the start, but no demonstrable infection. However, hemolytic staphylococcus aureus was cultured from the Neutropenia (Agranulocytosis). Fatigue as an Etiologi- patient's nasopharynx and, because of this, staphylococcus cal Factor and Monocytosis as a Prognostic Sign. By antitoxin was employed. After the start of the anti- PAUL RFEZNIKOFF, New York, N. Y. toxin, many bullous lesions developed over the buttocks, Of the four etiological factors important in the causa- arms, back and face. These lesions contained pure cul- tion of neutropenia-fatigue, drugs, menstruation and in- tures of hemolytic staphylococcus aureus. No beneficial fection-fatigue previous to the onset of illness was change occurred in the white cell count or progress of found to be the most prominent predisposing factor in the disease with the use of 70 cc. or 50,000 units of anti- 11 of 13 patients. No inquiry was made into this feature toxin. in the 2 remaining cases. Drugs known to be of etiologi- The staphylococcus toxoid was used in immunizing cal significance in this disease were taken in 9 cases; in doses on a fourth case of leukemia without infection, in 3, no history of their use could be elicited. One patient which the white blood cell count was controlled with who had never taken drugs before her attacks received Fowler's solution. Here again the white blood cell 1.62 grams of amidopyrine as a sedative during her fourth count increased and immature cell forms were found in attack and recovered. Menstruation was a factor in 3 the blood smear. of the 9 female patients; 6 had passed the menopause. The data is too meager to state that infection in these Infections were of possible importance in 6 patients; in cases played any definite r6le in inducing or aggravating 4, no history of infections could be elicited, and in 3, no the leukemic process. previous infection could be found. The most constant hematological sign of recovery was Erythrocyte Sedimentation. Clinical Significance and a pronounced monocytosis which usually appeared before Evaluation as a Quantitative Procedure. By THOMAS any other evidence of improvement. Only a sporadic or HALE HAM (introduced by Clark W. Heath), Boston, slight monocytic response was present in the 3 fatal cases. Mass. Variation in the stability of erythrocytes in suspension Plasma Proteins in Aneminas. By CHARLES L. BROWN and (by invitation) I. W. GINSBURG, Philadelphia, Pa. was found to be a non-specific phenomenon which was altered by: plasma fibrinogen, serum globulins, lipoids, This report consists of a correlation study of the viscosity, hematocrit, mean corpuscular volume of eryth- plasma proteins with the size and hemoglobin content of rocytes, anticoagulant, diameter of sedimentation tube the red blood cells in ten cases of severe or moderately and height of blood column. The sedimentation rate was severe anemia and fourteen cases of mild anemia, other a measure of the degree of erythrocyte instability and, as than pernicious anemia or anemia of pregnancy. These such, had no direct clinical importance. The clinical cases were classified as microcytic, normocytic, and interpretation of the sedimentation rates depended upon macrocytic in accordance with the classification of the significance of the abnormal blood constituent, and Wintrobe. not upon the altered suspension stability. Plasma protein studies included total serum protein, Employing the Rourke-Ernstene technique, 260 deter- serum albumin, serum globulin, albumin globulin ratio minations of the corrected sedimentation "index" on 65 and colloid osmotic pressure. Throughout the whole subjects showed linear correlation with the concentration group of cases the total protein tends to be normal with of plasma fibrinogen only when there were normal values the serum albumin lower than normal with resulting for serum globulins and in general for lipoids. The sedi- somewhat lowered albumin: globulin ratio. The colloid mentation rate of erythrocytes in defibrinated blood was osmotic pressure, while varying over a considerable observed with correction for variations in hematocrit in range shows no distinct constant variation referable to 72 subjects. These rates were extremely slow and al- the microcytic or macrocytic cases. most a constant in normal subjects; they were slightly These studies indicate that there is no constant rela- accelerated and variable in abnormal subjects with nor- tionship of the cell volume to the colloid osmotic pres- mal serum globulins and lipoids; but were strikingly ele- sure of the blood serum, and the increase in the size of vated in instances of increased serum globulins or lipoids. the red blood cell cannot be explained alone on an The corrected defibrinated sedimentation rate showed no osmotic basis. relation to the concentration of plasma fibrinogen. The sedimentation techniques of Wintrobe, Wester- The Longevity of Erythrocytes in Human Blood. By gren, Linzenmeier and Cutler produced less satisfactory MATTHEW C. RIDDLE (by invitation) and RAPHAEL correlation with plasma fibrinogen than the method of ISAACS, Ann Arbor, Mich. Rourke and Ernstene. However, none of the above tech- From a study of the rate of blood formation in over niques using whole blood, nor the technique employed 600 patients with various types of anemia, it is concluded 682 PROCEEDINGS OF THE TWENTY-NINTH ANNUAL MEETING that the increase or decrease in the erythrocyte count per insulin had its usual effect in lowering the blood sugar week (It) is equal to the difference between the number concentration after a test meal. In another group, no of new erythrocytes formed and the number destroyed effect of insulin was demonstrable, the curves being es- (P D) in a given weekly period (t). For pernicious sentially the same with and without insulin. In the anemia the weekly rate of destruction (D) =0.22 + third group of cases, the glucose tolerance after the ad- (0.176 times Eo, the initial red blood cell count). In ministration of insulin appeared diminished; so that the normal individuals, in certain anemias (acute hemor- resultant curve following insulin was a diabetic-like rhage, iron deficiency, pernicious anemia during remis- curve, whereas without insulin, the curve was such as is sion) and for transfused normal erythrocytes, D = 0.22 obtained in normal individuals after a glucose meal. Eo. The average period of erythrocyte survival in That insulin in normal individuals under certain circum- pernicious anemia in relapse varies from 1.6 to 4.54 stances may appear to lower sugar tolerance already has weeks, depending on the erythrocyte count. In the other been recognized. The reason for this finding is not al- conditions mentioned, the average duration is 4.54 weeks. together clear. In our experience, the activity of the The theory is advanced that erythrocytes, being no thyroid gland is one certain factor. The size of the longer living nucleated cells, persist " indefinitely " unless dose of insulin used is another factor in determining the they are fortuitously destroyed by trauma. " Wearing type of sugar tolerance test obtained. Possibly the ac- out " then, is not in the order of " age," but in degree of tivity of the anterior lobe of the pituitary gland is a trauma. Modifying factors are (a) total erythrocyte third factor, though our data on this score are not alto- concentration, (b) shape, (c) size, (d) elasticity, (e) gether convincing. nature of the capillary bed, (f) velocity of the stream, and (g) chemical environment. Comparable tissues in Parathyroid Diuresis. By CLARENCE L. ROBBINS (in- troduced by John P. Peters), New Haven, Conn. this respect are the hair and nails. Recent studies of the effect of injections of para- The Effect of Intramuscular Administration of a Globulin thyroid extract on the excretion of electrolytes in urine Substance Derived from Normal Human Plasma in indicate that the excretion of base and particularly Hemophilia. By FREDERICK J. POHLE and F. H. L. sodium is increased in the first few hours after injec- TAYLOR (introduced by George R. Minot), Boston, tion. Ellsworth and others had previously demonstrated Mass. the increased rate of excretion of phosphorus immedi- Patek and Taylor 1 have demonstrated the effective- ately following injection of parathyroid extract. In the studies here reported an attempt was made to ness of a single intravenous injection of a globulin sub- stance derived from normal human plasma in reducing determine whether the parathyroid extract specifically the coagulation time of the blood in hemophilia. influences the excretion rate of sodium and of phosphorus The present observations demonstrate that the globulin or whether the observed increases are simply a resultant of increased renal filtration. Human subjects who pre- substance may be given intramuscularly with similar sented no evidence of renal dysfunction were used for effectiveness. After either single intramuscular or in- control observations and for studies of excretion rates travenous injection there was a prompt reduction in the of sodium, chloride, phosphorus, pH changes and exoge- coagulation time followed by a gradual rise with return nous creatinine clearances before and after injection of to the pre-injection level in 24 hours. extract. were the intramuscular or parathyroid When injections repeated by In the first hour and continuing for three hours after intravenous route within 7 hours, it was not possible to maintain the coagulation time at the reduced level. This injection a significant rise in pH of urine and in the ex- refractory period does not last longer than 24 hours cretion rates of water, sodium and phosphorus occurred. after the last injection. Creatinine clearances remained unchanged. Chloride ex- cretion was not significantly influenced. However, during this refractory period the plasma or It is concluded that parathyroid extract exerts a di- blood of the injected hemophilic patient showed no loss uretic action by inhibiting tubular reabsorption and not of clot-promoting power when measured in vitro against by increasing glomerular filtration as measured by cre- a control blood. the re- second hemophilic Therefore, of fractory phase in the injected patient cannot be explained atinine clearances. Molecular ratios excess sodium to phosphorus greater than 15 suggest that phosphatemia, on the basis of a deficiency of globulin substance alone. immediately following parathyroid extract may be en- Experiences uith Insulin in Non-diabetic Individuals. tirely secondary to diminished reabsorption of sodium by By REGINALD FITz and (by invitation) BEN VIDGOFF, the renal tubules. Boston, Mass. Supra-Diaphragmatic Splanchnic Resection for Essential A series of non-diabetic individuals were given ordi- Hypertension: A Two Year Study of Results, Selec- nary glucose test meals with and without added insulin. tion of Cases, and Physiological Considerations. By Three types of curve were encountered. In the one, REGINALD H. SMITHWICK (by invitation) and ROBERT S. PALMER. Boston, Mass. 1 Patek, Arthur J., Jr., and Taylor, F. H. L., J. Clin. In thirty-four early or moderate cases of essential Invest., 1936, 16, 113. hypertension followed from a few months to two years, AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 683 a fall of blood pressure to within normal limits in two- low color index and mean corpuscular hemoglobin con- thirds, and almost to normal in the remaining third oc- centration, low hematocrit with low mean corpuscular curred. volume and small average red cell diameters, and reduc- There is marked symptomatic improvement in all. No tion in the blood volume and blood viscosity to normal marked fall in blood pressure is obtained in cases of ma- values. lignant hypertension and only a moderate fall in 50 per Rising values after 6 to 9 months have been readily cent of the cases of late hypertension. Symptomatic im- controlled by a few venesections. provement of moderate or marked degree is obtained in all of late benign essential hypertension, and likewise in A Delayed Disturbance of Nitrogen Metabolism Follow- all of 6 cases diagnosed malignant hypertension. Medi- ing Certain Infections. By HAROLD A. BuLGm, St. cal treatment causes a substantial fall in the blood pres- Louis, Mo. sure of over 50 per cent of mild and moderate cases, The mysterious relationship of infection to such local while 90 and 75 per cent respectively, either have no disturbances as arthritis or nephritis inspires an interest symptoms or are very much relieved. Medical treat- in any correlated metabolic changes. We have noted ment causes a substantial fall in the blood pressure in certain striking phenomena following some acute infec- one-third of the late cases, and there are no symptoms, tions. They have occurred after an intervening period or symptomatic relief is obtained in slightly less than 50 of one to several weeks of seemingly normal metabolism. per cent. The most notable change has been an extraordinary ex- Experiments on the blood flow in the arm after nova- cretion of amino nitrogen. There has been at the same caine block, indicate that vasomotor control is much time a reversion to a negative nitrogen balance. Most diminished. We suggest that the basis of essential cases of nephritis have shown a more or less marked in- hypertension may be at first a vasomotor instability, crease in amino nitrogen excretion. Even more striking gradually becoming conditioned to a state of "chronic has been a great increase in the output of amino nitro- emergency." By sympathectomy of a large area of the gen of certain cases of arthritis. The magnitude of this minute vessels the first barrier of the peripheral resist- change may exceed ten times the usual amounts. We ance is lowered. It is not expected that the capillary have noted an immediate fall after removal of foci of resistance depending on tissue needs is affected by this infection. It should be noted that as a rule this phe- procedure. In the early vasomotor stage essential hy- nomenon is not associated with any febrile reaction. pertension may be halted at its inception. Later it may be relieved by abolishing the variability so characteristic of essential hypertension, but it is unlikely that the level High Peripheral Venous Pressure. Its Lack of Rela- can be lowered to normal after arteriolar change re- tionship to Orthopnea and Dyspnea in the Absence of sulting from long continued hypertension has taken place. Congestive Failure. By EUGENE B. FERRIS, JR., and (by invitation) JOHNSON McGUIRE, Cincinnati, Ohio. The Treatment of Polycythemia Vera by the Production There is considerable clinical and experimental evi- of a Chronic Iron Defciency State. By WILLIAM dence that the dyspnea and orthopnea of cardiac failure DAMESHEK and (by invitation) HENRY H. HENSTELL, are not related to increased venous pressure. However, Boston, Mass. a number of observers have maintained that such a rela- tionship does exist, either directly through the effect of The treatment of polycythemia vera is eminently un- high venous pressure itself; or indirectly through stagna- satisfactory. Phenylhydrazine is exceedingly difficult to tion anoxemia which is assumed to occur with high control and probably damaging to the liver. Fowler's venous pressure, or through the associated increased in- solution is not well tolerated. X-ray therapy has been tracranial pressure. disappointing. Occasional venesections apparently stimu- We have observed thirteen patients having extremely late blood production. high venous pressures in the upper part of the body re- In 5 well-controlled cases previously treated with the sulting from superior vena caval obstruction and have above methods, a state of chronic iron deficiency was in- been impressed by the absence of dyspnea or orthopnea duced by multiple venesections and a diet grossly de- in the majority of such patients. Blood gas studies of ficient in iron. Venesections, usually 6 to 8 in number, blood obtained from the internal carotid artery and from of 500 cc. were done twice weekly until the hemoglobin the internal jugular vein, spinal fluid pressures, simul- reached about 70 to 80 per cent and the erythrocyte taneous cubital and femoral venous pressures, and clini- count about 5.0 million. The daily dietary iron content cal observations have been made on five consecutive pa- was reduced to less than 6 mgm. Frequent studies were tients having superior vena caval obstruction. made of the clinical status, the blood, hematocrit, blood Dyspnea and orthopnea were absent in all five patients, volume, and viscosity. although venous pressures and spinal fluid pressures as With this method, the patients were maintained symp- high as 50 cm. of water were recorded. The cerebral tom-free from 6 to 9 months, and there have occurred: blood flow was diminished in some cases and normal in great reduction in the various features of the plethoric others. Stagnation anoxemia, when present, was not ac- state, relatively low hemoglobin concentration with very companied by respiratory symptoms. .684 PROCEEDINGS OF TIRE TWENTY-NINTH ANNUAL MEETING A Method for Determining the Minimal Infective Dose ease has been reported previously, the available evidence of Treponema Pallidum in Experimental Syphilis. By indicating that ordinary pulmonary and circulatory fac- HUGH J. MORGAN and (by invitation) GEORGE P. tors are not responsible. Oxygen dissociation curves of VRYONIs, Nashville, Tenn. the blood, calculated on the basis of an assumed pH, in- Our method offers a means of quantitating the dose of dicated a displacement of the curve to the right in some virus necessary for establishing syphilis in the rabbit. of these cases. The present study confirms the presence At least, one can say how many visible organisms are in of oxygen unsaturation of the arterial blood in advanced an inoculum which produces an infection. The results cirrhosis. A study of the oxygen-hemoglobin combina- so far indicate that a certain minimal number are neces- tion in such cases, with measurement of pH. and pHe of sary before infection will occur. This is a matter of in- the arterial blood as drawn and as equilibrated, shows an terest since many experiments in rabbit syphilis are apparent decreased affinity of hemoglobin for oxygen. based on the assumption that, if any organisms are pres- This decreased affinity persists over a range of from 30 ent, an infection will occur. Moreover, the method may to 80 per cent saturation and is sufficient to account for be of some value in considerations of the question of a the observed anoxemia. The presence of hyperbilirubine- ultramicroscopic virus in syphilis. mia alone is not a factor. A study of laked blood, as contrasted to whole blood, in these cases, provides the necessary data to discriminate The Combination of Oxygen and Hemoglobin in the between alterations in the hemoglobin itself and abnor- Blood of Patients with Liver Disease. By ANCEL malities in the equilibrium across the cell membrane. The KEYS (by invitation) and ALBERT M. SNELL, Roches- evidence obtained to date indicates that the hemoglobin ter, Minn. itself, as in all pathological conditions which have been The occurrence of anoxemia in advanced hepatic dis- studied, is not physiologically altered.