774 American Federation for Clinical Research

TRANSPORT AND EXCRETION OF URIC ACID IN MAN. III. PHYSIOLOGIC SIGNIFICANCE OF THE URICOSURIC EFFECT OF CARONAMIDE. W. Q. Wolfson, M.D., C. Cohn, M.D., R.

Levine, M.D. and B. Huddlestun, M.D.

(by invitation), Chicago, Illinois. (From the Departments of Biochemistry and Me- tabolic and Endocrine Research, Medi- cal Research Institute, Michael Reese Hospital.)

In normal adults following oral administra- tion of a single 4.6 Gm. dose of caronamide the true urate excretion increases from 50 to 120 per cent within two hours. Simultaneously the plasma urate falls slightly and the urate clear- ance increases to about twice its original value. The glomerular filtration rate remains at about the fasting value.

This effect is similar to that produced by other drugs (cinchophen, salicylate, diodrast, salyrgan) all of which produce a simultaneous increase in minute excretion of urate and a de- crease in plasma urate cohcentration. This pat- tern of pharmacologic actions has been termed the “uricosuric effect.”

Most previous workers believed the uricosuric effect to be due to inhibition of tubular reab- sorption of urate but a number of considerations indicate that this is improbable. Both carona- mide and benzoate block the tubular excretion of penicillin; yet caronamide has a uricosuric effect while benzoate has precisely the opposite effect upon urate excretion. Both sorbitol and mannitol are cleared at the glomerular filtration rate; but ‘sorbitol gives a striking uricosuric effect while its stereoisomer, mannitol, does not. Certain other substances which produce the uricosuric effect are effective in such small amounts that it is difficult to believe their action to be due to direct blocking of a tubular reab- sorptive mechanism. A list of more than forty uricosuric agents which we have compiled in- cludes substances excreted by filtration and reabsorption, by filtration and tubular excre- tion, and by filtration alone. Such diversity of excretory mechanisms makes it improbable that all share the ability to block the reabsorption of urate by the tubules.

Elsewhere we have presented data which indicate that there is normally little or no tubular reabsorption of urate. All of the urate passing the glomerulus appears to be excreted in the urine, with the possible exception of a

small fraction undergoing back-diffusion. This appears to depend upon the fact that only a small proportion of the plasma urate is freely diffusible through the human glomerulus. The action of caronamide, and possibly that of the other uricosuric drugs, may be understood by postulating that such agents increase the frac- tion of the. plasma urate which passes the glomerular filter.

OCCURRENCE OF GASTRIC NEOPLASMS IN YOUTH. M. Block, M.D., A. H. Griep,

M.D. (by invitation) and H. M. Pollard,

M.D., Ann Arbor, Michigan. (From the Department of Internal Medicine, Uni- versity of Michigan.)

The primary obstacle to making a diagnosis of carcinoma of the stomach in youth appears to be the patient’s age. Since only limited in- formation is available, it was believed that the usual clinical dictum that a gastric lesion in a patient below the age of thirty-one is probably benign was not necessarily justified.

In a study of this problem the following in- formation was obtained: (1) A survey of the occurrence of carcinoma of the stomach during a twenty-year period (1925 to 1945) at the Uni- versity Hospital revealed that there were 1,913 carcinomas in a total of 453,400 registrations. This is an incidence of 0.42 percent. (2) Of the 1,913 carcinomas during this period, twenty cases occurred in patients below the age of thirty-one (an incidence of 1.04 per cent of all gastric carcinomas seen). Seventeen of these twenty cases had metastases when first examined, and the diagnosis of carcinoma was usually de- layed because benign gastric ulcer was generally considered in view of the patient’s youth. (3) During the same twenty-year period, fifty-three other gastric lesions occurred in the same age group (fifty benign gastric ulcers, two gastric lymphoblastomas and one gastric lues). (4) These figures demonstrate that all gastric lesions are rare in patients below the age of thirty-one, but when a gastric lesion does occur, the proba- bility of its being neoplastic is at least 30 per cent.

HEMOCHROMATOSIS WITH APLASTIC ANEMIA. F. R. Schemm, M.D., E. Hildebrand, M.D.

(by invitation), F. H. Crago, M.D. (by invi-

tation) and J. A. Layne, M.D., Great Falls, Montana. (From the Departments of Medicine and Pathology, Great Falls Clinic.)

American Federation for Clinical Research 775

Severe anemia is an uncommon finding in hemochromatosis. However, several cases of aplastic anemia accompanying hemochroma- tosis have been reported. We have observed a fifty year old man whose principal complaint was weakness. Physical examination was essen- tially normal. Examination of the blood revealed a slight anemia and leukopenia, a prolonged bleeding time and a complete lack of clot re- traction at forty-eight hours. The bone marrow was found to be active and the proportion of cells normal. There was no hematologic re- sponse to iron or liver therapy. The erythrocyte and leukocyte counts gradually declined. A diagnosis of primary splenic neutropenia was entertained and splenectomy was performed. A histopathologic diagnosis of hemochromatosis was made. The patient failed to respond clinic- ally and the hemotologic findings remained unchanged. Repeated blood transfusions were necessary to maintain life. Glycosuria was never demonstrated but the glucose tolerance curve was elevated. About four years after onset of symptoms the patient died. Necropsy revealed iron pigment in most of the parenchymatous organs except the pancreas.

This man w&s continuously employed for many years in a copper refinery. Mallory and others have drawn attention to the association of hemochromatosis with exposure to copper. This case supports this concept.

QUANTITATIVE ESTIMATION OF STERNAL BONE MARROW ACTIVITY IN PERNICIOUS ANE- MIA. A. S. Weisberger, M.D. (by invitation) and R. W. Heinle, M.D., Cleveland, Ohio. (From the Department of Medicine, School of Medicine, Western Reserve University.)

Estimation of the activity of the sternal mar- row based upon the values of the nucleated cell count, myeloid-erythroid volume and fat con- tent obtained from 1.0 ml. of aspirated material is frequently unreliable. When these values are compared with the actual histologic appearance of the marrow, wide discrepancies are sometimes encountered. This is especially true in cases in which the bone marrow is composed of densely packed cohesive cells, as in pernicious anemia in relapse.

In this study the histologic appearance of the sternal marrow was compared with the values for the nucleated cell count and volumetric

AMERICAN JOURNAL OF MEDICINE

pattern obtained from 1.0 ml. of aspirated ma- terial in cases of pernicious anemia. Histologic sections of marrow particles, the nucleated cell count and the volumetric pattern were all ob- tained from the same sample.

In most patients with pernicious anemia in relapse, low values were obtained for the nu- cleated cell count and myeloid-erythroid vol- ume, indicating normal or decreased activity. However, the histologic sections revealed densely packed, markedly hyperactive marrow. In the cases of treated pernicious anemia the values for the nucleated cell count and myeloid-erythroid volume were within normal limits and the his- tologic sections showed normal cellular activity.

The lack of correlation between the nucleated cell count, myeloid-erythroid volume and his- tologic appearance in cases of pernicious anemia in relapse is thought to be due to the density and cohesiveness of the marrow which resists separation on aspiration.

ABSORPTION AND EXCRETION OF CHORIONIC GONADOTROPHIN. W. E. Brown, M.D. and J.’ i. Bradbury, Sc.D. (by invitation), Iowa City, Iowa. (From the Department of Obstetrics and Gynecology, University of Iowa.)

Human chorionic gonadotrophin has been shown to have a luteotrophic function in the woman. In appropriate dosage it will induce a pseudopregnancy as demonstrated by a delay in menses, persistence of pregnandiol excretion, prolongation of the life of the corpus luteum, decidual changes in the endometrium and a positive Aschheim-Zondek reaction. Five thou- sand I. U. daily was shown to be a minimum effective dose when the hormone was given in- tramuscularly in aqueous solution.

Because of the cost and difficulty in preparing a pryrogen-free material for intramuscular use, studies were undertaken to find alternate methods for administering this hormone. Chori- onic gonadotrophin was given by various routes to a series of women in doses ranging from 2,500 to l,OOO,OOO I.U. Urinary excretion of chorionic hormone was determined by the Aschheim- Zondek reaction in rats.

After intramuscular injection of 10,000 I. U. of gonadotrophin the hormone appeared in the urine in such quantities that it could be demon- strated in urine volumes equivalent to a three- minute output. Excretion occurred in the first