Howard B. Lewis

The Occurrence of Cystinuria in Healthy Young Men and Women

Excerpt Cystinuria has been considered a relatively rare error of metabolism. Since the report of the first cystine calculus of the urinary tract by Wollaston in 1810, the number of observed cases ...

Experimental Lathyrism in the White Rat.

Lathyrism, associated with the consumption of considerable amounts of certain species of legumes of the genus Lathyrus, has been a common disease of man in India, northern Africa, and occasionally in other countries. 1 Lathyrism has also been observed to occur in domestic animals and has been produced experimentally in laboratory animals. The outstanding symptoms are muscular weakness and paralysis of the extremities. Neither Zagami, 2 McCarrison, 3 nor Visco 4 was able to produce experimental lathyrism (Lathyrus sativus, L., and Lathyrus cicera) in white rats, although impaired growth and failure of normal organ development, particularly of the reproductive and skeletal systems, were observed. Geiger and coworkers 5 produced lathyrism in rats by feeding diets which contained Lathyrus odoratus, the flowering sweet pea, at levels of 80, 50, and 25% of the diet. Characteristic symptoms were lameness, paralysis, and curvature of the spine and sternum. Our experiments were carried out with finely ground meal (20 mesh sieve) prepared from decorticated sweet peas (Lathyrus odoratus) and as a control, with similar meal from the edible split pea of commerce† (Pisum sativum, subspecies arvense). These were incorporated into the diets of young white rats as follows: pea meal, 50%; casein (Labco, vitamin-free), 10%; corn starch, 27%; sucrose, 5%; salt mixture (modified Osborne-Mendel), 4%; cod liver oil, 2%; corn oil, 2%. Each rat received approximately 200 mg of a dried yeast tablet (Mead Johnson and Co.) daily. The casein was added to the diet to insure a satisfactory protein content, since the proteins of many legumes are known to be inadequate if fed as the sole source of protein. The total protein of the mixed diet was calculated to be 26% (16% derived from the peas).

Experimental lathyrism in the white rat and mouse.

Summary 1. Young white mice of 12 to 15 g body weight fed diets containing 50% Lathyrus odoratus meal grew well and showed no development of experimental lathyrism in 17 weeks, although young white rats which received a similar diet developed experimental lathyrism in from 3 to 6 weeks. 2. Diets containing Lathyrus latifolius meal (50%) were toxic for both rats and mice, death occurring in from 3 to 8 days (rats) and 5 to 12 days (mice). The extraction of seed of Lathyrus latifolius meal with 30% ethanol removed the toxic principle. Mice fed the extracted meal survived and appeared normal over a period of 18 days. 3. Mice fed Lathyrus sylvestris seed died with symptoms of acute toxicity in 4 to 7 days.

The synthesis and rate of elimination of hippuric acid after benzoate ingestion in man

Ten grams of sodium benzoate were administered to a healthy man on a diet of milk, butter, and cane sugar, i. e., glycocoll-free. The urine was collected at two hour intervals, and the relation between the elimination of hippuric acid and urea studied. As compared with the corresponding control periods on the same diet, there was observed a diminution of the urea-nitrogen eliminated during the first six hours after the benzoate ingestion, a diminution corresponding to the nitrogen eliminated as hippuric acid-nitrogen. If the hippuric acid-nitrogen be subtracted from the undetermined N (shown in parentheses), the undetermined N is comparable with that of the control periods. This indicates that in man as in rabbits and pigs, the glycocoll available for synthesis into hippuric acid may be derived at the expense of substances whose N normally appears in the urine as urea-nitrogen. At the end of six hours the greater part of the hippuric acid had been eliminated and the urea elimination had become normal again. No free benzoic acid nor glycuronates could be detected in the urine, indicating a complete conversion to hippuric acid and a very rapid elimination. In order to ascertain whether the rapidity of elimination was influenced by the liquid diet of the preceding experiment, the work was repeated on the same subject on a mixed diet, and on a purine-free diet. In both experiments, the greater part (85-95 per cent) of the hippuric acid was eliminated within six hours. Another subject received six grams of sodium benzoate and eliminated the greater part of the hippuric acid within six hours. An amount of sodium hippurate equivalent to the benzoate fed was administered, and the elimination of the hippuric acid studied.

Evaluation of some iodine-containing organic compounds as X-ray contrast media.

Summary 1. After intravenous injection into dogs, the following compounds were found to be good cholecystographic dyes: N-(3-amino-2,4,6-triiodobenzoyl) e-amino-n-caproic acid (Compound 6); 2-(4-hydroxy-3,5-diiodo-benzyl) benzoic acid (Compound S); 3-cap-roylamino-2,4,6-triiodobenzoic acid (Compound 5) and 3-butyrylamino-2,4;6-triiodo-benzoic acid (Compound 4). After oral administration, only Compounds S and 6 produced satisfactory visualization of the gall bladder and biliary tract 16 hr after feeding. 2. Analyses of the tissues of rats after intravenous administration of the compounds (1-6 inclusive and S) gave the following results: In the liver, Compound 6 was present in greater concentration than any of the others tested; in the kidney, Compounds 3-formyl-amino-2,4,6-triiodobenzoic acid, 3-acetylami-no-2,4,6-triiodobenzoic acid, 3-propionylami-no-2,4,6-triiodobenzoic acid, and 3-butyryl-amino-2,4,6-triiodobenzoic acid were present in high concentration during the initial intervals, but fell to a relatively low level at the end of 3 hr. It was found that the rates of excretion of these compounds by the kidney decreased with the increase in the length of the acyl group.

The histidine content of the urine in pregnancy

Abstract 1.1. The bromine method of Chattaway 11 for the determination of histidine in urine has been modified so that interference of urea is avoided and the estimation of total histidine is satisfactory. 2.2. The creatinine: histidine ratio has been determined in the urine of a large number of pregnant and nonpregnant women and of men. 3.3. Eighty-eight per cent of the pregnancy urines (169) examined showed low ratios, while only 9 per cent of the urines of nonpregnant women (59) and of men (50) had ratios as low as 1.70. There was no detectable difference in the ratios of nonpregnant women and men. 4.4. The increased excretions of urinary histidine, as evidenced by low creatinine: histidine ratios of the urine, were not found before the third month of pregnancy and cannot, therefore, be used as an aid in the early diagnosis of pregnancy.

Excretion of Homogentisic Acid After Oral Administration of Phenylalanine to Alcaptonuric Subjects

Summary Oral administration of 10 to 15 g daily of l(-)-phenylalanine to two alcaptonuric brothers resulted in a notable increase in the excretion of homogentisic acid in the urine, corresponding to about 70% of the amount theoretically obtained by complete conversion of the phenylalanine fed to homogentisic acid. The excretion of the extra homogentisic acid began promptly and was nearly complete within 12 hours after the phenylalanine was fed.

Gystine in Normal and Gystinuric Human Blood

It is usually stated that cystine is not present in detectable quantities in normal human blood. 1 The failure of the satisfactory recovery of small amounts of cystine added to blood has been attributed, by Harding and Gary, 2 to difficulties in the preliminary deproteinization necessary prior to cystine determination. They have reported the presence of little, if any, free cystine in cow blood plasma. The amino nitrogen of normal blood (4-7 mg. %) should include small amounts of cystine nitrogen. If loss of cystine in deproteinization could be avoided and if a sufficiently delicate method for the determination of cystine were available, it should be possible to detect cystine in normal blood. By the use of ultrafiltrates of oxalate-fluoride plasma, mechanical loss of cystine by deproteinization has been avoided and the application of the method of Sullivan to the determination of cystine in such ultrafiltrates has been made possible by the use of the Pulf rich photometer. The details of the preparation of the ultrafiltrates and the determination of cystine will be presented elsewhere in connection with studies of the intermediary sulfur metabolism of experimental animals. Recovery of small amounts of cystine added to blood has been satisfactory. Application of the above procedure to normal human blood has indicated the presence of approximately 1.0 mg. % of cystine in plasma ultrafiltrates. Samples of blood of one of us (B.H.B.), taken after fasting periods of 12 to 18 hours, have given values of 0.71, 0.80, 0.92 and 0.93 mg. % of cystine in the plasma ultrafiltrate and values of 0.80, 0.91 and 1.05 mg. after meals. The ultrafiltrate of the blood of the same individual, withdrawn 3 hours after the oral administration of 6 gm. of cystine in gelatine capsules, contained 1.72 and 1.40 mg. % of cystine, respectively in 2 experiments. In a third study, in which 7 gm. of cystine were fed, 1.30 and 0.88 mg. % of cystine were present in the plasma ultrafiltrates of blood samples taken 3 and 5 hours later, respectively. In 4 other normal subjects, cystine values ranging from 0.82 to 1.13 mg. were obtained. The plasma ultrafiltrate of the blood of a cystinuric patient (S.P.) 3 contained 1.13 mg. % of cystine, a value slightly higher than our average normal value, but, we believe, within the upper limit of the range of values for normal human blood. To this subject, 5.6 gm. of methionine were administered in 2 equal portions at the morning and midday meals. The plasma ultrafiltrate of a sample of blood withdrawn at 3 :45 P. M. contained 0.92 mg. % of cystine. It may be noted that, while the isolation of cystine from cystinuric blood has been claimed, 4 , 5 no quantitative data have been reported. It should be noted that no attempt was made to determine the possible presence of cysteine in these ultrafiltrates. The values reported represent “total” cystine, i. e., values obtained by the application of the Sullivan procedure to the ultrafiltrates after reduction with cyanide. This research was made possible by a grant to one of us (H.B.L.) from the Faculty Research Fund of the University of Michigan for the study of cystinuria.

Occurrence of Cystine in Sweat of Cystinurics.

In 1871, Dewar and Gamgee 1 stated that, in some cases, cystine was present in the sweat of cystinurics, apparently basing their conclusions largely upon the observation that, in cases where cystine was present in the urine, silver coins carried in the pocket were observed rapidly to become blackened. Garrod, 2 however, was unable to obtain evidence of the presence of cystine in the sweat in the one case studied by him. We have had under observation a cystinuric whose daily cystine excretion (determined by the colorimetric method of Folin and Looney) varied from 1.0 to 1.8 gm., whose urine frequently contained large amounts of cystine crystals, and who occasionally passed cystine calculi. From this patient we collected by the use of pilocarpine and heat, 100 cc. of sweat in 50 minutes. ∗ No cystine could be detected by the colorimetric method of Folin and Looney. 35 cc. of sweat were deproteinized by the use of heat and alumina cream and the filtrate was evaporated to dryness. The residue was extracted with dilute ammonium hydroxide and the extract treated with acetic acid. No cystine crystals were observed microscopically. Wollastons test (formation of cystine hydrochloride crystals) was also negative.

Can taurine replace cystine in the diet of the young white rat

Mitchell 1 has reported that taurine and cystine were equally efficient in promoting growth in white mice on a diet (source of protein, casein) in which cystine was the limiting factor. In the present series of experiments, young white rats have been maintained on the milk powder-starch diet of Sherman, 2 supplemented by vitamin B yeast concentrate tablets. On this basal diet slow growth was possible. When the basal diet was supplemented with cystine (0.3 per cent) marked increase in the rate of growth was obtained. When taurine (prepared from ox bile) was used as a supplement (1 per cent), no increase in the rate of growth as compared with the controls on the basic diet could be noted. Typical results on two litter units follow in the table. From our data no evidence is to be obtained in support of the contention that the young white rat can use taurine for the purposes of growth in the absence of sufficient cystine.