J. B. Allison

The determination of the nitrogen balance index in normal and hypoproteinemic dogs.

Food protein nitrogen, entering into the dynamic equilibrium of the body, develops a characteristic nitrogen balance, reflecting the retention of nitrogen by the body. Recognizing the fundamental nature of the fraction of nitrogen retained in the body, Mitchell and others (1944) have called i t the “biological value” of the protein. The significance of “biological value” ( B V ) correlated with nitrogen balance ( N B ) and absorbed nitrogen ( A N ) , was illustrated by Allison and Anderson (1945), in the following equation:

The Nutritive Value of Dietary Proteins

Publisher Summary This chapter discusses the nutritive value of dietary proteins. All estimates of the nutritive value of a dietary protein involve a direct or indirect measurement of the retention of nitrogen in the body for maintenance and growth. Maintenance and growth of the whole body is an algebraic sum of gains and losses within the various cells and tissues. The relationship between body weight gain and nitrogen intake can be extended into the region of body weight loss when nitrogen intake is decreased to very low values including zero intake. The rise in catabolism and reduction in synthesis of certain tissue proteins, when the caloric intake is reduced, is a complex response to lack of energy intake. Given an adequate intake of calories and also of metabolites other than amino acids, the nutritive value of a dietary protein can be essentially a function of the pattern of indispensable amino acids absorbed into the body, the relative percentage of these amino acids to those considered dispensable, and the nitrogen intake. Supplementation involves an attempt to improve the pattern of absorbed amino acids and the amount of nitrogen intake.

Elimination of Nitrogen from the Body

Publisher Summary This chapter provides an overview on the elimination of nitrogen from the body. It presents a summary of the elimination of nitrogen from the body to introduce the concept of nitrogen balance. There is only a limited variability in the composition of the body fluids that will permit normal living; variations beyond these limits produce abnormalities, even irreparable damage to cells. The kidneys are the chief organs of the body operating to maintain a constant composition of the internal environment through the excretion of a water solution (urine), of a composition to help correct tendencies toward abnormal changes in the body fluids. Thus, the work of the kidneys involves the excretion of substances present in excessive quantities, of waste products, and of toxic substances. The chapter also presents a study of the composition of urine contributes much toward an understanding of the physiological state of the individual.

Effect of Protein Depletion on Plasma Proteins in the Dog Measured by Electrophoretic Analysis

Summary and Conclusions Electro-phoretic analyses of plasma showed that protein depletion in dogs resulted in marked decrease in circulating albumin, and slight decrease in γ globulin. In contrast to these decreases the a globulin content remained essentially unchanged or increased. The α globulins, however, always increased in concentration, which was in part due to the accompanying fall of plasma volume. The Howe method for the determination of albumin: globulin ratios resulted in higher ratios than those obtained by electrophoretic analyses, because of the contamination of globulins in the “albumin” fraction.

The effect of feeding excess glycine, L-arginine, and DL-methionine to rats on a casein diet.

Summary In these experiments on rats, the addition of 4.8% glycine, 4.8% DL-methionine or 4.8% glycine plus 4.8% DL-methionine to a 12% casein diet did not alter the nitrogen balance as compared to controls receiving 12% casein alone but did reduce the nitrogen balance index, the excess amino nitrogen not contributing to the retention of nitrogen in the animal. The data indicates, on the other hand, that excess arginine (1.7%) contributes in part, to the retention of nitrogen. The addition of 4.8% glycine or 4.8% glycine plus 1.7% L-arginine to a casein diet containing excess methionine counteracted the weight loss and in part the kidney hypertrophy caused by the excess methionine. The slight increases in thyroid weights, associated with excess methionine, were also antagonized by glycine and arginine. Under the conditions of these experiments urinary creatinine and creatine excretion was not increased in rats by feeding excess glycine. The significance of these results is discussed.

III. Chemotherapy of Tumors in Rats with Certain Ethylenephosphoramides.

Summary 1. About 70% of the King A rats with Sarcoma 231 and 72% of the Sprague-Dawley rats with Flexner-Jobling carcinoma were cured by treatment with N,N′,N′′-Triethylenephosphoramide (I). 2. a piperidyl, or morpholyl or azetidyl group did not affect the oncolytic properties significantly but did reduce the effect on testes; with a dose of .85 mg/kg/D of (I) given once daily for 45 days weight of testes of Sprague-Dawley rat was only about 35% of that of the normal controls, with a similar dose of (III) given in the same way for the same time it was about 79% of normal. Similarly, with a dose of .44 mg/kg/D of (I), once daily for 45 days the weight of the testes was 57% of normal while with a similar dose of (IV) given for 51 days weight of testes was 81% of normal. 3. The Flexner-Jobling tumor in the Sprague-Dawley rat regressed completely in about 70% of the animals treated with (III) and in about 80% of those treated with (IV). 4. At doses of about .2 mg/kg/D of (III) and (IV) good therapeutic results were obtained and weight of testes was but slightly below normal; when drug treatment was discontinued testes weight became normal. 5. The substitution of all groups resulted in compound (VI) which was inactive. 6. Compound (V) behaved like (III) and (VII), and (VIII) like (I) and (IV). 7. T.E.M. at a dose level of .04 mg/ kg/D, cured 75% of the rats treated and weight of testes was normal. 8. Spleen enlargement and neutrophylic leukocytosis accompanied growth of all tumors studied. Animals recovered from both conditions when tumors regressed completely. 9. Sarcomas 3 and 7 in the Lewis rat did not respond to treatment with any of the ethylenephosphor-amides nor with T.E.M. 10. The Walker tumor in the Sprague-Dawley rat responded to treatment better when therapy was started early; 3 days after implantation instead of later.

A pilot study of preoperative (Pre-op), single-dose ipilimumab (Ipi) and/or cryoablation (Cryo) in women (pts) with early-stage/resectable breast cancer (ESBC).

67 Background: Intratumoral cryo combined with immune modulation generates a potent systemic anti-tumor immune response that might improve recurrence free survival in ESBC. In this study, we evaluate the safety of pre-op cryo and/or ipi (10mg/kg) in pts with ESBC. Radiographic correlates and intratumoral/serologic immune responses are also explored. METHODS Eligible pts are ≥18y of age with operable ≥1.5 cm invasive ESBC, no history of autoimmune disease and planned mastectomy. Pts are sequentially assigned to receive pre-op: cryo alone (Group-A), ipi alone (B), or ipi with cryo (C). Cryo is administered 7-10d prior to surgery. Ipi is administered 8-15d prior to surgery (1-5d prior to cryo). If at least 5/6 pts in each group proceed with surgery without delay, the regimen will be considered safe/tolerable. Toxicity evaluation continues for 12 wks after ipi administration for Groups B and C. RESULTS As of May 1, 2013, 7/7 pts were enrolled to Group-A (expanded after a possible technical failure in 1 pt) and 6/6 pts were enrolled to Group-B. The median age was 45y (range 39-69y). All 13 pts in Groups A and B underwent mastectomy without delay. Group C is now accruing with 1/6 patients enrolled and awaiting surgery. 6/7 pts in Group-A and none in Group-B had ischemic tumor necrosis/infarction in the mastectomy tissue. Overall, pre-op cryo or ipi alone have been well tolerated with no study related grade 3/4 adverse events (AE) reported (Table). CONCLUSIONS To date, pre-op cryo or ipi is safe and tolerable in pts with ESBC. A Phase II study of pre-op ipi and cryo in ESBC is planned. CLINICAL TRIAL INFORMATION NCT01502592. [Table: see text].

Some Effects of Depletion and Repletion in Proteins on Body Fluids in Adult Dogs.

Summary The plasma albumin decreases markedly while the total plasma globulins decrease slightly below control values in the protein-depleted animal. The dogs are very susceptible to disease in the depleted state, a susceptibility which is reduced upon repletion in proteins. The plasma volume drops and the available fluids increase as the total circulating plasma albumin is reduced by the process of depletion. This nutritional edema is corrected rapidly by repletion in plasma albumin. The excretion of urine nitrogen gradually increases during the feeding of protein nitrogen in the repletion period. This gradual increase is the result of a decrease in the utilization of the protein and of an increase in the excretion of nitrogen from body stores. The decrease in urine nitrogen excretion below normal which occurs in the hypoproteinemic dog is primarily the result of a decrease in ammonia and urea nitrogen.

Effects of Excess Dietary d/-Methionine and/or /-Arginine on Rats∗

Summary When excess /-arginine is added to casein, the nitrogen balance index is reduced slightly. An excess of d/-methionine on the other hand reduces the nitrogen balance index markedly and the excretion of creatinine is increased. When both /-arginine and d/-methionine are added to casein the nitrogen balance index is not reduced as much as it is in the presence of casein plus methionine, but the creatinine excretion is increased. The animals receiving 12% casein and pair-fed with the group receiving 12% casein plus 4.8% d/-methionine lose weight slightly over a 20-day period. Those receiving 12% casein plus 4.8% methionine lose weight markedly, a loss which is overcome in part by adding 1.7% /-arginine to the methionine diet. The decrease in weight in the presence of a large excess of methionine is associated with a loss in body nitrogen and fat. The addition of d/-methionine increases the amount of nitrogen in the liver and reduces the amount of fat. Feeding d/-methionine plus casein increases the size of the kidney, an effect which is antagonized by /-arginine.

Protective Effect of Riboflavin on the Toxicity of 2-Acetylaminofluorene in Rats.

Summary The carcinogen, 2-acetylaminofluorene, produced a riboflavin deficiency in rats, reducing the liver riboflavin below control values. Increasing the riboflavin content of the diet prevented the appearance of the deficiency, keeping the liver riboflavin at normal levels. In the absence of protein in the diet, however, the increased riboflavin did not prevent the development of the deficiency.