Increased whole-body protein turnover in sick children with newly diagnosed leukemia or lymphoma.

Using a single dose, [15N]glycine turnover technique, whole body rates of proteins synthesis and breakdown were assessed in six healthy children and in eight children with newly diagnosed leukemia (DeWys, W. D. Cancer Res., 42: 721s-726s, 1982) or lymphoma (Baracos, V., Rodemann, H. P., Dinarello, C. A., and Goldberg, A. L. N. Engl. J. Med., 308: 553-558, 1983). Based on excretion of 15N as urinary ammonia, synthesis (g protein per kg body weight per day) was significantly (p less than 0.025) higher in the cancer patients [5.4 +/- 1.5 (S.D.)] compared to the controls (3.6 +/- 0.9); breakdown was also higher (p less than 0.02) in the patients (5.5 +/- 1.8) compared to the controls (3.1 +/- 1.1). When only the seven patients with leukemia were considered, there also were significant increases in synthesis (5.4 +/- 1.6, p less than 0.05) and breakdown (5.4 +/- 1.9, p less than 0.025) compared to controls. Increases in both synthesis and breakdown were also observed in the patients when the protein turnover data were expressed as a function of the rate of creatinine excretion or the calculated lean body mass. We conclude that whole body protein turnover is increased in sick children at the time of diagnosis with some forms of newly diagnosed cancer.

Amino acid utilization and urine protein excretion in children treated with succinylated Acinetobacter glutaminase-asparaginase.

Amino acid utilization was evaluated in seven children with acute lymphocytic leukemia treated with succinylated Acinetobacter glutaminase-asparaginase. All patients received food p.o. ad libitum and glucose-electrolyte solutions i.v.; four patients received an i.v. amino acid supplement (1.5 g/kg/day). Although all patients were in negative energy balance, there was a significant linear regression between nitrogen balance and nitrogen intake during Days 1 to 7 and Days 8 to 14 of the study. The slope of the regression line, reflecting exogenous nitrogen utilization, was not significantly different from that found in healthy young men ingesting adequate or subadequate energy intakes. The Y-intercept (-210 mg/kg/day) indicated an obligatory nitrogen loss that was much greater than normal. Most of the nitrogen loss was due to urinary excretion. Ammonia and urea accounted for 77 to 91% of the urine nitrogen. Urinary glutamate accounted for 4 to 10% of this loss. Urine protein excretion was abnormally high in each of the patients, ranging from 987 to 3440 mg/day. Urine excretion of N-acetyl-beta-glucosaminidase and beta 2-microglobulin was also abnormally high, despite normal blood urea nitrogen and serum creatinine, suggesting that these children had renal tubular dysfunction. The antileukemic effect of succinylated Acinetobacter glutaminase-asparaginase did not appear to be altered by amino acid supplementation. These data indicate that amino acid supplementation can improve nutritional status in patients treated with succinylated Acinetobacter glutaminase-asparaginase.

Nitrogen utilization in mice bearing Ehrlich ascites tumor treated with Acinetobacter glutaminase-asparaginase.

The effects of Acinetobacter glutaminase-asparaginase (AGA) on protein and energy requirements were evaluated in mice bearing Ehrlich ascites tumors. In an initial experiment with normal mice, a zero protein diet resulted in a significant decrease in carcass nitrogen, liver nitrogen, and carcass energy relative to the animals on a normal, low, or high protein diet. In a second experiment, mice bearing Ehrlich ascites tumors were randomized into diet groups (zero or normal protein) and treatment groups (daily injections of AGA or 0.9% NaCl solution). In both treatment groups, the zero protein diet resulted in significant decreases in weight, liver nitrogen, carcass nitrogen, and carcass energy. Neither tumor nor AGA treatment affected body composition or the efficiency of nitrogen utilization. By Day 8, either the zero protein diet or AGA treatment significantly reduced ascites volume and tumor nitrogen content relative to controls. In a modification of Experiment 2, AGA treatment was stopped on Day 8, and all animals were given a normal protein diet. AGA, but not the zero protein diet, significantly enhanced ultimate survival. These experiments indicate that the requirements and utilization of energy and nitrogen are normal in mice with Ehrlich ascites tumor whether or not they are treated with AGA.

Tissue nitrogen-sparing effect of high protein diet in mice with or without ascites tumor treated with Acinetobacter glutaminase-asparaginase.

Forty-eight tumor-free mice and 32 mice bearing Ehrlich ascites tumor were randomized into 2 treatments, Acinetobacter glutaminase-asparaginase (AGA) (600 IU/kg/day for 7 days) and 0.9% NaCl controls, and into 2 or 3 isocaloric diets, normal protein (NP) (20 g protein/100 g diet), high protein (HP) (58 g protein/100 g diet), and zero protein (ZP) (tumor-free mice only). In tumor-free, NP-fed mice, AGA caused percentage reductions (P less than 0.01) in the nitrogen content of liver (50%), intestine (42%), thymus (89%), spleen (75%), and carcass (20%), but HP prevented this effect on intestine and carcass and caused percentage increases in the nitrogen content of liver (53%), intestine (36%), thymus (122%), and carcass (25%). In Ehrlich ascites tumor mice (NP or HP fed) AGA caused markedly lower (P less than 0.01) tumor burdens and increased nitrogen content of intestine (HP), kidney (NP and HP), and spleen (NP and HP). Ehrlich ascites tumor, AGA-treated, HP-fed mice ate 31% less food (P less than 0.01) (compared to NP) but HP resulted in percentage increases in the nitrogen content of liver (18%; P = 0.05), intestine (25%; P less than 0.05), and thymus (164%; P less than 0.01). In the Ehrlich ascites tumor, AGA group the HP diet caused higher hematocrit and serum total protein (both, P less than 0.05). Adverse nutritional effects of AGA seen in normal mice were markedly diminished in tumor-bearing animals. The observed nitrogen-sparing effects of the high protein: energy ratio may be relevant to humans and to other forms of neoplasia and chemotherapy.

Protein-energy nutritional status of pediatric cancer patients.

Surveys of protein-energy nutritional status were conducted in pediatric cancer outpatients (28) and inpatients (71). In the outpatients, the approximate prevalences of severe (greater than 40%) deviations of weight, triceps skinfold, and arm muscle area below the medians for height-age were respectively 0, 14, and 0%. In the inpatients, these prevalences were respectively 1, 20, and 6%. The percentages of inpatients with abnormally low (less than 5th percentile) weight-for-height, triceps skinfold, and arm muscle area were 14, 14, and 20%, respectively. All inpatients with triceps skinfold or arm muscle area less than 60% of the median for height-age had corresponding percentile values of less than 15.

Manifestations of chronic selenium deficiency in a child receiving total parenteral nutrition.

A child receiving total parenteral nutrition for about 1 1/2 yr developed intermittent leg muscle pain and tenderness and elevation in serum activities of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and creatine kinase. Approximately 6 months later he developed white fingernail beds. Detailed cardiological evaluation revealed no evidence of cardiac muscle cell damage despite markedly elevated serum activities of the MB isoenzyme of creatine kinase. Retrospective analyses of serum and 24 hr urine samples collected during this period demonstrated very low serum Se concentration (0.003 to 0.007 micrograms/g) and urine excretion (0.0 to 8.9 micrograms/day) Se. Intravenous Se supplementation (42 micrograms/day elemental Se as H2SeO3) and a prospective study of biochemical Se status were begun 33.5 months after initiation of total parenteral nutrition. Serum Se concentration and whole blood glutathione peroxidase activity and Se concentration were respectively 0.020 mu/g, 3.5 EU/g Hb, and 0.018 microgram/g, 1 month after intravenous Se therapy was started. These very low values increased after further Se therapy. Serum enzyme activities markedly improved and the fingernail bed abnormalities resolved after therapy.

In vivo lactose digestion in preterm infants.

In vitro studies of intestinal lactase activity and breath-hydrogen studies have suggested that the capacity for lactose digestion in preterm infants is less than the usual intake. To explore this question using an in vivo approach, we determined the fraction of dietary lactose hydrolyzed to glucose (and galactose) in 14 preterm infants with a gestational age of 26-31 wk at the time of birth but a postconceptional age of 31-37 wk at the time of study. The percentage of lactose digested was estimated after 6-h, primed, constant gastric infusions of [1-(13)C]glucose and D-[-1-(13)C]lactose on alternate days. A coefficient of lactose fermentation was derived from the rates of pulmonary excretion of hydrogen and carbon dioxide. Mean (+/- SD) lactose digestion was 79 +/- 26%. There was a significant inverse rank (r = -0.799, P < 0.01) and linear (r = -0.587, P < 0.05) correlation between this variable and postconceptional age. The percentage of lactose fermented averaged 35 +/- 27%.

Low serum reverse T3 concentration in burned children: its relationship to nutritional state.

The correlation between protein turnover and serum thyroid hormone levels was studied in 10 children, ages 1 to 16 years subsequent to severe burn injuries. In contrast to published studies that have shown depression of triiodothyronine (T3) and elevations of reverse T3 (rT3) in stressed patients, no change was found in the mean level of T3 and a 69% decrease in rT3 compared to healthy controls of similar age. Whole body rates of protein synthesis and breakdown were determined using a [15N]glycine turnover technique. The difference between synthesis and breakdown was negatively correlated with the ratio, rT3/T3 in serum. Thus, in burned children, a decrease in N balance was associated with a rise in rT3/T3 which is qualitatively similar to that observed in fasted individuals or in stressed patients who may be semistarved.

Fecal characteristics in healthy young adults consuming defined liquid diets or a free-choice diet.

Fat and nitrogen absorption and fecal characteristics were studied in 10 healthy, young adults who ingested a free-choice diet for 12 days and then isocaloric amounts of one of two nutritionally complete liquid defined formula diets during a succeeding 12-day period. Apparent fat absorption was 98 to 99% of intake with both defined formula diets and 95% of intake on the free-choice diet. Nitrogen digestibility was determined during the liquid diet period, and averaged 95 to 98% of intake. There were no statistically significant differences between the liquid diets and the free-choice diets with respect to fecal wet or dry weight, transit time, or stool frequency. Individual stool weights averaged 83 to 96 g on the free-choice or liquid formula diets and were comparable to other values reported in the literature. These results support the theory that a critical volume of feces must accumulate in the colon before defecation occurs, regardless of diet composition.

A method for assessing carbohydrate energy absorption and its application to premature infants.

A method was developed for assessing indirectly the fecal excretion of carbohydrate-derived energy. Then, eight healthy premature infants (28 to 32 wk gestation, postnatal age 12 to 30 days) were randomly assigned to receive one of two formulas that differed only in the carbohydrate source: 100% lactose or 50% lactose: 50% glucose polymer (lactose + glucose polymer). Excreta collections were analyzed for total nitrogen, urea nitrogen, ammonia, fat, and total energy. Carbohydrate energy absorption was calculated. The formulas were well tolerated and stool frequency, energy intake, weight gain, and nitrogen balance were not different in the two formula groups. Also, there were no significant intergroup (lactose versus lactose + glucose polymer) differences in the coefficients (%) (x +/- SD) of fat absorption (90 +/- 6 versus 93 +/- 5) or carbohydrate energy absorption (96 +/- 1 versus 95 +/- 3). Thus, net carbohydrate-energy absorption appeared normal in these premature infants who showed no clinical formula intolerance.

Dietary carbohydrate assimilation in the premature infant: evidence for a nutritionally significant bacterial ecosystem in the colon.

Carbohydrate energy absorption and breath hydrogen concentration were measured in 12 premature infants 28-32 wk gestational age and 2-4 wk postnatal age. Each of two groups of six infants were randomly assigned to receive one of two formulas that differed only in carbohydrate source: 100% lactose (LAC) or 50% lactose: 50% glucose polymer (LAC + GP). In 11 infants the peak breath hydrogen concentration suggested extensive colonic fermentation (range 44-239 ppm/5% CO2 or 44-239 microL/L per 50 mL/L CO2). An approximate 100% increase in lactose intake in the LAC group was associated with a similar increase in breath hydrogen concentration at 30, 60, and 120 min. None of the infants exhibited diarrhea or vomiting or developed delayed gastric emptying. Carbohydrate energy absorption (mean +/- SD) was, respectively, 86 +/- 5% and 91 +/- 3% in the LAC and the LAC + GP groups (p greater than 0.05). Thus, colonic bacterial fermentation may be critical to energy balance and to the prevention of osmotic diarrhea in premature infants fed lactose.

Effects of feeding on protein turnover in healthy children and in children with cystic fibrosis.

We hypothesized that there is less suppression of whole-body protein breakdown with feeding in patients with cystic fibrosis (CF) who exhibit decreased insulin secretion after a single meal. Using [1-13C]leucine, we measured rates of nonoxidative leucine disappearance (whole-body protein synthesis) and protein breakdown in nine CF patients (6-11 y of age) and five healthy control subjects (8-10 y of age) during feeding and fasting. In the CF patients, synthesis and breakdown (x +/- SD) were 172 +/- 61 and 157 +/- 67 mumol.kg-1.h-1 during feeding and 140 +/- 24 and 178 +/- 26 mumol.kg-1.h-1 during fasting. The respective control values were 129 +/- 27 and 114 +/- 20 mumol.kg-1.h-1 during feeding and 136 +/- 13 and 173 +/- 18 mumol.kg-1.h-1 during fasting. Leucine balance was nearly identical in the two groups. By analysis of variance, there was a significant effect of feeding on protein breakdown but no difference between the groups. However, when each group was analyzed separately, feeding resulted in a 34% decrease in breakdown in the control subjects (P = 0.001) and a 23% increase in synthesis in the CF group (P = 0.058). Plasma insulin concentrations did not differ in the two groups. Thus, feeding may affect protein turnover differently in children with CF than in control children independently of plasma insulin concentration.

Vitamin E-deficient spinocerebellar syndrome due to intestinal lymphangiectasia.

A 23-year-old woman with congenital intestinal lymphangiectasia developed a progressive spinocerebellar syndrome and neuropathy. The clinical findings were typical of vitamin E deficiency, which was documented in the patient. Intestinal lymphangiectasia is an additional vitamin E-deficient disease that may cause this neurologic syndrome.

Thermal environment change in growing premature infants: effect on general somatic growth and subcutaneous fat accumulation.

Fourteen growing, healthy premature infants were moved from heated incubators to cribs at different points in their growth. Group A (six babies) was moved when babies reached a weight of 1,600 to 1,700 gm; group B (eight babies) when babies reached a weight of 1,800 to 1,900 gm. All other conditions of rearing were kept the same. The effect on their growth and thermal stability was measured during the week before and after the temperature change. All infants tolerated the change well. There was no drop in abdominal temperature in an environment cooler by 5 C. The rate of weight gain correlated with gross energy intake only and did not differ within or between the two groups. The rate of growth of the skinfolds increased dramatically after the infants were moved from the incubator. A cooler environment in a growing premature infant (weight greater than 1,600 gm) may promote faster deposition of subcutaneous fat. This might be an important factor in efficient gain in cold resistance.

Whole-body protein synthesis and breakdown rates in children before and after reconstructive surgery of the skin.

The effects of minor surgery on dynamic aspects of whole-body nitrogen metabolism were explored in healthy children aged 4--15 yr. A continuous administration of 15N-glycine was used to estimate rates of whole-body protein synthesis and breakdown both before reconstructive surgery of the skin and 5 days afterward. Mean preoperative values for protein synthesis and protein breakdown were 3.9 and 3.4 g protein/kg body weight/day, respectively. Protein synthesis decreased by 15% (p less than 0.05) postoperatively, but body weight, intake of protein and calories, nitrogen balance, and protein breakdown did not differ significantly between the two periods. Protein synthetic rate correlated (p less than 0.05) with protein (r = +0.75) and calorie (r = +0.58) intake. These results indicate that minor surgery causes a small decrease in the rate of whole-body protein synthesis even though calorie and nitrogen balance are maintained.

Isotopic estimation of CO2 production during exercise before and after endurance training.

Endurance training reduces the rate of CO2 release (i.e., VCO2) during submaximal exercise, which has been interpreted to indicate a reduction in carbohydrate oxidation. However, decreased ventilation, decreased buffering of lactate, and/or increased fixation of CO2 could also account for a lower VCO2 after training. We therefore used a primed continuous infusion of NaH13CO3 to determine the whole body rate of appearance of CO2 (RaCO2) in seven men during 2 h of cycle ergometer exercise at 60% of pretraining peak O2 uptake (VO2peak) before and after endurance training. RaCO2 is independent of the above-described factors affecting VCO2 but may overestimate net CO2 production due to pyruvate carboxylation and subsequent isotopic exchange in the tricarboxylic acid cycle. Training consisted of cycling at 75-100% VO2peak for 45-90 min/day, 6 days/wk, for 12 wk and increased VO2peak by 28% (P < 0.001). VCO2 during submaximal exercise was reduced from 86.8 +/- 3.7 to 76.2 +/- 4.2 mmol/min, whereas RaCO2 fell from 88.9 +/- 4.0 to 76.4 +/- 4.4 mmol/min (both P < 0.001). VCO2 and RaCO2 were highly correlated in the untrained (r = 0.98, P < 0.001) and trained (r = 0.99, P < 0.001) states, as were individual changes in VCO2 and RaCO2 with training (r = 0.88, P < 0.01). These results support the hypothesis that endurance training decreases CO2 production during exercise. The magnitude and direction of this change cannot be explained by reported training-induced alterations in amino acid oxidation, indicating that it must be the result of a decrease in carbohydrate oxidation and an increase in fat oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative analysis of fecal content of medium and long chain triglycerides using two methods.

Accurate assessment of apparent total fat absorption in individuals receiving medium chain triglycerides (MCT) as the predominant source of dietary fat depends upon the method used for fecal fat analysis. Erroneous conclusions may be drawn if the method does not give quantitative recovery of MCT. A simple, previously described, gravimetric technique is shown in this paper to give comparable MCT recoveries to another somewhat more arduous method.

Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency.

Late-onset multiple carboxylase deficiency is characterized clinically by skin rash, alopecia, seizures and ataxia and occasionally by candidiasis and developmental delay. Biochemically, these individuals exhibit findings consistent with a combined deficiency of the biotin-dependent carboxylases. We have found that the activity of the enzyme biotinidase is also deficient in the sera of five affected children (0 to 3% of mean control activity, 5.80 +/- 0.89 nmol X min-1 X ml-1 serum), and believe that it represents the primary biochemical defect in this disease. Biotinidase catalyzes the removal of biotin from the epsilon-amino group of lysine, through which biotin is covalently bound to the four known human carboxylases, thereby regenerating biotin for reutilization. The deficient activity in our patients was not due to an inhibitor, particularly biotin. It is also not a consequence of feedback control in affected individuals under treatment with pharmacologic doses of biotin. The biotinidase activities of the parents of those children who were available for study were intermediate between deficient and normal values (46% to 65% of mean normal activity). Children lacking biotinidase activity are unable to recycle biotin, and are thus entirely dependent upon exogenous biotin to prevent deficiency. Our findings indicate that the primary biochemical defect in late-onset multiple carboxylase deficiency is in biotinidase activity which is inherited as an autosomal recessive trait.

Digestion, absorption, and fermentation of carbohydrates.

Newborn infants born after a term gestation appear to have an adequate capacity for small intestinal digestion and absorption of carbohydrate. Premature infants do not have a mature level of intestinal lactase activity. Apparently, in the premature infant, colonic fermentation serves an important, if not the only major route, for lactose carbon absorption, and it also appears that signs of fermentation activity such as increased BH2 are not indicative of disease. Important questions remaining in the premature infant relate to developmental aspects of colonic fermentative activity, effects of systemic antibiotic treatment on colonic salvage, the effects of various fermentation pathways on energy balance, the capacity for absorption of sugars, SCFA, and electrolytes by colonic epithelia, and the effects of fermentation products on metabolism and on the mucosal cells of the intestine or colon. Research addressing these questions may have relevance in the following areas: further development of formula diets for healthy premature infants and for patients of all ages with intestinal or colon dysfunction; the effects of colonic disease or surgical resection; the nutritional or clinical effects of dietary fiber; and the effects of antibiotic therapy on intestinal and colon function.

Energy expenditure in adolescents during low intensity, leisure activities.

We sought to determine how a stationary activity such as playing a stringed instrument may affect energy expenditure (EE) in adolescents. Using automated indirect calorimetry, we measured EE in eight adolescents (1 male, 7 females, 14.2 +/- 2.1 yr) while they each performed the following activities: watching television (TV) (60 min), playing a stringed instrument (60 min), and walking at 40% of peak oxygen uptake (43 min). Measurements were made during three, 6- to 7-min steady state periods of each activity. EE (mean +/- SD) was lower during TV (1.0 +/- 0.2 kcal.min-1) and instrument playing (1.4 +/- 0.2 kcal.min-1) than during walking (3.4 +/- 0.4 kcal.min-1) (P < 0.05). EE during instrument playing was 41% greater than during television viewing (P < 0.05). We conclude that relatively sedentary activities such as playing a stringed instrument can elevate EE. Conceivably, other stationary, leisure activities performed by adolescents may increase EE and have substantial, cumulative effects on long-term energy balance and fat accretion.