Regulation of energy metabolism in Morris hepatoma 7777 and 7800.

The pathway of fat oxidation in two experimental hepatomas was studied in order to demonstrate that a specific deficit in the energy metabolism of a tumor might contribute to the cachexia of the host. Forty-eight male Buffalo rats were divided into four groups of 12 each. One group was implanted s.c. with Morris hepatoma 7777 and one group was implanted with Morris hepatoma 7800, whereas the other two groups served as controls. All groups were fed standard rat chow diet ad libitum until the tumors reached 2 cm in diameter. The animals were then fasted for 24 hr prior to sacrifice and excision of tumor and liver for assays. During the period of tumor growth, the animals bearing the 7777 hepatoma lost weight, but the weight of the 7800 hepatoma-bearing rats did not differ significantly from that of the control animals. The livers of both groups of animals showed evidence of fatty acid oxidation in vivo and in vitro, and, as expected, during fasting, pyruvate dehydrogenase was inactivated and the rate of fatty acid synthesis was low. A qualitatively similar picture was seen with the better-differentiated 7800 hepatoma. In contrast, the 7777 hepatoma exhibited low levels of fatty acyl coenzyme CoA, no appreciable activity of carnitine palmitoyl transferase and fortified homogenates of the tumor were unable to oxidize palmitate. In keeping with these observations, pyruvate dehydrogenase remained in the active form, and fatty acid synthesis continued unabated in the fasted state in these tumors. Ketone bodies could not be oxidized by fortified homogenates of the liver or by either tumor, probably due to the lack of 3-ketoacid thiotransferase, which was undetectable in these tissues. We hypothesize that flow-through pyruvate dehydrogenase during fasting in Morris hepatoma 7777, occurring as a result of the defect in fat oxidation, contributes to the weight loss of these animals.

Protein metabolism during treatment of chest infection in patients with cystic fibrosis.

Six cystic fibrosis patients with pulmonary exacerbations were studied to determine the effect of antibiotic treatment on protein nutritional status. Indirect calorimetry, nitrogen balance, protein turnover, urinary 3-methylhistidine, plasma albumin, prealbumin transferrin, and cortisol were measured before and after treatment. N loss averaged 16 and 17% on each balance. N in the sputum was up to 4.5% of absorbed N intake. At the peak of infection, protein synthesis, degradation, and urinary 3-methylhistidine were significantly higher than during recovery (31%, 28%, and 60%, respectively). On recovery a significant fall in blood sugar, albumin, morning cortisol and sputum N and a rise in prealbumin was found. Basal metabolic rate and N balance did not change. For patients in the fed state, active infection is associated with higher rates of protein synthesis and degradation. Antimicrobial treatment alters protein dynamics but does not alter measured N balance or the difference between measured protein synthesis and breakdown.

In vivo measurements of body protein based on the determination of nitrogen by prompt gamma analysis.

Measurement of nitrogen in the human body gives a measure of total protein in the body. Nitrogen (N) may be measured in vivo by a nuclear technique in which the characteristic nitrogen gamma rays emitted after capture of neutrons are detected and counted. The accuracy (as determined by comparison of the measurement of nitrogen in a pig by nuclear and chemical methods) is better than 10%. The reproducibility is less than 6%. The radiation dose is about 5 millirads. This method had been used with 43 patients and 23 normal volunteers and the results are reported. The data are presented in the from of total N content, percentage N by weight, and as a comparison of N and potassium (K) in the body. It is found that the mean percentage of N in the normal males is 2.5%, giving a value of 1.75 kg in the 70-kg standard man. The mean percentage values are not greatly different between normal volunteers and malnourished patients. Taking all subjects, N/K ratios ranged from 7.5 to 20 g/g. Thus K cannot be used as a predictor of N. Nitrogen content of normals correlates well (r = 0.68) with height squared; for malnourished patients there is again a good correlation (r = 0.81) but the regression line for patients is approximately 34% below that for the volunteers consistent with their depleted state.

Whole-body protein turnover in adult hemodialysis patients as measured by 13C-leucine.

Muscle wasting may occur in patients with chronic renal failure (CRF). To determine whether this is due to a decrease in the synthesis or an increase in the breakdown of muscle protein, we evaluated postabsorptive whole-body protein breakdown, oxidation, and synthesis rates at steady state during a primed, continuous infusion of 13C-leucine. This was done in seven subjects on chronic maintenance hemodialysis (MHD) and in seven normal control subjects. The protein breakdown rate in MHD was not different from that in controls (103 +/- 19 and 106 +/- 19 mumol leucine.kg-1.h-1, respectively). In MHD, however, the protein oxidation rate was 43% greater than that in controls (20 +/- 6 and 14 +/- 4 mumol leucine.kg-1.h-1, p less than 0.05), whereas net protein synthesis was less (p less than 0.05). Reduced net synthesis and increased oxidation rates of protein in the postabsorptive state may therefore contribute to the muscle-wasting syndrome in patients with CRF.

Lipid peroxidation and plasma antioxidant micronutrients in Crohn disease.

BACKGROUND: In Crohn disease (CD), the increased production of reactive oxygen species from activated neutrophils may reduce plasma concentrations of antioxidant vitamins and result in increased oxidative stress. OBJECTIVE: We compared lipid peroxidation, a measure of reactive-oxygen-species production, and plasma antioxidant vitamin concentrations between CD patients and healthy control subjects. DESIGN: Thirty-seven nonsmoking CD patients (22 women and 15 men) were compared with an equal number of healthy control subjects who were matched by age, sex, and body mass index. In patients the mean CD activity index (CDAI) was 141.2 +/- 18.7 (range: 9.0-514), and 11 of 37 patients (30%) had a CDAI > or =150. Seventy-eight percent of patients were taking > or = 1 medication. Medication use by subjects included the following: 5-aminosalicylic acid (40% of subjects), antibiotics (22%), oral corticosteroids (30%), and immunosuppressants (19%). RESULTS: Lipid peroxidation as measured by breath pentane output (CD patients, 7.47 +/- 0.98 pmol x kg(-1) x min(-1); control subjects, 4.97 +/- 0.48 pmol x kg(-1) x min(-1); P < or = 0.025), breath ethane output (CD patients, 11.24 +/- 1.17 pmol x kg(-1) x min(-1); control subjects, 5.46 +/- 0.71 pmol x kg(-1) x min(-1); P < or = 0.0005) and F2-isoprostane (CD patients, 78.6 +/- 8.0 ng/L; control subjects, 60.6 +/- 3.7 ng/L; P < or = 0.047) were significantly higher in CD patients than in control subjects. Plasma antioxidant vitamins (ascorbic acid, alpha- and beta-carotene, lycopene, and beta-cryptoxanthin) were all significantly lower in CD patients than in control subjects. There were no significant differences in macro- and micronutrient intakes between groups. CONCLUSION: Patients with CD are oxidatively stressed, which was observed even though 70% of patients had a CDAI < or =150 and 78% of them were taking medications to treat CD.

Evaluation of sodium acetate as a source of alkali therapy in an experimental aerobic model of lactic acidosis due to decreased pyruvate oxidation.

An "in vitro" model of one type of lactic acidosis was produced in rat hemi-diaphragms with inhibitors of pyruvate oxidation. In order to obtain this inhibition in the absence of hypoxia, two actions were sought; inhibiting the mitochondrial pyruvate transporter and lowering the rate of pyruvate diffusion into these mitochondria. alpha-Cyano-3-hydroxy cinnamate (CNCM) was utilized because it is a specific inhibitor of the mitochondrial pyruvate transporter. Aminooxyacetate (AOA) was employed because it leads indirectly to inhibition of the entry of cytoplasmic reducing power into mitochondria. As a result of the addition of this latter compound, pyruvate levels fell and this should decrease the rate of pyruvate diffusion into the mitochondria. Glucose was the only substrate provided to this tissue and its entry into the cells was promoted by insulin. The oxidation of U-14C glucose to 14CO2 was significantly reduced in the presence of CNCM and AOA, presumably reflecting the inhibition of pyruvate oxidation. Under these conditions, lactate accumulated and pyruvate fell; however, there was a significant accumulation of lactate plus pyruvate during the incubation period. This "in vitro" lactic acidosis was markedly diminished when acetate was also present. These results are consistent with the hypothesis that provision of an alternate substrate to the TCA cycle for ATP synthesis could lead to a decreased rate of glycolysis and thereby to a decreased rate of lactic acid accumulation in this "in vitro" model of lactic acidosis.

Protein conversion to glucose: an evaluation of the quantitative aspects.

The amount of glucose that can be synthesized from a protein depends on its amino acid (AA) composition. This value is about 60 g from 100 g of liver or muscle protein and is based on a knowledge of the total AA content and the proportion of each AA that can be converted to pyruvate. The maximum quantity of glucose in grams that can be synthesized from administered AA solutions is the sum of the products of the number of moles of each AA times its percent convertible to pyruvate times the molecular weight of that AA.

Evaluating the accuracy of nutritional assessment techniques applied to hospitalized patients: methodology and comparisons.

Herein we describe a methodology which can be used to evaluate the predictive accuracy of nutritional assessment techniques. We use this methodology to compare seven techniques of nutritional assessment in terms of their ability to predict one nutrition associated hospital complication (infection) by dividing a sample of 59 surgical patients into high risk and low risk groups. One technique was subjective global assessment (SGA) of the patient's nutritional status on admission to hospital. Five techniques were single objective measurements (albumin, transferrin, delayed cutaneous hypersensitivity, anthropometry, and creatinine-height index). The 7th technique was the prognostic nutritional index. The best combination of sensitivity (0.82) and specificity (0.72) was found with SGA. The second best combination (0.88 and 0.45) was found by using either the prognostic nutritional index or creatinine-height index. We also found that combining the five objective measurements with SGA into a single index did not increase the discriminatory (or predictive) power over that of SGA alone in a clinically significant way. We conclude that a larger study comparing these approaches should be undertaken to confirm these findings and to develop methods which improve the predictive properties of SGA.

Chronic lactic acidosis in a patient with cancer: therapy and metabolic consequences.

Lactic acidosis is a life-threatening disorder in some cases. Treatment should be directed at the primary cause. Sodium bicarbonate should be added if the acidosis is very severe, or if the rate of hydrogen ion production is very rapid and not controlled. In contrast, with moderate degrees of steady state lactic acidosis and poor dietary intake, the risks of therapy with sodium bicarbonate or dichloroacetate may actually outweigh the benefits in a cachectic patient unless a dietary glucose and/or protein load is given.

Gastric hemorrhage complicating percutaneous transgastric jejunostomy.

The first occurrence at the authors' institution of serious gastrointestinal tract hemorrhage complicating percutaneous transgastric jejunostomy and its management by a modified technique are reported. The 0.7% frequency of this complication (one in 130 procedures) compares favorably with the frequency of hemorrhage reported for surgical gastrostomy (0.9%-1.4%). Percutaneous transgastric jejunostomy represents no greater risk of hemorrhage than does surgical gastrostomy and should continue to be an alternative to the latter procedure.

Theoretical aspects of weight loss in patients with cancer. Possible importance of pyruvate dehydrogenase.

In the analysis of weight loss in cancer patients, consideration must be given to decreased caloric intake, increased caloric expenditure and abnormal losses of calories. When these factors do not adequately explain the degree of weight loss, this may be due to a specific loss of lean body mass, as the caloric density of muscle is much less than that of fat. The key enzyme for the protection of lean body mass in hypocaloric states is pyruvate dehydrogenase (PDH). During fasting, fast oxidation in host tissues leads to inactivation of PDH, preventing irreversible loss of pyruvate precursors which would have to be replaced by protein breakdown. A tumor in which PDH activity remains high in the fasting state would cause loss of lean body mass in the host. This report suggests that this phenomenon may be important in certain patients with cancer cachexia.

Effect of exercise on protein metabolism in humans as explored with stable isotopes.

Exercising for 3.75 h on a treadmill at 50% VO2 max in the fed state induced an increased excretion of 71 mg nitrogen/kg over the 18 h after exercise. However, measurements of the time course of changes in 13CO2 excretion from ingested [1-13C]leucine indicated that all of this increased nitrogen production occurs during the exercise period. Because of the reduced renal clearance and slow turnover of the urea pool, urea excretion lags behind urea production. Measurements of nitrogen flux from the plateau labeling of urinary ammonia achieved by repeated oral doses of 15N-labeled glycine indicated that the nitrogen loss resulted from an increase in protein degradation and a decrease in protein synthesis. Further studies with [1-13C]leucine indicated that a 2-h treadmill exercise induced an increase in the nitrogen loss from 5.4 to 16 mg . kg-1 . h-1 measured with a primed constant infusion of [1-13C]leucine. This resulted from a fall in whole-body protein synthesis. Glucose given at the rate of 0.88 g . kg-1 . h-1 depressed the rate of whole-body protein degradation and appeared to suppress the exercise-induced increase in nitrogen excretion. When leucine oxidation rates were measured at increasing work rates, a linear relationship between percentage of VO2 max and leucine oxidation was observed up to 89% VO2 max when 54% of the flux of leucine was oxidized. These changes may involve nonmuscle as well as muscle tissue. Thus the source of the increased nitrogen losses is probably liver. In muscle, protein degradation is actually decreased judged by methylhistidine excretion, whereas in liver, protein degradation may be increased. Also the fall in whole-body protein synthesis may reflect changes in nonmuscle tissues because in running rats protein synthesis in muscle is maintained. As far as leucine metabolism is concerned, because the increase in leucine oxidation occurs when leucine and its keto acid concentration falls, exercise must specifically activate the 2-oxoacid dehydrogenase.

Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting.

1. Measurements have been made of whole-body and skeletal muscle protein synthesis in fed and fasted adults with L-[1-13C]leucine. 2. The marked increase in whole-body synthesis on feeding largely reflects the changes in protein synthesis in muscle, which doubles on feeding, compared with a 40% increase in that of the rest of the body. 3. Skeletal muscle in fed man contributes more than half to total protein synthesis occurring in the whole body.

The prevalence of Campylobacter pylori gastritis among asymptomatic adults.

To determine the prevalence of Campylobacter pylori colonization in the healthy population we studied 54 asymptomatic volunteers and 65 patients referred because of gastrointestinal symptoms. All subjects underwent gastroscopy and gastric biopsy. C. pylori was isolated from 6 volunteers (11%) and 36 patients (55%). Histologic evidence of inflammation was present in 98% of the culture-positive subjects. Linear regression analysis revealed that the prevalence of C. pylori colonization increased with age. There was no difference in the isolation rate between the two groups when adjusted for age. Four of the six culture-positive volunteers underwent repeat endoscopy and gastric biopsy 1 year later; despite remaining asymptomatic, all still had positive culture results and histologic evidence of gastritis. We conclude that the prevalence of C. pylori-associated gastritis among symptomatic patients increases with age and that the organism may be present in the gastrointestinal tract for prolonged periods without symptoms or evidence of disease progression.