High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.

BACKGROUND: Conventional nutritional supplements are not or only partly successful in inducing protein accretion in advanced cancer, suggesting an attenuated anabolic response. To prevent muscle wasting and its deleterious consequences, generating an anabolic response is crucial. Dietary essential amino acids (EAA) have anabolic properties in other wasting diseases; however, data in advanced cancer are lacking. PATIENTS AND METHODS: In 13 patients with advanced nonsmall-cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects, we measured protein synthesis and breakdown of the whole body, and net protein anabolism (difference between protein synthesis and breakdown) after intake of 14 g of free EAA with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein, according to a randomized, double-blind, crossover design. RESULTS: Protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001), independent of presence of cancer. A highly significant linear relationship between net protein anabolism and the amount of EAA available in the systemic circulation (R(2): 0.85, P < 0.001) was found in both groups. The presence of muscle or recent weight loss, systemic inflammatory response, or length of survival did not influence this relationship. High leucine levels in the EAA/leucine mixture was of no anabolic benefit. CONCLUSIONS: There is no anabolic resistance or attenuated anabolic potential to intake of 14 g of EAA/leucine or balanced amino acid mixture in advanced (mainly stage III) NSCLC. The high anabolic potential of dietary EAA in cancer patients is independent of their nutritional status, systemic inflammatory response or disease trajectory, suggesting a key role of EAA in new nutritional approaches to prevent muscle loss, thereby improving outcome of patients with advanced cancer. CLINICALTRAILSGOV: NCT01172314.

Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients.

BACKGROUND & AIMS: Transjugular intrahepatic stent-shunt (TIPSS) insertion, in patients with uncontrolled gastro-intestinal bleeding, often results in worsening of the systemic hemodynamics which can be associated with intracranial hypertension but the underlying mechanisms are unclear. This study explored the hypothesis that TIPSS insertion results in acute endotoxemia which is associated with increased nitric oxide production resulting in systemic and cerebral vasodilatation. METHODS: Twelve patients with cirrhosis who were undergoing TIPSS for uncontrolled variceal bleeding were studied prior to and 1-h after TIPSS insertion. Changes in cardiac output (CO) and cerebral blood flow (CBF) were measured. NO production was measured using stable isotopes using l-[guanidino-(15)N(2)] arginine and l-[ureido-(13)C;5,5-(2)H(2)] citrulline infusion. The effect of pre- and post-TIPSS plasma on nitric oxide synthase (NOS) activity on human endothelial cell-line (HUVEC) was measured. RESULTS: TIPSS insertion resulted in a significant increase in CO and CBF. Endotoxin and induced neutrophil oxidative burst increased significantly without any significant changes in cytokines. Whole body NO production increased significantly and this was associated with increased iNOS activity in the HUVEC lines. The change in NO production correlated with the changes in CO and CBF. Brain flux of ammonia increased without significant changes in arterial ammonia. CONCLUSIONS: In conclusion, the insertion of TIPSS results in acute endotoxemia which is associated with increased nitric oxide production possibly through an iNOS dependent mechanism which may have important pathophysiological and therapeutic relevance to understanding the basis of circulatory failure in the critically ill cirrhotic patient.

Predictor Biomarkers of Nonelective Hospital Readmission and Mortality in Malnourished Hospitalized Older Adults.

BACKGROUND: 90-day mortality and rehospitalizations are important hospital quality metrics. Biomarkers that predict these outcomes among malnourished hospitalized patients could identify those at risk and help direct care plans. OBJECTIVES: To identify biomarkers that predict 90-day (primary) and 30-day (secondary) mortality or nonelective rehospitalization. DESIGN AND PARTICIPANTS: An analysis of the ability of biomarkers to predict 90- and 30-day mortality and rehospitalization among malnourished hospitalized patients. SETTING: 52 blood biomarkers were measured in 193 participants in NOURISH, a randomized trial that determined the effects of a nutritional supplement on 90-day readmission and death in patients >65 years. Composite outcomes were defined as readmission or death over 90-days or 30-days. Univariate Cox Proportional Hazards models were used to select best predictors of outcomes. Markers with the strongest association were included in multivariate stepwise regression. Final model of hospital readmission or death was derived using stepwise selection. MEASUREMENTS: Nutritional, inflammatory, hormonal and muscle biomarkers. RESULTS: Mean age was 76 years, 51% were men. In univariate models, 10 biomarkers were significantly associated with 90-day outcomes and 4 biomarkers with 30-day outcomes. In multivariate stepwise selection, glutamate, hydroxyproline, tau-methylhistidine levels, and sex were associated with death and readmission within 90-days. In stepwise selection, age-adjusted model that included sex and these 3 amino-acids demonstrated moderate discriminating ability over 90-days (C-statistic 0.68 (95%CI 0.61, 0.75); age-adjusted model that included sex, hydroxyproline and Charlson Comorbidity Index was predictive of 30-day outcomes (C-statistic 0.76 (95%CI 0.68, 0.85). CONCLUSIONS: Baseline glutamate, hydroxyproline, and tau-methylhistidine levels, along with sex and age, predict risk of 90-day mortality and nonelective readmission in malnourished hospitalized older patients. This biomarker set should be further validated in prospective studies and could be useful in prognostication of malnourished hospitalized patients and guiding in-hospital care.

Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.

Renal glutamine uptake and subsequent urinary ammonia excretion could be an important alternative pathway of ammonia disposal from the body during liver failure (diminished urea synthesis), but this pathway has received little attention. Therefore, we investigated renal glutamine and ammonia metabolism in midly hyperammonemic, portacaval shunted rats and severely hyperammonemic rats with acute liver ischemia compared to their respective controls, to investigate whether renal ammonia disposal from the body is enhanced during hyperammonemia and to explore the limits of the pathway. Renal fluxes, urinary excretion, and renal tissue concentrations of amino acids and ammonia were measured 24 h after portacaval shunting, and 2, 4, and 6 h after liver ischemia induction and in the appropriate controls. Arterial ammonia increased to 247 +/- 22 microM after portacaval shunting compared to controls (51 +/- 8 microM) (P < 0.001) and increased to 934 +/- 54 microM during liver ischemia (P < 0.001). Arterial glutamine increased to 697 +/- 93 microM after portacaval shunting compared to controls (513 +/- 40 microM) (P < 0.01) and further increased to 3781 +/- 248 microM during liver ischemia (P < 0.001). In contrast to controls, in portacaval shunted rats the kidney net disposed ammonia from the body by diminishing renal venous ammonia release (from 267 +/- 33 to -49 +/- 59 nmol/100 g body wt per min) and enhancing urinary ammonia excretion from 113 +/- 24 to 305 +/- 52 nmol/100 g body wt per min (both P < 0.01). Renal glutamine uptake diminished in portacaval shunted rats compared to controls (-107 +/- 33 vs. -322 +/- 41 nmol/100 g body wt per min) (P < 0.01). However, during liver ischemia, net renal ammonia disposal from the body did not further increase (294 +/- 88 vs. 144 +/- 101 nmol/100 g body wt per min during portacaval shunting versus liver ischemia). Renal glutamine uptake was comparable in both hyperammonemic models. These results indicate that the rat kidney plays an important role in ammonia disposal during mild hyperammonemia. However, during severe liver insufficiency induced-hyperammonemia, ammonia disposal capacity appears to be exceeded.

Methods using stable isotopes to measure nitric oxide (NO) synthesis in the L-arginine/NO pathway in health and disease.

Nitric oxide (NO) is an important gaseous radical involved in many physiological processes. It is produced from the amino acid L-arginine by the action of nitric oxide synthases (NOS) in what is called the L-arginine/NO pathway. Tracking its metabolic fate in biological fluids is of particular interest as it may indicate how the human body responds in health and disease. However, due to its short life span (a few seconds) it is very difficult to accurately monitor any up- or down-regulation in body fluids in vivo. As a consequence, methods have been developed based on the measurement of the NO-derived products nitrite and nitrate or on the substrate of NO, L-arginine and its simultaneously generated product, L-citrulline. Considering only a fraction of the endogenous L-arginine pool is used for the synthesis of NO, NO-production cannot be estimated by measuring changes in the concentrations of L-arginine and/or L-citrulline alone. Instead, to estimate NO-related changes in the L-arginine and/or L-citrulline pools a form of tagging these metabolites for the NOS-mediated reaction is required. The application of stable isotopes is an elegant way to track NOS-mediated changes. The present paper is focussed on the application of various combinations of chromatography and mass spectrometry to measure isotopic enrichments resulting from the conversion of L-arginine to NO and L-citrulline in a one-to-one stoichiometry. In addition, the various aspects and principles involved in the application of stable isotopes in metabolic studies in general and the study of the activity of NOS in particular are discussed.

Application of liquid chromatography-mass spectrometry to measure the concentrations and study the synthesis of short chain fatty acids following stable isotope infusions.

A new method involving zinc sulphate deproteinization was developed to study short chain fatty acids (SCFA) production in the colon and subsequent occurrence of SCFA in blood. SCFA were baseline separated in a 30 min cycle using ion-exclusion chromatography and detected by mass spectrometry. Concentrations could be measured down to 10 microM and isotopomeric distributions could be assessed, enabling the conduction of tracer studies to study changes in SCFA synthesis. The applicability of the method was tested in an extensively characterized pig model yielding portal SCFA concentrations ranging from 70 microM (butyric acid) to 150 microM (propionic acid) to 440 microM (acetic acid) prior to butyrate tracer infusion, reaching butyric acid isotopic steady state within 2 h.

ESPEN expert group recommendations for action against cancer-related malnutrition.

Patients with cancer are at particularly high risk for malnutrition because both the disease and its treatments threaten their nutritional status. Yet cancer-related nutritional risk is sometimes overlooked or under-treated by clinicians, patients, and their families. The European Society for Clinical Nutrition and Metabolism (ESPEN) recently published evidence-based guidelines for nutritional care in patients with cancer. In further support of these guidelines, an ESPEN oncology expert group met for a Cancer and Nutrition Workshop in Berlin on October 24 and 25, 2016. The group examined the causes and consequences of cancer-related malnutrition, reviewed treatment approaches currently available, and built the rationale and impetus for clinicians involved with care of patients with cancer to take actions that facilitate nutrition support in practice. The content of this position paper is based on presentations and discussions at the Berlin meeting. The expert group emphasized 3 key steps to update nutritional care for people with cancer: (1) screen all patients with cancer for nutritional risk early in the course of their care, regardless of body mass index and weight history; (2) expand nutrition-related assessment practices to include measures of anorexia, body composition, inflammatory biomarkers, resting energy expenditure, and physical function; (3) use multimodal nutritional interventions with individualized plans, including care focused on increasing nutritional intake, lessening inflammation and hypermetabolic stress, and increasing physical activity.

Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.

ESPEN Guidelines on Enteral Nutrition: Intensive care.

Enteral nutrition (EN) via tube feeding is, today, the preferred way of feeding the critically ill patient and an important means of counteracting for the catabolic state induced by severe diseases. These guidelines are intended to give evidence-based recommendations for the use of EN in patients who have a complicated course during their ICU stay, focusing particularly on those who develop a severe inflammatory response, i.e. patients who have failure of at least one organ during their ICU stay. These guidelines were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1985. They were discussed and accepted in a consensus conference. EN should be given to all ICU patients who are not expected to be taking a full oral diet within three days. It should have begun during the first 24h using a standard high-protein formula. During the acute and initial phases of critical illness an exogenous energy supply in excess of 20-25 kcal/kg BW/day should be avoided, whereas, during recovery, the aim should be to provide values of 25-30 total kcal/kg BW/day. Supplementary parenteral nutrition remains a reserve tool and should be given only to those patients who do not reach their target nutrient intake on EN alone. There is no general indication for immune-modulating formulae in patients with severe illness or sepsis and an APACHE II Score >15. Glutamine should be supplemented in patients suffering from burns or trauma.

Lobular patterns of expression and enzyme activities of glutamine synthase, carbamoylphosphate synthase and glutamate dehydrogenase during postnatal development of the porcine liver.

Carbamoylphosphate synthase and glutamine synthase show a complementary distribution in the liver lobule of the rat. In the human liver lobule, which is approximately 2-fold larger than that of the rat, an intermediate, 'empty' zone is present between the periportal carbamoylphosphate synthase-positive and the pericentral glutamine synthase-positive zone. To investigate whether these differences in gene expression can be attributed to the size of the liver lobule, we investigated the patterns of expression of carbamoylphosphate synthase, glutamine synthase and glutamate dehydrogenase during postnatal development of the pig, a species in which the total number of lobules does not increase after birth. We demonstrate that lobular size increases 3-fold between 1 week and 8 months after birth. In the same developmental period the number of hepatocytes on the porto-central axis increases 2-fold, resulting in a 3-fold increase in cellular volume. However, the lobular patterns of expression of carbamoylphosphate synthase, glutamate dehydrogenase and glutamine synthase do not change anymore after 1 month, i.e., when lobular diameter is comparable to that in rat liver, showing that lobular size is not a major determinant of the heterogeneous patterns of expression of these enzymes. The adult patterns of expression of glutamine synthase, glutamate dehydrogenase and, in particular carbamoylphosphate synthase in the porcine liver resemble those of man. Changes in the enzyme activities of glutamate dehydrogenase and carbamoylphosphate synthase are not related to the lobular size. However, the 70% decrease of GS activity in the 8-month-old pigs corresponds with the gradual 2-3-fold decrease in the size of the GS-positive compartment during postnatal development. During adulthood GS activity increases again to values observed 1 week after birth demonstrating a 2-fold increase in cellular glutamine synthase content. The present data show that the pig is an excellent model to study the regulation and functional implication of zonation of gene expression in the human liver.

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model.

Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and nonmalignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To combine these requirements, we have developed a nonmyeloablative conditioning regimen, consisting of low-dose total body irradiation and cyclophosphamide-based chemotherapy. In a haploidentical F1 --> F1 mouse model, this nonmyeloablative transplantation protocol resulted in stable full donor chimerism, but also in the development of severe GVHD. Administration of keratinocyte growth factor (KGF) reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis, compared to saline-treated controls. KGF preserved plasma citrulline and tumor necrosis factor-alpha levels, both indicative for reduced injury to the gastrointestinal tract. This was confirmed by histological findings. At 6 months after transplantation, survival rates were significantly higher in KGF-treated animals as compared to phosphate buffered saline-treated controls. These results indicate that KGF preserves gut integrity and might therefore contribute substantially to reduction of lethal GVHD in (nonmyeloablative) haploidentical transplantation.

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers.

RATIONALE: Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort. OBJECTIVES: The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied. METHODS: Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3-4 h after taking the CP mixture. RESULTS: The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found. CONCLUSIONS: The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.

Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders.

BACKGROUND: Acute tryptophan (TRP) depletion was evaluated in healthy volunteers with or without a family history of major affective disorder (FH+ versus FH-). METHODS: Twenty-seven subjects (16 FH+, 11 FH-) received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind cross-over design and a diet devoid of TRP for the next 24 hours. RESULTS: The ratio TRP/large neutral amino acids declined to 22% of baseline values after 6 hours, and increased during the night reaching 85% of baseline after 24 hours. Overall, after 6 hours, TRP depletion lead to a lowering of mood, but after 24 hours, these changes were no longer detected. Mood changes and gastrointestinal side effects were significantly more evident in FH+ subjects than in FH- subjects. CONCLUSIONS: Our data support the hypothesis that subjects with a positive family history for depression are predisposed to increased vulnerability to the adverse consequences of serotonergic imbalance.

Factors contributing to alterations in skeletal muscle and plasma amino acid profiles in patients with chronic obstructive pulmonary disease.

BACKGROUND: There is increasing evidence of abnormal protein metabolism in patients with chronic obstructive pulmonary disease (COPD), as reflected by lower plasma branched-chain amino acid (BCAA) concentrations and different muscle amino acid (AA) patterns than in age-matched control subjects. OBJECTIVE: We examined whether the low plasma BCAA concentrations in COPD reflect an imbalance between anabolic and catabolic processes as evidenced by a low fat-free mass (FFM) and alterations in the anabolic hormone insulin and whether discrepancies in muscle AA concentrations between studies are related to different patient characteristics. DESIGN: AA profiles in arterial plasma and quadriceps femoris muscle and insulin concentrations in venous plasma were analyzed in 28 postabsorptive COPD patients (14 with and 14 without macroscopic emphysema) and in 28 control subjects. FFM was measured by dual-energy X-ray absorptiometry. RESULTS: The lower sum of plasma BCAAs in the COPD group than in the control subjects was the result of a lower leucine concentration (P: < 0.001); no significant difference in valine and isoleucine was found between the groups. In the COPD group, the lower leucine concentrations were associated with low FFM (P: < 0.01). Compared with the control group, the muscle-to-plasma leucine gradient was higher in the COPD group (P: < 0.001) and was associated with a higher insulin concentration (P: < 0.01). Several muscle AA concentrations were higher or tended to be higher in the group without emphysema than in the control group, whereas nearly all AA concentrations were lower in the group with emphysema. CONCLUSIONS: Leucine metabolism is altered in COPD patients and is associated with low FFM and high insulin concentrations. There were striking differences in the skeletal muscle AA profile between the COPD subtypes.

The concentrations of glutamine and ammonia in commercially available cell culture media.

The amino acid glutamine is an essential nutrient for cells in culture. In aqueous solutions such as liquid culture media, glutamine spontaneously decomposes into ammonia. In this study, we examined the toxicity of ammonia for two different cell lines. In mouse hybridoma cell cultures, viable cell counts were reduced at exogenous ammonia concentrations of 1000 microM. In the human promyelocytic cell line however, viable cell counts were shown to be reduced at exogenous ammonia concentrations of 300 microM. Next, we determined ammonia and glutamine levels in 11 commercially available media on the day of delivery. It was found that all media contained significantly less glutamine than prescribed. Ammonia was found in all media with concentrations ranging up to 1000 microM. Storage at both 4 degrees C and 20 degrees C caused a further degradation of glutamine and significant accumulation of ammonia in all media. The degradation curves of the various media were used to calculate the first order degradation constant k, which can be used to determine the kinetics of the spontaneous decomposition in culture media. These results suggest that precautions must be taken to avoid the deterioration of commercially available culture media, because of the decay of glutamine. Long storage times lead to a rapid decay of glutamine and an accumulation of the toxic degradation product ammonia.

Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation.

Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain.

Specificity of the tryptophan depletion method.

Thirteen healthy subjects were subjected to tryptophan (TRP) depletion, lysine (LYS) depletion, and a placebo condition in a double blind cross-over study. The aim of the study was to test the specificity of psychological effects induced by TRP depletion. Subjects ingested a 100 g amino acid mixture with or without TRP or LYS. Six hours later, plasma TRP levels had decreased by 77% in the TRP depletion test and LYS levels by 51% in the LYS depletion condition. After 6 h of TRP depletion, subjects reported significantly more tiredness and lowering of mood, compared to subjects in the placebo group, and memory performance declined. After 6 h of LYS depletion, no significant differences in mood and memory compared to placebo were found. We conclude that the effects of TRP depletion on mood and memory are specific for the depletion of TRP and are not caused by the depletion of an amino acid per se. This supports the hypothesis that TRP depletion affects brain serotonin metabolism and not only brain protein metabolism in general.

Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat.

In contrast to humans, a tryptophan (TRP)-free amino acid (AA) mixture only leads to moderate depletion in plasma TRP levels in adult rats. In this study we evaluated the effects of an acute administration of a TRP-free protein-carbohydrate nutritional mixture in adult male Wistar rats. Plasma amino acid levels were examined at 2 and 4h starting after the first administration. Furthermore, the concentrations of amino acid, serotonin (5-HT), dopamine (DA) and their metabolite (5-hydroxyindolacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively) were measured within the striatum, hippocampus and cortex. In the TRP depleted animals, the TRP/sigmaLNAA ratio (LNAA: large neutral amino acids) was substantial decreased at 2 and 4h after the first administration of the oral administration (by 71 and 78%, respectively). Four hours after treatment central TRP and 5-HT concentrations were decreased by 50%. Both peripheral and central TRP levels returned to basal values in the group treated with the nutritional mixture supplemented with TRP. Surprisingly, tyrosine levels were also reduced after oral administration of the protein-carbohydrate mixture without affecting central DA concentrations. In conclusion, the TRP-free protein-carbohydrate nutritional mixture appears to be an efficient tool to substantially reduce plasma and central TRP levels in adult rat.

Partial enterectomy in the rat does not diminish muscle glutamine production.

The hypothesis was posed that consumption of the amino acid glutamine by the splanchnic tissues is an important regulating mechanism for its production in muscle. Therefore, glutamine consumption or production in portal-drained viscera (PDV), liver, and hindquarter was measured by determining fluxes and intracellular concentrations after 80% enterectomy or SHAM operation in rats. Moreover, fluxes and intracellular concentrations of several other amino acids, ammonia, and liver urea production were determined concomitantly. After enterectomy, arterial glutamine concentration was increased, PDV glutamine consumption was decreased by 77%, and liver glutamine consumption was unchanged compared with values in SHAM-operated rats. Although hindquarter glutamine production remained unchanged after enterectomy, intracellular glutamate concentration (glutamine precursor) was lower, suggesting that enterectomy induces changes in muscle metabolism without changing the flux of glutamine. For the remaining gut, it was calculated that after enterectomy glutamine consumption per gram remaining gut tissue increased. These results cast doubt on the hypothesis that diminished splanchnic glutamine uptake can reduce muscle glutamine production.