Nicolaas E. P. Deutz

Glutamine and the preservation of gut integrity

Parenteral glutamine dipeptide improves nitrogen balance in postoperative patients on total parenteral nutrition (TPM). Animal studies show that the structure and function of the gut is preserved by glutamine. It is not known if this is the case in human beings. 20 patients admitted to hospital for total parenteral nutrition were randomly allocated to receive parenteral nutrition enriched with glycyl-L-glutamine (Gln TPN), or standard parenteral nutrition (STPN). Mucosal biopsy specimens were taken from the second part of the duodenum before starting parenteral nutrition, and after two weeks. The ratio between the urine concentrations of lactulose and mannitol after enteral administration was used to measure intestinal permeability. After two weeks of parenteral nutrition in the GlnTPN group, intestinal permeability was unchanged, whereas permeability in the STPN group increased. Villus height was unaltered in the GlnTPN group but in the STPN group it decreased. The addition of glutamine to parenteral nutrition prevents deterioration of gut permeability and preserves mucosal structure.

Nutritional recommendations for the management of sarcopenia.

The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.

Rapid routine determination of amino acids in plasma by high-performance liquid chromatography with a 2-3 μm Spherisorb ODS II column

A rapid fully automated method for the determination of amino acids is described based on high-performance liquid chromatography and pre-column o-phthaldialdehyde derivatization. Using a 150 mm x 4.6 mm I.D. HPLC column filled with a recently introduced 2-3 microns Spherisorb ODS II packing material, 30 physiological amino acids could be determined within 28 min (injection to injection), while 95 samples could be processed unattended within 45 h. For most amino acids, the coefficient of variation (C.V.) for the peak areas measured was below 3%, both in aqueous standards and in plasma. Providing a pre-column change every 200-300 runs, the separation remained unaltered for about 1500-2000 runs on a single column.

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

Abstract 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.

Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers

Animal and human studies have provided evidence for serotonergic modulation of cognitive processes. However, the exact nature of this relationship is not clear. We used the acute tryptophan depletion (ATD) method to investigate the effects of lowered serotonin synthesis on cognitive functions in 17 healthy young volunteers. The study was conducted according to a placebo-controlled, double-blind, crossover design. Cognitive performance and mood were assessed at baseline and 5 and 9 h after administration of ATD. A specific impairment of word recognition, without effects on short-term memory, occurred during ATD. No memory deficits were seen if ATD was induced after acquisition of new words. The Stroop Test and dichotic listening task demonstrated a modality independent improvement of focussed attention after ATD. Fluency was also improved after ATD. ATD did not alter speed of information processing, divided attention or planning functions. These results indicate that serotonin is essential in the process of long-term memory consolidation, primarily in the first 30 min after acquisition. Improvement of specific cognitive processes by lowered 5-HT function may be linked to the removal of inhibitory actions of 5-HT in the cortex.

Dose-dependent satiating effect of whey relative to casein or soy.

Dietary protein plays a role in body weight regulation, partly because of its effects on appetite. The objective was to compare the effects of high or normal casein-, soy-, or whey-protein breakfasts on appetite, specific hormones, amino acid responses and subsequent energy intake. Twenty-five healthy subjects (mean+/-SEMBMI:23.9+/-0.3 kg/m2; age:22+/-1 years) received standardized breakfasts: custards with either casein-, soy, or whey-protein with either 10/55/35 (normal) or 25/55/20 (high)En% protein/carbohydrate/fat in a randomized, single-blind design. Appetite profile (Visual Analogue Scales) and amino acid concentrations were determined for 4 h whereas plasma glucose, insulin, active Glucagon-like Peptide 1 (GLP-1), and active ghrelin concentrations were determined for 3 h; the sensitive moment for lunch was determined. Subjects returned for a second set of experiments and received the same breakfasts, ad lib lunch was offered 180 min later; energy intake (EI) was assessed. At 10En%, whey decreased hunger more than casein or soy (p <0.05), coinciding with higher leucine, lysine, tryptophan, isoleucine, and threonine responses (p<0.05). At 25En% there were no differences in appetite ratings. Whey triggered the strongest responses in concentrations of active GLP-1 (p<0.05) and insulin (p<0.05) compared with casein and/or soy. There were no differences in EI. In conclusion, differences in appetite ratings between different proteins appeared at a normal concentration; at 10En% whey-protein decreased hunger more than casein- or soy-protein. At 25En% whey-protein triggered stronger responses in hormone concentrations than casein- or soy-protein. The results suggest that a difference in appetite ratings between types of protein appears when certain amino acids are above and below particular threshold values.

Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production

BACKGROUND L-Arginine is an important precursor of nitric oxide (NO) and protein synthesis. Arginine is produced in the body (mainly kidney) by de novo production from citrulline and by protein breakdown. Arginine availability appears to be limited in sepsis. OBJECTIVE The objective was to compare arginine and citrulline metabolism in septic patients and nonseptic control patients in an intensive care unit (ICU) and in healthy control subjects. DESIGN Ten patients with septic shock, 7 critically ill control patients, and 16 healthy elderly subjects were studied. Metabolism was measured by using a primed continuous (2 h) stable-isotope infusion protocol. NO production was calculated as the conversion rate of arginine to citrulline; de novo arginine production was calculated as the conversion rate of citrulline to arginine. Arterial blood (arterialized venous blood in healthy subjects) was collected for the measurement of amino acid enrichment and concentrations. Data are reported as means +/- SDs. RESULTS Whole-body citrulline production was significantly lower in septic patients (4.5 +/- 2.1 micromol . kg(-1) . h(-1)) than in ICU control patients (10.1 +/- 2.9 micromol . kg(-1) . h(-1); P < 0.01) and in healthy control subjects (13.7 +/- 4.1 micromol . kg(-1) . h(-1); P < 0.001). Accordingly, de novo arginine production was lower in patients with sepsis (3.3 +/- 3.7 micromol . kg(-1) . h(-1)) than in healthy controls (11.9 +/- 6.6 micromol . kg(-1) . h(-1); P < 0.01) and tended to be lower in septic patients than in ICU control patients (10.9 +/- 9.4 micromol . kg(-1) . h(-1); P = 0.05). NO production was lower in septic patients than in healthy control subjects (P < 0.01), whereas a larger part of arginine was converted to urea in sepsis. CONCLUSIONS Citrulline production is severely low in patients with sepsis and is related to diminished de novo arginine and NO production. These metabolic alterations contribute to reduced citrulline and arginine availability, and these findings warrant further studies of therapeutic nutritional interventions to restore arginine metabolism in sepsis.

Regulation of nitric oxide production in health and disease.

Purpose of reviewThe purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism. Recent findingsThe role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency. SummaryBoth lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.

Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure

Background. During orthotopic liver transplantation (OLT) for acute liver failure (ALF), some patients develop acute increases in intracranial pressure (ICP). The authors tested the hypothesis that increases in ICP during OLT for ALF can be prevented by moderate hypothermia. Methods. Sixteen patients with ALF undergoing OLT were studied. Depending on the measured ICP before OLT, the patients were divided into three groups as follows: group I (n=6), did not require treatment for increased ICP (ICP <15 mm Hg); group II (n=5), had episodes of increased ICP that were controlled by conventional treatment (group I and group II patients were maintained normothermic during OLT); and group III (n=5), had uncontrolled increased ICP before OLT for which they had been cooled and underwent OLT with the median core temperature of 33.4°C (92.1°F) (range, 31.9°–33.8°C [89.4°–92.8°F]) Results. There was a significant increase in ICP during the dissection and reperfusion phases in the patients in groups I and II (P =0.004 and P =0.006, respectively). Patients in group III had no significant increase in ICP during the OLT. The increase in ICP in groups I and II was associated with an increase in cerebral blood flow, which was not observed in group III. The increase in ICP was corrected during the anhepatic phase of the operation. There was no difference in the requirement of transfusions or incidence of postoperative infection between the groups. Conclusions. Moderate hypothermia is safe and successfully prevents increases in ICP during OLT for ALF.

Sepsis: an arginine deficiency state?

Objective:Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid l-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis. Data Source:This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO. Data:In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall. Conclusions:Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.