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Summary Background & aims Dietary amino acid (AA) requirements increase after a surgical stress while the systemic AA availability from the diet decreases with age, due to splanchnic sequestration. While immune-enhancing diets (IEDs) have been recommended for the nutritional management of surgical patients, the systemic bioavailability of their AA supply has not been evaluated in elderly surgical patients. This was determined in surgically-stressed IED-fed aged rats. Methods Thirty-four 5-month- or 21-month-old male Sprague–Dawley rats were used. After a gastrostomy and placement of a jugular vein catheter and a one-week recovery period, the animals underwent two 24 h-enteral feedings with an arginine-enriched IED (Impact®, Nestle Health Science) before (healthy state) and 18 h after a standardized laparotomy, used as a model of surgical stress. During enteral nutrition, blood samples were repeatedly collected to measure plasma AA bioavailability (incremental areas under the curve) at 2, 5 and 24 h. Surgical stress was evaluated from urinary catecholamines and plasma protein profile. Results Whatever the age or stress situation, IED feeding was associated with decreased plasma glycine and increased alanine, proline and arginine. Aging was mainly associated with a delayed plasma AA accumulation in the first hours after the initiation of enteral nutrition. Stress was associated with higher plasma arginine increase and lower histidine, methionine, phenylalanine and tyrosine accumulation. Age and stress interactions seem limited. Conclusions AA bioavailability from an arginine-enriched IED seems to be maintained whatever age and stress situation. Aging appears to be mainly associated with a delay in plasma AA accumulation probably related to age-associated splanchnic sequestration of AAs. Additional effects of surgical stress per se seem limited.

BACKGROUND: Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE: Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN: This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS: NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS: Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.

Summary During cancer therapy many patients experience significant malnutrition, leading to decreased tolerance to chemotherapy and decreased survival. Dietary citrulline supplementation improves nutritional status in situations such as short bowel syndrome and aging, and is of potential interest in oncology. However, a mandatory prerequisite is to test this amino acid for interaction with tumor growth and chemotherapy response. Dietary citrulline (Cit; 2%), or an isonitrogenous mix of non-essential amino acids (control), was given to Ward colon tumor-bearing rats the day before chemotherapy initiation. Chemotherapy included 2 cycles, one week apart, each consisting of one injection of CPT-11 (50 mg/kg) and of 5-fluorouracil (50 mg/kg) the day after. Body weight, food intake and tumor volume were measured daily. The day after the last injection, rats were killed, muscles (EDL, gastrocnemius), intestinal mucosa, tumor, spleen and liver were weighed. Muscle and intestinal mucosa protein content were measured. Phosphorylated 4E-BP1 was measured in muscle and tumor as a surrogate for biosynthetic activation. FRAPS (Ferric Reducing Ability of Plasma) and thiols in plasma, muscle and tumor were evaluated and plasma amino acids and haptoglobin were measured. Numerous parameters did not differ by diet overall: a) response of tumor mass to treatment, b) tumor antioxidants and phosphorylated 4E-BP1 levels, c) relative body weight and relative food intake, d) weight of EDL, gastrocnemius, intestinal mucosa, spleen and liver and e) plasma haptoglobin concentrations. Moreover, plasma citrulline concentration was not correlated to relative body weight, only cumulated food intake and plasma haptoglobin concentrations were correlated to relative body weight. Citrulline does not alter the tumor response to CPT-11/5FU based therapy but, has no effect on nutritional status, which could be due to the anorexia and the low amount of citrulline and protein ingested.

International audience; Objectives: Supplementing diet with citrulline has proved an efficient means of preserving nitrogen balance and improving nutritional status after massive intestinal resection. The aim of this study was to model the action of citrulline in gut-resected rats using a dose-ranging study focused on skeletal muscle nitrogen homeostasis.Methods: Forty-six rats were randomly assigned to one of the following groups: citrulline 0.5 g.kg.d(-1) (n = 9), citrulline 1 g.kg.d(-1) (n = 7), citrulline 2.5 g.kg.d(-1) (n = 8), citrulline 5 g.kg.d(-1) (n = 8), control (n = 6), and sham (n = 8). The sham group underwent transection and the other groups underwent resection of 80% of the small intestine. All rats were then fed enteral nutrition (EN; all diets were isocaloric and isonitrogenous). After 10 d, the rats were sacrificed to measure and analyze animal weight; duodenum, jejunum, and ileum weight; and muscle trophicity. Protein fractional synthesis rate (FSR) and mammalian target of rapamycin complex (mTORC)1 activation were measured in the tibialis muscle.Results: There was a significant dose-dependent association between rat weight and citrulline dose up to 2.5 g.kg.d(-1) (P = 0.004). There was a significant improvement in tibialis weight correlated to plasma citrulline. Net protein FSR in the tibialis tended to be greater after resection and tended to return to baseline after citrulline supplementation. Citrulline supplementation significantly decreased the activated phosphorylated forms of S6 K1 (P = 0.003) and S6 RP (P = 0.003), with a significant positive association between myofibrillar FSR and activation of S6 K1 (r = 0.614; P = 0.02) and S6 RP (r = 0.601; P = 0.023). Jejunum weight was significantly positively correlated with plasma citrulline (r = 0.319; P = 0.0345).Conclusion: Citrulline promotes body weight gain, preserves muscle trophicity, and enhances intestinal adaptation in a dose-dependent manner in a model of resected rats.

Summary Background & aims Metastatic non-small cell lung cancer (NSCLC) is the first cause of cancer death worldwide. Increased resting energy expenditure (REE) is frequent among cancer patients and may contribute to cancer cachexia. The aim of this study was to examine the prognostic value of increased REE in metastatic NSCLC patients. Methods This observational study was conducted between June 2012 and November 2017 in the outpatient unit of the oncology department of Cochin hospital, Paris. Consecutive patients with newly diagnosed stage IV NSCLC underwent measurement of REE by indirect calorimetry before treatment initiation. Uni- and multivariate analysis of overall survival (OS, Cox models) included age, sex, smoking habit, histological subtype, performance status, body mass index, weight loss, albumin and CRP levels and the ratio of measured REE to the REE predicted by the Harris Benedict formula (mREE/pREE). Results 144 patients were enrolled: mean age 64 years, 63% male, 90% non-squamous carcinoma, including 17% with ALK/EGFR alteration. In univariate analysis, tobacco consumption (p = 0.007), histo-molecular subtype (p vs ≤ 120%: HR = 2.16, p and ≤120%, respectively. In multivariate analysis, histo-molecular subtype (non-squamous ALK/EGFR mutated vs squamous carcinoma: HR = 0.25, p = 0.006), weight loss (>vs ≤ 5%: HR = 1.98, p = 0.004), albumin (≥vs vs ≤120%: HR = 1.90, p = 0.004) were identified as independent prognostic factors. Conclusions Elevated resting energy expenditure emerges as an independent prognostic factor in metastatic NSCLC.

Summary The value of transthyretin (TTR) measurement for assessing malnutrition is under debate due to its sensitivity to inflammation and frequent confusion over its meaning (i.e. as a marker of diagnosis, prognosis, or efficacy of refeeding). Moreover, there is still no ESPEN/ASPEN guideline on its use and cut-off values. Here the aim was to evaluate the overall perception of the value of this parameter and its utilization worldwide. A panel of international experts in the field were surveyed on the use of TTR in clinical practice in their country, on the guidelines issued by their national health authorities, and on the cut-off values used to diagnose malnutrition. A total of 31 experts (nutrition [n = 9], surgery [n = 8], critical care [n = 4], geriatrics [n = 4], biology [n = 3], pediatrics [n = 1], internal medicine [n = 1] and gastroenterology [n = 1]) from 16 countries participated. TTR only appears in Italian, Polish, British and French national guidelines giving cut-off values for mild/moderate/severe malnutrition. TTR is frequently used in research yet rarely if ever in clinical practice in most countries, the reasons cited being lack of evidence for its usefulness, lack of specificity, or its high cost/effectiveness ratio. Given the difficulty of finding a consensus tool for the diagnosis of malnutrition, there is every reason to consider such a simple and inexpensive marker as TTR. However, further studies are needed to define and unify international guidelines on the use of TTR in terms of inflammation level and the associated cut-off values.

Alterations of nutritional and performance status (PS) are associated with higher risk of chemotherapy toxicity. Increased resting energy expenditure (REE) is frequent in cancer patients and may contribute to cachexia. We investigated whether abnormal energetic metabolism could predict early acute limiting toxicities (ELT) of anticancer treatments.In this observational monocentric study, REE was measured by indirect calorimetry before treatment initiation. Based on the ratio of measured REE to REE predicted by the Harris-Benedict formula, patients were classified as hypometabolic (90%), normometabolic (90-110%) or hypermetabolic (110%). Body mass index, weight loss, PS, albumin, transthyretin, C-reactive protein (CRP) and muscle mass (CT-scan) were studied. Were defined as ELT any unplanned hospitalization or any adverse event leading to dose reduction or discontinuation during the first cycle of treatment.We enrolled 277 patients: 76% had metastatic disease; 89% received chemotherapy and 11% targeted therapy; 29% were normometabolic, 51% hypermetabolic and 20% hypometabolic. Fifty-nine patients (21%) experienced an ELT. Toxicity was associated with abnormal metabolism (vs normal: OR = 2.37 [1.13-4.94], p = 0.023), PS (2-3 vs 0-1: OR = 2.04 [1.12-3.74], p = 0.023), albumin (35 vs ≥35 g/l: OR = 2.39 [1.03-5.54], p = 0.048), and inflammation (CRP ≥10 vs10 mg/l: OR = 2.43 [1.35-4.38], p = 0.004). To predict toxicity, the most sensitive parameter was the REE (83%) followed by PINI (63%), GPS (59%), CRP (55%), PS (41%), NRI (37%), and albumin (16%). In multivariate analysis, elevated CRP was an independent predictor of toxicity (p = 0.047).Abnormal basal energy metabolism identifies patients at higher risk of treatment-related acute complications.

Objective In critically ill patients, acute injury alters gut function, causing greater risk for sepsis and malnutrition. Peptide-enriched diets may promote nitrogen absorption, whereas ω3-enriched diets reduce alterations in gut barrier function. The aim of this study was to assess the effectiveness of a peptide- and ω3-enriched diet on the metabolic response to injury and the gut barrier function in a model of prolonged catabolism in the rat. Given the intestinal trophic effect of glutamine, we tested for a synergistic effect of glutamine. Methods We randomized 40 male Sprague-Dawley rats (250 g) into four groups to enterally receive a standard high-protein diet (S), or a peptide- and ω3-enriched diet either alone (IMN) or supplemented with glutamine and alanine supplied as dipeptide (DIP) or as free amino acids (AAs) for 4 d. Metabolic response to injury was induced by turpentine injections on days 1 and 3. At sacrifice, nutritional and inflammatory biomarkers and intestinal and liver function were assessed. Results Weight gain (+45–62%) and nitrogen balance (+33–56%) were significantly higher in all groups than in the S group. In jejunal mucosa, total glutathione was significantly higher (+20–30%) and myeloperoxidase activity significantly lower in all groups compared with the S group. Hepatic triacylglycerol content was significantly lower in the AA (0.30 ± 0.04 μM/g) and DIP (0.43 ± 0.08 μM/g) groups than in the S group (0.71 ± 0.08 μM/g). Conclusions In this model of prolonged catabolism, compared with a standard diet, a peptide- and ω3-enriched diet improved metabolic response to injury, with better nitrogen balance and weight recovery, and decreased intestinal myeloperoxidase activity. Only marginal additional effects of glutamine supplementation were observed with decreased hepatic fat content.

International audience; Objectives: A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mechanism is unknown. The aim of this study was to determine the effect of CIT administration on locomotor activity and dopamine activity in healthy aged rats.Methods: Sixty adult (3-mo-old) and aged (20-mo-old) rats were divided into four groups (n ¼ 15 each) stratified by age (adult versus old) and diet (control versus CIT; i.e., Ad-Control, Ad-CIT, Old-Control, Old-CIT) and fed for 4 d on either a CIT-enriched diet (5 g/kg daily; Ad-CIT and Old-CIT) or an isonitrogeneous control diet (Ad-Control and Old-Control). Locomotor activity was evaluated in a Y-maze. On day 5, animals were sacrificed and brain (striatum) was removed to determine total and phosphorylated forms of tyrosine hydroxylase (TH) by immunohistochemistry.Results: CIT restored locomotor activity in aged rats (arm visits: Old-CIT 28 ± 1 versus Old-Control 23 ± 1; P < 0.05), associated with an increase in total TH (Old-CIT 668 ± 27 versus Old-Control 529 ± 22; P < 0.05) and phosphorylated forms of TH (Old-CIT 1012 ± 39 versus Old-Control 589 ± 69; P < 0.05).Conclusion: In aged rats, CIT is able to stimulate locomotor activity via the dopaminergic pathway.

Background: Cachexia is a major cause of death in cancer patients. The role of hypermetabolism in cancer cachexia remains unclear.Objective: We studied the relation between resting energy expenditure (REE), the estimated energy balance, clinical and biological markers of cachexia, and survival.Design: REE was measured with the use of indirect calorimetry in cancer patients before the initiation of anticancer therapies. Hypermetabolic, normometabolic, and hypometabolic patients were identified with the use of Boothby's standard. Weight loss, performance status (PS), C-reactive protein (CRP), albumin, the nutritional risk index, daily energy intake, energy balance (equal to daily energy intakes minus the REE), and survival were recorded.Results: Of 390 enrolled patients, 49% of subjects were hypermetabolic, 30% of subjects were normometabolic, and 21% of subjects were hypometabolic. Mean daily energy intakes did not differ significantly between the 3 groups. Hypermetabolic patients, compared with normometabolic patients, were more likely to have a negative energy balance [45% compared with 32%, respectively; OR: 1.74 (95% CI: 1.05, 2.91); P = 0.024], weight loss >5% [48% compared with 34%, respectively; OR: 1.83 (95% CI: 1.11, 3.04); P = 0.013], PS ≥2 [40% compared with 29%, respectively; OR: 1.70 (95% CI: 1.01, 2.88); P = 0.038], and CRP concentrations ≥10 mg/L [52% compared with 33%, respectively; OR: 2.2 (95% CI: 1.33, 3.66); P = 0.001]. In metastatic patients, compared with normometabolism, hypermetabolism was associated with a reduced median survival [14.6 compared with 21.4 mo, respectively; OR: 1.48 (95% CI: 1.01, 2.17); P = 0.044].Conclusions: Hypermetabolism is correlated with clinical and biological markers of cancer cachexia and is associated with a shorter survival in metastatic cancer patients. The development of therapeutic strategies that aim to blunt hypermetabolism appears warranted. This trial was registered at www.controlled-trials.com as ISRCTN46152275.

N-carbamoyl putrescine (NCP), the decarboxylation derivative of citrulline, metabolically related to polyamines, may exert biological effects in mammals. The aim of this study was (i) to evaluate the nutritional properties of NCP in healthy rats and (ii) to determine the effect of NCP administration on muscle metabolism in malnourished old rats. The nutritional properties of NCP were first evaluated in 20 8-week-old male rats randomized to receive for two weeks a standard diet either alone (C group) or supplemented with NCP, 5 or 50 mg/kg/d. In a second study, 29 malnourished 18-month-old male rats were studied either before or after a 4-day refeeding with a standard diet either alone (REN group) or supplemented with NCP, 1 or 10 mg/kg/d. NCP had no effect on weight gain and body composition in either of the two studies. In healthy rats, muscle protein content was significantly increased in the soleus with NCP 5 mg/kg/d. A decrease in plasma glutamine and kidney spermine was observed at the 50 mg/kg/d dose, otherwise, no significant changes in plasma chemistry and tissue polyamines were observed. In malnutrition-induced sarcopenic old rats, refeeding with NCP 10 mg/kg/d was associated with higher tibialis weight and a trend for increased protein content in extensor digitorum longus (EDL). While the muscle protein synthesis rate was similar between groups, ribosomal protein S6 kinase was increased in tibialis and higher in the EDL in NCP-treated rats. The muscle RING-finger protein-1 expression was decreased in tibialis and urinary 3-methyl-histidine to creatinine ratio slightly lower with the supply of NCP. However, this initial period of refeeding was also associated with elevated fasted plasma triglycerides and glucose, significant in NCP groups, suggesting glucose intolerance and possibly insulin resistance. NCP was well-tolerated in healthy young-adults and in malnourished old rats. In healthy adults, NCP at 5 mg/kg/d induced a significant increase in protein content in the soleus, a type I fiber-rich muscle. In malnourished old rats, NCP supply during refeeding, may help to preserve lean mass by limiting protein breakdown, however, these effects may be limited in our model by a possible immediate refeeding-associated glucose intolerance.

N-carbamoyl putrescine (NCP), the decarboxylation derivative of citrulline, metabolically related to polyamines, may exert biological effects in mammals. The aim of this study was (i) to evaluate the nutritional properties of NCP in healthy rats and (ii) to determine the effect of NCP administration on muscle metabolism in malnourished old rats. The nutritional properties of NCP were first evaluated in 20 8-week-old male rats randomized to receive for two weeks a standard diet either alone (C group) or supplemented with NCP, 5 or 50 mg/kg/d. In a second study, 29 malnourished 18-month-old male rats were studied either before or after a 4-day refeeding with a standard diet either alone (REN group) or supplemented with NCP, 1 or 10 mg/kg/d. NCP had no effect on weight gain and body composition in either of the two studies. In healthy rats, muscle protein content was significantly increased in the soleus with NCP 5 mg/kg/d. A decrease in plasma glutamine and kidney spermine was observed at the 50 mg/kg/d dose; otherwise, no significant changes in plasma chemistry and tissue polyamines were observed. In malnutrition-induced sarcopenic old rats, refeeding with NCP 10 mg/kg/d was associated with higher tibialis weight and a trend for increased protein content in extensor digitorum longus (EDL). While the muscle protein synthesis rate was similar between groups, ribosomal protein S6 kinase was increased in tibialis and higher in the EDL in NCP-treated rats. The muscle RING-finger protein-1 expression was decreased in tibialis and urinary 3-methyl-histidine to creatinine ratio slightly lower with the supply of NCP. However, this initial period of refeeding was also associated with elevated fasted plasma triglycerides and glucose, significant in NCP groups, suggesting glucose intolerance and possibly insulin resistance. NCP was well-tolerated in healthy young-adults and in malnourished old rats. In healthy adults, NCP at 5 mg/kg/d induced a significant increase in protein content in the soleus, a type I fiber-rich muscle. In malnourished old rats, NCP supply during refeeding, may help to preserve lean mass by limiting protein breakdown; however, these effects may be limited in our model by a possible immediate refeeding-associated glucose intolerance.

Summary Background Symptoms and clinical presentations of OTC deficiency vary widely according to the remaining activity of the enzyme. Three factors determine the residual enzyme activity. First, as the OTC gene is carried on the X chromosome, a complete inactivation of this enzyme in a newborn boy results an acute ammonia intoxication. Second, the female mosaicism due to lyonization (differential randomized X-inactivation) leads to differential OTC expression in hepatocytes. Third, the degree of severity depends on the mutation and the level of remaining activity it leaves to the protein. Published cases of OTC deficiency during pregnancy are scant. Most often, diagnosis of the metabolic disease is made before pregnancy or during the post-partum period. Methods We report the case of a 22-year-old woman's successful pregnancy with a moderate form of ornithine transcarbamylase (OTC) deficiency, unsuspected before pregnancy, biochemically consistent with plasma aminoacidogram and orotic acid analysis, and initially masked by malnutrition. Results - conclusion Although maternal ammonia was subnormal and the neonate was safe, an OTC deficiency was revealed by stress factors such as the pregnancy itself and infection, and associated with uncontrollable maternal vomiting and psychiatric syndrome. However, this metabolic disease, revealed by aminoacidogram and urine orotic acid analysis, fortunately did not prevent a successful pregnancy. Even if infrequent, this situation deserves to be highlighted.

While effects of the two classes of proteins found in milk (i.e., soluble proteins, including whey, and casein) on muscle protein synthesis have been well investigated after a single bout of resistance exercise (RE), the combined effects of these two proteins on the muscle responses to resistance training (RT) have not yet been investigated. Therefore, the aim of this study was to examine the effects of protein supplementation varying by the ratio between milk soluble proteins (fast-digested protein) and casein (slow-digested protein) on the muscle to a 9-week RT program. In a double-blind protocol, 31 resistance-trained men, were assigned to 3 groups receiving a drink containing 20g of protein comprising either 100% of fast protein (FP(100), n = 10), 50% of fast and 50% of slow proteins (FP(50), n = 11) or 20% of fast protein and 80% of casein (FP(20), n = 10) at the end of training bouts. Body composition (DXA), and maximal strength in dynamic and isometric were analyzed before and after RT. Moreover, blood plasma aminoacidemia kinetic after RE was measured. The results showed a higher leucine bioavailability after ingestion of FP(100) and FP(50) drinks, when compared with FP(20) (p< .05). However, the RT-induced changes in lean body mass (p < .01), dynamic (p < .01), and isometric muscle strength (p < .05) increased similarly in all experimental groups. To conclude, compared with the FP(20) group, the higher rise in plasma amino acids following the ingestion of FP(100) and FP(50) did not lead to higher muscle long-term adaptations.

Resume La nutrition est une discipline a composantes cliniques et biologiques visant a apporter de facon optimale l’ensemble des nutriments dont l’organisme a besoin pour croitre et assurer ses differentes fonctions. L’apport de la biologie a cette discipline s’est longtemps limite, dans ses applications cliniques, a l’evaluation du statut nutritionnel des patients, au calcul de leurs besoins quantitatifs ainsi qu’au suivi de l’efficacite de la renutrition. Les avancees de la recherche ont permis d’elargir ses champs d’application avec notamment la mise au point d’un test d’evaluation des apports qualitatifs optimaux en acides amines. Cette methode, basee sur des principes pharmacocinetiques simples, permet un ajustement individuel des apports en acides amines aboutissant a une amelioration du bilan azote de patients de reanimation et donc un gain possible en termes de morbi-mortalite. A cote de ces perspectives ameliorant la prise en charge nutritionnelle en tant que telle, la nutrition semble destinee a integrer l’utilisation de bio-marqueurs dans la demarche diagnostique, pronostique et therapeutique. Un bon exemple est l’utilisation de la citrulline plasmatique en tant que bio-marqueur de la fonctionnalite intestinale. L’exemple de ces deux domaines d’application temoigne de l’apport de la biologie dans la prise en charge nutritionnelle et medicale des patients.

International audience; Perturbations of energy balance induce compensatory processes that may alter expected weight loss. In obese patients, our aim was to investigate the relationships that occurred between fasting plasma concentrations of anorexigenic peptides and metabolic parameters, appetite, physical capacity, and weight loss in the 5 first days of a program associating exercise and caloric reduction. Thirteen obese women were monitored from day 1 to day 5 with 2 exercise sessions in day 2 and day 4. We measured, in a fasted state, changes in body weight, hunger ratings, and plasma concentrations of fatty acids, triglycerides, leptin, insulin, amylin, peptide YY, and insulin-resistance index. Physical performance was assessed by a 6-min walking test. The program resulted in significantly reduced body weight (0.75±0.4 kg; p=0.001), of plasma concentrations of triglycerides, insulin, amylin, peptide YY, and the insulin-resistance index, and also increased fatty acids (p

Taurine is the most abundant amino acid in the retina. In the 1970s, it was thought to be involved in retinal diseases with photoreceptor degeneration, because cats on a taurine-free diet presented photoreceptor loss. However, with the exception of its introduction into baby milk and parenteral nutrition, taurine has not yet been incorporated into any commercial treatment with the aim of slowing photoreceptor degeneration. Our recent discovery that taurine depletion is involved in the retinal toxicity of the antiepileptic drug vigabatrin has returned taurine to the limelight in the field of neuroprotection. However, although the retinal toxicity of vigabatrin principally involves a deleterious effect on photoreceptors, retinal ganglion cells (RGCs) are also affected. These findings led us to investigate the possible role of taurine depletion in retinal diseases with RGC degeneration, such as glaucoma and diabetic retinopathy. The major antioxidant properties of taurine may influence disease processes. In addition, the efficacy of taurine is dependent on its uptake into retinal cells, microvascular endothelial cells and the retinal pigment epithelium. Disturbances of retinal vascular perfusion in these retinal diseases may therefore affect the retinal uptake of taurine, resulting in local depletion. The low plasma taurine concentrations observed in diabetic patients may further enhance such local decreases in taurine concentration. We here review the evidence for a role of taurine in retinal ganglion cell survival and studies suggesting that this compound may be involved in the pathophysiology of glaucoma or diabetic retinopathy. Along with other antioxidant molecules, taurine should therefore be seriously reconsidered as a potential treatment for such retinal diseases.

International audience; Adequate nutritional support is a major challenge in brain injury patients, because malnutrition cannot be reversed by standard enteral nutrition. We hypothesized that an oligomeric formula could improve nutritional status by restoring intestinal trophicity. Eighteen male Sprague-Dawley rats (300-330 g) underwent gastrostomy on day-7 (D-7) and traumatic brain injury (TBI) by hydraulic percussion (D0) and were then fed for 4 days with either a polymeric formula (Sondalis® HP, TBIP, n = 9), or an oligomeric formula (Peptamen® HN, TBIO, n = 9). In addition, a control group of healthy gastrostomized rats was fed the polymeric diet (control, n = 8). All rats were weighed daily. On D+4, the rats were euthanized. Blood was collected for plasma amino acid determination. Organs were removed and weighed. Intestinal morphometry was studied. Protein content was assessed on intestine and muscles. Enterobacterial translocation and dissemination were evaluated. Results were expressed as means ± SEM and compared using analysis of variance+Newman-Keuls test. TBI induced a significant decrease in whole body weight (TBIP vs. control, p < 0.05) that was totally blunted by the oligomeric diet (TBIP vs. TBIO, p < 0.01). Thymus weight significantly decreased after TBI (TBIP vs. control, p < 0.05) and was restored by the oligomeric formula (TBIO vs. TBIP, p < 0.05). Glutamine (GLN) concentration was improved by the oligomeric diet in both plasma (TBIO: 688 ± 19 vs. control: 591 ± 45 and TBIP: 615 ± 42 μmol/L, p < 0.05) and soleus muscle. These results show that the use of an oligomeric diet may limit response to injury after brain injury and could be a simple nutritional strategy in this setting.

The best storage temperature in liver transplantation remains an unsolved question.After storage for 24h in University of Wisconsin solution at +4°C, +1°C, or -0.5°C, rat livers were subjected, or not, to 15min of warm ischemia, rinsed with Ringer lactate, and subsequently reperfused with oxygenated Krebs-Henseleit buffer.In the presence of warm ischemia, for livers stored at +4°C, creatine kinase (CK) peaked at 21±5IUg(-1)h(-1), hepatic resistance at 34,700±1500dynscm(-5), bile flow reached 18±4μLg(-1)h(-1) after 10min, and oxygen consumption stabilized at about 25μmolg(-1)h(-1) after 20min. When livers were stored at +1°C, CK and hepatic resistance were lowered, bile production was 33±6μLg(-1)h(-1) (P0.05 versus +4°C), and oxygen consumption was 105±10μmolg(-1)h(-1) (P0.001). For livers stored at-0.5°C, results were not statistically different from those of the +1°C group except for bile flow, which was significantly lower. Without warm ischemia, the peak of CK (P=0.015) and the peak hepatic resistance (P0.001) of the +4°C group were significantly increased compared with the +1°C or -0.5°C groups. However, no difference in bile flow or oxygen consumption was observed. The number of trypan blue-positive nonparenchymal cells (P=0.003) and the gain in liver weight during the reperfusion (P=0.015) were minimal after storage at +1°C.Static storage at +1°C improved liver function compared with +4°C or -0.5°C. Main beneficial effect was observed with parameters reflecting sinusoidal cells injury.

Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control.

Background Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and autoimmune cytopenia. Objectives Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant. Methods Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death. Results We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait. Conclusion FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination.

Objective Critically ill diabetic and obese patients are at high risk of complications. Arginine availability is lowered in diabetes and in stress situations, yet arginine is necessary for immune response, mainly by its action through nitric oxide (NO). These facts argue for arginine-supplemented diets in critically ill patients. However, studies have raised concerns about possible adverse effects of such diets in intensive-care patients. We therefore analyzed the metabolic and immunologic effects of an arginine-enriched diet in stressed diabetic-obese rats. Methods Zucker Diabetic Fatty rats ( fa / fa ) were made endotoxemic by an intraperitoneal injection of lipopolysaccharide and then fed 4-d enteral nutrition enriched with arginine (ARG group) or a non-essential amino acid mix (NEAA group). The two groups each were subdivided into three subgroups: the ARG subgroups received 0.5 g (ARG0.5), 2 g (ARG2), and 5 g (ARG5) of arginine per kilogram daily, and the NEAA groups were made isonitrogenous with the corresponding ARG subgroups (NEAA0.5, NEAA2, and NEAA5). Plasma and urinary biomarkers were measured. Cytokine and NO production levels and inducible NO synthase and arginase protein levels were determined from peritoneal macrophages. Results The survival rate was lower in the ARG5 and NEAA5 subgroups than in all the other subgroups. The nitrogen balance was higher in the ARG5 group than in the NEAA5 group. Plasma triacylglycerol levels were lower in the ARG2 group than in the NEAA2 group. Interleukin-6, tumor necrosis factor-α, and NO production in the macrophages decreased and arginase-1 was upregulated in the ARG-treated rats. Conclusions In this model, mortality was increased by the nitrogen burden rather than by arginine per se. Arginine improved nitrogen balance and had an anti-inflammatory action on macrophages by regulating NO production, probably through arginase-1 expression.

Purpose Taurine depletion is known to induce photoreceptor degeneration and was recently found to also trigger retinal ganglion cell (RGC) loss similar to the retinal toxicity of vigabatrin. Our objective was to study the topographical loss of RGCs and cone photoreceptors, with a distinction between the two cone types (S- and L- cones) in an animal model of induced taurine depletion. Methods We used the taurine transporter (Tau-T) inhibitor, guanidoethane sulfonate (GES), to induce taurine depletion at a concentration of 1% in the drinking water. Spectral-domain optical coherence tomography (SD-OCT) and electroretinograms (ERG) were performed on animals after 2 months of GES treatment administered through the drinking water. Retinas were dissected as wholemounts and immunodetection of Brn3a (RGC), S-opsin (S-cones), and L-opsin (L-cones) was performed. The number of Brn3a+ RGCs, and L- and S-opsin+ cones was automatically quantified and their retinal distribution studied using isodensity maps. Results The treatment resulted in a significant reduction in plasma taurine levels and a profound dysfunction of visual performance as shown by ERG recordings. Optical coherence tomography analysis revealed that the retina was thinner in the taurine-depleted group. S-opsin+cones were more affected (36%) than L-opsin+cones (27%) with greater cone cell loss in the dorsal area whereas RGC loss (12%) was uniformly distributed. Conclusions This study confirms that taurine depletion causes RGC and cone loss. Electroretinograms results show that taurine depletion induces retinal dysfunction in photoreceptors and in the inner retina. It establishes a gradient of cell loss depending on the cell type from S-opsin+cones, L-opsin+cones, to RGCs. The greater cell loss in the dorsal retina and of the S-cone population may underline different cellular mechanisms of cellular degeneration and suggests that S-cones may be more sensitive to light-induced retinal toxicity enhanced by the taurine depletion.

Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion.Randomized, controlled experimental study.University research laboratory.Zucker diabetic fatty rats.Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n=7) or with graded arginine supply (1-5 g/kg/day) (GA group, n=7) or a standard enteral nutrition (HP group, n=10).Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 3.7±0.8 ng/2×10⁶ cells·hr⁻¹; and HP: 1.7±0.6 ng/2×10⁶ cells·hr⁻¹; p.05 G vs. HP) and nitric oxide (G: 4.5±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 5.1±1.0 ng/2×10⁶ cells·hr⁻¹; and HP: 1.0±0.5 nmol/2×10⁶ cells·hr⁻¹; p.05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption.In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill diabetic and obese patients.

Introduction et but de l’etude Environ 30 % des 3,5 millions de nouveaux cas de cancer recenses en Europe en 2012 concernaient les personnes âgees de plus de 75 ans. Or, le cancer et le vieillissement sont deux situations s’accompagnant frequemment d’une denutrition, facteur de mauvais pronostic. Les modifications du metabolisme energetique liees au vieillissement pourraient majorer le risque de denutrition liee au cancer. Une etude menee au sein du service de cancerologie de notre hopital a montre une augmentation de la depense energetique de repos chez environ 50 % des patients atteints de cancer [1] . Les donnees concernant la reponse a l’agression chez la personne âgee sont rares, voire inexistantes dans le cas du cancer. L’objectif principal de notre travail etait d’etudier l’influence de l’âge sur la depense energetique de repos du patient atteint de cancer et les objectifs secondaires de mettre en evidence des determinants hormonaux et inflammatoires influencant cette depense energetique. Materiel et methodes Nous avons conduit une etude transversale cas/temoins dans deux groupes de patients âges respectivement de moins et de plus de 75 ans, tous atteints d’un cancer broncho-pulmonaire. Les patients ont ete soumis a une determination de la depense energetique de repos par calorimetrie indirecte et de la composition corporelle par extrapolation a partir du scanner en L3. Un bilan biologique hormonal (TSH, insuline, IGF1), inflammatoire (CRP, orosomucoide, TNFα, IL-1β, IL-4, IL-6, IL-10), nutritionnel (albumine, transthyretine) et metabolique (glucose, lactate, acides amines plasmatiques) a egalement ete realise. Analyse statistique : verification de la normalite (Shapiro-Wilk) et tests parametriques (Student, Pearson) ou non (Mann-Whitney, Spearman) ; seuil de significativite : p Resultats Entre janvier et juin 2016, nous avons pu inclure 20 patients âges de moins de 75 ans et sept patients âges de plus de 75 ans. La depense energetique de repos tendait a etre plus faible dans le groupe des patients les plus âges (1370 ± 424 kcal/j contre 1589 ± 328 kcal/j respectivement ; p = 0,16) mais cette difference disparaissait apres correction par la masse maigre (37,9 ± 10,1 kcal/j/kg contre 38,2 ± 6,1 kcal/j/kg ; p = 0,921). En ce qui concerne les objectifs secondaires, nous n’avons pas mis en evidence de correlation entre les parametres etudies et la depense energetique de repos en dehors d’une correlation negative entre la depense energetique de repos rapportee a la masse maigre et la concentration plasmatique en tryptophane (r = –0,509 ; p Conclusion Avec les reserves imposees par le manque de puissance statistique de notre etude, il semble que la variation de depense energetique de repos accompagnant le vieillissement chez le patient atteint d’un cancer bronchopulmonaire soit liee a celle de la composition corporelle associee au vieillissement. La relation negative existant entre tryptophane plasmatique et depense energetique de repos pourrait etre liee au role de la depletion en tryptophane dans la tolerance immunitaire au cancer.

Introduction et but de l’etude En depit de l’utilite demontree de la transthyretine dans le depistage de la denutrition, son utilisation demeure controversee principalement pour deux raisons : l’influence de l’etat inflammatoire sur sa valeur et l’absence de consensus sur les seuils a utiliser. Une etude retrospective menee sur une large cohorte nous a permis de proposer de nouveaux seuils ([transthyretine] [1] . Le but de la presente etude etait double : valider prospectivement ces seuils et demontrer l’utilite de la transthyretine y compris en presence d’une inflammation. Materiel et methodes L’etude prospective que nous avons conduite au sein de 29 services appartenant a notre centre hospitalo-universitaire a ete realisee entre octobre 2015 et mars 2016. Les patients, selectionnes en fonction de la valeur des concentrations de transthyretine (normale : ≥ 0,2 g/L ; basse : normale /CRP] basse ( n = 50), [transthyretine] normale /[CRP] haute ( n = 50), [transthyretine] basse /[CRP] haute ( n = 57), [transthyretine] basse /[CRP] basse ( n = 59). Le statut nutritionnel des participants (non denutris, n = 138 contre denutrition moderee, n = 43 contre denutrition severe, n = 35) etait determine cliniquement. Resultats Parmi les 216 patients selectionnes, les prevalences de denutrition etaient significativement differentes entre les groupes, qu’il y ait presence d’un syndrome inflammatoire biologique ([transthyretine] normale /[CRP] haute contre [transthyretine] basse /[CRP] haute : 30 % contre 50 %, Pearson χ 2 = 8,523 ; p = 0,014) ou non ([transthyretine] normale /[CRP] basse contre [transthyretine] basse /[CRP] basse : 14 % contre 49 %, Pearson χ 2 = 17,162 ; p n = 216, AUC = 0,674) permettait de depister la denutrition avec une bonne sensibilite (0,68) sans pour autant la surdiagnostiquer (specificite de 0,67). Chez les patients denutris, un seuil de 0,12 g/L ( n = 78, AUC = 0,609) permettait d’obtenir un bon compromis entre sensibilite et specificite pour caracteriser le degre de severite de la denutrition (sensibilite : 0,53 ; specificite : 0,73). Enfin, les valeurs des concentrations de proteine c-reactive et de transthyretine n’etaient pas correlees chez les patients denutris ( n = 78 ; Spearman r = −0,190 ; p = 0,096) ; ce qui n’etait pas le cas pour les patients indemnes de denutrition ( n = 138 ; Spearman r = −0,407 ; p Conclusion Des seuils de concentration de transthyretine a 0,17 g/L pour la denutrition et de 0,12 g/L pour determiner la severite de celle-ci semblent etre davantage adaptes pour diagnostiquer et caracteriser efficacement la denutrition, compares aux seuils actuellement proposes par la Haute Autorite de sante (concentration de transthyretine inferieure a 0,11 g/L pour la denutrition et a 0,05 pour la denutrition severe) qui sous-estiment clairement la denutrition [2] . En outre, nos donnees suggerent que la transthyretine puisse tout a fait etre utilisee en presence d’un syndrome inflammatoire biologique chez les patients denutris ; ce qui peut se reveler tres utile lorsqu’il s’agit de suivre l’efficacite de la renutrition, etant donne le manque d’outils suffisamment sensibles pour cela.

Background Sepsis considerably alters the intestinal barrier functions, which in turn modify the absorption and bioavailability of nutrients. However, the effects of septic shock on aminoacid (AAs) bioavailability are poorly documented. The aim of this study was to compare the bioavailability of citrulline, arginine and glutamine during endotoxemia. Materials and methods Thirty-six rats were randomised into two groups: control and lipopolysaccharides (LPS). The LPS group received an intraperitoneal injection of endotoxins (7AE 5m g⁄kg). After 12 h, each group was again randomised into three subgroups, each of which received an oral bolus of citrulline, arginine or glutamine (5AE7 mmol ⁄kg). Blood samples were collected at various times from 0 to 600 min after AA administration. The concentrations of citrulline, arginine, glutamine and their metabolites arginine and ornithine were measured to determine pharmacokinetic parameters Area Under Curve (AUC), Cmax and Tmax. Results The AUC values of citrulline decreased in LPS rats [citrulline, control: 761 ± 67 and LPS: 508 ± 72 lmol min ⁄mL (P =0 AE02)]. Maximum concentrations of citrulline were also significantly decreased by endotoxemia (P =0 AE01). The pharmacokinetic parameters of arginine and glutamine were not significantly modified by endotoxemia. The AUC value of arginine from citrulline conversion was diminished in endotoxemic rats. The other pharmacokinetic parameters of arginine were not significantly modified after arginine or citrulline supply in either group (control or LPS). Conclusion Endotoxemia affects the bioavailability of AAs differently according to the amino acid considered. This feature may be important for nutritional strategy in ICU patients.

Introduction et but de l’etude Les besoins nutritionnels en acides amines augmentent apres un stress chirurgical alors que la disponibilite systemique postprandiale des acides amines diminue avec l’âge, en raison de la sequestration splanchnique des acides amines (SSAA). Si l’immuno-nutrition (IED) est recommandee pour la prise en charge nutritionnelle des patients chirurgicaux, les consequences de la SSAA sur l’adequation de l’apport en acides amines chez les patients âges n’est pas connue. Cela a ete evalue chez le rat âge recevant une IED apres un stress chirurgical. Materiel et methodes Trente-quatre rats SD mâles de 5 ou 21 mois ont ete utilises. Apres gastrostomie, mise en place d’un catheter dans la veine jugulaire et une semaine de recuperation, les animaux ont recu une nutrition enterale (NE, Impact®, Nestle Health Science) continue pendant 24 h avant (etat sain) et 18 h apres une laparotomie (stress chirurgical). Au cours de la NE, des echantillons de sang ont ete recueillis a plusieurs reprises pour la mesure de l’enrichissement plasmatique en acides amines (et calcul des aires sous la courbe : AUC) a 5 et 24 h. Le stress chirurgical a ete evalue par la mesure des catecholamines urinaires et du profil des proteines plasmatiques. Analyse statistique : ANOVA a deux voies. Significativite : p Resultats et analyse statistique Les rats âges ont presente une reponse catecholaminergique a la chirurgie plus forte et une glycemie plus basse comparees aux rats adultes, mais un statut inflammatoire similaire. Les AUC des acides amines plasmatiques entre 0 et 5 h etaient similaires entre les 4 groupes. Sur les 24 h, les AUC de la Methionine, la Phenylalanine et l’Histidine, et de la Serine chez les adultes, etaient significativement plus faibles chez les rats stresses que chez les rats sains (−140 a −50 % p Conclusion L’administration de l’IED augmente de maniere similaire les concentrations plasmatiques des acides amines administres chez les rats stresses âges et adultes ; la disponibilite peripherique de l’Arginine et de la plupart des acides amines apportes par l’IED n’est pas affectee par le vieillissement dans cette situation de stress. L’enrichissement plasmatique plus faible en Asparagine, Glycine et Cysteine chez les rats âges stresses est probablement independant de la SSAA car cette difference apparait seulement apres 5 h de NE.

Introduction et but de l’etude La transthyretine (TTR, anciennement prealbumine) est un marqueur biologique pertinent pour evaluer l’etat nutritionnel [1] . Cependant, son interet reste l’objet de controverses car la TTR varie avec l’inflammation et il persiste une confusion concernant son utilisation en tant que marqueur diagnostique, pronostique ou permettant de mesurer l’efficacite d’une renutrition. De plus, aucune recommandation de l’ESPEN/ASPEN n’existe concernant son utilisation et ses valeurs-seuils. Le but de cette etude etait d’evaluer l’utilisation de ce marqueur dans la pratique bioclinique a l’echelle internationale. Materiel et methodes Un panel international d’experts (n = 45) a ete interroge sur l’utilisation de la TTR en pratique clinique, sur l’existence de recommandations par les autorites de sante ou les societes savantes ainsi que sur les valeurs-seuils definissant la denutrition dans leurs pays respectifs. Resultats et analyse statistique An total, 28 experts (chirurgie [8], nutrition [5], soins intensifs [4], geriatrie [4], biologie [4], pediatrie [1], medecine interne [1], gastro-enterologie [1]) de 15 pays ont participe. La TTR apparait dans des recommandations nationales en Italie, en Pologne, au Royaume-Uni (RU) et en France ( Tableau 1 ). La TTR est utilisee plus ou moins largement en Allemagne, au Chili, en Suisse et en Republique Tcheque. Elle est rarement utilisee en routine au RU et en Suede ou le dosage de ce marqueur est centralise dans des laboratoires de reference. En Argentine, au Bresil, au Canada, en Israel, au Japon, aux Pays-Bas et aux Etats-Unis, la TTR n’est pas ou plus utilisee par manque de preuve concernant son utilite, a cause de son manque de specificite ou pour son cout. Conclusion Bien que la TTR reste tres utilisee a des fins de recherche, elle n’est plus dosee en pratique clinique dans plusieurs pays. Etant donnee la difficulte de trouver un marqueur consensuel pour aider au diagnostic de la denutrition, un marqueur aussi simple et bon marche devrait pourtant retenir l’attention. Cependant, des etudes supplementaires sont necessaires pour definir des recommandations internationales relatives a son utilisation et a ses valeurs-seuils car celles preconisees en France et en Pologne sont clairement trop basses.

Immune-enhancing diets (IEDs) contain a mixture of nutrients claimed to have immunological properties. Therefore, it seemed relevant to determine the effect of each of their components. The aim of this study was to examine the role of arginine (Arg) and ω3 polyunsaturated fatty acids (ω3 PUFAs) in the effect of an IED (Crucial(®)) in a validated rat model of inflammation induced by turpentine (TI).Forty-two rats were randomized into five groups: AL (ad libitum), TI-EN (TI+standard enteral nutrition (EN): Sondalis(®)HP), TI-EN-Arg (TI+standard EN+Arg in equimolar concentration to Arg in the IED), TI-M-IED (TI+modified IED containing the same ω6/ω3 ratio as in standard EN) and TI-IED (TI+Crucial(®)). Blood was sampled to determine CD25 receptor density on lymphocytes. TNF-α, IL-6 and NO (production and expression) were evaluated on isolated macrophages. Mesenteric lymph nodes, spleen and liver were cultured for analysis of enterobacterial translocation and dissemination.CD25 density was decreased after TI and was corrected in the TI-EN-Arg, TI-M-IED and TI-IED groups (p0.05). TI induced an alteration of macrophage mRNA expression of IL-6, TNF-α and iNOS, corrected in the TI-EN-Arg and TI-M-IED groups (p0.05), but not by the IED. Enterobacterial translocation was observed in all treated groups, nevertheless the amount tended (p=0.054) to be lower in the TI-EN-Arg group.Arg and ω3 PUFAs make a major contribution to IED effects, but our study shows interaction between them on macrophage reactivity. This indicates that the individual properties of each pharmaconutrient are not additive in IEDs.

The purpose of the study was to evaluate the effect of head injury (HI) on the metabolic and energy functions of the liver and its consequences after cold storage. In male SD rats with HI, livers were isolated 4 days after injury and perfused either immediately (HI) or after 24 hours of cold preservation. Livers isolated from healthy rats were treated identically. The hepatic functions were explored with an isolated perfused liver model. Head injury induced a liver atrophy without significant difference in the intrahepatic energy level versus healthy rats. After cold storage, hepatic adenosine triphosphate and glycogen contents in HI rats were similar to those of healthy rats. The livers of the HI group that underwent cold preservation had a lower protein catabolism. The portal flow rate at the time of reperfusion was significantly increased in the HI group. In conclusion, static cold storage of livers harvested from HI rats revealed a net protein catabolism reduction and a modification of hepatic microcirculation.

OBJECTIVE Immune-enhancing diets (IEDs) rich in arginine (ARG) reduce morbi-mortality in trauma and surgical patients. Among the pharmaconutrients inducing these effects, ARG may be involved by generating active metabolites such as glutamine (GLN). However, the ability of an ARG-enriched diet to normalize GLN plasma levels in intensive care unit (ICU) patients has never been documented. To analyze plasma GLN and related amino acid (AA) kinetics in response to an ARG-enriched IED in ICU surgical patients. DESIGN This prospective, randomized, single-blind, comparative study was performed on 22 patients randomized to receive total enteral nutrition for 7 days with either an ARG-enriched IED or a standard formula (rendered isonitrogenous to the IED, S group, n = 11), providing 30 kcal/kg/day and 0.3 g N/kg/day. MEASUREMENTS Plasma AA concentrations were measured on day 5 after a 3-hour washout period (basal values = T0) and after 30, 60, 90, 120, 180, and 360 minutes of enteral nutrition. The primary end point was the variation in plasma GLN from T0 to T90. RESULTS Only the IED-fed patients showed an increase in plasma levels of GLN (differences [T90 - T0]: +40 +/- 6 vs. -35 +/- 18 micromol/L, mean +/- sem, p < 0.05, two-way analysis of variance), ARG (+35 +/- 5 vs.+1 +/- 4 micromol/L, p < 0.05), ornithine (+23 +/- 6 vs. -2 +/- 2 micromol/L, p < 0.05), and proline (+36 +/- 10 vs. -6 +/- 11 micromol/L, p < 0.05). CONCLUSION To our knowledge, this is the first reported pharmacokinetic study on an IED even though these products have been on the market for 20 years. Our main result is that administering an ARG-enriched IED causes a significant increase in plasma GLN probably from de novo GLN synthesis from ARG. This suggests that the ARG present in IED can serve to supply GLN to ICU patients, who are usually depleted in this conditionally essential AA during injury.

International audience; To determine whether glutamine (Gln) reduces the ratio of oxidized to total glutathione (GSSG/GSH) and extracellular signal-regulated kinase (ERK1/2) activation in dystrophic muscle. Four-week old mdx mice, an animal model for Duchenne muscular dystrophy and control (C57BL/10) received daily intraperitoneal injections of l-Gln (500 mg/kg/d) or 0.9% NaCl for 3 d. GSH and GSSG concentrations in gastrocnemius were measured using a standard enzymatic recycling procedure. Free amino acid concentrations in gastrocnemius were determined by ion exchange chromatography. Phosphorylated protein levels of ERK1/2 in quadriceps were examined using Western Blot. l-Gln decreased GSSG and GSSG/GSH (an indicator of oxidative stress). This was associated with decreased ERK1/2 phosphorylation. Muscle free Gln, glutamate (Glu), and the sum (Gln + Glu) were higher in mdx versus C57BL/10, at the basal level. Exogenous Gln decreased muscle free Glu and Gln + Glu in mdx only, whereas Gln was not affected. In conclusion, exogenous Gln reduces GSSG/GSH and ERK1/2 activation in dystrophic skeletal muscle of young mdx mice, which is associated with decreased muscle free Glu and Gln + Glu. This antioxidant protective mechanism provides a molecular basis for Gln's antiproteolytic effect in Duchenne muscular dystrophy children.

Chronic benign lymphoproliferation and autoimmune cytopenias are the main features requiring treatment in FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS).[1][1],[2][2] Successful use of the mTOR inhibitor rapamycin was initially reported in the treatment of refractory

International audience; BACKGROUND & AIMS: Ornithine α-ketoglutarate (OKG) is recognized to improve nutritional status in various catabolic states, such as burn injury, trauma, and sepsis. However, in wasting diseases, such as induced by cancer, the data are scarce and the precise mechanisms by which OKG acts on protein metabolism are still unclear. The aim of this study was to evaluate the ability of OKG to affect protein metabolism in an aggressive model of cancer and to modulate the ubiquitin-proteasome-dependent pathway, which in skeletal muscle is the critical degradative pathway implicated in many catabolic states, including cancer-associated cachexia. METHODS: Experiments were carried out in Yoshida sarcoma-bearing and healthy pair-fed rats. Three groups of 16 young male rats were studied during 9 days following tumor implantation: two groups of tumor-bearing rats fed a balanced regimen enriched with either OKG (5 g/kg body weight/day, OKG-K) or an isonitrogenous mixture of non-essential amino acids (C-K), and one group of healthy pair-fed rats (PF). RESULTS: As expected, Yoshida sarcoma induced muscle atrophy, decreased nitrogen balance, enhanced 3-methylhistidine (3-MH) excretion and increased mRNA levels for ubiquitin and 14-kDa ubiquitin-conjugating enzyme E2. OKG supplementation did not improve muscle mass or protein balance and did not reduce enhanced 3-MH excretion in Yoshida sarcoma-bearing rats. Furthermore, OKG did not suppress in the cancer rats the enhanced expression of ubiquitin and 14-kDa E2, despite OKG decreased by 23% the ubiquitination rate in cancer rats (OKG-K vs. C-K, P

Enteral arginine supplementation in the critically ill has become a matter of controversy. In this study, we investigated effects of the addition of 0.4 and 1.2 mmol/L arginine in a coculture model on markers of inflammation, enterocyte layer integrity, and amino acid transport. In this model, a monolayer of intestinal epithelial cells (Caco-2) separated compartments with nonpathogenic Escherichia coli and mononuclear leukocytes. Activation of enterocytes and leukocytes was assessed by the measurement of nitric oxide, TNF-alpha, IL-6, IL-8, IL-10, and IFN-gamma. Further outcomes were the transepithelial flux of 22 amino acids, their catabolism, and the integrity of the enterocyte layer assessed as permeability of fluorescein dextran (M(r) 4400). Bacterial stimulation of intestinal epithelial cells enhanced the basolateral concentration of nitric oxide and all cytokines measured. Supplementation with arginine did not affect epithelial integrity, production of any of the cytokines investigated, or the amount of nitric oxide. The amino acid used primarily by nonstimulated intestinal epithelial cells cocultured with leukocytes was glutamine. Activation of IEC with bacteria significantly enhanced the catabolism of serine, asparagine, and lysine, and reduced glutamine catabolism. Addition of arginine increased ornithine formation and moderately reduced transepithelial transport of methionine and other amino acids. Hence, arginine supplementation does not interfere with inflammation-associated cross-talk between human enterocytes and leukocytes. Because it also does not seem to affect the integrity of enterocyte layers, a detrimental role of arginine during septic-like conditions seems unlikely.

International audience; Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new concept of IED has been proposed combining extra glutamine sequentially with either antioxidants or other amino acids, in order to match patient requirements according to their response to injury. We evaluated whether this new IED elicits a more favorable response to stress when compared with two existing IEDs both enriched in arginine but with different levels of anti-oxidants, in a validated rat model combining head injury (HI) and infectious complications. Forty-eight HI rats were randomized into four groups (n = 11-13 per group) to receive, for 4 days, standard enteral nutrition (S), one of the two existing IEDs (IED1, IED2), or the new IED (IED3; providing glutamine and antioxidants for two days and glutamine and specific amino acids for two days). Two days after HI, the rats received an enteral bolus of luminescent Escherichia coli Xen14 to induce infection, and bacterial dissemination was evaluated. Body weight (BW) was recorded daily. Four days after HI, animals were euthanized; blood was sampled; organs were weighed; cumulated nitrogen balance (CNB) and nitrogen efficiency were determined. IED3 was more efficient than IED1 and IED2 in improving BW recovery from D3 (D3 vs. D1, p < 0.05) after HI. It significantly improved CNB and net protein utilization (IED3 vs. S, IED1, IED2, p < 0.05). An IED with sequential administration of anti-oxidants and glutamine may be better suited to meeting nutritional requirements in severe catabolic states. (C) 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

11 D´ epartement de G´ eriatrie, Hopitaux Universitaires Bichat et Beaujon, AP-HP, Facult´ ed e M´ Abstract Background: Aging is associated with profound metabolic disturbances, and citrulline may be of use to limit them. Objective: The aim of this work was to evaluate the long-term effect of citrulline supplementation on metabolism in healthy aged rats. Methods: Twenty-month-old male rats were randomly assigned to be fed (ad libitum) for 12 wk with either a citrulline- enriched diet (1 g kg 21 d 21 ) or a standard diet (rendered isonitrogenous by addition of nonessential amino acids (NEAAs)). Motor activity and muscle strength were measured, body composition was assessed, and muscle metabolism (protein structure, mitochondrial exploration, and transductional factors) and lipid metabolism (lipoprotein composition and sensitivity to oxidative stress) were explored. Results: Compared with the NEAA-treated group, citrulline supplementation was associated with lower mortality (0% vs. 20%; P = 0.05), 9% higher lean body mass (P < 0.05), and 13% lower fat mass (P < 0.05). Compared with the NEAA- treated group, citrulline-treated rats had greater muscle mass (+14-48% depending on type of muscle;P < 0.05 for tibialis, gastrocnemius, and plantaris). Susceptibility to oxidation of lipoproteins, as measured by the maximal concentration of 7-ketocholesterol after copper-induced VLDL and LDL oxidation, was lower in citrulline-treated rats than in NEAA-treated rats (187 6 8 mmol/L vs. 243 6 7 mmol/L; P = 0.0005). Conclusions: Citrulline treatment in male aged rats favorably modulates body composition and protects against lipid oxidation and, thus, emerges as an interesting candidate to help prevent the aging process. JN utrdoi: 10.3945/jn.114.200626.