-
1.
Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): A prospective, randomized, double-blind study.
Ma, C, Tsai, H, Su, W, Sun, L, Shih, Y, Wang, J
Journal of postgraduate medicine. 2018;(3):155-163
-
-
Free full text
-
Abstract
BACKGROUND Perioperative enteral nutrition (EN) enriched with immune-modulating substrates is preferable for patients undergoing major abdominal cancer surgery. In this study, perioperative EN enriched with immune-modulating nutrients such as arginine, glutamine, and omega-3 fatty acids was evaluated for its anti-inflammatory efficacy in patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST) receiving curative surgery. MATERIALS AND METHODS This prospective, randomized, double-blind study recruited 34 patients with gastric adenocarcinoma or gastric GIST undergoing elective curative surgery. These patients were randomly assigned to the study group, receiving immune-modulating nutrient-enriched EN, or the control group, receiving standard EN from 3 days before surgery (preoperative day 3) to up to postoperative day 14 or discharge. Laboratory and inflammatory parameters were assessed on preoperative day 3 and postoperative day 14 or at discharge. Adverse events (AEs) and clinical outcomes were documented daily and compared between groups. RESULTS No significant differences were observed between the two groups in selected laboratory and inflammatory parameters, or in their net change, before and after treatment. AEs and clinical outcomes, including infectious complications, overall complications, time to first bowel action, and length of hospital stay after surgery, were comparable between treatment groups (all P > 0.05). CONCLUSION Immune-modulating nutrient-enriched EN had no prominent immunomodulation effect compared with that of standard EN.
-
2.
Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.
White, TL, Monnig, MA, Walsh, EG, Nitenson, AZ, Harris, AD, Cohen, RA, Porges, EC, Woods, AJ, Lamb, DG, Boyd, CA, et al
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2018;(7):1498-1509
-
-
Free full text
-
Abstract
Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.
-
3.
Serum glutamine and hospital-acquired infections after aneurysmal subarachnoid hemorrhage.
Badjatia, N, Cremers, S, Claassen, J, Connolly, ES, Mayer, SA, Karmally, W, Seres, D
Neurology. 2018;(5):e421-e426
-
-
Free full text
-
Abstract
OBJECTIVE To understand nutritional and inflammatory factors contributing to serum glutamine levels and their relationship to hospital-acquired infections (HAIs) after aneurysmal subarachnoid hemorrhage (SAH). METHODS A prospective observational study of patients with SAH who had measurements of daily caloric intake and C-reactive protein, transthyretin, tumor necrosis factor α receptor 1a (TNFαR1a), glutamine, and nitrogen balance performed within 4 preset time periods during the 14 days after SAH. Factors associated with glutamine levels and HAIs were analyzed with multivariable regression. HAIs were tracked daily for time-to-event analyses. Outcome 3 months after SAH was assessed by the Telephone Interview for Cognitive Status and modified Rankin Scale. RESULTS There were 77 patients with an average age of 55 ± 15 years. HAIs developed in 18 (23%) on mean SAH day 8 ± 3. In a multivariable linear regression model, negative nitrogen balance (p = 0.02) and elevated TNFαR1a (p = 0.04) were independently associated with higher glutamine levels during the study period. The 14-day mean glutamine levels were lower in patients who developed HAI (166 ± 110 vs 236 ± 81 μg/mL, p = 0.004). Poor admission Hunt and Hess grade (p = 0.04) and lower glutamine levels (p = 0.02) predicted time to first HAI. Low 14-day mean levels of glutamine were associated with a poor recovery on the Telephone Interview for Cognitive Status score (p = 0.03) and modified Rankin Scale score (p = 0.04) at 3 months after injury. CONCLUSIONS Declining glutamine levels in the first 14 days after SAH are influenced by inflammation and associated with an increased risk of HAI.
-
4.
Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion.
Takeuchi, Y, Nakayama, Y, Fukusaki, E, Irino, Y
Biochemical and biophysical research communications. 2018;(1):761-767
Abstract
Cancer cells rapidly consume glutamine as a carbon and nitrogen source to support proliferation, but the cell number continues to increase exponentially after glutamine is nearly depleted from the medium. In contrast, cell proliferation rates are strongly depressed when cells are cultured in glutamine-free medium. How cancer cells survive in response to nutrient limitation and cellular stress remains poorly understood. In addition, rapid glutamine catabolism yields ammonia, which is a potentially toxic metabolite that is secreted into the extracellular space. Here, we show that ammonia can be utilized for glutamate production, leading to cell proliferation under glutamine-depleted conditions. This proliferation requires glutamate dehydrogenase 2, which synthesizes glutamate from ammonia and α-ketoglutarate and is expressed in MCF7 and T47D cells. Our findings provide insight into how cancer cells survive under glutamine deprivation conditions and thus contribute to elucidating the mechanisms of tumor growth.
-
5.
Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial.
Javitt, DC, Carter, CS, Krystal, JH, Kantrowitz, JT, Girgis, RR, Kegeles, LS, Ragland, JD, Maddock, RJ, Lesh, TA, Tanase, C, et al
JAMA psychiatry. 2018;(1):11-19
-
-
Free full text
-
Abstract
IMPORTANCE Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate. OBJECTIVE To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. INTERVENTIONS Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. MAIN OUTCOMES AND MEASURES Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. RESULTS Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. CONCLUSIONS AND RELEVANCE These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02134951.
-
6.
Perioperative Nutritional Support With Beta-hydroxy-beta-methylbutyrate, Arginine, and Glutamine in Surgery for Abdominal Malignancies.
Wada, N, Kurokawa, Y, Tanaka, K, Miyazaki, Y, Makino, T, Takahashi, T, Wada, H, Yamasaki, M, Yamasaki, M, Nakajima, K, et al
Wounds : a compendium of clinical research and practice. 2018;(9):251-256
Abstract
UNLABELLED Although beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) may contribute to wound healing, no prospective studies have investigated the efficacy of a compound consisting of HMB, Arg, and Gln (HMB/Arg/Gln) for reducing wound complications following open abdominal surgery. OBJECTIVE This study evaluates the usefulness of perioperative nutrition using HMB/Arg/Gln in patients who were scheduled to undergo open surgery for abdominal malignancies in a randomized controlled trial. MATERIALS AND METHODS Patients scheduled for open surgery for abdominal malignancies were randomized to receive HMB/Arg/Gln (1.2 g HMB, 7 g L-Arg, and 7 g L-Gln) or placebo (isocaloric juice). The supplements were provided once daily for 3 days preoperatively and once daily for 7 days postoperatively. The primary endpoint was the incidence of wound complications. Secondary endpoints included the incidence of other complications, postoperative duration of hospital stay, total-body skeletal muscle mass, handgrip strength, and skin water content. RESULTS Sixty-one patients were randomly assigned to either the HMB/Arg/Gln (n = 31) or the placebo (n = 30) group. One patient in the HMB/Arg/Gln group was ineligible because laparoscopic surgery was performed; thus, 60 patients were analyzed. The incidence of wound complications (20%) was the same in both groups (P = 1.000). There were no significant differences in the incidence of other complications, body composition, handgrip strength, or skin water content between the 2 groups. Serum growth hormone (GH) levels were significantly higher for patients whose total intake was > 80% of planned volume in the HMB/Arg/Gln group. CONCLUSIONS The incidence of wound complications would not be reduced by perioperative HMB/Arg/Gln administration in patients who underwent open surgery. The efficacy of HMB/Arg/Gln for increasing serum GH levels needs to be validated in another large-scale randomized controlled trial.
-
7.
Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations.
El Ansari, R, McIntyre, A, Craze, ML, Ellis, IO, Rakha, EA, Green, AR
Histopathology. 2018;(2):183-190
Abstract
Cancer cells must alter their metabolism in order to satisfy the demands of necessary energy and cellular building blocks. These metabolic alterations are mediated by many oncogenic changes that affect cellular signalling pathways, which result in sustained cell growth and proliferation. Recently, metabolomics has received great attention in the field of cancer research, and as the essential metabolic pathways that drive tumour growth and progression are determined the possibilities of new targets for therapeutic intervention are opened. More specifically, as breast cancer is a heterogeneous disease, there is growing evidence that differences in metabolic changes exist between molecular subtypes. In this review, the most recent findings in breast cancer cell metabolism are discussed, with particular emphasis on glutamine and its transporters, which is considered one of the key amino acids fuelling cancer growth. Furthermore, the metabolic differences between the molecular subtypes of breast cancer are examined, highlighting the clinical utility for breast cancer diagnosis and treatment.
-
8.
Effects of a Carbohydrate-, Glutamine-, and Antioxidant-Enriched Oral Nutrition Supplement on Major Surgery-Induced Insulin Resistance: A Randomized Pilot Study.
van Stijn, MFM, Soeters, MR, van Leeuwen, PAM, Schreurs, WH, Schoorl, MG, Twisk, JWR, De Bandt, JP, Bonnefont-Rousselot, D, Cynober, L, Ackermans, MT, et al
JPEN. Journal of parenteral and enteral nutrition. 2018;(4):719-729
Abstract
BACKGROUND Insulin resistance after surgery hampers recovery. Oxidative stress is shown to be involved in the occurrence of postoperative insulin resistance. Preoperative carbohydrate-rich oral nutrition supplements reduce but do not prevent insulin resistance. The aim of the present study was to investigate the effect of a carbohydrate-, glutamine-, and antioxidant-enriched preoperative oral nutrition supplement on postoperative insulin resistance. METHODS A double-blind randomized controlled pilot study in 18 patients with rectal cancer, who received either the supplement (S) or the placebo (P) 15, 11, and 4 hours preoperatively, was conducted. Insulin sensitivity was studied prior to surgery and on the first postoperative day using a hyperinsulinemic euglycemic 2-step clamp. RESULTS Hepatic insulin sensitivity (insulin-mediated suppression of glucose production) decreased significantly after surgery in both groups, with no differences between the groups. Peripheral insulin sensitivity (glucose rate of disappearance, Rd) was significantly decreased after surgery in both groups (S: 37.2 [19.1-50.9] vs 20.6 [13.9-27.9]; P: 23.8 [15.7-35.5] vs 15.3 [12.6-19.1] µmol/kg·min) but less pronounced in the supplemented group (P = .04). The percentage decrease in glucose Rd did not differ between the groups. Adipose tissue insulin sensitivity (insulin-mediated suppression of plasma free fatty acids) decreased to the same extent after surgery in both groups. CONCLUSION Rectal cancer surgery induced profound insulin resistance, affecting glucose and fatty acid metabolism. The preoperative nutrition supplement somewhat attenuated but did not prevent postoperative peripheral insulin resistance.
-
9.
Effects of Glutamine on Gastric Emptying of Low- and High-Nutrient Drinks in Healthy Young Subjects-Impact on Glycaemia.
Du, YT, Piscitelli, D, Ahmad, S, Trahair, LG, Greenfield, JR, Samocha-Bonet, D, Rayner, CK, Horowitz, M, Jones, KL
Nutrients. 2018;(6)
Abstract
Glutamine is a potent stimulus for the release of glucagon-like peptide-1, which increases postprandial insulin and slows gastric emptying (GE). We determined the effects of glutamine on GE of, and glycaemic responses to, low- and high-nutrient drinks in eight healthy males (mean age 21.6 ± 0.7 years and BMI 22.9 ± 0.7 kg/m²). Participants were studied on four occasions on which they consumed either a low-nutrient (beef soup; 18 kcal) or high-nutrient (75 g dextrose; 255 kcal) drink, each with or without 30 g of glutamine (120 kcal), in a randomised, crossover design. GE (2D ultrasound), blood glucose and plasma insulin concentrations were measured concurrently. Glutamine slowed GE (half emptying time (T50)) of both low- (45 ± 3 min vs. 26 ± 2 min, p < 0.001), and high-nutrient, (100 ± 5 min vs. 77 ± 5 min, p = 0.03) drinks, however, there was no effect on GE of the high nutrient drinks when expressed as kcal/min (3.39 ± 0.21 kcal/min vs. 3.81 ± 0.20 kcal/min, p = 0.25). There was no change in blood glucose after the low-nutrient drinks with or without glutamine, despite a slight increase in plasma insulin with glutamine (p = 0.007). The rise in blood glucose following the high-nutrient drink (p = 0.0001) was attenuated during the first 60 min by glutamine (p = 0.007). We conclude that in healthy subjects, glutamine slows GE of both low- and high-nutrient drinks comparably and attenuates the rise in blood glucose after the high-nutrient glucose drink.
-
10.
Changes in spectroscopic biomarkers after transcranial direct current stimulation in children with perinatal stroke.
Carlson, HL, Ciechanski, P, Harris, AD, MacMaster, FP, Kirton, A
Brain stimulation. 2018;(1):94-103
Abstract
BACKGROUND Perinatal stroke causes lifelong motor disability, affecting independence and quality of life. Non-invasive neuromodulation interventions such as transcranial direct current stimulation (tDCS) combined with intensive therapy may improve motor function in adult stroke hemiparesis but is under-explored in children. Measuring cortical metabolites with proton magnetic resonance spectroscopy (MRS) can inform cortical neurobiology in perinatal stroke but how these change with neuromodulation is yet to be explored. METHODS A double-blind, sham-controlled, randomized clinical trial tested whether tDCS could enhance intensive motor learning therapy in hemiparetic children. Ten days of customized, goal-directed therapy was paired with cathodal tDCS over contralesional primary motor cortex (M1, 20 min, 1.0 mA, 0.04 mA/cm2) or sham. Motor outcomes were assessed using validated measures. Neuronal metabolites in both M1s were measured before and after intervention using fMRI-guided short-echo 3T MRS. RESULTS Fifteen children [age(range) = 12.1(6.6-18.3) years] were studied. Motor performance improved in both groups and tDCS was associated with greater goal achievement. After cathodal tDCS, the non-lesioned M1 showed decreases in glutamate/glutamine and creatine while no metabolite changes occurred with sham tDCS. Lesioned M1 metabolite concentrations did not change post-intervention. Baseline function was highly correlated with lesioned M1 metabolite concentrations (N-acetyl-aspartate, choline, creatine, glutamate/glutamine). These correlations consistently increased in strength following intervention. Metabolite changes were not correlated with motor function change. Baseline lesioned M1 creatine and choline levels were associated with clinical response. CONCLUSIONS MRS metabolite levels and changes may reflect mechanisms of tDCS-related M1 plasticity and response biomarkers in hemiparetic children with perinatal stroke undergoing intensive neurorehabilitation.