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Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.
Chatchatee, P, Nowak-Wegrzyn, A, Lange, L, Benjaponpitak, S, Chong, KW, Sangsupawanich, P, van Ampting, MTJ, Oude Nijhuis, MM, Harthoorn, LF, Langford, JE, et al
The Journal of allergy and clinical immunology. 2022;(2):650-658.e5
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Abstract
BACKGROUND Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.
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Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts.
Eveleens Maarse, BC, Loh, NY, Karpe, F, Rosendaal, FR, van Heemst, D, Mook-Kanamori, DO, Willems van Dijk, K, Rensen, PCN, Kooijman, S, Christodoulides, C, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(12):2252-2261
Abstract
BACKGROUND AND AIMS Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. METHODS AND RESULTS Cross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (β (SE) = 0.064 (0.018) SD per 5 °C, p = 5.03e-4) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e-05) and leucine (0.111 (0.018) SD, p = 1.25e-09). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (-0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e-6)). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. CONCLUSIONS Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.
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Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial.
Heianza, Y, Sun, D, Li, X, DiDonato, JA, Bray, GA, Sacks, FM, Qi, L
Gut. 2019;(2):263-270
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Abstract
OBJECTIVE Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention. DESIGN We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated. RESULTS Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids. CONCLUSION Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism. TRIAL REGISTRATION NUMBER NCT00072995.
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Reduced Plasma Amino Acid Levels During Allogeneic Hematopoietic Stem Cell Transplantation Are Associated with Systemic Inflammation and Treatment-Related Complications.
Weischendorff, S, Kielsen, K, Nederby, M, Schmidt, L, Burrin, D, Heilmann, C, Ifversen, M, Sengeløv, H, Mølgaard, C, Müller, K
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019;(7):1432-1440
Abstract
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged by cytotoxic effects of the conditioning regimen, resulting in tissue damage, systemic inflammation, and increased metabolic demands for amino acids to regenerate damaged tissues, reconstitute hematopoietic cells, and establish antioxidant defenses. To date, few studies have addressed the role of plasma amino acid (PAA) levels during transplantation, and it remains unknown if amino acid deficiency can aggravate treatment-related morbidity. We determined plasma levels of the 23 human amino acids in 80 HSCT recipients (age 1.1 to 55.4 years) before conditioning and on days +7 and +21 post-transplant along with C-reactive protein (CRP) and IL-6 levels on day +7. Significant changes were observed in plasma concentrations of several human amino acids during HSCT. On day +7, numerous amino acids were inversely correlated with both CRP and IL-6, including glutamic acid, serine, alanine, glutamine, arginine, cysteine, glycine, histidine, lysine, tryptophan, threonine, taurine, proline, and methionine (r = -.22 to -.66; all P < .05). Patients who developed sinusoidal obstruction syndrome (SOS) had significantly lower mean total PAA levels compared with patients without SOS (2013 ng/L [95% confidence interval (CI), 1709 to 2318 ng/L] versus 2706 ng/L [95% CI, 2261 to 3150 ng/L]; P = .006), along with lower individual levels of glutamic acid, serine, arginine, glycine, lysine, valine, tryptophan, threonine, and proline on day +7 (all P < .05). Patients with severe acute graft-versus-host disease had a lower mean total PAA level (1922 ng/L [95% CI, 1738 to 2106 ng/L] versus 2649 ng/L [95% CI, 2244 to 3055 ng/L]; P = .014) and lower levels of serine, glutamine, cysteine, glycine, lysine, and threonine on day +7 (all P < .05). These results indicate a relationship between low concentrations of certain amino acids and the risk of treatment-related complications.
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Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial.
Welsh, P, Rankin, N, Li, Q, Mark, PB, Würtz, P, Ala-Korpela, M, Marre, M, Poulter, N, Hamet, P, Chalmers, J, et al
Diabetologia. 2018;(7):1581-1591
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Abstract
AIMS/HYPOTHESES We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. METHODS We performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. RESULTS In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012). CONCLUSIONS/INTERPRETATION We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
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Amino Acid-based Formula in Cow's Milk Allergy: Long-term Effects on Body Growth and Protein Metabolism.
Canani, RB, Nocerino, R, Frediani, T, Lucarelli, S, Di Scala, C, Varin, E, Leone, L, Muraro, A, Agostoni, C
Journal of pediatric gastroenterology and nutrition. 2017;(4):632-638
Abstract
OBJECTIVES The long-term effects of amino acid-based formula (AAF) in the treatment of cow's milk allergy (CMA) are largely unexplored. The present study comparatively evaluates body growth and protein metabolism in CMA children treated with AAF or with extensively hydrolyzed whey formula (eHWF), and healthy controls. METHODS A 12-month multicenter randomized control trial was conducted in outpatients with CMA (age 5-12 m) randomized in 2 groups, treated with AAF (group 1) and eHWF (group 2), and compared with healthy controls (group 3) fed with follow-on (if age <12 months) or growing-up formula (if age >12 months). At enrolment (T0), after 3 (T3), 6 (T6), and 12 months (T12) a clinical evaluation was performed. At T0 and T3, in subjects with CMA serum levels of albumin, urea, total protein, retinol-binding protein, and insulin-like growth factor 1 were measured. RESULTS Twenty-one subjects in group 1 (61.9% boys, age 6.5 ± 1.5 months), 19 in group 2 (57.9% boys, age 7 ± 1.7 months) and 25 subjects in group 3 (48% boys, age 5.5 ± 0.5 months) completed the study. At T0, the weight z score was similar in group 1 (-0.74) and 2 (-0.76), with differences compared to group 3 (-0.17, P < 0.05). At T12, the weight z score value was similar between the 3 groups without significant differences. There were no significant changes in protein metabolism in children in groups 1 and 2. CONCLUSION Long-term treatment with AAF is safe and allows adequate body growth in children with CMA.
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Amino acids intake and physical fitness among adolescents.
Gracia-Marco, L, Bel-Serrat, S, Cuenca-Garcia, M, Gonzalez-Gross, M, Pedrero-Chamizo, R, Manios, Y, Marcos, A, Molnar, D, Widhalm, K, Polito, A, et al
Amino acids. 2017;(6):1041-1052
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The aim was to investigate whether there was an association between amino acid (AA) intake and physical fitness and if so, to assess whether this association was independent of carbohydrates intake. European adolescents (n = 1481, 12.5-17.5 years) were measured. Intake was assessed via two non-consecutive 24-h dietary recalls. Lower and upper limbs muscular fitness was assessed by standing long jump and handgrip strength tests, respectively. Cardiorespiratory fitness was assessed by the 20-m shuttle run test. Physical activity was objectively measured. Socioeconomic status was obtained via questionnaires. Lower limbs muscular fitness seems to be positively associated with tryptophan, histidine and methionine intake in boys, regardless of centre, age, socioeconomic status, physical activity and total energy intake (model 1). However, these associations disappeared once carbohydrates intake was controlled for (model 2). In girls, only proline intake seems to be positively associated with lower limbs muscular fitness (model 2) while cardiorespiratory fitness seems to be positively associated with leucine (model 1) and proline intake (models 1 and 2). None of the observed significant associations remained significant once multiple testing was controlled for. In conclusion, we failed to detect any associations between any of the evaluated AAs and physical fitness after taking into account the effect of multiple testing.
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Amino acids in a targeted versus a non-targeted metabolomics LC-MS/MS assay. Are the results consistent?
Klepacki, J, Klawitter, J, Klawitter, J, Karimpour-Fard, A, Thurman, J, Ingle, G, Patel, D, Christians, U
Clinical biochemistry. 2016;(13-14):955-61
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BACKGROUND The results of plasma amino acid patterns in samples from kidney transplant patients with good and impaired renal function using a targeted LC-MS/MS amino acid assay and a non-targeted metabolomics assay were compared. METHODS EDTA plasma samples were prospectively collected at baseline, 1, 2, 4 and 6months post-transplant (n=116 patients, n=398 samples). Each sample was analyzed using both a commercial amino acid LC-MS/MS assay and a non-targeted metabolomics assay also based on MS/MS ion transitions. The results of both assays were independently statistically analyzed to identify amino acids associated with estimated glomerular filtration rates using correlation and partial least squares-discriminant analysis. RESULTS Although there was overlap between the results of the targeted and non-targeted metabolomics assays (tryptophan, 1-methyl histidine), there were also substantial inconsistencies, with the non-targeted assay resulting in more "hits" than the targeted assay. Without further verification of the hits detected by the non-targeted discovery assay, this would have led to different interpretation of the results. There were also false negative results when the non-targeted assay was used (hydroxy proline). Several of said discrepancies could be explained by loss of sensitivity during analytical runs for selected amino acids (serine and threonine), retention time shifts, signals above the range of linear detector response and integration of peaks not separated from background and interferences (aspartate) when the non-targeted metabolomics assay was used. CONCLUSIONS Whenever assessment of a specific pathway such as amino acids is the focus of interest, a targeted seems preferable to a non-targeted metabolomics assay.
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Weight-loss diets and 2-y changes in circulating amino acids in 2 randomized intervention trials.
Zheng, Y, Ceglarek, U, Huang, T, Li, L, Rood, J, Ryan, DH, Bray, GA, Sacks, FM, Schwarzfuchs, D, Thiery, J, et al
The American journal of clinical nutrition. 2016;(2):505-11
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BACKGROUND Circulating amino acids, such as branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), have been associated with diabetes risk; however, little is known about how a long-term dietary intervention for weight loss affects circulating amino acids. OBJECTIVES We examined the effects of weight-loss diets on long-term changes in plasma amino acids and the associations of these changes with weight loss and the improvement of insulin resistance. DESIGN We repeatedly measured plasma amino acid profiles over 2 y in overweight or obese participants from 2 randomized, dietary intervention, weight-loss trials [774 subjects from the POUNDS LOST (Preventing Overweight Using Novel Dietary Strategies Trial) and 318 subjects from the DIRECT (Dietary Intervention Randomized Controlled Trial)]. RESULTS Intervention diets consistently lowered most of the amino acid concentrations, including BCAAs and AAAs, in both trials. In the POUNDS LOST, average-protein diets (15% of daily energy) showed stronger effects than did high-protein diets (25% of daily energy) on reducing concentrations of the diabetes-associated BCAA valine at 6 mo independent of the weight change. In both trials, weight loss was directly related to the concurrent reduction of the BCAAs leucine and isoleucine, the AAAs tyrosine and phenylalanine, and 4 other amino acids. For example, per kilogram of weight loss, there was a 0.04-SD decrease in log tyrosine (∼0.6 μmol/L) in both trials. In addition, we showed that reductions in alanine and the AAA tyrosine were significantly related to improved insulin resistance (measured with the use of the homeostasis model assessment of insulin resistance), independent of weight loss, in both trials (both P < 0.05). For example, per 1-SD decrease in log tyrosine (∼17 μmol/L), there was a 0.04-SD (∼3%) improvement in insulin resistance in the POUNDS LOST and a 0.13-SD (∼8%) improvement in insulin resistance in the DIRECT. CONCLUSION Our findings underscore the potential importance of dietary interventions in improving amino acid profiles (i.e., reducing diabetes risk-enhancing amino acid concentrations) along with and beyond weight loss. The POUNDS LOST and the DIRECT were registered at clinicaltrials.gov as NCT00072995 and NCT00160108, respectively.
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Cerebrolysin combined with rehabilitation promotes motor recovery in patients with severe motor impairment after stroke.
Chang, WH, Park, CH, Kim, DY, Shin, YI, Ko, MH, Lee, A, Jang, SY, Kim, YH
BMC neurology. 2016;:31
Abstract
BACKGROUND Cerebrolysin is a neuropeptide preparation with neuroprotective and neurorestorative effects. Combining Cerebrolysin treatment with a standardized rehabilitation program may have a potential synergistic effect in the subacute stage of stroke. This study aims to evaluate whether Cerebrolysin provides additional motor recovery on top of rehabilitation therapy in the subacute stroke patients with moderate to severe motor impairment. METHODS This phase IV trial was designed as a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. A total of 70 patients (Cerebrolysin n = 35, placebo n = 35) with moderate to severe motor function impairment were included within 7 days after stroke onset and were randomized to receive a 21-day treatment course of either Cerebrolysin or placebo, given in addition to standardized rehabilitation therapy. Assessments were performed at baseline, immediately after treatment as well as 2 and 3 months after stroke onset. The plasticity of motor system was assessed by diffusion tensor imaging and with resting state functional magnetic resonance imaging. RESULTS Both groups demonstrated significant improvement in motor function (p < 0.05); however, no significant difference was found between the two groups. In the stroke patients with severe motor impairment, the Cerebrolysin group exhibited significantly more improvement in motor function compared with the placebo group (p < 0.05). Effects of Cerebrolysin were demonstrated as restricted increments of corticospinal diffusivity and as recovery of the sensorimotor connectivity. CONCLUSION The combination of standard rehabilitation therapy with Cerebrolysin treatment in the subacute stroke has shown additional benefit on motor recovery and plastic changes of the corticospinal tract in patients with severe motor impairment. TRIAL REGISTRATION NCT01996761 (November 5, 2013).