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BACKGROUND: Anxiety disorders (AnxDs) are highly prevalent and often untreated or unresponsive to treatment. Although proton magnetic resonance spectroscopy (1H-MRS) studies of AnxDs have been conducted for over 25 years, a consensus regarding neurometabolic abnormalities in these conditions is lacking. METHODS: A systematic review and meta-analysis of 1H-MRS studies of AnxDs (social anxiety disorder, generalized anxiety disorder, and panic disorder) identified 25 published datasets meeting inclusion criteria. These compared neurometabolites between 370 patients and 342 controls, including n-acetlyaspartate (NAA), total creatine, total choline (tCho), myo-inositol, glutamate, glutamate+glutamine, GABA, and lactate. RESULTS: Across AnxDs, tCho was significantly reduced in prefrontal cortex and across all cortical regions. Effect sizes for cortical tCho were significantly more negative in studies with better measurement quality, with Hedges' g = -0.64 and an 8% mean reduction. NAA was unchanged in prefrontal cortex but reduced across all cortical regions (after exclusions). These abnormalities did not differ between the three disorders. No other neurometabolites differed significantly. DISCUSSION: Reduced choline-containing compounds in cortical regions is a consistent, transdiagnostic abnormality in AnxDs. Notably, arousal-related neuromodulators, including norepinephrine, alter membrane phospholipid homeostasis and methylation reactions, which influence brain tCho levels. This suggests that chronically elevated arousal in AnxDs may increase neurometabolic demand for choline compounds without a proportionate increase in brain uptake, leading to reduced tCho levels. Reduced cortical NAA suggests compromised neuronal function in AnxDs. Future studies may clarify the clinical significance of reduced cortical tCho and the possibility that appropriate choline supplementation could have therapeutic benefit in anxiety disorders. © 2025. The Author(s).

Peripartum supplementation of rumen-protected choline has been shown to improve cow health and milk production by improving liver function through a reduction in hepatic lipidosis. However, the optimal dose range remains undetermined. To evaluate the effects of supplemented choline chloride on lactation performance and health of dairy cows, a systematic review and dose-response meta-analysis were conducted. This meta-analysis followed the preferred reporting items for systematic reviews and meta-analyses guidelines and used the population (dairy cows), intervention (choline supplementation), comparison (control group vs. choline supplementation), and outcome framework to select studies on dairy cows supplemented with choline. A total of 30 studies from 19 articles and 1 dissertation, identified through Web of Science, Scopus, Google Scholar, and PubMed, were included. The analysis focused on DMI, milk yield and composition, BW, and BCS. Study quality and risk of bias were evaluated using systematic review center for laboratory animal experimentation's risk of bias tool. A 1-stage random-effects meta-analysis with a restricted cubic spline model was employed to assess dose-response relationships, with REML used for variance estimation. Subgroup and sensitivity analyses were performed to address heterogeneity and robustness, and publication bias was assessed using funnel plots and adjusted with the trim-and-fill method. This meta-analysis showed the significant effects of choline supplementation on intake and lactation performance of dairy cows. Optimal DMI was reached at 13 to 14 g/d, resulting in an increase of 0.48 kg/d (95% CI: 0.10, 0.87), whereas milk yield peaked at 13 g/d, with an increase of 1.29 kg/d (95% CI: 0.17, 2.41). A significant dose-response relationship for 3.5% FCM yield was observed across 21 trials, with efficacy significantly increasing steadily between 15 and 21 g/d, and a predicted mean difference of 2.19 kg/d at 21 g/d (95% CI: 0.48-3.90). Milk fat yield increased significantly by 0.09 kg/d at a dose of 24 g/d (95% CI: 0.01, 0.17), whereas milk protein yield improved significantly in the 13 to 20 g/d range despite considerable heterogenei

BACKGROUND: Alcohol impairs early cognitive development, especially in utero exposures. Nutrient supplementation may avert some of its consequences. OBJECTIVE: We reviewed whether prenatal and postnatal choline supplementation could improve neurocognitive development in children of alcohol-exposed pregnancies. METHODS: A systematic literature search was conducted in Medline, Embase, and Cochrane Library databases to identify randomized controlled trials published up to May 01, 2024. Data were analyzed using Standardized Mean Difference (SMD) with 95 % Confidence Intervals (CI) and a random-effects model. Sensitivity analyses and the posterior probability of benefit (Pr) were calculated using a Bayesian Markov chain Monte Carlo model. RESULTS: Five trials were included in this review. Prenatal supplementation likely benefits memory (SMD 0.61, 95 % CI 0.19 to 1.02; Pr(SMD>0) = 96.29 %; I2 = 0 %; 2 trials; 94 participants; moderate-certainty evidence). Postnatal supplementation may improve global cognition (SMD 0.78, 95 % CI 0.21 to 1.34; Pr(SMD>0) = 96.94 %; I2 = 13 %; 2 trials; 62 participants; low-certainty evidence) and a small benefit to attention was only demonstrated in the Bayesian analysis (postnatal: SMD 0.44, 95 % CI -0.73 to 1.61; Pr(SMD>0) = 91.80 %; I2 = 84 %; 2 trials; 83 participants; low-certainty evidence). CONCLUSION: Supplementation of choline in either period could benefit neurocognitive development in children of heavy-drinking mothers. REGISTRATION: CRD42024537733 (PROSPERO).

BACKGROUND: DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear. OBJECTIVES: The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation. METHODS: A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation. RESULTS: Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as "high risk" or "some concerns." Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significa

BACKGROUND: Cognitive impairment is a staggering personal and societal burden; accordingly, there is a strong interest in potential strategies for its prevention and treatment. Nutritional supplements have been extensively investigated, and citicoline seems to be a promising agent; its role in clinical practice, however, has not been established. We systematically reviewed studies on the effect of citicoline on cognitive performance. METHODS: We searched the PubMed and Cochrane Library databases for articles published between 2010 and 2022. Relevant information was extracted and presented following the PRISMA recommendations. Data were pooled using the inverse-variance method with random effects models. RESULTS: We selected seven studies including patients with mild cognitive impairment, Alzheimer's disease or post-stroke dementia. All the studies showed a positive effect of citicoline on cognitive functions. Six studies could be included in the meta-analysis. Overall, citicoline improved cognitive status, with pooled standardized mean differences ranging from 0.56 (95% CI: 0.37-0.75) to 1.57 (95% CI: 0.77-2.37) in different sensitivity analyses. The overall quality of the studies was poor. DISCUSSION: Available data indicate that citicoline has positive effects on cognitive function. The general quality of the studies, however, is poor with significant risk of bias in favor of the intervention. Other: PubMed and the Cochrane Library.

We studied associations between prenatal and early postnatal choline intake, brain development, and neurocognitive function of children. We conducted a systematic review followed by a meta-analysis and critical appraisal of human studies published from 1997 to 2021. Thirty publications were identified. The meta-analysis included 5 of 7 case-control studies studying neural tube defects (NTDs) in relation to maternal choline intakes/circulating concentrations. Low maternal choline intake/circulating concentrations were associated with a higher OR for NTDs among 1131 mothers of newborns with NTDs and 4439 control mothers (pooled estimate = 1.36; 95% CI: 1.11, 1.67). The 95% prediction intervals were 0.78, 2.36. Findings and critical evaluation of 10 publications with interventional designs showed that higher maternal choline intakes during the second half of pregnancy and early postnatal period (550 mg up to 1 g/d on top of the diet) or a child intake of 513 to 625 mg/d from supplements were safe and likely to demonstrate favorable effects on several domains of child neurocognition, such as memory, attention, and visuospatial learning versus the comparators. Findings from observational studies (n = 13) partly supported the association between maternal choline intake/serum concentrations and child neurocognition, but there was low confidence in the use of plasma choline concentrations as a choline intake marker. In conclusion, low maternal choline intakes were associated with a higher OR for NTDs. The risk could be up to 2.36-fold in some populations. Despite limitations of available trials and observational studies, higher maternal choline intake was likely to be associated with better child neurocognition/neurodevelopment. The results should be used to guide choline intake recommendations in pregnancy and lactation, especially because most young women are not achieving the reference intake of choline. This meta-analysis is registered at PROSPERO as CRD42021233790. © The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE: This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". METHODS: The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION: This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.

Erratum in J Dairy Sci. 2024 Mar;107(3):1825. doi: 10.3168/jds.2024-107-3-1825. The objectives were to use meta-analytic methods to determine the effects of amount of supplemental choline ion as rumen-protected choline (RPC) starting prepartum on production and health of dairy cows. The literature was systematically reviewed and 21 experiments, with up to 66 treatment means and 1,313 prepartum parous cows, were included. All experiments had a treatment with no supplemental choline (0 g/d; n = 30 treatment means), and the amount of choline ion supplemented to treated cows ranged from 5.6 to 25.2 g/d (n = 36 treatment means). Duration of pre- and postpartum feeding of RPC averaged (±standard deviation) 22.0 ± 6.0 and 57.5 ± 42.2 d, respectively. Data collected included the ingredient composition and chemical analyses of pre- and postpartum diets, amount of choline ion supplemented, number of cows per treatment, frequency of health events, and the least squares means and respective standard error of the means for production responses, liver composition, and blood parameters. The concentrations of net energy for lactation and metabolizable amino acids and protein (MP) in pre- and postpartum diets were predicted for each treatment mean using National Research Council (2001). Mixed model meta-analysis was conducted including the random effect of experiment and weighting by the inverse of the standard error of the means squared. Increasing supplementation of choline ion during transition linearly increased pre- (β = 0.0184 ± 0.00425) and postpartum dry matter intake (β = 0.0378 ± 0.00974), and yields of milk (β = 0.436 ± 0.112), energy-corrected milk (ECM; β = 0.422 ± 0.0992), fat (β = 0.00555 ± 0.000793), and protein (β = 0.0138 ± 0.00378). Nevertheless, an interaction between choline and postpartum metabolizable methionine as a percent of MP (METMPPo) was observed for yields of milk, ECM, and protein because as METMPPo increased, the positive response to choline on yields of milk, ECM, and protein decreased. Supplementing choline during transition tended to reduce the risks of retained placenta and mastitis, but it had no effect on metritis, milk fever, displaced ab

A number of human and animal in vitro or in vivo studies have investigated the relationship between dietary choline and betaine and cancer risk, suggesting that choline and betaine consumption may be protective for cancer. There are also a few epidemiologic studies exploring this relationship, however, with inconsistent conclusions. The PubMed and Embase were searched, from their inception to March 2016, to identify relevant studies and we brought 11 articles into this meta-analysis eventually. The pooled relative risks (RRs) of cancer for the highest versus the lowest range were 0.82 (95% CI, 0.70 to 0.97) for choline consumption only, 0.86 (95%CI, 0.76 to 0.97) for betaine consumption only and 0.60 (95%CI, 0.40 to 0.90) for choline plus betaine consumption, respectively. Significant protective effect of dietary choline and betaine for cancer was observed when stratified by study design, location, cancer type, publication year, sex and quality score of study. An increment of 100 mg/day of choline plus betaine intake helped reduce cancer incidence by 11% (0.89, 95% CI, 0.87 to 0.92) through a dose-response analysis. To conclude, choline and betaine consumption lowers cancer incidence in this meta-analysis, but further studies are warranted to verify the results.

Research studies presented inconsistent results on the effects and action of choline in dairy cow diets. A meta-analysis was conducted to quantify the effects of dietary rumen-protected choline on production characteristics of dairy cows. Dry matter intake (kg/d), milk yield (kg/d), milk fat (% and kg/d), and milk protein (% and kg/d) were evaluated as dependent variables in models. The number of treatment means varied from 20 obtained in 7 studies for milk fat and protein contents to 34 from 11 studies (12 experiments) for milk yield. Accounting for experiment as a random effect, DMI, milk yield, milk protein content, and milk protein yield could adequately be related to levels of dietary rumen-protected choline chloride by a logistic model. Marginal responses in milk yield decreased from 131.5 to 0.037 g of milk/g of dietary rumen-protected choline chloride when supplementation increased from 6 to 50 g/d. From estimated values for the metabolizable Met supplied by diets, it appears that dietary rumen-protected choline chloride functions as a methyl donor to spare Met for milk protein synthesis. However, more accurate input data on Met status of diets are needed to confirm this. Within the range of 6 to 50 g/d of rumen-protected choline chloride, milk fat content decreased linearly at a rate of 0.00339% for a 1g/d increase in dietary rumen-protected choline chloride. This illustrates that dietary rumen-protected choline chloride has no effect on milk fat content. Numerous physiological and dietary factors probably related to responses obtained with dietary rumen-protected choline supplementation, and the precise mechanism of choline action in the lactating dairy cow warrants further investigation. Copyright (c) 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

BACKGROUND: Choline is an essential nutrient, and insufficient intake negatively affects the liver, brain, and muscles. In the United States, habitual choline intake remains below the adequate intake (AI). To date, no circulating metabolites have been validated to distinguish between low and adequate choline intake. OBJECTIVES: We tested whether plasma concentrations of choline and its metabolites could discriminate adequate compared with low dietary choline intake and whether liver elastography (FibroScan) could detect diet-induced changes in liver fat. METHODS: In a double-blind, randomized, crossover feeding study, participants followed three 15-d dietary arms providing ∼100%, 50%, and 25% of the choline AI in the form of choline chloride. On day 12 of each dietary arm, participants consumed a single bolus of 2.2 mmol trimethyl-d9-choline. Targeted assays quantified plasma choline, betaine, phosphatidylcholine (PtdCho), and total homocysteine (tHcy) concentrations. Liver fat content was measured using FibroScan. RESULTS: Plasma concentrations of d9-choline, betaine, and their isotopic enrichment ratio (IER) varied with dietary intake (q < 0.0001), and PtdCho IER also differed significantly (q = 0.001). In targeted analysis, choline and betaine concentrations were highly responsive to dietary choline intake, whereas PtdCho and tHcy were not. Compared with the 100% AI arm, plasma choline was lower in the 25% AI arm [β= -2.20, 95% confidence interval (CI): -2.72, -1.68]. Receiver operator characteristic analysis showed strong discrimination for plasma choline [area under the curve (AUC) = 0.81, 95% CI: 0.74, 0.88], and betaine (AUC = 0.80, 95% CI: 0.73, 0.88), with improved discrimination when combined (AUC = 0.85, 95% CI: 0.79, 0.91). Fibroscan identified a subset of participants with increased liver fat in response to the 25% AI compared with 100% AI choline diet, though patterns varied among individuals. CONCLUSIONS: Plasma choline and betaine concentrations discriminate low compared with AI under controlled feeding. These findings support targeted metabolite profiling to improve choline intake assessment and reveal individual differences in liver response to

Background/Objectives: Choline plays an important role in maintaining normal cellular function and overall physiology. Endogenous choline availability depends on the synthesis of phosphatidylcholine via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway. Expression of PEMT is influenced by estrogen, as its promoter contains multiple estrogen-responsive elements that enhance enzyme activity. How a low estrogenic condition like menopause influences choline's effect on the brain is not yet fully understood. Methods: In this pilot study, 20 women participated in two study days, with 1650 mg of oral choline bitartrate or a matching placebo administered three hours before a functional and structural magnetic resonance imaging (MRI) scan. Blood oxygen level dependent (BOLD) functional MRI scans were collected on each study day while subjects performed an N-back working memory task. Results: In this pilot study, no differences in working memory performance were observed, but decreased activation was found for the choline compared to the placebo during the 2-back compared to 0-back conditions in regions of the right temporal lobe (p < 0.001 voxel-level threshold, and p-FDR < 0.05 cluster-size threshold). When we seeded the right planum temporale to examine its functional connectivity with the rest of the brain, we found that choline modulated a large portion of the working memory network during the difficult memory load condition. Conclusions: These results in this pilot study illustrate the effect of choline on working memory-related brain activation and functional connectivity in postmenopausal women. We propose that choline may increase brain functional efficiency in low estrogenic conditions like menopause, but further studies are needed.

BACKGROUND: The randomized controlled multicentre APACH2 trial showed that first-line [18F]F-choline (FCH1) PET/CT is superior to [99mTc]Tc-sestaMIBI (MIBI1) SPECT/CT for referring patients with primary hyperparathyroidism (pHPT) to effective minimally invasive parathyroidectomy (MIP). The aim of this study was to weigh this clinical gain against the increase in imaging costs. METHODS: The effectiveness criterion per imaging strategy was the rate of normocalcemia at one month post true-positive first-line imaging-guided MIP. The medico-economic analysis, carried out from the payer's perspective, integrated direct hospital costs up to 6 months after randomization. The result of the cost-effectiveness analysis was calculated in the form of an incremental cost-effectiveness ratio (ICER), establishing the average cost necessary to cure an additional person by switching from the usual MIBI1 strategy to the new FCH1 strategy. Sensitivity analyses were used to test the robustness of the ICER. RESULTS: The APACH2 trial enrolled 57 patients from November 2019 to May 2022 in four centres, randomized between FCH1 (n = 29) or MIBI1 (n = 28). The differential cost between FCH1 and MIBI1 strategies was €136.5 (average cost FCH1 €3,843.5 (95% CI: 3442.5-4244.5) vs MIBI1 €3,707.0 (95% CI: 3606.9- 3807.6), p = 0.53), with a differential effectiveness of 29% (average effectiveness FCH1 85% (95% CI: 0.71-0.99) vs MIBI1 56% (95% CI: 0.36-0.76), p = 0.037). The ICER of FCH1 compared to MIBI1 was €471 for referring one additional patient to MIP followed by normocalcemia. Deterministic sensitivity analysis showed ICER to vary from €-567 to €1,507. The probabilistic sensitivity analysis showed the robustness of our finding that the FCH1 strategy is slightly more expensive but also more effective than the MIBI1 strategy. CONCLUSION: First-line FCH PET/CT in the surgical management of pHPT allows more patients to be referred directly to successful outpatient MIP at a minimal additional cost from a health insurance point of view. © 2025. The Author(s).

PURPOSE: The aim of the MultiVeg study, a double-blind, randomised controlled trial (RCT), was to investigate the nutritional status of healthy vegans following 4 months of multinutrient supplementation. METHODS: A double-blind, RCT was conducted with 72 vegan adults (19-57 years) in Germany. Data on anthropometric parameters, dietary nutrient intake, and nutritional status were collected. The nutritional status of the participants was assessed at baseline and after 4 months. The results were compared between groups using ANCOVA. The results for vitamins and choline are presented here. RESULTS: After adjustment for baseline values, age, sex, and multiple testing, no significant between-group differences in biomarker concentration changes from baseline to 4 months were observed for vitamin A, retinol-binding protein, transthyretin, beta-carotene, methylmalonic acid, homocysteine, choline, total osteocalcin, carboxylated and undercarboxylated osteocalcin, and folate. In contrast, significant between-group differences in changes were observed for flavin adenine dinucleotide (FAD), serum vitamin B12, holotranscobalamin, and the combined vitamin B12 status indicator (cB12) after adjustment. CONCLUSION: A multinutrient supplement containing 82 µg of vitamin B12 per day significantly positively affected vitamin B12 blood biomarkers in healthy vegans. REGISTRATION: This study was registered in the German Clinical Trials Register (DRKS00028151). © 2025. The Author(s).

BACKGROUND/OBJECTIVES: Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite from L-carnitine and choline (abundant in meat and eggs), is linked to CVD and T2D. This study investigated whether TMAO responses to animal-based foods differ between individuals with and without metabolic syndrome (MetS), in relation to their gut microbiota composition. SUBJECTS/METHODS: In a randomized crossover trial, 12 MetS (≥3 criteria according to the Adult Treatment Panel III: elevated waist circumference, fasting glucose, triglycerides, and blood pressure or reduced HDL cholesterol) and 21 non-MetS subjects consumed two test meals (3 hard-boiled eggs or 170 g meat balls) after overnight fasting, with ≥1-week washout. Blood was collected at baseline and 0.5, 1, 2, 4, and 6 h postprandially; urine was collected over 6 h. Fecal samples (collected pre-first day of intervention) underwent 16S rRNA sequencing. Plasma and urinary TMAO, TMA, choline, and carnitine were quantified using UPLC-MS/MS. RESULTS: MetS subjects exhibited a non-significant trend towards higher incremental AUCs for plasma TMA, TMAO, choline, and carnitine after consuming both foods, with a 30-50% higher urinary TMAO excretion (but similar for TMA) versus non-MetS subjects. This exploratory analysis also indicated that MetS subjects had reduced gut microbial diversity, featuring decreased Blautia glucerasea (butyrate producer) and increased Ruminococcus torques (pro-inflammatory), a profile associated with inflammation but not TMA production. CONCLUSION: No significant increase in plasma methylamines after choline and carnitine challenge was observed in subjects with MetS compared with non-MetS. In MetS subjects (without CVD and T2D), gut microbiota composition was characterized by increased pro-inflammatory bacteria rather than TMAO-generating bacteria. The lack of statistical significance with regard to plasma TMAO response could be due to an insufficient sample size rather than the absence of an effect. Nevertheless, the observed elevation might still be clinically relevant, supported by concurrent differences in microbiota composition. These preliminary findings warrant validation in larger coho

BACKGROUND/OBJECTIVES: Vitamin C plays a vital role in human health, functioning as a powerful antioxidant and enzymatic cofactor. Although vitamin C bioavailability from food versus supplements has been debated, few studies have examined how intake form affects absorption and physiological markers. METHODS: This randomized, controlled, crossover trial aimed to compare the bioavailability of vitamin C consumed as a supplement, through raw fruits and vegetables, or through fruit and vegetable juice. Twelve healthy adults underwent three 1-day crossover trials, each separated by a 2-week washout. Participants consumed 101.7 mg of vitamin C via powder, raw fruits and vegetables (186.8 g), or juice (200 mL). Plasma and urinary vitamin C concentrations, urinary metabolites (1H NMR), and antioxidant activity (ORAC and TRAP) were assessed over 24 h. RESULTS: All interventions elevated plasma vitamin C levels, with juice yielding the highest AUC (25.3 ± 3.2 mg/dL·h). Urinary vitamin C increased in all groups. Metabolomics revealed increased urinary excretion of mannitol, glycine, taurine, dimethylglycine (DMG), and asparagine, and decreased choline and dimethylamine (DMA). Notably, urinary mannitol increased only in the morning. Choline significantly decreased after powder intake (p = 0.001), with similar trends observed in the other groups. DMG and glycine increased following raw and juiced vegetable intake. Antioxidant activity showed transient ORAC elevation post-powder but no sustained improvements. CONCLUSIONS: Vitamin C is bioavailable from all intake forms, with juice providing the most efficient absorption. Urinary metabolite changes suggest microbiota-related modulation, while antioxidant activity improvements were limited.

Objective: The metabolite trimethylamine N-oxide (TMAO) is a biomarker influenced by diet and linked to atherosclerosis, thrombosis, and cardiovascular disease (CVD). Choline is a crucial nutrient involved in maintaining cell structure, promoting liver health, and neurotransmission. However, human evidence is limited whether cocoa extract (CE) changes TMAO and choline levels over time. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized, placebo-controlled, 2 × 2 factorial trial testing a CE supplement (containing 500 mg d-1 flavanols) and a daily multivitamin for chronic disease prevention in 21 442 older adults. We conducted a pilot study of the impact of CE on 1 year changes in TMAO and choline in COSMOS participants to facilitate sample size calculations for larger analyses of this trial in the future. In a pilot intention to treat analyses, linear mixed effect models were used to explore serum TMAO and choline trajectories in relation to CE assignment, adjusting for age, sex, and the other randomization arm. Methods: We randomly selected 40 COSMOS participants with blood samples at baseline and year 1. TMAO and choline were measured in plasma samples by liquid chromatography with stable isotope dilution tandem mass spectrometry. We excluded 3 of 40 participants due to extreme TMAO values ≥32.9 μM. Results: The mean age at baseline was 77 ± (5.5) years, and 18 (48.7%) were female. Randomization successfully distributed baseline demographic, clinical, behavioral, and dietary characteristics by treatment group. Among the 37 COSMOS participants, those assigned to take a CE supplement, as compared to placebo, had similar TMAO and choline levels at baseline but showed trends toward lower levels of TMAO (-0.60 [95% CI, (-3.76, 2.55)]) at 1 year. However, the between-group differences in the 1 year changes in TMAO (CE minus placebo) were not statistically significant (-1.16 [95% CI, (-5.81, 3.50)]; P = 0.62). In contrast, the group assigned CE showed trends toward higher levels of choline (0.84 (-1.57, 3.25)) at year 1, but the between-group differences in the 1 year changes in choline were again not statistically significant (2.23 [95% CI

Traumatic brain injury (TBI) is a global health problem. Amantadine and citicoline showed considerable effects on neurorecovery from TBI. In a randomized controlled trial, the effects of amantadine and citicoline and their combinations were compared on arousal and behavioral consequences in the early phase of moderate TBI. Patients were divided into three groups (15 patients each) with moderate TBI; group C (citicoline) received 1 g citicoline every 12 h for 7 days. Participants received 500 mg oral drops syrup twice a day or the same dose as oral drops syrup of citicoline through a nasogastric tube (NG) or percutaneous endoscopic gastrostomy (PEG) tube in a total dose of 1000 mg/day for a 30-day study period. Group A (amantadine) received 200 mg of amantadine sulfate in a 500 mL solution every 12 h for 7 days. Participants received two 100-mg tablets twice a day or through an NG or PEG tube as 400 mg for a 30-day study period. Group CA (Citicoline + Amantadine) received 1 g citicoline every 12 h and 200 mg of amantadine sulfate in a 500 mL solution every 12 h for 7 days, then 500 mg of citicoline syrup twice daily plus 200 tablets twice daily amantadine for a 30-day study period. Glasgow Coma Scale (GCS), Disability Rating Scale (DRS), and mini-mental state (MMS) were used to assess the patient's conditions on the 1st, 4th, and 7th days (acute phase) in the intensive care unit (ICU), then 30 days after injury. The endpoints of the study were either the death of the patient or the completion of the study period of 30 days. The number of mechanically ventilated patients, the number of ventilated days, mortality, total ICU, and hospital length of stay were measured. GCS on days 4, 7, and 30 were significantly higher in group A and group CA compared with group C, with no significant differences between groups A and CA. DRS in days 4 and 7 became significantly lower in groups A and CA compared with group C, with no significant differences between groups A and CA. MMS in days 4, 7, and 30 became significantly lower in group C, with no significant differences between groups A and CA. The duration of mechanical ventilation, ICU, and hospital stay was significantly long

BACKGROUND: Despite dietary cholesterol not being considered a nutrient of concern, dietary guidelines still recommend that people with elevated LDL cholesterol limit their intake of egg yolks. OBJECTIVE: We examined the effects of the daily consumption of eggs in the context of the Dietary Approach to Stop Hypertension (DASH) diet for 8 weeks on cardio-metabolic risk factors in adults with hyperlipidemia. METHODS: The study was a randomized, controlled, single-blind, crossover trial involving 45 adults (mean age 59.5 years; 35 females, 10 males; 42 Caucasian, two African American, one Asian) with hyperlipidemia. Participants were randomly allocated to one of the two possible sequence permutations of two treatments: the DASH diet with eggs (I) and the DASH without eggs (C). There was a 4-week run-in phase before treatments and an 8-week washout period between treatments. Participants received menus and guidance from the study dietitian on adhering to the DASH diet. They also received advice to exclude or include two whole eggs daily for 8 weeks in their DASH diet while displacing other foods based on instructions to maintain an isocaloric intake. Primary outcome measures were LDL cholesterol and endothelial function assessed as flow-mediated dilation. Secondary outcome measures included insulin sensitivity, other lipids, blood pressure, C-reactive protein, and dietary intake. Data were analyzed using repeated measures ANOVA. RESULTS: Daily addition of eggs to the DASH (ΔI) compared with DASH without eggs (ΔC) did not negatively affect endothelial function (ΔI: 2.7 ± 10.8% versus ΔC: 3.7 ± 19.9% versus ΔI - ΔC = -1.1, p = 0.767) or LDL cholesterol (ΔI: 13.0 ± 23.5 mg/dL versus ΔC: 8.9 ± 19.6 mg/dL; ΔI - ΔC = 4.2, p = 0.317). The DASH diet with eggs compared with the DASH without eggs relatively increased the consumption of choline (ΔI: -29.6 ± 136.8 mg/d versus ΔC: -148.2 ± 146.3 mg/d; ΔI - ΔC = 118.6, p = 0.002) while the intake of carbohydrates decreased (ΔI: -26.4 ± 327.3 kcal/d versus ΔC: 147.7 ± 282.3 kcal/d; ΔI - ΔC = -174.1, p = 0.032). Compared with DASH diet without eggs, the addition of 2 eggs per day in the DASH did not impact other cardio-metabolic ri

OBJECTIVE: To investigate the effect of krill oil (KO) supplementation during alternate-day fasting (ADF) on body composition and muscle function in healthy adults with overweight. METHODS: In a randomized trial, during the 8-week ADF, participants consumed four capsules per day containing krill oil (KO group) or vegetable oil (placebo group). Each capsule of KO contained 191 mg EPA, 94 mg DHA, 78 mg choline, and 100 mcg astaxanthin. Body mass, fat-free mass (FFM), and handgrip strength (HGS) were measured before and after the intervention. Data were analyzed using ANOVA. RESULTS: The study was completed by 41 (25 women and 16 men) participants (age: 39 ± 10 years, BMI: 31.1 ± 4.2 kg/m2). Body weight reduction was not different (p > 0.05) between groups (KO, -4.6 ± 1.4 kg; Placebo, -4.5 ± 1.9 kg). The KO group had no change (p > 0.05) in FFM (-0.2 ± 0.9 kg) or HGS (-0.2 ± 0.5 kg). The placebo group experienced a reduction (p < 0.05) in FFM (-1.2 ± 2.0 kg) and HGS (-0.9 ± 0.7 kg). Changes in FFM and HGS were different (p < 0.05) between groups. CONCLUSIONS: KO supplementation during body weight loss attenuates the decline in FFM and muscle strength. TRIAL REGISTRATION: ClinicalTrials.gov Identifier (NCT06001632). © 2025 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.

The development of the infant brain relies on key nutrients such as choline and docosahexaenoic acid (DHA). However, their distinct physicochemical properties pose a challenge, as single supplementation typically results in poor stability and low bioavailability. In this study, DHA and choline were co-encapsulated using microencapsulation technology, resulting in stable microcapsules with an average particle size of approximately 590 nm and a DHA encapsulation efficiency of 85.2 %. Thermogravimetric analysis and Fourier-transform infrared spectroscopy further confirmed that DHA and choline were successfully encapsulated by the wall materials, thereby enhancing the thermal stability and structural integrity of the microcapsules. In addition, the content of fishy-flavor volatiles in the microcapsules was significantly lower than that in commercial DHA algal oil powder, making them more suitable for use in infant formula cereals. Animal experiments demonstrated that the DHA-choline microcapsules significantly improved the recognition index in the novel object recognition test and reduced escape latency in the Morris water maze, indicating enhanced learning and memory.

BACKGROUND: The synergistic use of Danggui (Angelica sinensis, As) and Huangqin (Scutellaria baicalensis or Scutellaria baicalensis Georgi, SbG; As-SbG) exhibits a notable therapeutic effect on metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying pharmacological mechanisms of their synergistic action have not yet been fully elucidated. PURPOSE: This study aims to evaluate the therapeutic efficacy of the synergistic application of As-SbG on MASH induced by various dietary patterns, and to identify the specific potential active compounds, underlying pharmacological mechanisms, and key therapeutic targets responsible for its anti-MASH effects. METHODS: Two MASH animal models induced by methionine- and choline- deficient (MCD) diet and high-fat/high-cholesterol (HFHC) diet were constructed to compare the efficacy of As, SbG and As-SbG synergistic treatment on adipose tissue and liver tissue during MASH progression. Potential mechanistic pathways and key molecular targets were identified through proteomics analysis. The chemical components of As-SbG were characterized using ultrahigh performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). The interactions between the identified bioactive components and the key targets from proteomics were further validated using molecular docking methods, focusing on As-SbG's therapeutic potential. Based on these bioinformatics findings, qRT-PCR, immunofluorescence staining, and Western blotting were employed to elucidate the regulatory mechanisms of As-SbG combination therapy on lipid metabolism, inflammation, and apoptosis-related pathways in both in vitro and in vivo MASH models. RESULTS: Compared with single-flavor administration of As and SbG, As-SbG synergistic administration significantly restored the balance among different phenotypes, functions, and sizes of various adipose tissues in MASH-induced mice under different dietary conditions, ameliorated hepatic steatosis and liver damage. Proteomic analysis revealed that the potential synergistic therapeutic effects of As-SbG on MASH were primarily associated with pathways involved in fat metabolism, anti-inflammatory response

Copper (Cu) and polyvinyl chloride microplastics (PVC-MPs), each known for their toxic effects, combine to create a hazardous synergy, posing a dual threat to aquatic ecosystems. Our study investigates the chronic (60-day) neurotoxic impacts of environmentally relevant concentrations of Cu (0.85 mg/L) and PVC-MPs (0.5 mg/L), both individually and in combination, in freshwater food-fish Channa punctatus. The neurotoxic effects were evaluated through reactive oxygen species (ROS) generation; oxidative damage to lipids, proteins, and nucleic acids; disruption of neurotransmitters; neuro-architectural damage, and neuronal cell death. For the first time, we identified neural apoptosis in fish via the BDNF/miR132/FOXO3a axis upon exposure to Cu, PVC-MPs, and their mixture. Cu accumulation peaked in brains treated with Cu-PVC-MPs combination. Higher ROS levels were seen in the exposed brain tissue, along with signs of oxidative damage, such as increased lipid peroxidation (LPO), protein carbonyls (PC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increased monoamine oxidase (MAO) activity led to dopamine and serotonin depletion, while cholinergic dysfunction was marked by reduced choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and acetylcholine (ACh). Additionally, severe neuro-architectural damage was observed. Molecular alterations were amplified in brains exposed to the copper-PVC-MPs mixture. Transcriptional analyses revealed downregulation of bdnf, miR132 and bcl2, with concurrent upregulation of foxo3a, bim, bax, apaf1, cas9, and cas3, further validated apoptosis. Principal Component Analysis (PCA) and Pearson Correlation analyses were also performed to validate these findings. Our results underscore the growing environmental threat posed by combined copper and MPs pollution, with PVC acting as a vehicle for increased toxicity in aquatic life.

BACKGROUND: Exposure to ionizing radiation is inevitable due to its extensive use in industrial and medical applications. The search for effective and safe natural therapeutic agents as alternatives to chemical drugs is crucial to mitigate their side effects. This study aimed to evaluate the effects of citicoline as a standalone treatment or in combination with the anti-hepatotoxic drug silymarin in protecting against liver injury caused by γ-radiation in rats. METHODS AND RESULTS: The rats were exposed to γ-radiation (7 Gy) and treated with citicoline (300 mg/kg/day) and/or silymarin (50 mg/kg/day). The results showed that citicoline alleviated liver damage in irradiated rats by reducing hepatic malondialdehyde levels, serum aspartate aminotransferase activity, and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and nuclear factor-kappa B (NF-κB). It also increased acetylcholine (ACh) levels and the gene expression of the anti-inflammatory protein α7 nicotinic acetylcholine receptor (α7nAChR). Additionally, citicoline improved serum triiodothyronine (T3) levels, thyroid hormone receptor beta (TRβ) gene expression, and iodothyronine deiodinase type 1 activity in hepatic tissues of irradiated rats. Furthermore, citicoline enhanced the effects of silymarin on thyroxine (T4), TRβ, ACh, and α7nAChR when co-administered in irradiated rats. Histopathological analysis confirmed these findings, demonstrating improved liver tissue structure. CONCLUSIONS: Citicoline mitigates γ-radiation-induced liver damage by reducing oxidative stress, activating the cholinergic anti-inflammatory pathway, and modulating thyroid hormone metabolism. These findings support the use of citicoline as a safe standalone treatment or as an adjuvant with silymarin for managing liver damage and thyroid hormone disturbances caused by γ-irradiation. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

BACKGROUND: Peripheral neuropathic pain is a result of damage/illness of the peripheral nerves. The mechanisms caused by its pathophysiology are not completely understood. METHODS: Imipramine is a tricyclic antidepressant that is sometimes used to treat neuropathic pain. Moreover, citicoline is considered a novel adjuvant for painful disorders such as neuropathic pain. So, a possible interaction between imipramine and citicoline on pain behavior was examined in nerve-ligated mice using tail-flick and hot plate tests. RESULTS: The results indicated that induction of neuropathic pain by sciatic nerve ligation caused hyperalgesia in nerve-ligated mice. On the other hand, intraperitoneal (i.p.) administration of citicoline (50, 75, and 100 mg/kg), and imipramine (2.5 and 5 mg/kg) induced anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Furthermore, citicoline potentiated the anti-hyperalgesic and anti-nociceptive effects of imipramine when they were co-administrated in nerve-ligated mice. Interestingly, there was an additive effect between imipramine and citicoline upon induction of anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. CONCLUSION: Therefore, it can be concluded that citicoline (as an adjuvant substance) enhanced the efficacy of imipramine for the modulation of pain behavior in nerve-ligated mice. © 2024 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

OBJECTIVES: Bupropion is an atypical antidepressant that shows robust efficacy in the regulation of neuropathic pain. Citicoline is a dietary supplement which is used as a neuroprotective agent for central nervous system (CNS) disorders. The probable interaction between bupropion and citicoline on neuropathic pain was assessed in male mice. METHODS: Neuropathic pain was induced by sciatic nerve ligation. Neuropathic pain was examined in nerve-ligated mice using tail-flick and hot-plate tests. RESULTS: The results indicated that intraperitoneal (i.p.) administration of citicoline (50 and 100 mg/kg) induced an anti-nociceptive effect in nerve-ligated animals. Similarly, i.p. injection of bupropion (2.5 and 5 mg/kg) induced anti-nociceptive effects in nerve-ligated mice. Co-administration of different doses of bupropion (2.5 and 5 mg/kg) along with a low dose of citicoline (25 mg/kg) caused an anti-nociceptive effect by enhancement of tail-flick and hot plate latencies. Interestingly, there is an additive effect between bupropion and citicoline upon the induction of the anti-nociceptive effect. CONCLUSIONS: Based on these results, it can be concluded that there is an interaction between bupropion and citicoline upon induction of an anti-nociceptive effect in nerve-ligated mice.

Endogenous biomarkers are discussed as tools for detection of drug-drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra-study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated DDIs. © 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Optimization of the choice of neuroprotective therapy regimens in patients with CVD, taking into account the synergism of drug interactions, is basic in real clinical practice. Unfortunately, in modern pharmacology there is no unified way to establish the synergistic spectrum of action of drugs, which would allow systematic investigation of the effects of combinations of drugs. By the method of studying the subtle mechanisms of action, combinations of drugs that are as synergistic as possible (summation and potentiation of effects) for various therapies of neurological diseases are proposed. Examples of rational neuroprotection are considered on the preparations Cortexin, citicoline, antioxidants. Publisher: Оптимизация выбора схем нейропротективной терапии у пациентов с цереброваскулярными заболеваниями (ЦВЗ) с учетом синергизма лекарственных взаимодействий является базовым подходом в клинической практике. К сожалению, в современной фармакологии нет унифицированного способа установления синергического спектра действия препаратов, который позволял бы систематически исследовать эффекты комбинаций препаратов. Методом изучения тонких механизмов действия предложены комбинации лекарственных препаратов, максимально синергичных (суммирование и потенцирование эффектов) для различных направлений терапии неврологических заболеваний. Примеры рациональной нейропротекции рассмотрены на препаратах Кортексин, цитиколин, антиоксиданты.

CONTEXT: Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. OBJECTIVE: The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. MATERIALS AND METHODS: The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. RESULTS: Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 μg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC0-∞ (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1β, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. DISCUSSION AND CONCLUSIONS: Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.

The prevention of tau protein aggregations is a therapeutic goal for the treatment of Alzheimer's disease (AD), and hydromethylthionine (HMT) (also known as leucomethylthioninium-mesylate [LMTM]), is a potent inhibitor of tau aggregation in vitro and in vivo. In two Phase 3 clinical trials in AD, HMT had greater pharmacological activity on clinical endpoints in patients not receiving approved symptomatic treatments for AD (acetylcholinesterase (AChE) inhibitors and/or memantine) despite different mechanisms of action. To investigate this drug interaction in an animal model, we used tau-transgenic L1 and wild-type NMRI mice treated with rivastigmine or memantine prior to adding HMT, and measured changes in hippocampal acetylcholine (ACh) by microdialysis. HMT given alone doubled hippocampal ACh levels in both mouse lines and increased stimulated ACh release induced by exploration of the open field or by infusion of scopolamine. Rivastigmine increased ACh release in both mouse lines, whereas memantine was more active in tau-transgenic L1 mice. Importantly, our study revealed a negative interaction between HMT and symptomatic AD drugs: the HMT effect was completely eliminated in mice that had been pre-treated with either rivastigmine or memantine. Rivastigmine was found to inhibit AChE, whereas HMT and memantine had no effects on AChE or on choline acetyltransferase (ChAT). The interactions observed in this study demonstrate that HMT enhances cholinergic activity in mouse brain by a mechanism of action unrelated to AChE inhibition. Our findings establish that the drug interaction that was first observed clinically has a neuropharmacological basis and is not restricted to animals with tau aggregation pathology. Given the importance of the cholinergic system for memory function, the potential for commonly used AD drugs to interfere with the treatment effects of disease-modifying drugs needs to be taken into account in the design of clinical trials. © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.