Immune Dysregulation Is Associated with Neurodevelopment and Neurocognitive Performance in HIV Pediatric Populations—A Scoping Review

HIV-1 is known for its complex interaction with the dysregulated immune system and is responsible for the development of neurocognitive deficits and neurodevelopmental delays in pediatric HIV populations. Considering that HIV-1-induced immune dysregulation and its association with neurodevelopmental and neurocognitive impairments in pediatric populations are not well understood, we conducted a scoping review on this topic. The study aimed to systematically review the association of blood and cerebrospinal fluid (CSF) immune markers with neurocognitive deficits and neurodevelopmental delays in pediatric HIV populations. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Studies were selected based on a set eligibility criterion. Titles, abstracts, and full texts were assessed by two independent reviewers. Data from the selected studies were extracted and analyzed by two independent reviewers. Seven studies were considered eligible for use in this context, which included four cross-sectional and three longitudinal studies. An average of 130 (±70.61) children living with HIV, 138 (±65.37) children exposed to HIV but uninfected and 90 (±86.66) HIV-negative participants were included across the seven studies. Results indicate that blood and CSF immune markers are associated with neurocognitive development/performance in pediatric HIV populations. Only seven studies met the inclusion criteria, therefore, these limited the number of significant conclusions which could have been made by using such an approach. All considered, the evidence suggests that immune dysregulation, as in the case of adult HIV populations, also has a significant association with neurocognitive performance in pediatric HIV populations

Characterizing Marathon-Induced Metabolic Changes Using 1H-NMR Metabolomics

Although physical activity is a health-promoting, popular global pastime, regular engage-ment in strenuous exercises, such as long-distance endurance running races, has been associated with a variety of detrimental physiological and immunological health effects. The resulting altered physiological state has previously been associated with fluctuations in various key metabolite con-centrations; however, limited literature exists pertaining to the global/holistic metabolic changes that are induced by such. This investigation subsequently aims at elucidating the metabolic changes induced by a marathon by employing an untargeted proton nuclear magnetic resonance (1H-NMR) spectrometry metabolomics approach. A principal component analysis (PCA) plot revealed a natu-ral differentiation between pre- and post-marathon metabolic profiles of the 30-athlete cohort, where 17 metabolite fluctuations were deemed to be statistically significant. These included reduced concentrations of various amino acids (AA) along with elevated concentrations of ketone bodies, glycolysis, tricarboxylic acid (TCA) cycle, and AA catabolism intermediates. Moreover, elevated concentrations of creatinine and creatine in the post-marathon group supports previous findings of marathon-induced muscle damage. Collectively, the results of this investigation characterize the strenuous metabolic load induced by a marathon and the consequential regulation of main energy-producing pathways to accommodate this, and a better description of the cause of the physiological changes seen after the completion of a marathon

A urinary biosignature for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS)

We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A > G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.Peer reviewe

The metabolic recovery of marathon runners: an untargeted 1H-NMR metabolomics perspective

Introduction: Extreme endurance events may result in numerous adverse metabolic, immunologic, and physiological perturbations that may diminish athletic performance and adversely affect the overall health status of an athlete, especially in the absence of sufficient recovery. A comprehensive understanding of the post-marathon recovering metabolome, may aid in the identification of new biomarkers associated with marathon-induced stress, recovery, and adaptation, which can facilitate the development of improved training and recovery programs and personalized monitoring of athletic health/recovery/performance. Nevertheless, an untargeted, multi-disciplinary elucidation of the complex underlying biochemical mechanisms involved in recovery after such an endurance event is yet to be demonstrated.Methods: This investigation employed an untargeted proton nuclear magnetic resonance metabolomics approach to characterize the post-marathon recovering metabolome by systematically comparing the pre-, immediately post, 24, and 48 h post-marathon serum metabolite profiles of 15 athletes.Results and Discussion: A total of 26 metabolites were identified to fluctuate significantly among post-marathon and recovery time points and were mainly attributed to the recovery of adenosine triphosphate, redox balance and glycogen stores, amino acid oxidation, changes to gut microbiota, and energy drink consumption during the post-marathon recovery phase. Additionally, metabolites associated with delayed-onset muscle soreness were observed; however, the mechanisms underlying this commonly reported phenomenon remain to be elucidated. Although complete metabolic recovery of the energy-producing pathways and fuel substrate stores was attained within the 48 h recovery period, several metabolites remained perturbed throughout the 48 h recovery period and/or fluctuated again following their initial recovery to pre-marathon-related levels

The metabolomics of acute alcohol abuse

Thesis (M.Sc. (Biochemistry))--North-West University, Potchefstroom Campus, 2010.Alcohol is a substance used and abused by many individuals. The metabolic perturbations caused by excessive alcohol consumption are widespread throughout the human body. One of the primary consequences of alcohol abuse, particularly acute alcohol abuse, is very high levels of NADH formed from excessive ethanol oxidation. A high NADH:NAD+ ratio shifts the redox potential of the cells, shifting the normal physiological equilibrium, particularly within NAD-dependent dehydrogenase-catalyzed reactions. These particular reactions occur within various metabolic pathways, such as: citric acid cycle, glycolysis and branched-chain amino acid catabolism. As such, a disruptive effect within these metabolic pathways results in the slight accumulation of perturbation markers that can be associated with alcohol abuse. Isolation and identification of these widespread perturbation markers is difficult as they only occur in quantities only slightly higher than normal physiological values. Metabolomics makes for a very aptly used technique as it takes a holistic approach, taking into consideration the entire metabolic profile; and, with the aid of bioinformatics, is able to isolate and identify particular variables/metabolites of interest and accredit them as the variables responsible for the greatest variation between control and experimental groups. A novel approach used within this investigation effectively reduced the voluminous metabolomics data generated allowing for more efficient multivariate analysis. Application of three separate statistical models, namely: (1) Unfolding PCA, (2) Cross-sectional PCA, and (3) ANOVA Simultaneous Component Analysis (ASCA), were used for analyzing the complex 3-dimensional data set created within this acute alcohol abuse investigation. Each model presented certain strengths and difficulties. Taking into consideration the results from all 3 models, the first phase of this investigation confidently illustrates the differentiation between control cases and individuals administered an acute alcohol dose and, subsequently allow for variables responsible for this separation to be: identified as variables of importance, selected and categorized into specific pathways and, finally, labelled as perturbation markers. Through experimental observation it was noted that a large number of perturbation markers associated with the branched-chain amino acid pathway were present within the experimental cases. A hypothesis was created from this observation, re-enforcing the principle that metabolomics is a hypothesis-generating system. The subsequent second phase of this investigation involves a targeted experimental protocol aimed at evaluating the proposed hypothesis, with a focus on three secondary metabolites of the isoleucine catabolism pathway (ethylhydracrylic acid, tiglylglycine and 2-methyl-3hydroxybutyric acid). Results of this targeted approach show a definite perturbance, similar to a very minor inherited metabolic disorder, occurs within the isoleucine catabolism pathway in response to an acute alcohol dose. As to our knowledge, no information pertaining to the influences of acute alcohol abuse (or even chronic alcohol abuse) within the branched-chain amino acid pathway exists within the current literature, as of date. As such, the experimental observations presented and evaluated within this investigation provide a novel and more in-depth insight into the ethanol-induced perturbances within human metabolism.Master

Miniaturized 1H-NMR method for analyzing limited-quantity samples applied to a mouse model of Leigh disease

Introduction The analysis of limited-quantity samples remains a challenge associated with mouse models, especially for multi-platform metabolomics studies. Although inherently insensitive, the highly specific characteristics of nuclear magnetic resonance (NMR) spectroscopy make it an advantageous platform for global metabolite profiling, particularly in mitochondrial disease research. Objectives Show method equivalency between a well-established standard operating protocol (SOP) and our novel miniaturized 1H-NMR method. Method The miniaturized method was performed in a 2 mm NMR tube on a standard 500 MHz NMR spectrometer with a 5 mm triple-resonance inverse TXI probe at room temperature. Results Firstly, using synthetic urine spiked with low (50 µM), medium (250 µM) and high (500 µM) levels (n = 10) of nine standards, both the SOP and miniaturized method were shown to have acceptable precision (CV  0.95), except for taurine. Furthermore, statistical equivalence was shown using the two one-sided test. Secondly, pooled mouse quadriceps muscle extract was used to further confirm method equivalence (n = 3), as well as explore the analytical dynamics of this novel approach by analyzing more-concentrated versions of samples (up to 10× concentration) to expand identification of metabolites qualitatively, with quantitative linearity. Lastly, we demonstrate the new technique’s application in a pilot metabolomics study using minute soleus muscle tissue from a mouse model of Leigh syndrome using Ndufs4 KO mice. Conclusion We demonstrate method equivalency, supporting our novel miniaturized 1H-NMR method as a financially feasible alternative to cryoprobe technology—for limited-quantity biological samples in metabolomics studies that requires a volume one-tenth of the SO

Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis

CITATION: Mason, S., Reinecke, C. J. & Solomons, R. 2017. Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis. Frontiers in Neuroscience, 11:534, doi:10.3389/fnins.2017.00534.The original publication is available at https://www.frontiersin.orgBackground: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.https://www.frontiersin.org/articles/10.3389/fnins.2017.00534/fullPublisher's versio