Related Metabolic Changes Research Articles

Feelings from the Heart Part II: Simulation and Validation of Static and Dynamic HRV Decrease-Trigger Algorithms to Detect Stress in Firefighters

Several mobile devices have multiple sensors on board and interact with smartphones. This allows for a complex online evaluation of physiological data, important for interactive psychophysiological assessments, which targets the triggering of psychological states based on physiological data such as heart rate variability (HRV). However, algorithms designed to trigger meaningful physiological processes are rare. One exception is the concept of additional HRV reduction (AddHRVr), which aims to control for metabolic-related changes in cardiac activity. In this study we present an approach, based on data of a previous study, which allows algorithm settings to be derived that could be used to automatically trigger the assessment of psychosocial states by online-analysis of transient HRV changes in a sample of 38 firefighters. Settings of a static and a dynamic AddHRVr algorithm were systematically manipulated and quantified by binary triggers. These triggers were subjected to multilevel models predicting increases of objective stress during a period of 24 h. Effect estimates (i.e., odds) and bootstrap power simulations were calculated to inform about the most robust algorithm settings. This study delivers evidence that a dynamic AddHRVr algorithm can trigger transitions of stress, which should be further validated in future interactive psychophysiological assessments.

O11 - Cabazitaxel activity and related metabolic changes in RB1 mutated prostate cancer models

O11 - Cabazitaxel activity and related metabolic changes in RB1 mutated prostate cancer models

Disturbed microbial ecology in Alzheimer\u2019s disease: evidence from the gut microbiota and fecal metabolome

BackgroundGut microbiota (GMB) alteration has been reported to influence the Alzheimer’s disease (AD) pathogenesis through immune, endocrine, and metabolic pathways. This study aims to investigate metabolic output of the dysbiosis of GMB in AD pathogenesis. In this study, the fecal microbiota and metabolome from 21 AD participants and 44 cognitively normal control participants were measured. Untargeted GMB taxa was analyzed through 16S ribosomal RNA gene profiling based on next-generation sequencing and fecal metabolites were quantified by using ultrahigh performance liquid chromatography-mass spectrometry (UPLC-MS).ResultsOur analysis revealed that AD was characterized by 15 altered gut bacterial genera, of which 46.7% (7/15 general) was significantly associated with a series of metabolite markers. The predicted metabolic profile of altered gut microbial composition included steroid hormone biosynthesis, N-Acyl amino acid metabolism and piperidine metabolism. Moreover, a combination of 2 gut bacterial genera (Faecalibacterium and Pseudomonas) and 4 metabolites (N-Docosahexaenoyl GABA, 19-Oxoandrost-4-ene-3,17-dione, Trigofoenoside F and 22-Angeloylbarringtogenol C) was able to discriminate AD from NC with AUC of 0.955 in these 65 subjects.ConclusionsThese findings demonstrate that gut microbial alterations and related metabolic output changes may be associated with pathogenesis of AD, and suggest that fecal markers might be used as a non-invasive examination to assist screening and diagnosis of AD.

Feelings from the heart: Developing HRV decrease-trigger algorithms via multilevel hyperplane simulation to detect psychosocially meaningful episodes in everyday life.

Heart rate variability (HRV) has been associated with diverse psychosocial concepts, like stress, anxiety, depression, rumination, social support, and positive affect, among others. Although recent ecological momentary assessment research devoted the analysis of cardiac‐psychosocial interactions in daily life, traditional time sampling designs are compromised by a random pairing of cardiac and psychosocial variables across several time points. In this study, we present an approach based on the concept of additional heart rate and additional HRV reductions, which aims to control for metabolic‐related changes in cardiac activity. This approach allows derivation of algorithm settings, which can later be used to automatically trigger the assessment of psychosocial states by online‐analysis of transient HRV changes. We used an already published data set in order to identify potential triggers offline indexing meaningful HRV decrements as related to low quality social interactions. First, two algorithm settings for a non‐metabolic HRV decrease trigger (i.e., the number of HRV decreases in a specified time window) were systematically manipulated and quantified by binary triggers (HRV decrease detected vs. not). Second, triggers were then entered in multilevel models predicting (lower levels of) social support. Effect estimates and bootstrap power simulations were visualized on hyperplanes to determine the most robust algorithm settings. A setting associated with 13 HRV decreases out of 29 min seems to be particularly sensitive to low quality of social interactions. Further algorithm refinements and validation studies are encouraged.

Prognostic implications of longitudinal strain in hypertensive patients

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): University Hospital of Tlemcen Introduction Hypertension is a well-established risk factor for cardiovascular disease. It causes left ventricular (LV) pressure overload, and, in turn, changes in cardiac geometry and LV hypertrophy (LVH). Early impairment of LV function, detected by a reduced GLS, is associated with long-lasting, uncontrolled HBP, overweight, related metabolic changes, and is more pronounced in patients with LVH. This decline in longitudinal function may be a determining factor in the occurrence of cardiovascular complications and therefore an increase in cardiovascular morbidity and mortality. Purpose : This study sought to investigate the associations of left ventricular (LV) strain and its serial change with major adverse cardiac events in hypertensive patients. Methods We retrospectively studied 400 asymptomatic patients with hypertension of which, 182 patients had abnormal global longitudinal strain(GLS) and 218 patients had normal GLS, between 2016 and 2019. Global longitudinal strain (GLS) was measured using speckle tracking. Patients were followed for admission because of heart failure, myocardial infarction, atrial fibrillation and strokes, over median of 4 years. At the start of study, all patients had preserved LV ejection fraction. Résultats : The control of patients noted 25 cases (6.25%) of attacks of heart failure in the arm hypertension with low GLS against only 4 cases (1%) in the arm hypertension + normal GLS (P <0.001). The same, 19 ( 4.75%) hypertensive patients with low GLS had a stroke compared to only 5 (1.25%) hypertensive patients with normal GLS. A significant difference in the incidence of onset of acute coronary syndromes was also noted in the hypertension arm with abnormal GLS (P = 0.002). As for rhythmic complications, 26 (6.5%) hypertensive patients with abnormal GLS developed atrial fibrillation compared to only 9 (2.25%) hypertensive patients with normal GLS (P <0.0001). Conclusion : GLS and its deterioration are associated with cardiovascular complications in asymptomatic hypertensive heart disease. Although LVEF will remain a cornerstone of LV function assessment, the addition of GLS enables detailed phenotyping and improved risk assessment and is a tool for present and future therapeutic advancement. A risk score incorporating strain was useful for predicting risk of cardiac events.

Longer Leukocyte Telomere Length Predicts Stronger Response to a Workplace Sugar-Sweetened Beverage Sales Ban: An Exploratory Study.

ABSTRACTBackgroundShorter leukocyte telomere length (LTL) is associated with increased risk of a number of metabolic diseases including insulin resistance and the development of type 2 diabetes mellitus. Shorter LTL is also associated with stress reactivity suggestive of a possible role for LTL to predict response to behavioral interventions. However, few studies have evaluated how interventions, such as weight loss or dietary changes, are associated with LTL changes or whether LTL can predict behavioral responses to interventions.ObjectivesWe evaluated metabolic changes in relation to LTL changes and LTL at baseline in a cohort of at-risk adults in response to a 10-mo workplace-based sugar-sweetened beverage (SSB) intervention.MethodsAt baseline, metabolic health and LTL measurements were assessed through standard blood draws on 212 participants. Multivariable linear regression models were used to assess changes in anthropometrics, SSB consumption, and 13 blood-based metabolic risk factors, in relation to LTL at baseline and changes in LTL.ResultsLonger LTL at baseline was associated with decreases in SSB consumption over the 6-mo follow-up period (B = −29.67; P = 0.04). Slower LTL attrition rates were associated with decreases in waist circumference (B = −0.27; P = 0.03), HDL cholesterol (B = −0.20; P = 0.05), and apoA1 (B = −0.09; P = 0.01).ConclusionsLonger LTL at baseline predicted a favorable overall response to a behavioral intervention: decreases in SSB consumption. Abdominal adiposity losses paralleled slower declines in LTL suggestive of overall health benefits, but we found differences in the relations between metabolic changes and LTL at baseline compared with LTL attrition rates. Longer LTL may be a proxy marker of a positive behavioral response.This trial was registered at clinicaltrials.gov as NCT02585336.

Seasonally related metabolic changes and energy allocation associated with growth and reproductive phases in the liver of male goldfish (Carassius auratus)

Reproduction and growth follow a seasonal pattern in many fish species involving changes in gonadal development, growth, and metabolism. Significant metabolic energy is needed during gametogenesis in both female and male to produce hundreds of eggs and billions of sperms. Seasonal variations are controlled by the hormones of brain-pituitary-peripheral axis and are accompanied by significant metabolic changes. There is evidence that GnRH and GnIH are among the key neurohormones that regulate the reciprocal control of growth and reproduction. The objective of this study was to investigate changes in metabolic profile and energy allocation patterns at different stages of reproduction, using goldfish as a model organism and LC-MS as analytical platform for metabolic analysis. Goldfish undergoes a clear seasonal cycle of growth and reproduction. In vivo experiments were conducted at three different time point of the annual cycle: regressed gonadal phase (peak growth phase), mid gametogenesis and late gametogenesis. Emphasis is placed on changes in liver metabolic pathways to energetically sustain the physiological processes related to growth and reproduction. Moreover, we tested the hypothesis that GnRH and GnIH may play a role in the regulation of metabolism by investigating acute effects of these peptides at different stages of reproductive cycle. SignificanceThe findings in this paper provide novel information on the seasonal changes in basal metabolism during different stages of reproductive cycle, and evidence for differential allocation of energy during reciprocal control of reproduction and growth in goldfish. Chemometrics combined with pathway-driven bioinformatics elucidated a shift in the metabolic profile, indicating distinct patterns of energy allocation in the reproductive and growth seasons. Furthermore, to our knowledge this is the first study to provide evidence for a possible regulatory role of GnRH and GnIH in liver metabolism and energy allocation patterns associated with growth and reproductive processes. Together our findings present a framework for better understanding of the hormonally induced changes in metabolism to energetically sustain growth and reproduction in fish and other oviparous species undergoing seasonal cycle.

Identification of blood immune and metabolic indicators explaining the variability of growth of pigs under contrasted sanitary conditions

BackgroundHealth and growth of pigs are affected by the hygiene of housing. Lower growth performance observed in poor hygiene of housing conditions is explained by reduced feed intake and metabolic changes caused by the activation of body defences. In a previous experiment, we reported contrasted average values of body weight gain, concentrations of circulating metabolites, redox and immune indicators in blood of pigs housed in good or poor hygiene conditions during the growing period. This study addressed inter-individual variability in these responses to determine whether a particular blood profile explains average daily gain (ADG) of the pig.ResultsThe data originated from 160 growing pigs, half of which subjected to a hygiene challenge for 6 weeks (W0 to W6) and the others housed in good hygiene conditions. Pigs originated from two lines divergently selected for residual feed intake (RFI). Individual body weights were recorded during this period, and relative ADG (rADGW0-W6) was calculated as the ADG corrected by the initial body weight measured at W0. Blood samples were taken before (W0) and 3 weeks (W3) after the beginning of the challenge. The analysed dataset consisted of 51 metabolites and indicators of immune and inflammatory responses measured on 136 pigs having no missing value for any variables, when calculated as the differences W3 minus W0 in circulating concentrations. An algorithm tested all possible linear regression models and then selected the best ones to explain rADGW0-W6. Six variables were identified across the best models and correlated with rADGW0-W6 with a goodness of fit (adjusted R2) of about 67%. They were changes in haptoglobin, global antioxidant capacity of plasma (Biological Antioxidant Power or BAP), free fatty acids, and 3 amino acids: leucine, tryptophan, and 1-methylhistidine. The effects of housing conditions and RFI lines were comprised in the variables of the selected models and none of these conditions improved accuracy of the predictive models, leading to genericity of the pinpointed metabolic changes in relation to variability of ADG.ConclusionsThis approach allows us to identify blood variables, whose changes in blood concentrations correlated to ADG under contrasted sanitary conditions.

The Arachidonic Acid Metabolism Mechanism Based on UPLC-MS/MS Metabolomics in Recurrent Spontaneous Abortion Rats.

Recurrent spontaneous abortion (RSA) remains a critical and challenging problem in reproduction. To discover novel biomarkers for RSA, ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) metabolomics approach was applied to detect RSA serum metabolic profiles and explore its possible pathogenesis and mechanism. The abortion rat model was established, and a metabolomics analysis was performed to evaluate the differentially expressed metabolites between the control and model groups. Immunohistochemistry (IHC), qRT-PCR, and Western blot further examined the expression of Arachidonic acid metabolism-related genes in uterus tissues. To identify arachidonic acid metabolism-related changes in RSA, ELISA’s potential mechanisms were further confirmed in serum. Ninety-one metabolites were significantly different between the two groups, as indicated by a VIP ≥1, fold change ≥1. The metabolic pathways involving arachidonic acid metabolism pathway (P = 0.00044) are related to RSA. Verification by experimental showed that compared with the control rats, the expression of the COX-1, COX-2, PTGFR, and TBXA2R genes associated with the arachidonic acid metabolism pathway has significantly increased the uterus and serum of RSA rats (P < 0.05). Regulation of the arachidonic acid metabolism pathway might serve as a promising therapeutic strategy for relieving RSA women’s symptoms.

Predictive value of metabolic and perfusion changes outside the seizure onset zone for postoperative outcome in patients with refractory focal epilepsy.

The value of functional molecular changes outside the seizure onset zone as independent predictive factors of surgical outcome has been scarcely evaluated. The aim of this retrospective study was to evaluate relative metabolic and perfusion changes outside the seizure onset zone as predictors of postoperative outcome in patients with unifocal refractory focal epilepsy. Eighty-six unifocal epilepsy patients who underwent 18F-FDG PET prior to surgery were included. Ictal and interictal perfusion SPECT was available in 65 patients. Good postoperative outcome was defined as the International League against Epilepsy class 1. Using univariate statistical analysis, the predictive ability of volume-of-interest based relative metabolism/perfusion for outcome classification was quantified by AUC ROC-curve, using composite, unilateral cortical (frontal, orbitofrontal, temporal, parietal, occipital) and central volumes-of-interest. The results were cross-validated, and a false discovery rate (FDR) correction was applied. As a secondary objective, a subgroup analysis was performed on temporal lobe epilepsy patients (N = 64). Increased relative ictal perfusion in the contralateral central volume-of-interest was significantly associated with the good surgical outcome both in the total population (AUC 0.79, pFDR = 0.009) and the temporal lobe epilepsy subgroup (AUC 0.80, pFDR = 0.028). No other significant associations between functional molecular changes and postoperative outcome were found. Increased relative ictal perfusion in the contralateral central region significantly predicted outcome after epilepsy surgery in patients with refractory focal epilepsy. We postulate that these relative perfusion changes could be an expression of better preoperative neuronal network integration and centralization in the contralateral central structures, which is suggested to be associated with better postoperative outcome.

Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies.

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.

Baseline interleukin1beta expression in peripheral blood monocytes predicts the extent of weight loss and nonalcoholic fatty liver improvement in obese subjects with prediabetes or type 2 diabetes

Abstract Background Non-alcoholic fatty liver disease (NAFLD) represents a hallmark of metabolic syndrome. Interleukin-1β (IL-1β), a well-studied cytokine involved in obesity-related systemic inflammation as well as in the pathogenesis of type 2 diabetes (T2D), promotes hepatic steatosis by stimulating triglycerides and cholesterol accumulation in primary liver hepatocytes and lipid droplets formation. The most compelling evidence for a major role for IL-1β in metabolic imbalance and inflammation comes from the recent Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOs)trial, where inhibition of IL-1β pathway was associated with a reduction of cardiovascular events in high-risk patients. Purpose The present study was designed to determine: i)whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on NAFLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; ii)whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. Methods Thirty-two metformin-treated obese subjects with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n=16)] or newly diagnosed T2D (n=16), were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/d) or lifestyle counselling until achieving a modest and comparable weight loss (−7% of initial body weight). Visceral (VAT) and adipose tissue distribution were assessed by magnetic resonance. Gene expression of IL-1β in peripheral blood mononuclear cells was assessed by real time PCR. Results At baseline, IL-1β positively correlated to body mass index (BMI) (rho=0.421, p=0.016), fasting plasma glucose (rho=0.415, p=0.018), HbA1c (rho=0.349, p=0.050), VAT (rho=0.388, p=0.028), NAFLD (rho=0.454, p=0.009), platelet count (rho=0.510, p=0.003), chemerin (rho=0.455, p=0.009) and interleukin-1 receptor agonist (IL1-RA) (rho=0.519, p=0.002). After achievement of the weight loss target in the two groups, a comparable reduction of IL-1 β (p&amp;lt;0.001 lifestyle changes; p=0.029 liraglutide treatment) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C-reactive protein (CRP),BMI and NAFLD. Furthermore, basal levels of IL-1β correlated directly with delta BMI (p=0.015) and delta NAFLD (p=0.002) (Figure 1). Conclusion In obese patients with initial impairment of glucose metabolism, IL-β-driven inflammation correlates with glycaemic control, adipose tissue distribution and platelet count. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction of both IL-1β levels and NAFLD degree. Of interest, basal levels of IL-1β predicts the extent of weight loss and NAFLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a levels as a drug-response biomarker. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by a grant from the Italian Ministry of University and Research (PRIN no. 2010JS3PMZ to F.S.).

Induction of Innate Immune Memory by Engineered Nanoparticles in Monocytes/Macrophages: From Hypothesis to Reality.

The capacity of engineered nanoparticles to activate cells of the innate immune system, in particular monocytes and macrophages, is considered at the basis of their toxic/inflammatory effects. It is, however, evident that even nanoparticles that do not directly induce inflammatory activation, and are therefore considered as safe, can nevertheless induce epigenetic modifications and affect metabolic pathways in monocytes and macrophages. Since epigenetic and metabolic changes are the main mechanisms of innate memory, we had previously proposed that nanoparticles can induce/modulate innate memory, that is, have the ability of shaping the secondary response to inflammatory challenges. In light of new data, it is now possible to support the original hypothesis and show that different types of nanoparticles can both directly induce innate memory, priming macrophages for a more potent response to subsequent stimuli, and modulate bacteria-induced memory by attenuating the priming-induced enhancement. This evidence raises two important issues. First, in addition to overt toxic/inflammatory effects, we should consider evaluating the capacity to induce innate memory and the related epigenetic and metabolic changes in the immunosafety assessment of nanomaterials, since modulation of innate memory may be at the basis of long-term unwanted immunological effects. The other important consideration is that this capacity of nanomaterials could open a new avenue in immunomodulation and the possibility of using engineered nanomaterials for improving immune responses to vaccines and resistance to infections, and modulate anomalous immune/inflammatory reactions in chronic inflammatory diseases, autoimmunity, and a range of other immune-related pathologies.

Deep brain stimulation of the internal globus pallidus does not affect the limbic circuit in patients with Parkinson's disease: a PET study.

Internal globus pallidus (GPi) deep brain stimulation (DBS) is a safe and effective alternative treatment in Parkinson's disease (PD) for patients with cognitive impairment. However, no study has yet investigated metabolic changes within a large series of patients undergoing GPi stimulation. We assessed motor, cognitive and psychiatric changes, as well as modifications in brain glucose metabolism measured with FDG-PET, before and after bilateral GPi-DBS. In the same week, 32 patients with PD underwent a motor, cognitive and psychiatric assessment and a resting-state FDG-PET scan, 4months before and 4months after GPi-DBS surgery. For the voxelwise metabolic change assessment, the p value was controlled for multiple comparisons using the family wise error rate. After GPi-DBS surgery, patients showed a significant overall improvement in motor status. No cognitive or psychiatric changes were observed after surgery. Nor were any clusters with significantly relative metabolic changes found in the limbic circuit after surgery. Clusters with significantly relative metabolic changes were observed in the left and right Brodmann area (BA) 6, the right BA 9, the right and left BA 39 and the left BA 17. The present study confirmed that GPi-DBS is an effective treatment in patients with advanced PD, owing to metabolic changes in the areas involved in motor execution. The absence of relative metabolic decrease in the limbic circuit and the few changes affecting the associative circuit could explain why GPi-DBS is cognitively safe.

Mycobacterium tuberculosis curli pili (MTP) deficiency is associated with alterations in cell wall biogenesis, fatty acid metabolism and amino acid synthesis.

In an effort to find alternative therapeutic interventions to combat tuberculosis, a better understanding of the pathophysiology of Mycobacterium tuberculosis is required. The Mycobacterium tuberculosis curli pili (MTP) adhesin, present on the surface of this pathogen, has previously been shown using functional genomics and global transcriptomics, to play an important role in establishing infection, bacterial aggregation, and modulating host response in vitro and in vivo. This investigation aimed to determine the role of MTP in modulating the metabolism of M. tuberculosis, using mtp gene-knockout mutant and complemented strains. Untargeted two-dimensional gas chromatography time-of-flight mass spectrometry, and bioinformatic analyses, were used to identify significant differences in the metabolite profiles among the wild-type, ∆mtp mutant and mtp-complemented strains, and validated with results generated by real-time quantitative PCR. A total of 28 metabolites were found to be significantly altered when comparing the ∆mtp mutant and the wild-type strains indicating a decreased utilisation of metabolites in cell wall biogenesis, a reduced efficiency in the breakdown of fatty acids, and decreased amino acid biosynthesis in the former strain. Comparison of the wild-type to mtp-complement, and ∆mtp to mtp-complemented strains revealed 10 and 16 metabolite differences, respectively. Real-time quantitative PCR results supported the metabolomics findings. Complementation of the ∆mtp mutant resulted in a partial restoration of MTP function. The lack of the MTP adhesin resulted in various bacterial cell wall alterations and related metabolic changes. This study highlights the importance of MTP as a virulence factor and further substantiates its potential use as a suitable biomarker for the development of diagnostic tools and intervention therapeutics against TB.

Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways.

The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother–child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement (p < 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, p = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC (p = 0.0002) and in VDAART (p = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.

Analysis of plasma metabolic profile, characteristics and enzymes in the progression from chronic hepatitis B to hepatocellular carcinoma.

Hepatitis B virus (HBV) infection is an important factor causing hepatocellular carcinoma (HCC). The aim of this study was to investigate the metabolic characteristics and related metabolic enzyme changes during the progression from chronic hepatitis B (CHB) to liver cirrhosis (LC) and, ultimately, to HCC. An untargeted metabolomics assay was performed in plasma from 50 healthy volunteers, 43 CHB patients, 67 LC patients, and 39 HCC patients. A total of 24 differential metabolites (DMs) were identified. Joint pathway analysis suggested striking changes in amino acid metabolism and lipid metabolism from CHB to HCC. The panel of L-serine, creatine and glycine distinguished LC from CHB, and L-serine, cystathionine, creatine and linoleic acid distinguished HCC from LC. Bioinformatic analysis of publicly available data showed that differential metabolite profile-associated enzyme genes, including alanine-glyoxylate aminotransferase-2 (AGXT2), D-amino-acid oxidase (DAO), and cystathionine gamma-lyase (CTH), were downregulated, while bisphosphoglycerate mutase (BPGM), cystathionine-β-synthase (CBS), phosphoserine phosphatase (PSPH) and acyl-CoA thioesterase 7 (ACOT7) were upregulated, in HCC, all of which correlated with a poor prognosis for HCC patients. Our results indicated that serum metabolites and related enzymes are of considerable significance for the diagnosis and prognosis of HCC and can provide a theoretical basis and therapeutic index for future diagnosis and treatment.

1272 Control of Sleep-Associated Respiratory Distress with a Mandibular Advancement Oral Appliance in an Unusual Case of a Patient with a Mild Rather Persistent Nocturnal Baseline Hypoventilation/Hypoxia

Abstract Introduction Normal respiratory function is crucial for adequate sleep. Sleep Related Breathing Disorders, namely Obstructive Sleep Apnea (OSA) are frequent conditions among a large spectrum of obstructive events in the upper airway which are often linked to significant sleep related oxyhemoglobin dessaturation levels compared to those observed in baseline PSG-oximetry recorded. On the other hand, low baseline oxygen saturation (LBOS) is commonly linked to symptomatic cardiorespiratory disturbances which may adversely impact respiratory outcomes either awake or during sleep. Therefore it is relevant to be aware of the baseline ventilatory status in order to optimize the therapeutic care. Report of Case We present an unusual case of a patient with moderate OSA which was successfully controlled with a Mandibular Advancement Oral Appliance (OAm). Despite the control with the OAm, the patient still maintained a nocturnal pattern of hypoventilation/hypoxia. The 53 yo female patient with normal weight/height ratio (BMI=25,2) complaining of non restorative sleep, tiredness, impaired memory, excessive diurnal sleepiness (Epworth Sleepiness Scale - ESS=10 and bruxism with a PSG diagnosis of moderate OSA (BaselineO2Sat=94%; IAH=17,4 ev/h; ODI=32,9 ev/h; T90=34,7% of TST) was referred for treatment with a OAm. A PM Type 1 positioner was inserted and titrated until 12 mm of advancement (80% of maximal measured protrusion). Within 6 months follow up and after clinical titration, there was a clear symptomatic and objective improvement with resolution of all major complaints including sleepiness (ESS=5). Titration PSG showed a normalization in all parameters (IAH=1,4 ev/h;ODI=4 ev/h;T90=0,1% of TST). Baseline O2 Sat however remained low (93%) in the titration PSG even though no symptoms or signs of a disorder existed even after discounting for Ph related metabolic changes (normal levels of HCO3) Conclusion This is an interesting case of an unusual patient who presented with a LBOS level in the diagnostic PSG. Despite the therapeutic success of the OAm in controlling the sleep related respiratory condition, measured by all otherwise normalized PSG based sleep and respiratory parameters, maintained a LBOS in the titration PSG without any signs or symptoms of disease.

A urinary metabolomic study from subjects after long-term occupational exposure to low concentration acrylamide using UPLC-QTOF/MS

Because long-term occupational exposure to low concentrations of acrylamide (ACR) has the potential to cause neurological damage, it is important to identify biomarkers that can be used to evaluate this risk. In the present study, urine metabolomics of the ACR-exposed and non-exposed groups to identify potential metabolites was carried out using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry. Serum biochemical indexes of the exposed and non-exposed groups were also determined. Principal component analysis showed a differential separation between exposed group and non-exposed group and a total of 7 metabolites were identified in positive and negative ionization modes; Area under curve of anthranilic acid, β-guanidinopropionic acid and mesobilirubinogen were 0.980, 0.843 and 0.801 respectively and these metabolites showed high sensitivity and specificity. The 13 biochemical indexes were divided into three classes based on physiological functions. Only biomarkers of dysregulated liver function including alanine aminotransferase, aspartic transaminase, total bilirubin, direct bilirubin and triglyceride were significantly higher in the exposed group than in the non-exposed group. This study identifies important related metabolic changes in the bodies of workers after long-term occupational exposure to low concentration ACR and suggests new biomarkers of nervous system injury caused by ACR. The study also provides a sound basis for exploring the biochemical mechanisms and metabolic pathways of nervous system toxicity caused by ACR.

CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage.

Despite the multifactorial pathogenesis of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), augmentation of cerebral blood flow (CBF) is still considered essential in the clinical management of DCI. The aim of this prospective observational study was to investigate cerebral metabolic changes in relation to CBF during therapeutic hypervolemia, hemodilution, and hypertension (HHH) therapy in poor-grade SAH patients with DCI. CBF was assessed by bedside xenon-enhanced CT at days 0-3, 4-7, and 8-12, and the cerebral metabolic state by cerebral microdialysis (CMD), analyzing glucose, lactate, pyruvate, and glutamate hourly. At clinical suspicion of DCI, HHH therapy was instituted for 5 days. CBF measurements and CMD data at baseline and during HHH therapy were required for study inclusion. Non-DCI patients with measurements in corresponding time windows were included as a reference group. In DCI patients receiving HHH therapy (n = 12), global cortical CBF increased from 30.4 ml/100 g/min (IQR 25.1-33.8 ml/100 g/min) to 38.4 ml/100 g/min (IQR 34.2-46.1 ml/100 g/min; p = 0.006). The energy metabolic CMD parameters stayed statistically unchanged with a lactate/pyruvate (L/P) ratio of 26.9 (IQR 22.9-48.5) at baseline and 31.6 (IQR 22.4-35.7) during HHH. Categorized by energy metabolic patterns during HHH, no patient had severe ischemia, 8 showed derangement corresponding to mitochondrial dysfunction, and 4 were normal. The reference group of non-DCI patients (n = 11) had higher CBF and lower L/P ratios at baseline with no change over time, and the metabolic pattern was normal in all these patients. Global and regional CBF improved and the cerebral energy metabolic CMD parameters stayed statistically unchanged during HHH therapy in DCI patients. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was a common occurrence, possibly explained by mitochondrial dysfunction despite improved microcirculation.