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1
Kelly, Barbara M. "The analysis of biological fluids for acylcarnitines." Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326566.
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Ferro, Fabio. "Régulation des canaux ioniques cardiaques par les acylcarnitines." Thesis, Tours, 2012. http://www.theses.fr/2012TOUR3315/document.
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Plusieurs maladies entraînent soit une augmentation soit une diminution du taux des acides gras (AG) et de leurs dérivés circulants, notamment les acyl-carnitines (AC). Ce changement a été soupçonné comme étant la cause de importants dérangements électriques. Nous avons montré que les AC à chaine longue (LCAC) du côté extracellulaire modulent le canal hERG de façon spécifique, modulant sa amplitude de courant et sa cinétique. Aucun AC testé n’a eu d’effet en intracellulaire. La CAR et les MCAC n’ont eu aucun effet. Les AC ne modulent pas les courants IKS et IK1. Le canal Cav1.2 est modulé par C16-CAR et le C16 dans la lignée HEK293-ICaL et dans des cardiomyocytes de rat. En condition physiologique il existe donc un lien strict entre le métabolisme énergétique et activité électrique cardiaque qui entraine une modulation permanente du canal hERG par les LCAC. La régulation par les LCAC du canal hERG et peut être celle du canal ICaL, pourraient participer au dérangement électrique à l’origine du déclenchement de troubles du rythme cardiaque retrouvé dans certaines maladiesSeveral diseases can cause either an increase or a decrease in the rate of fatty acids (FAs) and their derivatives circulating, including acyl-carnitines (AC). This change is suspected as being the cause of major cardiac electrical perturbations. We have shown that long-chain AC (LCAC) modulate specifically by the extracellular side the hERG channel, regulating its current amplitude and kinetics. All AC tested had no effect when applied intracellularly. Carnitine and medium chain AC had no effect on hERG. LCAC does not modulate IK1 and IKS. Cav1.2 channel is modulated by C16 and C16-CAR in line HEK293-ICaL and rat cardiomyocytes. In physiological conditions there exists a strict link between energy metabolism and cardiac electrical activity which causes a permanent modulation of hERG channel by the LCAC. Regulation by the LCAC of the hERG channel and maybe ICaL, could participate in the electrical disturbance causing the onset of cardiac arrhythmia found in certain diseases
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Meadows, Jamie. "Carnitine and O-acylcarnitines in Pseudomonas aerguinosa: metabolism, transport, and regulation." ScholarWorks @ UVM, 2015. http://scholarworks.uvm.edu/graddis/409.
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Pseudomonas aeruginosa is found in numerous environments and is an opportunistic pathogen affecting those who are immunocompromised. Its large genome encodes tremendous metabolic and regulatory diversity that enables P. aeruginosa to adapt to various environments. We are interested in how P. aeruginosa senses and responds to the host-derived compounds, carnitine and acylcarnitines. Acylcarnitines can be hydrolyzed to carnitine, where the liberated carnitine and its catabolic product glycine betaine can be used as osmoprotectants, for induction of the virulence factor phospholipase C, and as sole carbon, nitrogen, and energy sources. P. aeruginosa is incapable of de novo synthesis of carnitine and acylcarnitines and therefore imports these compounds from exogenous source. Short-chain acylcarnitines are imported by the ABC transporter CaiX-CbcWV. Medium- and long-chain acylcarnitines are hydrolyzed extracytoplasmically and the liberated carnitine is transported through CaiX-CbcWV. Once in the cytoplasm, short-chain acylcarnitines are hydrolyzed by the L-enantiomer specific hydrolase, HocS. The transcriptional regulator CdhR is divergently transcribed from the carnitine catabolism operon and we have identified the upstream activating region, the binding site sequence, and essential residues required for CdhR binding and induction of the carnitine operon. Carnitine catabolism is repressed by glucose and glycine betaine at the transcriptional level. Furthermore, using two different cdhR translational fusions we show that CdhR enhances its own expression and that GbdR, a related transcription factor, contributes to cdhR expression by enhancing the level of basal expression. These studies are the first to determine the mechanism of O-acylcarnitine transport, metabolism, and the regulation of these processes, which contribute to utilization of these compounds for P. aeruginosa survival in diverse environments.
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Angiletta, Chris. "The Role of Fasting Acylcarnitines in Metabolic Flexibility from Short Term High Fat Feeding." Thesis, Virginia Tech, 2018. http://hdl.handle.net/10919/82401.
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Metabolic flexibility plays a significant role in energy homeostasis by regulating fuel selection in correspondence to energy demand. Obese and type II diabetic populations have displayed a hindered ability to properly transition from fat oxidation while in a fasted state to carbohydrate oxidation once fed, leading to a buildup of mitochondrial metabolites such as acylcarnitines. Carnitine, essential for fatty acyl-CoA transport through the inner and outer mitochondrial membranes, can be an indicator of mitochondrial distress as elevated levels tend to spill over into plasma suggesting a disruption in oxidation. The current study was designed to examine the effect of short term, high fat feeding on plasma acylcarnitine species diversity and levels and if acylcarnitines are associated with metabolic flexibility. 13 healthy, non-obese, sedentary males, aged 18-40 years participated in this study. Following a 12-hour overnight fast a biopsy was taken from the quadricep before and 4 hours after a high fat meal. Blood draws were obtained pre-biopsy while fasted and every hour for 4 hours post high fat meal consumption. Acylcarnitines from plasma were converted to their butyl esters and analyzed by electrospray ionization tandem mass spectrometry (MS/MS). Changes were observed in acetylcarntine (P=0.0125), glucose oxidation (P=0.0295), C16:1/C16:0 desaturation index (P= 0.0397), and C18:1/C18:0 desaturation index (P=0.0012). We did not find that individual changes in flexibility correlated with circulating acylcarnitine measurements in a fasted stateMaster of Science
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Lowes, Stephen. "Development of gas chromatography/mass spectrometry analysis of urinary acylcarnitines : application to metabolism studies." Thesis, Open University, 1991. http://oro.open.ac.uk/57333/.
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The metabolism of fatty acids in humans is recognized as an important source of energy. It is especially vital to newborn infants when metabolic pathways are often stressed as the early stages of life demand fundamental changes and developments of body processes. Defective fatty acid oxidation pathways can rapidly lead to a life-threatening situation. It has been suggested that such disorders may be responsible for a proportion of "cot death" or sudden infant death syndrome (SID S) cases. Recently, it has been found that the levels of acylcarnidnes in body fluids and tissue are potential indicators of fatty acid metabolism status. This is due to carnitine esters being produced and excreted in an attempt to alleviate the toxic accumulation of incompletely metabolized acyl units in the mitochondrion. However, clinical studies have been limited by a lack of convenient, unambiguous, sensitive and affordable analytical techniquesf or the measuremenot f physiological acylcarnitmnes. The nature of carnitine and its acyl esters presents analysis problems. They are involatile, zwitterionic compounds which makes them unsuitable for direct gas chromatography (GC) and combined gas chromatography/mass spectrometry (GCIMS). The latter of these is the favoured technique for normal urinary organic acid assays and is ideal in terms of selectivity and sensitivity. The work reported here details the development of a simple unambiguous and novel derivatization procedure in which acylcarnitines are cyclized to give volatile lactones, amenable to GC and GC/MS. The technique was subsequently applied to acylcarnitines extracted from urine. As such, the method has been used to identify acylcarnitine metabolites in the urine of children with diseases of fatty acid oxidation and amino acid catabolism. Investigations of the metabolism of exogenous 3-phenylpropionic and valproic acids was also conducted. The preliminary results from the application of capillary zone electrophoresis methods to acylcarnitine analysis are also reported.
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Brauer, Romy. "Einfluss präanalytischer Faktoren auf die Untersuchung des Aminosäure- und Acylcarnitinstoffwechsels." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-92011.
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Quantitative Untersuchungen krankheitsspezifischer oder krankheitsassoziierter metabolischer Signaturen in humanen Körperflüssigkeiten („Clinical Metabolomics“) haben zum Ziel neue Ansätze für diagnostische oder therapeutische Konzepte zu entwickeln. Die simultane quantitative Analytik von Aminosäuren (AS) und Acylcarnitinen (AC) mittels Tandem-Massenspektrometrie (MS/MS) ermöglicht die Erfassung wichtiger Stoffwechselwege des humanen Metabolismus. Hierzu zählen der Stoffwechsel der ketogenen AS, des Harnstoffzyklus oder der β-Oxidation langkettiger Fettsäuren. Allerdings wird die Konzentration der verschiedenen metabolischen Parameter in humanen Körperflüssigkeiten durch eine Vielzahl präanalytischer in vitro Störfaktoren und in vivo Einflussgrößen beeinflusst. Diese können zu signifikanten Veränderungen der Laborergebnisse führen.
Im Rahmen meiner Promotionsarbeit wurden in vitro Störfaktoren (Probenmaterial, Lagerung u. a.) und in vivo Einflussgrößen (Ernährung, physische Aktivität) untersucht und ein standardisiertes Präanalytik-Protokoll entwickelt. Dazu wurden pro Probe 3 µL Trockenblut (TB), 10 µL Serum oder Plasma nach Butylierung mittels Elektrospray-Ionisations-MS/MS analysiert und jeweils 26 AS und 35 AC in 1,5 Minuten simultan bestimmt.
Als Ergebnis der zahlreichen systematischen Präanalytik-Untersuchungen konnten signifikante Konzentrationsunterschiede der Metabolite zwischen kapillärer und venöser Blutentnahme sowie in Abhängigkeit des Hämatokrits gefunden werden. Im Vergleich zu Serum und antikoaguliertem Plasma (EDTA, Citrat, Heparin) waren die Konzentrationen der langkettigen AC im TB 5-fach höher. Nahrungsaufnahme und körperliche Aktivität führten ebenfalls zu signifikanten Veränderungen der AS- und AC-Konzentrationen. Durch Optimierung des Probenaufarbeitungsprotokolls konnte die Variabilität zwischen den Messtagen für 17 AS und 6 AC auf < 20 % gesenkt werden.
Die Ergebnisse meiner Promotionsarbeit unterstreichen den Einfluss präanalytischer Faktoren auf die Metabolomanalytik. Durch Etablierung und Einhaltung standardisierter präanalytischer Protokolle kann die präanalytische Varianz der Ergebnisse deutlich verringert werden. Sie stellen somit eine wichtige Voraussetzung für eine qualitativ hochwertige Metabolomanalytik im Rahmen klinischer Studien zur Identifizierung neuer Biomarker dar.
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Van, Noolen Laetitia. "Syndrome d’apnées obstructives du sommeil et métabolisme lipidique : étude animale et étude clinique préliminaire." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV035/document.
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Le syndrome d’apnées obstructives du sommeil (SAOS) est une pathologie caractérisée par des épisodes d’hypoxie intermittente (HI) nocturnes et est un problème de santé publique par sa prévalence dans la population générale (5-20%) et ses nombreuses complications métaboliques et cardiovasculaires. La répétition des épisodes d’HI est considérée comme le facteur principal responsable de cette morbidité cardiovasculaire dont l’athérosclérose fait partie. Le traitement de référence du SAOS par la pression positive continue présente dans certains cas une efficacité limitée, en particulier sur les conséquences cardiovasculaires qui nécessitent d’autres thérapeutiques plus spécifiques. Les mécanismes reliant SAOS et athérosclérose ne sont pas encore totalement connus. Cependant, des perturbations du métabolisme des acides gras (AG) en lien avec le processus athéromateux ont déjà été rapportées au cours du SAOS. Elles concernent en particulier le métabolisme de l’acide arachidonique (AG n-6) avec une augmentation d’eicosanoïdes pro-inflammatoires. Par ailleurs, les AG n-3 peuvent avoir une influence sur le développement et la progression des maladies cardiovasculaires, notamment grâce à une modification de la balance AG n-6 / AG n-3. Ainsi l’objectif de ce travail a donc été dans un premier temps de caractériser expérimentalement l’effet d’une supplémentation en AG n-3 sur le développement de l’athérosclérose dans le contexte d’HIC, et d’évaluer cliniquement la distribution AG n-6 / AG n-3 au niveau érythrocytaire chez des patients atteints d’un SAOS. Nous avons démontré que la supplémentation en AG n-3 permet de prévenir l’accélération de l’athérosclérose dans le contexte de l’HIC et est associée à une modulation de l’expression de certains médiateurs inflammatoires. Ces résultats prometteurs incitent à envisager une étude interventionnelle chez les patients SAOS. Dans un second temps, nous nous sommes intéressés au métabolisme des AG, via la β-oxydation mitochondriale, et aux métabolites intermédiaires produits, les acylcarnitines (ACs). Ces métabolites sont de plus en plus étudiés dans le contexte des pathologies cardiovasculaires. Nous avons étudié l’impact du SAOS sur la β-oxydation et ses conséquences sur la fonction vasculaire. L’étude de ces métabolites semble prometteuse et permettra peut-être l’émergence de marqueurs biologiques en relation avec l’état cardiovasculaire des patientsObstructive sleep apnea (OSA) syndrome is a disease characterized by recurrent episodes of nocturnal intermittent hypoxia (IH). OSA is a major public health problem due to its frequency in general population (5 to 20%) and its numerous metabolic and cardiovascular complications. Repetitive apneas lead to IH which is responsible of early atherosclerosis and cardiovascular complications. Gold standard treatment of OSA, that is to say continuous positive airway pressure, has poor effects on OSA cardiovascular consequences in some patients, underlining the need of alternative therapeutic strategies. Underlying mechanisms linking OSA to atherosclerosis are still poorly understood. Nevertheless, a link between polyunsaturated fatty acids (PUFAs) metabolism changes and atheromatous process has already been report during OSA syndrome. Arachidonic acid (n-6 PUFA) metabolism leads to increased biosynthesis of pro-inflammatory eicosanoids during OSA. Moreover, n-3 PUFAs influence cardiovascular complications progression especially by modifying n-6 FA / n-3 FA balance. The aim of this work was first to evaluate the influence of n-3 PUFAs supplementation on a CIH induced atherosclerosis progression model, and to clinically evaluate erythrocyte n-6 PUFA / n-3 PUFA distribution in OSA patients. We have shown that n-3 PUFAs supplementation prevents atherosclerosis acceleration in CIH exposed mice and is associated with a modulation of inflammatory mediators. These promising results encourage us to consider an interventional clinical study in OSA patients. In a second time, we have studied FA mitochondrial β-oxidation metabolism via acylcarnitines (ACs) metabolites. These ACs are increasingly studied especially in cardiovascular diseases context. OSA impact on β-oxidation metabolism and its vascular function consequences have been evaluated. ACs study is promising and will perhaps allow biological markers emergence in relation to cardiovascular pattern
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Sim, Keow Giak. "Quantitative Fibroblast Acylcarnitine Profiling In The Diagnostic and Prognostic Assessment of Mitochondrial fatty acid [beta]-oxidation disorders." Thesis, The University of Sydney, 2002. http://hdl.handle.net/2123/801.
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Mitochondrial fatty acid ß-oxidation disorders are a group of clinically and biochemically heterogeneous defects mainly associated with intolerance to catabolic stress. The diseases are potentially fatal, but treatable and the prognosis for most diagnosed disorders is generally favourable. Early diagnosis is thus important to prevent morbidity and mortality. This project describes an improved and validated quantitative fibroblast acylcarnitine profile assay for the investigation of suspected fatty acid ß-oxidation disorders. Intact cells were incubated with deuterium-labelled hexadecanoate and L-carnitine, and the accumulated acylcarnitines in the medium analysed using electrospray tandem mass spectrometry. This modified procedure is less demanding technically, requires fewer cells and better reflects the in vivo acylcarnitine status than previously published methods. Mitochondrial fatty acid ß-oxidation is coupled to the respiratory chain. Functional defects of one pathway may lead to secondary alterations in flux through the other. The diagnostic specificity and the prognostic potential of the in vitro acylcarnitine profile assay were investigated in fibroblasts from 14 normal controls, 38 patients with eight enzyme deficiencies of fatty acid ß-oxidation presenting with various phenotypes, and 16 patients with primary respiratory chain defects including both isolated and multiple enzyme complex defects. All fatty acid ß-oxidation deficient cell lines revealed disease-specific acylcarnitine profiles related to the sites of defects irrespective of the severity of symptoms or of different mutation. Preliminary studies suggested a correlation between severity of symptoms and higher concentrations of long-chain acylcarnitine species. However, the fibroblast acylcarnitine profiles from some patients with respiratory chain defects were similar to those of controls, whereas others had abnormal profiles resembling those found in fatty acid ß-oxidation disorders. In vitro acylcarnitine profiling is useful for the detection of fatty acid ß-oxidation deficiencies, and perhaps the prediction of disease severity and prognostic evaluation facilitating decisions of therapeutic intervention and genetic counselling. However, abnormal profiles do not exclusively indicate these disorders, and primary defects of the respiratory chain remain a possibility. Awareness of this diagnostic pitfall will aid in the selection of subsequent confirmatory tests and therapeutic options.
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GRELLET, GREGORY. "Etude de sels d'ammonium quaternaire par spectrometrie de masse : application a la detection du profil des acylcarnitines dans le sang chez le nouveau-ne." Paris 6, 2000. http://www.theses.fr/2000PA066194.
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Le but de ce travail de these est la mise au point d'une methode de detection des esters methyliques d'acylcarnitines dans le sang, a l'aide du couplage entre la chromatographie liquide (h. P. L. C. ) et la spectrometrie de masse en tandem (triple quadripole). Cette methode nous a permis de diagnostiquer les erreurs du metabolisme du cycle de degradation des acides gras (-oxydation mitochondriale) et du cycle de degradation des acides amines a chaines ramifiees, chez le nouveau-ne. La mise au point de la methode passe par deux etapes. Tout d'abord on determine les ions permettant d'identifier chacun des composes recherches (ions diagnostics). Cette identification a ete deduite des schemas de fragmentations induites par collision avec l'argon de chacune des acylcarnitines et de chacun des esters methyliques correspondants. Parmi tous les fragments, le seul ion commun a toutes les acylcarnitines est l'ion m/z 85. Il est deplace a la masse m/z=99 pour les derives methyles. Une sensibilite plus grande est obtenue a partir des derives methyles. Ainsi, les profils seront etablis en recherchant les parents de leur ion diagnostic (m/z 99). La deuxieme etape consiste en la mise au point et la validation de l'extraction de nos produits a partir d'une goutte de sang deposee sur un papier filtre de type guthrie. Il a ete necessaire d'optimiser la nature du solvant et sa quantite. La derivation des acylcarnitines en esters methyliques d'acylcarnitines a egalement ete optimisee : nature du groupe protecteur, quantite, temps et temperature de reaction. A l'heure actuelle, ces tests ont ete effectues sur les prelevements de 200 patients et cette methode a ete validee pour 6 erreurs du metabolisme. Une application au dosage de l'octanoylcarnitine
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Sim, Keow Giak. "Quantitative Fibroblast Acylcarnitine Profiling In The Diagnostic and Prognostic Assessment of Mitochondrial Fatty Acid �-Oxidation Disorders." University of Sydney. Paediatrics and Child Health, 2002. http://hdl.handle.net/2123/801.
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Mitochondrial fatty acid �-oxidation disorders are a group of clinically and biochemically heterogeneous defects mainly associated with intolerance to catabolic stress. The diseases are potentially fatal, but treatable and the prognosis for most diagnosed disorders is generally favourable. Early diagnosis is thus important to prevent morbidity and mortality. This project describes an improved and validated quantitative fibroblast acylcarnitine profile assay for the investigation of suspected fatty acid �-oxidation disorders. Intact cells were incubated with deuterium-labelled hexadecanoate and L-carnitine, and the accumulated acylcarnitines in the medium analysed using electrospray tandem mass spectrometry. This modified procedure is less demanding technically, requires fewer cells and better reflects the in vivo acylcarnitine status than previously published methods. Mitochondrial fatty acid �-oxidation is coupled to the respiratory chain. Functional defects of one pathway may lead to secondary alterations in flux through the other. The diagnostic specificity and the prognostic potential of the in vitro acylcarnitine profile assay were investigated in fibroblasts from 14 normal controls, 38 patients with eight enzyme deficiencies of fatty acid �-oxidation presenting with various phenotypes, and 16 patients with primary respiratory chain defects including both isolated and multiple enzyme complex defects. All fatty acid �-oxidation deficient cell lines revealed disease-specific acylcarnitine profiles related to the sites of defects irrespective of the severity of symptoms or of different mutation. Preliminary studies suggested a correlation between severity of symptoms and higher concentrations of long-chain acylcarnitine species. However, the fibroblast acylcarnitine profiles from some patients with respiratory chain defects were similar to those of controls, whereas others had abnormal profiles resembling those found in fatty acid �-oxidation disorders. In vitro acylcarnitine profiling is useful for the detection of fatty acid �-oxidation deficiencies, and perhaps the prediction of disease severity and prognostic evaluation facilitating decisions of therapeutic intervention and genetic counselling. However, abnormal profiles do not exclusively indicate these disorders, and primary defects of the respiratory chain remain a possibility. Awareness of this diagnostic pitfall will aid in the selection of subsequent confirmatory tests and therapeutic options.
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Miller, John H. IV. "A NEW APPROACH TO DRIED BLOOD SPOT ANALYSIS FOR NEWBORN SCREENING USING HIGH RESOLUTION LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2906.
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The primary purpose of newborn screening is to quickly identify children that are at risk of having a specific disorder in order to start treatment, prevent early death and reduce the chances of permanent physical or mental damage. The current and widely accepted approach used for identification of metabolism disorders involves a flow injection analysis with mass spectrometry detection of acylcarnitines and amino acids. Although this approach is widely accepted and has shown to be sufficient for identification of multiple metabolism disorders the method is not fully quantitative and results often have to be confirmed by second-tier tests. The primary focus of this research was to improve the accuracy and selectivity of this screening method by employing a high resolution chromatographic separation for the combined analysis of twelve acylcarnitines and seven amino acids. This method is an improvement over the current methodology allowing for separation of key isomers that are diagnostic for different metabolism disorders, reducing the need for multiple second-tier tests to confirm results and shortening the time to diagnosis. In order to further improve the efficiency of newborn screening we developed an in-line desorption device, which allows for direct analysis of DBS eliminating the need for punching disks from the filter paper cards. Our device was the first published paper that demonstrated the ability to directly analyze dried blood spots, without the need for any offline sample processing. Using this device, we validated a method to quantify biomarkers related to Maple Syrup Urine Disease, a disorder that requires a second-tier test for confirmation. To further improve the accuracy of dried blood spot analysis we evaluated a technique to correct the sample volume in low and high hematocrit samples. The level of hematocrit in blood spotted on filter paper cards affects the volume of sample analyzed, leading to errors in accuracy. Diffuse reflectance was used to relate differences in sample hematocrit on dried blood spots. We validated our technique with eighteen donor samples at various levels of hematocrit. Correcting sample volume for hematocrit showed improved precision and accuracy over the standard approach, ultimately reducing the potential to misidentify samples.
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Schmidt, Julie Andersen. "Epidemiology of metabolite profile and prostate cancer risk." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:468ca322-16a3-4f61-8fcc-bac9b918300c.
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Insulin-like growth factor-I (IGF-I) is the only known potentially modifiable risk factor for prostate cancer. Intake of dietary protein, especially from dairy products, might also be associated with risk and with circulating IGF-I, but it is not clear if amino acids play a role in these relationships. Moreover, investigations of circulating concentrations of metabolites might reveal novel risk factors for prostate cancer. This thesis investigates plasma concentrations of amino acids and other metabolites in relation to protein intake, IGF-I, and prostate cancer risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). To characterise plasma metabolite profile in men consuming markedly different amounts and types of animal products (meat-eaters, fish-eaters, vegetarians and vegans), cross-sectional analyses of 392 men in the EPIC-Oxford sub-cohort were conducted. Of 21 amino acids, six varied significantly by diet group, and the metabolite profile of vegans was different from those of other diet groups owing to lower concentrations of several glycerophospholipids and sphingolipids. In a case-control study nested within EPIC, with a mean follow-up time of seven years, the relationship of plasma metabolites with risk of prostate cancer overall, by time to diagnosis, by tumour characteristics, and with risk of prostate cancer death, was investigated. Data from 1,077 matched sets suggested that seven metabolites, from various classes, were associated with risk of prostate cancer overall (p < 0.05). After correction for multiple testing, 12 glycerophospholipids were inversely associated with risk of advanced prostate cancer (the strongest OR1SD = 0.54; 95%CI: 0.40-0.72). In multivariate analyses, including data from 1,593 matched sets, principal component analysis (PCA) and treelet transform (TT) were used to identify patterns in metabolite profile, five of which were associated with risk of more aggressive tumour sub-types (high grade, advanced and aggressive disease) and/or prostate cancer death. There was a ≈ 50% lower risk of advanced and high grade prostate cancer in men with metabolite profiles characterised by high glycerophospholipids and sphingolipids (for advanced ORTT, top vs bottom third = 0:48; 95%CI: 0:31-0:74), with similar results for high grade and PCA). To investigate if associations between protein intake and circulating IGF-I may be mediated by plasma amino acid concentrations, cross-sectional analyses of amino acid concentrations with protein intake and IGF-I concentrations were carried out in 1,697 and 1,142 control participants, respectively, from the nested case-control study. Dairy protein intake was positively associated with concentrations of branched-chain amino acids and several other essential amino acids, while plant protein intake was strongly associated only with histidine. Serum IGF-I was positively associated with arginine and inversely with ornithine and certain amino acid ratios. In conclusion, men with different dietary habits with respect to the consumption of protein types have different amino acid and metabolite profiles, and metabolite concentrations may be associated with risk of more high-risk prostate cancer sub-types (high grade, advanced and aggressive disease) and prostate cancer death. Further large-scale studies are needed to determine if metabolites play a role in aetiology or are markers of sub-clinical prostate cancer.
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Roussel, Julien. "Effets d’une variation de la concentration en acyl-carnitine sur le remodelage ventriculaire et les troubles du rythme." Thesis, Montpellier 2, 2014. http://www.theses.fr/2014MON20034.
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La contraction cardiaque nécessite un apport énergétique important, dont la source principale est l'oxydation des acides gras dans la mitochondrie. Ces acides gras pénètrent dans la mitochondrie sous la forme d'acyl-carnitine. Lors du couplage excitation-contraction, il y a une communication entre la contraction et le métabolisme assurée par les variations de potentiel et les variations calciques concomitantes. Cette communication permet d'adapter la quantité d'énergie synthétisée en fonction des besoins contractiles. Des observations cliniques et expérimentales indiquent que le métabolisme module également les mécanismes de contraction. En effet de fortes modifications de la balance énergétique observée lors de pathologie comme le syndrome métabolique ou le déficit primaire en carnitine induisent des dysfonctions contractiles et des troubles du rythme cardiaque. L'homéostasie mitochondriale semble tenir un rôle important dans cette communication, mais les mécanismes impliqués restent encore mal connus. Dans ce travail nous nous sommes intéressés à comprendre les comment de fortes variations d'acyl-carnitine influencent l'apparition de troubles du rythme et participent au remodelage ventriculaire. Lors d'une approche intégrative nous avons mis en évidence le rôle central de l'adenine nucleotide transporteur (ANT) dans la genèse des troubles du rythme induit par une forte concentration en palmitoyl-carnitine. De plus des études in vivo sur des animaux déficients en carnitine, ont permis de décrire pour la première fois une relation entre une diminution de l'intervalle QT (QT court) avec un désordre métaboliqueHeart contraction requires a considerable amount of energy. Mitochondrial fatty acid oxidation is the major source of energy production in the heart. Fatty acids diffuse through the mitochondrial membrane in the acyl-carnitine form. During excitation-contraction coupling, variations of membrane potential and calcium concentration allow the communication between contraction and metabolism. This communication allows the adaption of energy production into contractile function. Clinical and experimental observations indicate that metabolism modulates contraction mechanisms. In particular, the energetic imbalance observed in metabolic syndrome or primary carnitine deficiency induces a contractile disturbance and arrhythmias. Mitochondrial homeostasis seems to be an important participant though the mechanisms involved in this phenomenon remain to be completely elucidated. In this study, we examined the influence of acylcarnitine concentration variations on cardiac rhythm and ventricular remodeling. Through an integrative approach, we have demonstrated the pivotal role of the adenine nucleotide transporter (ANT) in the apparition of high acylcarnitine concentration associated arrhythmia. Furthermore, in vivo studies with carnitine deficient mice reveal, for the first time, a relationship between the QT interval duration (short QT) and metabolic disturbance
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Femppel, Christina [Verfasser]. "Evaluation einer Methode zur Bestimmung der Acylcarnitine und Acylglycine im Urin mittels Fließinjektion und tandem-massenspektrometrischer Detektion / Christina Femppel." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/105253001X/34.
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Sutherland, Sarah C. "Characteristics Associated with Neonatal Carnitine Levels: A Systematic Review & Clinical Database Analysis." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23744.
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Newborn screening programs measure analyte levels in neonatal blood spots to identify individuals at high risk of disease. Carnitine and acylcarnitine levels are primary markers used in the detection of fatty acid oxidation disorders. These analytes may be influenced by certain pre/perinatal or newborn screening related factors. The primary objective of this study was to explore the association between these characteristics and levels of blood carnitines and acylcarnitines in the newborn population. The study was composed of two parts: a systematic review and a clinical database analysis of existing newborn screening data. The systematic review results suggested considerable variability across studies in the presence and directionality of associations between analyte levels and birth weight, gestational age, age at time of blood spot collection, type of sample, and storage time. Sex was not significantly associated with carnitine or acylcarnitine levels in neonatal blood. We identified a need to more fully investigate a potential interaction between gestational age and birth weight in regard to analyte levels. The secondary data analyses indicated a statistically significant relationship between analyte levels and all perinatal / infant and newborn screening related factors of interest, but effect sizes were generally small. The interaction between gestational age and birth weight was significant in all models; when further explored through graphical analysis with conditional means, extremely premature neonates stood out as having distinct analyte patterns in relation to birth weight. Variation in the ratio of total acylcarnitine to free carnitine was better accounted for by the perinatal and newborn factors than was variation in any individual carnitine or acylcarnitine, indicating that proportions of carnitine and acylcarnitines may be more important in understanding an individual’s metabolic functioning than individual analyte levels. A low proportion of variation was explained in all multivariate models, supporting the use of universal algorithms in newborn screening and suggesting the need for further large scale empirical research targeted at previously unaccounted for perinatal factors such as birth stress.
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Klupsch, Birgit. "Neue Methoden des Therapiemonitorings bei Patienten mit Propionazidämie und Methylmalonazidämie durch die Quantifizierung der Acylcarnitine im Trockenblut mittels Tandemmassenspektrometrie Referenzwerte bei gesunden Erwachsenen /." [S.l. : s.n.], 2003. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10733035.
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Rosas-Garcia, Victor Manuel. "Towards the Design of Carnitine Acyltransferase Inhibitors: Modeling the Conformational Behavior of (R)-Carnitine, (R)-Acetylcarnitine, Morpholinium rings, and 2-Oxo-1,3,6-dioxazaphosphacinium rings." Diss., Virginia Tech, 1997. http://hdl.handle.net/10919/79727.
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Full grid-search semiempirical calculations (AM1 and AM1/COSMO) on zwitterionic acetylcarnitine and carnitine, cationic acetylcholine and choline, and 3-acetoxypropanoate and 3-hydroxypropanoate in the gas phase and solution were performed. The calculated ΔHhydr for hydrolyses of acetylcarnitine to carnitine and of acetylcholine to choline show reasonable agreement with the experimental values in unbuffered solution (acetylcarnitine: -4.63 kcal/mol calc. vs. -7.43 kcal/mol exp.; acetylcholine: -3.20 kcal/mol calc. vs. -3.06 kcal/mol exp.) The results suggest that a change in the conformational populations of acetylcarnitine-carnitine upon hydrolysis maintains a nearly constant polarity, which keeps the work of desolvation of the products to a minimum. Acetylcholine-choline and acetoxypropanoate-hydroxypropanoate present a much higher work of desolvation, therefore yielding a lower free enthalpy of hydrolysis. Ab initio calculations at the RHF/6-31G* level for the carnitines and the cholines, and RHF/6-31+G for the propanoates, were done to calibrate the quality of the AM1 results for both the gas phase and in solution. The calculations in the gas phase involved full optimization of the AM1-optimized structures at the RHF/6-31G* level and RHF/6-31+G level, and single points at the MP2//RHF/6-31G* and MP2//RHF/6-31+G level to estimate correlation effects. The ab initio calculations in solution were single points on the AM1-optimized geometries and used the Tomasi solvent model. The ab initio results confirmed the qualitative reliability of the semiempirical results.
The conformational behavior of several 4,4-dimethylmorpholinium rings and 4,4-dimethyl-2-oxo-1,3,6-dioxazaphosphacinium rings was examined by molecular mechanics (AMBER* and AMBER*-GB/SA). The contrast between the behavior of these heterocycles and that of the parent saturated hydrocarbon systems formed a picture of the conformational behavior of these six- and eight-membered heterocycles. Influences of factors such as shortened bond lengths, varied bond angles, presence or absence of lone pairs and substituents, and dipolar alignment are described. Morpholinium rings show increased stabilization of the twist-boat with 1,1,3,3-digem substitution, as compared to the parent cyclohexane systems. In the gas phase, the lowest chair/twist-boat energy gap is found in 2-(hydroxymethyl)-2,4,4-trimethylmorpholinium at 1.14 kcal/mol. The gap in the congruent hydrocarbon system is 5.23 kcal/mol. Differential solvation destabilizes the lowest energy twist-boat found in the gas phase, increasing the energy gap to 2.62 kcal/mol. The lowest chair/twist-boat energy gap in GB/SA water amounts to 1.45 kcal/mol, stabilized by solvation from an initial 2.13 kcal/mol in the gas phase.
In the dioxazaphosphacinium rings, the preferred conformation in the gas phase is the boat-chair (BC) and the populations are conformationally heterogeneous. As substituents approach a 1,1,3,3-digem pattern, the twist-chair (TC) and twist-boat (TB) conformers are stabilized. Solvation favors boat-boat (BB) conformers, with the substituents exerting influence on the conformational preference only to stabilize the TB in two instances (cis-substituted ring and disubstituted ring). Solvation reduces the heterogeneity of the conformational populations.
Modeling of phosphonate moieties required development of molecular mechanics parameters for dimethyl methylphosphonate. Dimethyl methylphosphonate conformations were calculated at the RHF/6-31+G* level. Charges were calculated by the CHelpG scheme. The results were used to generate AMBER* parameters for modeling of alkylphosphonates in the gas phase and in solution. Comparison of the results of our AMBER* parameters against three other common force fields (MM2*, MMX and UFF) showed that AMBER* reproduced better the ab initio results when comparing absolute deviations in bond lengths, bond angles and torsion angles. The modified AMBER* reproduced better than the other three force fields several X-ray geometries of alkylphosphonates.Ph. D.
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Ehlers, Kerstin Christina [Verfasser], Johann Josef [Akademischer Betreuer] Hauner, and Martin [Akademischer Betreuer] Klingenspor. "From GWAS to functionality: association of rs2014355 in the ACADS gene locus with acylcarnitine ratio and postprandial metabolic and inflammatory activation of human PBMC / Kerstin Christina Ehlers. Gutachter: Martin Klingenspor ; Johann Josef Hauner. Betreuer: Johann Josef Hauner." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1049281098/34.
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Mallah, Khalil. "In depth systemic biology analysis of central nervous system injuries." Thesis, Lille 1, 2018. http://www.theses.fr/2018LIL1S108/document.
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Dans un contexte d’étude des altérations biologiques survenant après un impact sur le système nerveux central (SNC), ma thèse porte sur l’étude des modifications protéomiques et lipidiques survenant après une lésion du SNC. Une étude spatio-temporelle a été menée sur un modèle TBI de rat afin d'identifier des marqueurs spécifiques de la lésion. En utilisant le MALDI-MSI, nous avons effectués une reconstruction 3D du cerveau lésé 3 jours post-lésion et nous avons représentés les molécules lipidiques spécifiques à la lésion. Après, cette analyse est réalisé avec d’autres délais après l’impact: 1, 3, 7 et 10 jours. En parallèle, une analyse microprotéomique est réalisée sur des coupes de tissus dans une approche visant à corréler les modifications lipidiques et protéiques. Nos résultats ont permis d'identifier une famille de lipides, les acylcarnitines, exprimés dans le cortex lésé avec une intensité maximale à 3 jours post-impact. Les données de protéomiques ont montrés une régulation positive de l’expression de protéines liées à la maladie de Parkinson. Dans l’ensemble, nos résultats décrivent un lien entre le TBI léger et la maladie de Parkinson dès 3 jours après l’impact, avec un rôle possible de l’acylcarnitine. Cette même famille de molécules est aussi présente dans les lésions médullaires. Dans une approche thérapeutique, les résultats précédents ont montrés que la protéine RhoA est un candidat majeur dans SCI. Après avoir utilisé un inhibiteur de RhoA, une étude protéomique a été réalisée pour évaluer l’impact sur ces lésions. Les résultats montrent que les traitements in-vivo et in-vitro avec l’inhibiteur stimule la croissance neuritique et la régénération axonaleIn the context of studying biological alterations occurring post impact to the central nervous system, my thesis was focused on studying the proteomic and lipid changes occurring post injury to the brain and spinal cord. A fundamental spatio-temporal study was conducted on an open-head rat TBI model to identify potential injury-specific markers. Using MALDI MSI, we performed 3D reconstruction of the injured brain at 3 days after injury and depicted lesion-specific m/z lipid molecules. After, MALDI MSI was applied on the acute/sub-acute time frame post impact: 1 day, 3 days, 7 days, and 10 days. In parallel, a microproteomic analysis was carried out on tissue segments directly consecutive to the imaged ones in an approach to correlate both lipid and protein changes. Our results yielded the identification of a family of lipids, acylcarnitines, which are expressed within the injured cortex with maximum intensity 3 days post impact. These lipid molecules also were found to be expressed in the substantia nigra and microproteomics data showed an upregulation in expression of Parkinson’s related proteins. Taken altogether, our results depict a role of link between mild-TBI and Parkinson’s disease as early as 3 days post impact, with a possible role of acylcarnitine. This same family of molecules was also present in SCI. In a therapeutic approach previous results showed RhoA protein as a major candidate post impact in SCI. After using RhoA inhibitor treatment, a proteomic study was carried out to investigate its impact on SCI. The results showed that both in-vivo and in-vitro treatment with RhoA inhibitor stimulated neurite outgrowth and helped in axonal regeneration
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Brauer, Romy. "Einfluss präanalytischer Faktoren auf die Untersuchung des Aminosäure- und Acylcarnitinstoffwechsels." Doctoral thesis, 2011. https://ul.qucosa.de/id/qucosa%3A11565.
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Quantitative Untersuchungen krankheitsspezifischer oder krankheitsassoziierter metabolischer Signaturen in humanen Körperflüssigkeiten („Clinical Metabolomics“) haben zum Ziel neue Ansätze für diagnostische oder therapeutische Konzepte zu entwickeln. Die simultane quantitative Analytik von Aminosäuren (AS) und Acylcarnitinen (AC) mittels Tandem-Massenspektrometrie (MS/MS) ermöglicht die Erfassung wichtiger Stoffwechselwege des humanen Metabolismus. Hierzu zählen der Stoffwechsel der ketogenen AS, des Harnstoffzyklus oder der β-Oxidation langkettiger Fettsäuren. Allerdings wird die Konzentration der verschiedenen metabolischen Parameter in humanen Körperflüssigkeiten durch eine Vielzahl präanalytischer in vitro Störfaktoren und in vivo Einflussgrößen beeinflusst. Diese können zu signifikanten Veränderungen der Laborergebnisse führen.
Im Rahmen meiner Promotionsarbeit wurden in vitro Störfaktoren (Probenmaterial, Lagerung u. a.) und in vivo Einflussgrößen (Ernährung, physische Aktivität) untersucht und ein standardisiertes Präanalytik-Protokoll entwickelt. Dazu wurden pro Probe 3 µL Trockenblut (TB), 10 µL Serum oder Plasma nach Butylierung mittels Elektrospray-Ionisations-MS/MS analysiert und jeweils 26 AS und 35 AC in 1,5 Minuten simultan bestimmt.
Als Ergebnis der zahlreichen systematischen Präanalytik-Untersuchungen konnten signifikante Konzentrationsunterschiede der Metabolite zwischen kapillärer und venöser Blutentnahme sowie in Abhängigkeit des Hämatokrits gefunden werden. Im Vergleich zu Serum und antikoaguliertem Plasma (EDTA, Citrat, Heparin) waren die Konzentrationen der langkettigen AC im TB 5-fach höher. Nahrungsaufnahme und körperliche Aktivität führten ebenfalls zu signifikanten Veränderungen der AS- und AC-Konzentrationen. Durch Optimierung des Probenaufarbeitungsprotokolls konnte die Variabilität zwischen den Messtagen für 17 AS und 6 AC auf < 20 % gesenkt werden.
Die Ergebnisse meiner Promotionsarbeit unterstreichen den Einfluss präanalytischer Faktoren auf die Metabolomanalytik. Durch Etablierung und Einhaltung standardisierter präanalytischer Protokolle kann die präanalytische Varianz der Ergebnisse deutlich verringert werden. Sie stellen somit eine wichtige Voraussetzung für eine qualitativ hochwertige Metabolomanalytik im Rahmen klinischer Studien zur Identifizierung neuer Biomarker dar.
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Silva, Liliana Adelina Gonçalves da. "Conjugation of fatty acids with coenzyme A, carnitine or glycine : role in mitochondrial energy metabolism and detoxification." Master's thesis, 2013. http://hdl.handle.net/10451/11552.
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Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2013Carnitine and glycine conjugation are two distinct phase II reactions with relevance for detoxification, and share common substrates, the acyl-Coenzyme A (CoA) esters. The metabolism of valproic acid (VPA), an “epigenetic” drug in clinical practice for decades, has been used within our group as a model system to elucidate drug-induced mitochondrial dysfunction and liver disease, probably common to other carboxylic acid xenobiotics which may be activated to CoA esters. The pharmacotoxicological properties of VPA and their unequivocal interaction with mitochondrial energy metabolism are at the basis of the current project, whose prime objectives were: 1.) the characterization in biological samples of metabolites biomarkers of mitochondrial energy metabolism dysfunction; 2.) application of high resolution chromatographic methods coupled to mass spectrometry to the study of metabolites conjugates, namely the glycine and carnitine esters (acylglycines and acylcarnitines, respectively). Both studies may provide information on the homeostasis of the precursors, acyl-CoAs, and ultimately, the fatty acids and organic acids. A thorough approach on the metabolic significance of acylglycines in biological fluids was undertaken, using stable isotope dilution gas chromatography coupled to mass spectrometry to measure propionyl-, butyryl-, isobutyryl-, 2-methylbutyryl-, isovaleryl-, 3-methylcrotonyl-, hexanoyl- and suberylglicine. The in vivo profiles of these intermediary metabolites were evaluated in biological samples from Wistar rats subjected to a VPA regimen; pediatric patients undergoing chronic treatment with VPA and patients identified with inborn errors of metabolism. The accumulation of acyl-CoA esters intermediates gave rise to a VPA-associated increase on the corresponding products, acylglycines. In addition, novel insights on VPA biotransformation were achieved. As predicted, propionyl-CoA, the end product of VPA thiolytic cleavage was converted to propionylglycine adding a novel phase II reaction to VPA metabolism. Moreover, we initiated the set-up of a new method in our laboratory for the qualitative characterization of carnitine and acylcarnitines using positive electrospray tandem mass spectrometry in plasma and urine. The characterization of short- to long-chain acylcarnitines profiles was performed and additional studies are in course to validate the procedure and quantify the compounds. The differential determination of free carnitine and acylcarnitines levels including acetylcarnitine or palmitoylcarnitine, will support the study of fatty acid oxidation flux, the functional analysis of carnitine acyltransferases activity or the biomonitoring of carnitine or acetylcarnitine as potential therapeutic agents. The overall obtained results allowed to study not only the intermediary metabolism in vivo, which reflects the function and/or dysfunction in cell, but also the biochemical pathways of VPA detoxification, potentially common to other acidic drugs, their metabolites or endogenous molecules.
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Thompson, Legault Julie. "L'application de la métabolomique à la découverte de nouveaux biomarqueurs chez les patients atteints d'acidose lactique." Thèse, 2013. http://hdl.handle.net/1866/11247.
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L’acidose lactique du Saguenay-Lac-St-Jean, ou syndrome de Leigh de forme canadienne-française (LSFC), est une maladie mitochondriale neurodégénérative causée par des mutations du gène LRPPRC et caractérisée par des crises d’acidose menant au décès en bas âge. On ne comprend pas encore les causes exactes de ces crises, et aucun traitement n’est actuellement disponible. L’objectif de cette étude a été de comparer le profil des métabolites sanguins et urinaires chez des sujets LSFC et des témoins, avant et après un repas, par une approche métabolomique ciblée. Le projet s’inscrit dans une démarche à long terme visant l’identification de biomarqueurs prédictifs des crises, permettant d'intervenir plus rapidement afin d’éviter le décès. Les échantillons biologiques ont été prélevés chez 9 sujets atteints du LSFC et 9 témoins appariés, à jeun et 90 minutes après un repas standardisé. Les analyses incluent un bilan biochimique et hormonal, un profil des acides aminés, des acides gras, des acides organiques et des acylcarnitines. Les métabolites significativement modifiés chez les patients peuvent être classés en deux catégories : (i) le reflet d’une dysfonction mitochondriale, et plus particulièrement de l’accumulation d’équivalents réduits en amont de la chaîne respiratoire, et (ii) des indices de risque cardiométabolique, qui s’observent davantage chez les patients adultes malgré leur jeune âge. Ainsi, il serait intéressant d’inclure au traitement des stratégies visant la diminution des facteurs de risque cardiométabolique, notamment par une modification des habitudes de vie. Notre étude démontre la pertinence d’avoir recours à la métabolomique dans l’étude des désordres de la phosphorylation oxydative.L’acidose lactique du Saguenay-Lac-St-Jean, ou syndrome de Leigh de forme canadienne-française (LSFC), est une maladie mitochondriale neurodégénérative causée par des mutations du gène LRPPRC et caractérisée par des crises d’acidose menant au décès en bas âge. On ne comprend pas encore les causes exactes de ces crises, et aucun traitement n’est actuellement disponible. L’objectif de cette étude a été de comparer le profil des métabolites sanguins et urinaires chez des sujets LSFC et des témoins, avant et après un repas, par une approche métabolomique ciblée. Le projet s’inscrit dans une démarche à long terme visant l’identification de biomarqueurs prédictifs des crises, permettant d'intervenir plus rapidement afin d’éviter le décès. Les échantillons biologiques ont été prélevés chez 9 sujets atteints du LSFC et 9 témoins appariés, à jeun et 90 minutes après un repas standardisé. Les analyses incluent un bilan biochimique et hormonal, un profil des acides aminés, des acides gras, des acides organiques et des acylcarnitines. Les métabolites significativement modifiés chez les patients peuvent être classés en deux catégories : (i) le reflet d’une dysfonction mitochondriale, et plus particulièrement de l’accumulation d’équivalents réduits en amont de la chaîne respiratoire, et (ii) des indices de risque cardiométabolique, qui s’observent davantage chez les patients adultes malgré leur jeune âge. Ainsi, il serait intéressant d’inclure au traitement des stratégies visant la diminution des facteurs de risque cardiométabolique, notamment par une modification des habitudes de vie. Notre étude démontre la pertinence d’avoir recours à la métabolomique dans l’étude des désordres de la phosphorylation oxydative.
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Klupsch, Birgit [Verfasser]. "Neue Methoden des Therapiemonitorings bei Patienten mit Propionazidämie und Methylmalonazidämie durch Quantifizierung der Acylcarnitine im Trockenblut mittels Tandemmassenspektrometrie : Referenzwerte bei gesunden Erwachsenen unter verschiedenen Bedingungen / vorgelegt von Birgit Klupsch." 2003. http://d-nb.info/968364500/34.
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