Dissertations / Theses on the topic 'Metabolic disorders'
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Shaham, Oded. "A metabolic profiling approach to human disorders of energy metabolism." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/54670.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.Cataloged from PDF version of thesis.
Includes bibliographical references.
The integrated network of biochemical reactions known collectively as metabolism is essential for life, and dysfunction in parts of this network causes human disease - both rare, inherited disorders and common diseases such as diabetes mellitus. The study of metabolic disease depends upon quantitative methods which are traditionally custom-tailored to a given compound. Recent advances in technologies such as mass spectrometry now enable the simultaneous measurement of a diverse metabolite collection spanning multiple biological pathways, an approach known as metabolic profiling or metabolomics. This dissertation describes the development of one such metabolic profiling system and its application to the study of two major topics in human energy metabolism: the fasting:feeding transition and mitochondrial disease. In the first study, we profile human plasma in response to glucose ingestion, detecting dozens of metabolite changes and identifying several distinct effects of insulin. Based on these observations, we propose a multivariate view of insulin sensitivity, and show that individuals at risk for developing diabetes mellitus can differ in their insulin response profile, a concept of potential value for estimating disease risk and progression. In the second study, we elucidate a metabolic signature of human mitochondrial disease that reflects substrate oxidation, biosynthesis and energy charge.
(cont.) We demonstrate that the culture media profile of a cellular disease model of mitochondrial dysfunction reflects the plasma profile of human patients, an approach that could be applicable to other diseases as well. In addition, we show that a combination of metabolites distinguishes individuals with mitochondrial disease from healthy individuals better than the currently used diagnostic markers. Our findings provide insight into human disorders of energy metabolism, and demonstrate the utility of a profiling approach for the understanding of metabolic disease.
by Oded Shaham.
Ph.D.
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Swetye, Michael Harrison. "Monitoring, identification, and intervention for metabolic disorders in veterans with psychotic disorders." [New Haven, Conn. : s.n.], 2008. http://ymtdl.med.yale.edu/theses/available/etd-12092008-164555/.
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Gkrania-Klotsas, Effrossyni. "Infections and metabolic diseases." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610669.
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Steinberg, Steven Jeffrey. "Biochemical characterisation and genetic complementation analysis of generalised peroxisomal disorders and Niemann-Pick disease type C." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294755.
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Spathaky, Jane Mary. "A novel method for the isolation of genes encoding peroxisomal matrix proteins." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361693.
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Grosbellet, Edith. "Reciprocal relationships between circadian disruptions and metabolic disorders." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ060.
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Tous les organismes présentent des rythmes biologiques sous le contrôle d’horloges internes synchronisées sur le cycle jour-nuit. La perturbation des horloges (travail posté chez l’homme) conduit souvent à des troubles métaboliques. A l’inverse, obésité et diabète sont associés à des perturbations circadiennes. Mon but est de comprendre les mécanismes impliqués dans le lien réciproque entre perturbations circadiennes et troubles métaboliques. Une première partie révèle le rôle de la leptine dans les troubles circadiens de souris génétiquement obèses, au niveau central et périphérique. Dans une seconde partie, nous montrons que l’altération des cycles jour-nuit induit une désynchronisation circadienne chez un rongeur diurne, entraînant un état pré-diabétique et un vieillissement prématuré des cellules hépatiques. Nos résultats ouvrent la voie à des traitements préventifs visant à diminuer les troubles circadiens des patients obèses et les troubles métaboliques des travailleurs postésMost organisms exhibit biological rhythms, generated endogenously by circadian clocks, which are synchronized on the light-dark cycle. Disrupting circadian clocks (e.g, shiftwork) lead in most cases to the occurrence of metabolic disorders. Conversely, obesity and diabetes are associated with circadian disruptions. The aim of my project is to provide new insights in the understanding of mechanisms underlying the reciprocal relationships between circadian disruptions and metabolic disorders. We show in a first part that leptin is involved in circadian disturbances of genetically obese mice, at both central and peripheral levels. In a second part, by altering the light-dark cycle, we induce the circadian desynchronization of a diurnal rodent, which leads in turn to a pre-diabetic state associated with accelerated aging of hepatic cells. Our results pave the road to preventive treatments aiming at reducing circadian disruptions in obese patients and metabolic disorders in shiftworkers
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Marsland, C. H. "Chirality of urinary metabolites in inherited metabolic disorders." Thesis, Sheffield Hallam University, 1989. http://shura.shu.ac.uk/20019/.
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An important group of inherited metabolic disorders in man produce abnormal excretion of organic acids in the urine. Diagnosis is usually based on identification of the abnormal metabolites, working back from there to characterise the defect at enzymatic level. The chirality of these metabolites may be significant in that the different enantiomers of a substance usually have different metabolic origins. Thus, knowledge of the chirality of a metabolite aids in the understanding of the mechanism of the disorder. The chirality of a number of urinary metabolites in inherited metabolic disease was examined using gas chromatography-mass spectrometry, most of the analyses being performed using single ion monitoring. This analytical method requires the use of chiral reference compounds of known configuration. Chiral lactic and glyceric acids are available commercially, but a range of chiral beta-hydroxy acids were prepared by the reduction of the corresponding beta-ketocarboxylic acid esters with fermenting baker's yeast. After hydrolysis of the esters, separation of the enantiomers is based on their reaction with a suitable chiral reagent to form a volatile mixture of the diastereoisomers which are resolved by gas-liquid chromatography using a capillary column with a non-chiral stationary phase. Information from the analysis of the chiral standards was used to assign the absolute configuration of the following urinary metabolites; lactic acid in an unusual case of lactic aciduria, glyceric acid in the glyceric acidurias, beta-hydroxybutyrate in ketonuria, beta-hydroxyvalerate in propionic acidaemia, 2-methyl beta-hydroxybutyrate in beta-ketothiolase deficiency and beta-hydroxyadipic acid in hydroxydicarboxylic aciduria. The biochemical significance of the chirality of each of these metabolites is discussed. The assigning of configuration to urinary beta-hydroxyvalerate in propionic acidaemia, 2-methyl beta-hydroxybutyrate in beta-ketothiolase deficiency and beta-hydroxyadipic acid in hydroxydicarboxylic aciduria represents original work and has helped to elucidate the metabolic origins of these compounds.
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Kaushanska, O. V. "Peculiarities of gout in patients with metabolic disorders." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18590.
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Lorbeer, Roberto [Verfasser]. "Endocrine-metabolic markers and subclinical cardiovascular disorders / Roberto Lorbeer." Greifswald : Universitätsbibliothek Greifswald, 2012. http://d-nb.info/1022132911/34.
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Foletti, Mara. "Role of metabolic disorders in estrogen induced reproductive cancer." kostenfrei, 2007. http://e-collection.ethbib.ethz.ch/view/eth:30023.
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Bozkurt, Ozlem. "Study Of Bone Characteristics And Muscle Quality In Metabolic Disorders." Phd thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12614561/index.pdf.
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Although the effects of diabetes on bone mineral content has been studied, little is known about the structural alterations in collagen, maturation of apatite crystals and carbonate content in diabetic bone. The first part of this study aimed to investigate the mineral and organic properties of cortical, trabecular and growth plate regions of rat femur tissues in type I diabetes using FTIR microspectroscopy and Vickers microhardness test. A decrease in mineral content (degree of mineralization), decrease in microhardness, increase in carbonate content, increase in size and maturation of hydroxyapetite crystals, which are the implications of increased osteoporosis, were observed in diabetic bone. In addition, a decreased carbonate substitution into bone apatite and an increase in labile type carbonate was observed in diabetic bone. There was a decrease in the level of crosslinking of collagen in cortical and trabecular regions of diabetic femurs, implying a decrease in bone collagen quality that may contribute to bone fragility.
Recent evidence implies that intramyocellular lipid accumulation is directly correlated with insulin resistance, a key parameter in the generation of obesity. The second part of this study is mainly focused on the determination of the structural and compositional characterization of macromolecules of longissimus dorsi and quadriceps muscles of Berlin fat mouse inbred (BFMI) lines using ATR-FTIR spectroscopy and FTIR microspectroscopic imaging, together with the quantification of fiber specific distribution of lipids in these muscles by the use of confocal microscopy. The study groups included 10 weeks old standard breeding diet fed (juvenile) and 20 weeks old high fat diet fed control and BFMI lines. The results revealed the loss of unsaturation in lipids, increased triglyceride content, increased amount of lipids having shorter chain length, increased lipid peroxidation and fiber specific accumulation of lipids in type IIa and intermediate fibers in skeletal muscles of both 10 weeks old and 20 weeks old BFMI lines, emphasizing their obese phenotype. However, the alterations were more prominent in skeletal muscles of 20 weeks old high fat diet fed BFMI lines, displaying a more severe obesity phenotype. The results of the characterization revealed that BFMI860 and BFMI861 lines are convenient models for the study of spontaneous obesity and studies to enlighten the genetic basis of obesity.
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Schuhmann, Kai. "Shotgun lipidomics of metabolic disorders by high resolution mass spectrometry." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-101305.
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The characterization of lipids is performed by mass spectrometry based on structure specific fragments or by accurate mass measurements of intact precursor ions. The latter method, termed ’top-down lipidomics’, is due to its robustness, simplicity and speed a valuable tool for medical research to elucidate the molecular background of lipid metabolic disorders.
The current thesis aims to improve the established lipidomics methods.
Therefore, a new top-down lipidomics method was introduced that increased the analysis throughput, lipidome coverage and accuracy of quantification, compared to previous approaches, by rapid successive acquisition of high resolution Fourier transform mass spectra in positive and negative ion modes. Furthermore, the characterization of molecular lipid species by utilizing high energy collisional dissociation was achieved on Orbitrap instruments. The mass accuracy of acquired MS/MS spectra increased the confidence in identification for unusual very-long chain polyunsaturated phosphatidylcholine species and a new lipid class, the maradolipids. Beyond that, effort was made to enhance the accuracy and comparability of MS/MS based bottom-up lipidomics data. In this respect, lipids with varying degree of unsaturation were analyzed and revealed discrete fragmentation properties.
The technical refined lipidomics methods allowed insight into the lipid composition of lipoproteins and changes of the blood plasma induced by apheresis. Lipidomics screening of blood plasma uncovered an altered lipid pattern in consequence of impaired glucose metabolism and type 2 diabetes. The lipidomics characterization of islet allowed their quality assessment.
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Yung, Emily. "Childhood adversity and metabolic outcomes in adults with mood disorders." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123331.
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Background: Metabolic syndrome is a clustering of conditions that increases the risk for cardiovascular disease. These metabolic disturbances are often comorbid with mood disorders, such as depression (MDD) and bipolar disorder (BP), and are associated with poorer psychiatric prognosis and worse functional impairment. Childhood adversity has been hypothesized to be a common risk factor for both metabolic disturbances and mood disorder. However the precise association between childhood adversity, metabolic disturbances, and mood disorders is still unknown. Objectives: (1) To examine the association between childhood adversity and metabolic outcomes. (2) To test whether specific types of childhood adversity (e.g. abuse, neglect, and family/household dysfunction) and type of mood disorder interact to worsen metabolic outcomes.Methods: This was a cross-sectional study of 68 adult outpatients from a university-based, tertiary-care mood disorders clinic with a DSM-IV defined depression (N=28) or bipolar type I or II disorder (N=40). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III clinical criteria for defining metabolic syndrome were measured. Childhood adversity was measured using the Adverse Childhood Experience self-report questionnaire which collects categories of adversity pertaining to abuse, neglect, and family/household dysfunction. Linear and logistic regressions adjusted for age, sex, and education were conducted to examine the association between childhood adversity and metabolic outcomes. Interaction analyses were conducted to test if type of mood disorder modified the effect of childhood adversity on metabolic outcomes.Results: Nearly one-third (32.3%) of the sample met the NCEP criteria for metabolic syndrome. Despite the majority of our sample being overweight (BMI = 25-29.9), all other metabolic outcomes were within a healthy range. Childhood adversity was highly prevalent in this mood sample, with 80.9% of the participants experiencing at least one category of childhood adversity. Childhood adversities included exposure to household mental illness/suicide (45.6%), emotional neglect (33.8%), alcohol/drug abuse (29.4%), emotional abuse (27.9%), physical abuse (25.0%), sexual abuse (25.0%), parental divorce/separation (23.5%), domestic violence towards mother (13.2%), physical neglect (2.9%), and imprisoned household member (1.5%). There were no statistically significant relationships between the total number of childhood adversities and the range of metabolic outcomes. Several associations between type of childhood adversity and metabolic outcomes were found. Firstly, parental divorce/separation was associated with a higher BMI (B = 3.3, p = 0.047), but after controlling for age, sex, and education, parental divorce/separation was no longer significant. Notably in interaction testing, type of mood disorder modified the effect of parental divorce/separation on BMI such that the association between parental divorce/separation and BMI was greater in the presence of BP versus MDD (B = -7.4, p = 0.016). Secondly, emotional neglect was associated with lower diastolic blood pressure (B = -7.0, p = 0.043). Conclusion: This study provides preliminary evidence linking childhood parental divorce/separation and emotional neglect to the specific metabolic risk factors of BMI and diastolic blood pressure. Systematic assessment of childhood experiences, regular monitoring of the metabolic indices, and promotion of healthy lifestyle habits should be emphasized in routine clinical care of individuals with mood disorders.Contexte: Le syndrome métabolique augmente le risque de maladies cardiovasculaires. Ces perturbations ont souvent une morbidité associée aux troubles de l'humeur, comme la dépression (MDD) et le trouble bipolaire (BP). Elles sont associées à un moins bon pronostic psychiatrique et une dépréciation fonctionnelle plus importante. L'hypothèse a été émise que l'adversité durant l'enfance est un facteur de risque commun pour les troubles métaboliques et les troubles de l'humeur. Cependant l'association précise entre l'adversité durant l'enfance, les troubles métaboliques et les troubles de l'humeur est encore inconnue.Objectifs: (1) Pour examiner l'association entre l'adversité durant l'enfance et les troubles métaboliques de l'hypertension artérielle, l'obésité abdominale, taux élevés de triglycérides, la glycémie à jeun élevée et peu de lipoprotéines de haute densité (HDL). (2) Pour tester si des types spécifiques d'adversité durant la petite enfance (abus, négligence, familles/ménages dysfonctionnels) et le type de trouble de l'humeur interagissent pour aggraver les résultats métaboliques.Méthodes: Ce fut une étude transversale de 68 patients ambulatoires adultes d'une clinique universitaire de soins des troubles de l'humeur avec une dépression telle que définie selon les critères du DSM-IV (N = 28) ou de trouble bipolaire de type I ou II (N = 40). Les critères cliniques définissant le syndrome métabolique du programme national d'éducation du cholestérol (NCEP), Panel de Traitement pour Adultes III, ont été mesurés. L'adversité durant l'enfance a été mesurée à l'aide de l'auto-questionnaire sur l'expérience adverse durant l'enfance qui recueille les catégories d'adversité relatives à l'abus, la négligence et la dysfonction des familles/ménages. Les régressions linéaires et logistiques ajustées pour l'âge, le sexe et le niveau d'éducation ont été effectuées afin d'étudier l'association entre l'adversité durant l'enfance et les résultats métaboliques. Les analyses d'interaction ont été menées afin de tester si le type de trouble de l'humeur (troubles bipolaires versus dépression) a modifié l'effet de l'adversité durant l'enfance sur les résultats métaboliques.Résultats: Près d'un tiers (32,3%) de l'échantillon répondait aux critères pour le syndrome métabolique. En dépit de la majorité de notre échantillon étant en surpoids (IMC = 25-29,9), tous les autres résultats métaboliques étaient se situaient à un niveau normal. L'adversité durant l'enfance était très répandue dans l'échantillon des troubles de l'humeur, avec 80,9 % des participants ayant connu au moins une catégorie de l'adversité durant l'enfance. Les adversités durant l'enfance incluent l'exposition des ménages à la maladie mentale ou au suicide (45,6 %), la négligence affective (33,8 %), l'abus d'alcool et/ou de drogues (29,4 %), la violence psychologique (27,9%), la violence physique (25,0%), les abus sexuels (25,0 %), et la séparation ou le divorce des parents (23,5%). Plusieurs associations entre type d'adversité durant la petite enfance et les résultats métaboliques ont été trouvées. Tout d'abord, le divorce ou la séparation des parents a été associée à un IMC plus élevé (B = 3,3 ; p = 0,047). Cependant, après ajustement pour l'âge, le sexe et le niveau d'éducation, le divorce ou la séparation des parents, cela n'était plus significatif. Deuxièmement, la négligence émotionnelle a été associée à une baisse de la pression diastolique du sang (B = -7,0 ; p = 0,043).Conclusion: Cette étude fournit des preuves préliminaires reliant le divorce ou la séparation des parents durant l'enfance et de la négligence émotionnelle à des facteurs de risque métaboliques tels l'IMC et la pression artérielle diastolique. L'évaluation systématique des expériences durant l'enfance, un suivi régulier des indices métaboliques et la promotion de saines habitudes de vie doivent être soulignés dans les soins cliniques de routine des personnes souffrant de troubles de l'humeur.
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Ernst, Agnes Stefanie. "Molecular analysis of preclinical models for mental and metabolic disorders." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610813.
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Kaushanska, O. V. "Therapy of patients with anxienty disorders with metabolic syndrome X." Thesis, БДМУ, 2022. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/19613.
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Shalimova, A., Валентина Григорівна Псарьова, Валентина Григорьевна Псарева, Valentyna Hryhorivna Psarova, M. Kochuieva, O. Kolesnikova, A. Isaieva, and K. Prosolenko. "Hemodynamic and metabolic disorders in obese patients with resistant hypertension." Thesis, Oxford University Press, 2020. https://essuir.sumdu.edu.ua/handle/123456789/86191.
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Patients with resistant hypertension differed from hypertensive obese patients without resistance with higher BMI and BP, higher levels of triglycerides, insulin, HbA1c, more pronounced IR, cardiovascular remodeling, imbalance of oxidative stress - antioxidant protection system, higher proinflammatory and RAAS activity. Patients with true resistance differed from pseudo-resistant patients with significantly lower BMI, higher aldosterone levels, more pronounced imbalance of the system of oxidative stress - antioxidant protection and less pronounced adipokines imbalance.
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Menzies, Caitlin. "Characterization of Metabolic Alterations in Mouse Models of Neurodevelopmental Disorders." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42256.
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Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans.
Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences.
Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts.
Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function.
Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.
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Papageorgiou, Katherina. "Impact of adipose tissue on endothelial cells: effect of metabolic disorders." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/126066.
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This thesis aims to progress in deciphering the effect of the cytokines secreted by the visceral adipose tissue of obese individuals with type 2 diabetes on the endothelium, and therefore contribute to the understanding of the complementary effect of hyperinsulinemia and hyperglycemia in these kind of injuries.
Taking into account the results obtained from this thesis under the conditions applied, we conclude following:
1. Treatment with metformin presents a partially beneficial action on the deleterious secretion of cytokines from the visceral adipose tissue of type 2 diabetic obese patients.
Both secretomes of simple obese and diabetic obese patients treated with metformin induced a comparative inflammatory injury on endothelial cells, but the secretomes of the obese diabetic patients treated with metformin induced the synthesis of a less thrombogenic subendothelial matrix.
2. Insulin does not increase the expression of proinflammatory adhesion molecules and the thrombogenicity of the subendothelial matrix of HUVECs by the cytokines secreted from the obese visceral adipose tissue.
Pharmacological levels of insulin induce the increased expression of NF-κB.
3. Glucose does not determine an increase of the endothelial proinflammatory and prothrombotic injury provoked by the cytoadipokines of the visceral obese secretome in HUVECs.
High levels of glucose, though, seem to decrease importantly the plaquetary adhesion capacity when acting in combination with the secretome.
4. Obesity, more than the regional distribution of fat pads, markedly affects the metabolic profile of adipose tissue secretomes before the clinical onset of other significant metabolic alterations aside from BMI. Visceral obese adipose depots present the greatest alterations.
Amino acid metabolism is blunted and BCAA catabolism overloaded in the obese adipose tissue. This may contribute to the altered and increased plasmatic amino acid metabolite pool, sustaining the deleterious actions of amino acids on the onset of metabolic carbohydrate disturbances in obesity.Esta tesis pretende avanzar en el intento de descifrar el efecto de las citoquinas secretadas por el tejido adiposo visceral de los individuos obesos con Diabetes Mellitus tipo 2 sobre el endotelio y a su vez contribuir a la comprensión del efecto complementario de la hiperinsulinemia y la hiperglucemia en este tipo de lesiones. Teniendo en cuenta los resultados obtenidos en esta tesis y bajo las condiciones aplicadas, se concluye lo siguiente: 1. El tratamiento con metformina, un método ampliamente utilizado para normalizar la glucosa de pacientes afectos de diabetes tipo 2, actúa sólo de manera parcial en la reducción de las citoquinas nocivas secretadas por el tejido adiposo visceral de pacientes diabéticos tipo 2. 2. La insulina, añadida al secretoma obeso visceral, no amplia ni reduce el daño inducido en el endotelio por el propio secretoma. 3. La glucosa no es capaz de inducir un incremento en la lesión endotelial, adicional al daño inducido por las citoadipoquinas del secretoma obeso visceral. 4. La huella metabólica de los secretomas del tejido adiposo se ve alterada por el estado de la obesidad en general. Los depósitos viscerales obesos presentan las mayores diferencias en el patrón de metabolitos de los secretomas. Las etapas tempranas de la obesidad, incluyendo la presencia de inflamación sistémica y la resistencia a la insulina, se caracterizan por una alteración en el metabolismo y la secreción de aminoácidos por el tejido adiposo.
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McCormack, Michael James. "Development of prenatal diagnosis of metabolic disorders using chorionic villus sampling." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317449.
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Livieratos, Achilleas. "Investigating circadian disruption in mouse models of neurological and metabolic disorders." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:a03f34d5-285d-464b-b676-21b493db7f56.
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Sleep and circadian rhythm disturbance has been widely observed in neurological disorders although the mechanistic basis for this association remains unknown. In order to understand this association further, a combination of rest/activity and molecular profiling was carried out on mouse models of Parkinson’s Disease (PD), Lysosomal Storage Disorders (LSDs) and schizophrenia. Data from rest/activity behavioural screening of new BAC (Bacterial Artificial Chromosome) transgenic PD models displayed scotophase hyperactivity and decreased fragmentation patterns. Interestingly, rest/activity profiles of LSD models displayed possible core clock defects under constant conditions (Hexb-/-) and potential re-entrainment deficits following a 6hr phase advance (Npc1-/-). Together these data suggest new associations between disruptions in rest/activity cycles and neurodegeneration. The blind-drunk (Bdr) mutant is a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes and phase advanced rest/activity cycles. Despite identification of phase advanced expression of signalling neuropeptides (e.g. arginine vasopressin) in the Bdr suprachiasmatic nucleus (SCN), the underlying mechanisms regulating circadian disruption in this model remain elusive; therefore, label-free shotgun proteomics was carried out over 24 hours to elucidate potential post-transcriptional pathways. A number of novel circadian patterns of protein expression were identified including myristoylated alanine-rich C-kinase substrate (MARCKS) which exhibited a robust phase advanced expression profile. This study has identified novel SCN post-transcriptional mechanisms that may link schizoaffective disorder biomarkers to dysfunctional rest/activity cycles.
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DiSilvestro, David Joel. "Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087.
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Ali, Manir. "The molecular biology of frutose intolerance." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388463.
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Naessén, Sabine. "Endocrine and metabolic disorders in bulimic women and effects of antiandrogenic treatment /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-003-6/.
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Stein, Sina Katharina [Verfasser]. "Determination of subclinical metabolic disorders in transition dairy cows / Sina Katharina Stein." Kassel : Universitätsbibliothek Kassel, 2017. http://d-nb.info/1126470627/34.
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McLoughlin, Gerard Andrew. "Metabonomic analysis of neurological disorders and the metabolic effects of neuropharmacological treatments." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508315.
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Karlsson, Roger. "Interference with biological rhythm : a novel approach to metabolic disorders in women." Doctoral thesis, Umeå universitet, Obstetrik och gynekologi, 1992. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-101301.
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Women seem to be largely protected against certain ‘welfare disorders’ such as cardiovacular disease and osteoporosis, during their fertile years.The metabolic changes observed during women’s non-menstrual states, i.e. during pregnancy, after the menopause and during use of oral contraceptives, indicate the importance of sex steroids and an undisturbed biological rhythm. Treatment with monophasic, combined oral contraceptives constitutes a model for the non-cyclic state.Growth hormone (GH) is a pituitary hormone that has major metabolic effects. The pattern of GH exposure to the target organ is of vital importance for the effects and changes in rhythm could possibly induce metabolic changes.Growth hormome, cholecystokinin (CCK), osteocalcin and angiotensinogen were used as markers for metabolic effects and the concentrations in serum were recorded in women during non-menstrual states. The clinical material comprised a total of 60 women: 18 healthy non-pregnant, 25 pregnant, one lactating woman and 16 postmenopausal women. Using a portable pump and a non-thrombogenic venous catheter, blood samples could be collected at 30-min intervals during 24-h periods. Furthermore, the effects of estrogen and GH in the regulation of angiotensinogen were investigated in an experimental model in the rat.Oral contraceptives were found to alter the secretion of GH towards a pattern of lower and more frequent peaks, though the total amount secreted during 24 h was unchanged. Oral contraceptives seem to induce a suppression of the 24-h concentrations of CCK, which may be important with respect to weight gain in some women. Osteocalcin in serum display a significant circadian variation. This emphasizes the need for careful timing of single point measurements and the value of continuous blood sampling. Oral contraceptives may reduce osteocalcin serum concentrations. The long-term effects on bone are unknown. During late pregnancy osteocalcin levels are extremely low, which could indicate osteoblast inhibition and reduced bone turnover. The mode of GH administration is important for the plasma concentration of angiotensinogen in the non-pregnant rat. Estrogen effects on this protein may be mediated via a modification of GH secretion. Oral contraceptives not only increase angiotensinogen concentrations in serum but also markedly enhance their variability. Further studies are needed to elucidate the relation between the individual pattern of angiotensinogen and hypertension.S. 1-42: sammanfattning, s. 43-88: 6 uppsatser
digitalisering@umu
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Palibroda, N. M. "Gastrointestinal motility disorders in patients with metabolic syndrome: a way of correction." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18596.
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Nguyen, Long The. "The roles of SIRT1 in maternal obesity-induced metabolic disorders in offspring." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18964.
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Obesity is a complex metabolic disease, attributed to diverse and interactive genetic and environmental factors. The associated health consequences of obesity are pleiotropic, with individuals being more susceptible to chronic diseases such as type 2 diabetes mellitus, fatty liver disease and chronic kidney disease. The contribution of maternal obesity to the offspring’s predisposition to both obesity and its complications is increasingly recognized. Understanding the mechanisms underlying these “transmissible” effects is critical to developing therapeutic interventions to reduce the risk for “programmed” obesity. Sirtuin (SIRT)1 is a NAD+-dependent deacetylase that regulates metabolic balance and stress responses in both central and peripheral tissues. Dysregulation of SIRT1 is a well-established mediator for the development and consequences of obesity. Nevertheless, their implication in the transmissible effects of maternal obesity across generations remains largely elusive. The thesis aims to examine the role of SIRT1 as a mediator of maternal obesity-induced complications in offspring. (Chapter 1) To achieve this aim, we employed six different animal models sharing the same characteristic that is maternal obesity, which is induced by high fat feeding of female rats/mice 6 weeks before mating, during gestation and lactation. First, in the Sprague-Dawley rat maternal obesity model, we investigated metabolic changes and SIRT1 expression in the offspring brain and found that maternal high-fat diet induces metabolic stress response disorders in the offspring hypothalamus (Chapter 2), which was subsequently found to be associated with hypothalamic SIRT1 downregulation. This result, together with other studies which showed reduced SIRT1 expression in mothers’ placenta and offspring’s liver tissues due to maternal obesity, provided the rationale for subsequent studies in this thesis. 2 By mating wild-type (WT) C57BL/6 mice with hemizygous SIRT1-transgenic (Tg) mice to produce both WT and Tg offspring, we were able to examine if SIRT1 overexpression in the obese mothers or their offspring can reverse the fetal programming effects of maternal obesity (Chapter 3). Our results suggest that Tg offspring born to WT obese dams have reduced body weight, improved metabolic profiles and liver health compared to the WT littermates. In parallel with the SIRT1 overexpression models, we also administered the SIRT1 activator SRT1720 to male offspring exposed to both maternal and postnatal high-fat diets to examine the effects of SIRT1 activation on the offspring’s metabolism and liver health. We found that SRT1720 attenuated obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption (Chapter 4), thus confirming that SIRT1 can be targeted for the treatment of the metabolic syndrome due to maternal obesity. We also took a further step to investigate the effects of maternal and paternal SIRT1 overexpression in the offspring of obese dams. We demonstrated that not only maternal SIRT1 overexpression but also paternal SIRT1 overexpression can reprogram offspring metabolic disorders due to maternal high-fat feeding (Chapter 5) to a varying extent. Improvements occurred in glucose and lipid homeostasis as well as liver oxidative stress and remodelling. Strikingly, such paternal effects of SIRT1 overexpression can be transmitted via the maternal lineage to the second-generation offspring (Chapter 6) 3 Using the same models of SIRT1 upregulation in the offspring, we examined kidney disorders due to maternal high-fat diet. Firstly we demonstrated that SIRT1 reduction is associated with sex-specific dysregulation of renal lipid metabolism and stress responses in the offspring of mothers fed a high-fat diet (Chapter 7), suggesting the relevance of SIRT1 in developmental programming of kidney disease. By means of genetic upregulation or agonist-mediated activation, we found that upregulation of SIRT1 attenuates renal lipid dysregulation, oxidative stress, inflammation and fibrosis in the offspring due to maternal high-fat feeding (Chapter 8). In summary (Chapter 9), we confirm the essential role of SIRT1 in fetal programming and suggest that SIRT1 therapy is a promising therapeutic to mitigate the developmental origin of metabolic disorders, chronic liver and kidney disease due to maternal obesity and hence to improve postnatal outcomes. The intervention through the paternal linage is particularly valuable given the unknown safety profiles of pharmacotherapies during gestation and early childhood.
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Li, Dan. "Identification of xanthones to ameliorate metabolic disorders through targeting adipose tissue inflammation." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3952496.
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Bava, Sunita. "Reduced microstructural white matter integrity in a genetic metabolic disorder a diffusion tensor MRI study /." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3274808.
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Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007.Title from first page of PDF file (viewed January 8, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 75-84).
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Mahat, Bimit. "The Effects of Hypoxia on Human Adipose Tissue Lipid Storage and Mobilization Functions: From Primary Cell Culture to Healthy Men." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36865.
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Adipose tissue plays a central role in the regulation of lipid storage and mobilization. A tight control between adipose tissue lipid storage and mobilization functions must be exerted to prevent an overload of lipids at other organs such as the heart, liver and skeletal muscles, and favor the risk of developing metabolic disorders, such as Type 2 diabetes and cardiovascular diseases (CVD). There is strong evidence from animal studies that low oxygen levels (hypoxia) are noted in adipose tissue as the mass of the organ excessively expands and, in turn, exacerbates some adipose tissue functions. Whether hypoxia exposure, which could be derived from reduced environmental oxygen availability, disease or a combination of both, affects adipose tissue lipid storage and mobilization functions in humans is not well known. Using in vitro and in vivo approaches, this thesis aimed at characterizing the effects of hypoxia on human adipose tissue lipid storage and lipid mobilization functions. Study I investigated how hypoxia can modulate human adipose functions such as lipid storage and lipid mobilization in vitro. Study II examined whether acute intermittent hypoxia, which simulates obstructive sleep apnea, affects adipose tissue lipid storage/mobilization functions and triglyceride levels in healthy young men in postprandial state. Study III tested the effect of an acute 6-hour continuous exposure to hypoxia (fraction of inspired oxygen (FIO2) = 0.12)) on plasma triglyceride levels in healthy young men in the fasting state. Study I indicates that both acute (24h) and chronic (14d) hypoxia (3%, and 10% O2) modulate human adipose tissue lipid storage and mobilization functions in a different manner. Study II demonstrates that acute exposure to intermittent hypoxia (6h) is sufficient to increase plasma non-esterified fatty acids (NEFA) levels, as well as insulin levels, but does not alter circulating triglyceride or subcutaneous adipose tissue lipid storage and/or mobilization capacity ex vivo in healthy men. Study III shows that acute exposure to normobaric hypoxia increases circulating NEFA and glycerol concentrations but did not translate in altering circulating triglycerides in fasting healthy men. In conclusion, our observations suggest that an exposure to reduced oxygen levels impairs human adipose tissue storage and/or mobilization functions, a phenomenon known in the development of metabolic disorders, such as Type 2 diabetes and CVD.
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Taylor, Carmen L. "The effects of varying exercise volumes on the metabolic syndrome in women." Virtual Press, 2003. http://liblink.bsu.edu/uhtbin/catkey/1273273.
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This study examined the trend of varying volumes of exercise on the risk factors embodying the metabolic syndrome in sedentary women (n=21, 49.2 ± 5.7 years). The following measurements: waist and hip circumference, weight, height, resting blood pressure, body composition, fasting levels of blood glucose, lipids, and insulin, peak V02 and treadmill time were measured at baseline and upon the completion of the study. Women were randomly assigned to one of three energy expenditure groups: 600 kcals/week (n=6), 800 kcals/week (n=8) or 1000 kcals/week (n=7). They were instructed to perform cardiovascular exercise three times a week for three months in a moderate exercise-training program with no modifications in their diet. The results revealed few significant changes in the risk factors embodying the metabolic syndrome. Nevertheless, these volumes of exercise were adequate in reducing at least one metabolic disorder in nearly half (48%) of our subject population. This impact of exercise on metabolic syndrome risk factors was clinically important because as metabolic disorders decreased so did the mortality risk from cardiovascular and coronary disease within these women.School of Physical Education
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Vidal, Jorge Marian. "High-resolution microdialysis applied to the study and treatment of brain metabolic disorders." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/454997.
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En las últimas dos décadas, tanto médicos como los investigadores han considerado la hipoxia cerebral isquémica y no isquémica, como la protagonista de la mayoría de las lesiones secundarias que ocurren en pacientes con un traumatismo craneoencefálico (TCE) grave. Tanto la lesión primaria como la isquemia cerebral desencadenan la liberación de neurotransmisores y un fallo energético que provoca flujos iónicos masivos, con el posterior movimiento osmótico del agua a través de las células seguido de edema cerebral. El edema cerebral es la principal causa de muerte y discapacidad en estos pacientes. Una mejor comprensión de los complejos trastornos iónicos que causan el edema beneficiaría el estudio y el tratamiento no sólo de los pacientes con un TCE, sino también de los pacientes con otras lesiones neurológicas agudas, como el infarto maligno de la arteria cerebral media (IMACM). La hiperoxia normobárica (HN) es una estrategia ya testada en modelos experimentales de TCE y en ensayos clínicos piloto. La potencial toxicidad de usar niveles supra-normales de O2 es la principal preocupación de utilizar esta terapia. Una FiO2 alta puede inducir vasoconstricción, exacerbar el estrés oxidativo (EO), aumentar la neuroinflamación, o inducir excitotoxicidad. Las técnicas actuales de neuromonitorización multimodal (NMM) permiten el estudio de los procesos que ocurren tras una lesión cerebral aguda. La microdiálisis cerebral (MD) es una técnica avanzada de NMM que permite el muestreo continuo del parénquima cerebral. Los objetivos principales de esta tesis fueron: 1) determinar el perfil iónico del espacio extracelular cerebral (ECC) en diferentes áreas del cerebro en pacientes con una lesión cerebral aguda, 2) evaluar la respuesta metabólica de pacientes con un TCE a la HN y determinar si la hiperoxia aumenta el EO y 3) reproducir in vitro los perfiles metabólicos cerebrales en la hipoxia de baja extractividad (HBE). En primer lugar, para analizar el perfil iónico de ECC se analizaron muestras de microdiálisis de 34 pacientes (TBI y IMACM) según la localización del catéter MD, mediante espectrometría de masas con plasma acoplado inductivamente (ICP-MS). Los resultados mostraron que la composición iónica del ECC cerebral difiere según la gravedad de la alteración tisular. Por lo tanto, los resultados deben interpretarse de acuerdo con la región del cerebro muestreada por el catéter de MD. La ICP-MS acoplada a los ensayos iónicos es una poderosa herramienta para una mejor comprensión de los complejos trastornos iónicos que se producen como consecuencia de estas lesiones. En segundo lugar, para evaluar la respuesta metabólica del cerebro lesionado a la HN y determinar si la hiperoxia aumenta el EO, se estudió el perfil metabólico y se determinó la presencia de EO usando un robusto indicador (8-iso-PGF2α), en 34 pacientes con un TCE. La NH incrementó los valores de PtiO2 tanto en el cerebro lesionado macroscópicamente normal como en regiones traumáticas en riesgo. Los resultados metabólicos sugirieron que los pacientes que muestran indicios de un metabolismo cerebral alterado podrían beneficiarse de recibir esta terapia. La HN provocó un incremento del EO, solo en aquellos pacientes que presentaban niveles basales de EO. Combinado con la creciente evidencia de que las crisis metabólicas son comunes en el TCE sin isquemia cerebral, estos hallazgos abren nuevas vías para el uso de esta estrategia terapéutica en pacientes con TCE. Finalmente, utilizando un modelo in vitro de astrocitos corticales humanos se determinó el perfil metabólico y los cambios en la maquinaria glicolítica de la LEH. Este es un primer paso para explorar las consecuencias de la HBE que permite profundizar en el conocimiento de formas más complejas de la hipoxia cerebral descritas en lesiones cerebrales agudas.In the past two decades, both clinicians and researchers have considered brain ischemic and non-ischemic cerebral hypoxia, the protagonist of most secondary lesions occurring in patients with severe traumatic brain injury (TBI). Both primary damage and cerebral ischemia trigger the release of neurotransmitters and an energy failure that causes massive ionic fluxes. Subsequent osmotic water movement across the cells is followed by brain edema. Brain edema is the major leading cause of death and disability in these patients. Better understanding of the complex ionic disturbances that cause edema would benefit the study and treatment of not only TBI patients but also patients with other acute neurological injuries, such as malignant middle cerebral artery infarct (MMCAI). Normobaric brain oxygen therapy (NBO) is one strategy already tested in experimental models of TBI and in pilot clinical trials. The main concern regarding NBO is the potential toxicity of using supranormal levels of partial pressure of arterial oxygen. High FiO2 could induce vasoconstriction, exacerbate oxidative stress (OxS), increase neuroinflammation, or induce excitotoxicity. Current multimodal neuromonitoring (MNM) techniques allow the study of the processes occurring after acute brain injury. Cerebral microdialysis (MD) is an advanced MNM technique that allows continuous sampling of the cerebral parenchyma. The main objectives of this thesis were: 1) to determine the ionic profile of brain extracellular space (ECS) in different brain areas in patients with acute brain injury, 2) to evaluate the metabolic response of TBI patients to 4 h of NBO and to determine whether hyperoxia increases OxS, and 3) to reproduce in vitro the abnormal brain metabolic profiles in one of the types of hypoxia described by Siggaar-Andersen in 1995 (low-extractivity hypoxia -LEH-). First, to analyze the ionic profile of brain ECS, microdialysate samples of 34 patients (TBI and MMCAI) were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The ionic profile was studied according to the position of the MD catheter. The results showed that the ionic composition of the brain ECS differs according to the severity of the tissue disturbance. Thus, the results should be interpreted according to the region of the brain sampled by the MD catheter. ICP-MS coupled to ionic assays creates a powerful tool for a better understanding of the complex ionic disturbances that occur after acute brain lesions. Secondly, 34 TBI patients were included to assess the metabolic response of the injured brain to NBO and to determine whether hyperoxia increases OxS. The results showed that NBO increased PtiO2 in both macroscopically normal injured brain and in traumatic regions at risk. NBO did not change energy metabolism in the entire group of patients. These results suggest that TBI patients would benefit from receiving NBO when they show indications of disturbed brain metabolism. The presence of OxS in MD samples was additionally measured using a robust indicator (8-iso-PGF2α). NBO maintained for 4 h did not induce OxS in patients without pre-existing OxS at baseline. However, for patients in whom OxS was detected at baseline, NBO induced a significant increase in 8-iso-PGF2α. Combined with the increasing evidence that metabolic crises are common in TBI without brain ischemia, these findings open new avenues for the use of this accessible therapeutic strategy in TBI patients. Finally, using an in vitro model of human cortical astrocytes, the energy metabolic profile and the changes in the glycolytic machinery of LEH were reproduced. This is a first step toward exploring the consequences of LEH in vitro for a better understating of the MD pattern found in neurocritical patients. Our aim was to acquire in-depth knowledge of more complex forms of brain hypoxia found in acute brain injuries.
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Delhey, Leanna M., Marie Tippett, Shannon Rose, Sirish C. Bennuri, John C. Slattery, Stepan Melnyk, S. Jill James, and Richard E. Frye. "Comparison of Treatment for Metabolic Disorders Associated with Autism:Reanalysis of Three Clinical Trials." FRONTIERS MEDIA SA, 2018. http://hdl.handle.net/10150/627117.
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Autism spectrum disorder (ASD) affects about 1 in 45 individuals in the United States, yet effective treatments are yet to be defined. There is growing evidence that ASD is associated with abnormalities in several metabolic pathways, including the inter-connected folate, methylation and glutathione pathways. Several treatments that can therapeutically target these pathways have been tested in preliminary clinical trials. The combination of methylcobalamin (mB12) with low-dose folinic acid (LDFA) and sapropterin, a synthetic form of tetrahydrobiopterin (BH4) have been studied in open label trials while high-dose folinic acid has been studied in a double-blind placebo controlled trial. All of these treatments have the potential to positively affect folate, methylation and glutathione pathways. Although the effect of mB12/LDFA and BH4 on methylation and glutathione metabolism have been examined in the open-label studies, these changes have not been compared to controls who received a placebo in order to account for the natural variation in the changes in these pathways. Furthermore, the recent study using high-dose folinic acid (HDFA) did not analyze the change in metabolism resulting from the treatment. Thus, we compared changes in methylation and glutathione metabolism and biomarkers of chronic oxidative stress as a result of these three treatments to individuals receiving placebo. In general, mB12/LDFA treatment had a significant effect on glutathione and cysteine metabolism with a medium effect size while BH4 had a significant effect on methylation and markers of chronic oxidative stress with a large effect size. HDFA treatment did not significantly influence biomarkers of methylation, glutathione or chronic oxidative stress. One caveat was that participants in the mB12/LDFA and BH4 studies had significantly worse markers of glutathione metabolism and chronic oxidative stress at baseline, respectively. Thus, the participants selected in these two clinical trials may have been those with the most severe metabolic abnormalities and most expected to respond to these treatments. Overall this study supports the notion that metabolic abnormalities in individuals with ASD may be amenable to targeted treatments and provide some insight into the mechanism of action of these treatments.
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Collins, Stephan Christopher. "Rat chromosome 1 as a paradigm for the genetic study of metabolic disorders." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400563.
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Glass, Jennifer Elaine. "CURRENT PRACTICES OF PEDIATRICIANS REGARDING SCREENING FOR METABOLIC DISORDERS AMONG INTERNATIONALLY ADOPTED CHILDREN." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244084138.
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Ybanez, Trissha Nicole G. "Effects of mood and metabolic disorders on mitochondrial function, infarct tolerance, and cardioprotection." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/418791.
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Introduction: Chronic psychological stressors and overconsumption of highly palatable foods are major risk factors in the development of metabolic, cardiovascular and mood disorders. The energy imbalance instigated by these disorders result in mitochondrial dysfunction over time, reportedly causing reduced infarct tolerance and responsiveness to cardioprotection. The effects of low-level mood and metabolic disturbances on mitochondrial function are however unclear. It is also unclear how combined mood and metabolic disturbances impact cardiac mitochondrial function. This study aims to investigate the effects of subclinical levels of chronic restraint stress (RS) and a Western diet (WD) on cerebral and cardiac mitochondrial function and the expression of proteins associated with mitochondrial function.
Methods: Sixty-four male C57Bl/6 mice were fed a control diet (CD, n = 16; 19% fat, 59% carbohydrates, 19% protein) or a WD (mild dietary stressor, n = 16; 32% fat, 57% carbohydrates, 11% protein) for 16 weeks, with RS (mild psychological stressor; 2 hr restraint/day) introduced in sub-sets of these dietary groups during the final 2 weeks of the study (CD+RS and WD+RS, n = 16 for each group). A subset of type 2 diabetic mice (T2DM, n = 15) from a separate study was also used to compare their mitochondrial function with the WD fed mice. The T2DM mice were injected with streptozotocin (75 mg/kg) and then fed a high fat diet (strong dietary stressor; 43% fat, 39.7% carbohydrates, 17.1% protein) for 16 weeks. Baseline and post-intervention behavioural tests (week 0 and week 17) were done through sucrose preference test (SPT) and open field test (OFT) to quantify anxiety-like and depressive-like outcomes, respectively (not including T2DM mice). After sacrifice, Langendorff perfusions were performed on hearts from all groups, and they were exposed to an ischaemia-reperfusion protocol (I/R) or subjected to ischaemic preconditioning (IPC) prior to I/R to assess post-ischaemic myocardial function responses. Select brain regions and the left ventricular (LV) myocardium were collected at sacrifice, homogenised and loaded into an Oroboros O2k-oxygraph to measure mitochondrial respiration or the tissue was used for western blotting to assess mitochondrial protein expression in the brain and the heart.
Results: The consumption of the WD significantly increased body weight over the 16 weeks of feeding while the introduction of RS induced weight loss in the RS groups. The WD fed and the WD+RS groups had reduced preference for the sucrose solution, 14 suggestive of depressive-like behaviour. Anxiety-like behaviours such as inactivity and wall-seeking were also present in both WD and RS groups in the open field tests. The WD impaired I/R tolerance and worsened post ischaemic cardiac function, while the introduction of IPC enhanced post-ischaemic recovery. The RS groups had improved cardiac function after I/R, but this beneficial effect of RS was lost with IPC. Coronary effluent LDH levels were unchanged in all intervention groups. Across all intervention groups, there was a trend towards a dysfunctional complex I respiration with preserved outer membrane integrity in hearts subjected to I/R. Mitochondrial respiration was unchanged by IPC in the WD hearts while IPC impaired maximal and spare respiratory capacity in the CD+RS hearts. Despite minor alterations in mitochondrial respiration and capacity, enhanced complex II respiration in hearts exposed to I/R and IPC normalised overall OXPHOS capacity (CI+CII-linked respiration) of the cardiac mitochondria, and this was significant in the CD+RS group. Cerebral mitochondrial respiration across all brain regions was impaired in the CD+RS groups but was unaltered with a WD. Both cardiac and cerebral mitochondria from T2DM mice were compared to WD and showed an improvement in all mitochondrial outcomes. Mitochondrial protein abundance studies revealed that the expression of mitochondrial PGC-1𝛼 was positively correlated with GSK-3β in both hearts exposed to I/R and IPC. Both parameters were also linked to decreased mitochondrial ETC complex protein expression. This observation suggests that PGC-1𝛼 and GSK-3β may act together to regulate OXPHOS capacity and the protein expression of the mitochondrial ETC complexes.
Conclusion: Mild alterations in behavioural outcomes and metabolism elicited compensatory adaptations in mitochondrial respiration and proteomic expression to support effective function of the heart and brain. These changes in the mitochondria, and particularly in the heart are seemingly governed, in part, by upstream proteins such as PGC-1𝛼 and GSK-3β, though this mechanism remains unclear and needs further investigation.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Pharmacy & Med Sci
Griffith Health
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Doimo, Mara. "Yeast models for the study of mitochondrial genetic defects and other metabolic disorders." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422068.
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Yeast is a versatile tool to study the function of genes involved in mitochondrial processes and in metabolic pathways. A large number of human genes involved in such pathways have yeast orthologues; moreover, yeast is easy to manipulate and it can switch from a fermentative to a respiratory metabolism, thus permitting to study mitochondrial phenotypes. For all these reasons, we employed S. cerevisiae for the functional characterization of different genes involved in inherited metabolic and mitochondrial disorders.
Gyrate atrophy of choroid and retina (GA) is an autosomal recessive disorder caused by mutations at the level of the ornithine aminotransferase (OAT), a mitochondrial matrix protein involved in the ornithine metabolism. We identified a number of missense mutations in OAT and we proved their pathogenicity in a model of S. cerevisiae deleted for CargB, the homologue of OAT. Moreover, analysis of protein stability and residual enzymatic activity permitted us to elucidate the mechanism by which the aminoacid substitution affects the protein function. However, these data did not allow to establish any genotype-phenotype correlation, suggesting that other factors than the specific OAT genotypes are responsible for the phenotypic variability present in the patients.
Yeast Cox23p is a mitochondrial protein with a twin CX9C domain, involved in the COX assembly and possibly in copper homeostasis. In our lab we identified using a bioinformatics approach its human homologue, hCOX23 and characterized its function. We demonstrated using mass spectrometry that the recombinant protein binds Cu(I), providing the first direct evidence of its copper binding. Upon silencing of COX23 we could not observe a phenotype in HeLa cells, but expression of human COX23 in S. cerevisiae deleted for the corresponding gene, showed that it can vicariate for the function of yCox23, confirming its involvement in COX biogenesis. We then demonstrated that it exerts its function in the intermembrane space (IMS) and that Cmc4p, another twin CX9C protein, has overlapping functions. Since the majority of primary COX deficiencies have not a known cause, the characterization of genes involved in the COX biogenesis is of primary importance to find new possible candidates in these disorders.
Coq6p is a monooxygenase involved in the synthesis of CoQ6 in yeast. Recently, point mutations in its human homologue have been associated with steroid resistant nephrotic syndrome (SRNS). We modelled the missense mutations on a yeast strain deleted for Coq6 and we demonstrated that all the human mutations reduce the ability of the human gene to rescue the phenotype of the deleted yeast. Moreover, we mutated the corresponding aminoacid on the yeast gene and we proved that all these allelic combinations retain some residual activity, supporting the notion that complete lack of CoQ biosynthesis is embryonically lethal.
OPA1 is a dynamin related protein mutated in dominant optic atrophy (ADOA), the most common inherited optic neuropathy. It is involved in different processes such as mitochondrial fusion and apoptosis. In human OPA1 is present with 8 different splicing variants, each of them processed to originate a long form, attached to the inner mitochondrial membrane (IMM) and a short, soluble form, localized in the IMS. The processing of OPA1 is strictly regulated, because the ratio between the two forms is important for the different protein functions. Several proteases have been implicated in the processing. To better characterise this mechanism and to understand the role of the specific splicing isoforms, we decided to employ a model of S. cerevisiae deleted for Mgm1, the homologue of OPA1. Expression of single OPA1 splicing variants cannot rescue the phenotype of the deleted strain while a hybrid form of the protein, containing the mitochondrial targeting and the processing sequences of Mgm1, restores the growth of ΔMgm1. These data indicate that the function of the active core of OPA1 is conserved among evolution and the lack of complementation of OPA1 is probably due to a different mechanism of processing in the two organisms. The hybrid gene will represent a simple tool to study the pathogenicity of missense OPA1 mutations identified in patients with ADOA and ADOA plus.
All together these data demonstrate that yeast represent a simple and effective system to characterize the function and to study the pathogenicity of a broad spectrum of conserved proteins such as the ones involved in mitochondrial respiration, mitochondrial morphology or other metabolic pathways.S. cerevisiae è un sistema molto versatile per studiare la funzione dei geni coinvolti in numerose vie mitocondriali e metaboliche. La maggior parte dei geni umani coinvolti in tali processi presentano ortologhi in lievito. Inoltre, questo organismo è facile da manipolare ed è in grado di produrre ATP sia attraverso la glicolisi che attraverso la catena respiratoria, sulla base della fonte di carbonio fornita; tale caratteristica permette lo studio fenotipi mitocondriali. Per tutte queste ragioni, abbiamo impiegato S. cerevisiae per la caratterizzazione funzionale di geni coinvolti in alcune malattie ereditarie metaboliche e mitocondriali. L’atrofia girata della retina e della coroide (GA) è una malattia autosomica recessiva causata da mutazioni a livello dell’enzima ornitina aminotransferasi (OAT), una proteina della matrice mitocondriale coinvolta nel metabolismo dell’ornitina. Abbiamo individuato una serie di mutazioni missenso nel gene OAT e ne abbiamo dimostrato la patogenicità in un modello di S. cerevisiae deleto per il gene CargB, l'omologo di OAT. Ulteriori studi sull’analisi della stabilità della proteina e la misurazione dell’attività enzimatica residua hanno permesso di chiarire il meccanismo attraverso il quale le differenti mutazioni missenso influiscono sulla funzione dell’enzima. Tuttavia questi dati non permettono di stabilire alcuna correlazione genotipo-fenotipo, suggerendo che altri fattori oltre la specifica variazione aminoacidica sono responsabili per la variabilità fenotipica osservata nei pazienti. Cox23p è una proteina di lievito localizzata nei mitocondri e coinvolta nell’ assemblaggio della COX, il complesso IV della catena respiratoria. Possiede il dominio twin CX9C, presente in altre proteine coinvolte nel trasporto del rame. Nel nostro laboratorio abbiamo identificato mediante un approccio bioinformatico il suo omologo umano, hCOX23 e ne abbiamo caratterizzato la funzione. Abbiamo dimostrato con tecniche di spettrometria di massa che la proteina ricombinante lega Cu (I), fornendo la prima prova diretta della sua abilità di legare il rame. Il silenziamento di COX23 in cellule HeLa non ha evidenziato alcun fenotipo. Al contrario, l’espressione del gene umano in un ceppo di lievito deleto per il gene corrispondente, ha dimostrato che COX23 può complementare il fenotipo, confermando il suo coinvolgimento nel processo di assemblaggio della COX. Abbiamo inoltre dimostrato che yCox23p è localizzato nello spazio intermembrana (IMS) e che Cmc4p, un'altra proteina contenente il dominio twin CX9C , ha funzioni rindondanti. Dal momento che la maggior parte dei deficit primari di COX non hanno ancora una causa nota, la caratterizzazione dei geni coinvolti nella biogenesi COX è di primaria importanza per trovare nuovi possibili candidati responsabili di queste patologia. Coq6p è una monoossigenasi coinvolta nella sintesi di CoQ6 in lievito. Recentemente mutazioni puntiformi nel suo omologo umano sono state associate con la sindrome nefrosica steroido-resistente (SRNS). Abbiamo espresso le mutazioni missenso in un ceppo di lievito deleto per il gene Coq6 e abbiamo dimostrato che tutte le mutazioni riducono o aboliscono la capacità del gene umano di complementare il fenotipo del lievito deleto. Le mutazioni umane sono state successivamente introdotte nei rispettivi residui conservati del gene di lievito. Questo ha permesso di dimostrare che tutte queste combinazioni alleliche presentano una certa attività residua. Tali dati supportano l’ipotesi che la mancanza totale di CoQ biosintesi è letale a livello embrionale. OPA1 è una proteina mitocondriale coinvolta in diversi processi cellulari tra cui la fusione mitocondriale ed l’apoptosi. Mutazioni a livello di questa proteina causano l’atrofia ottica dominante (ADOA), la più comune neuropatia ottica ereditaria. Nell’uomo il gene OPA1 è presente in 8 differenti varianti di splicing, ognuna delle quali può originare una forma lunga, attaccata alla membrana mitocondriale interna (IMM) e una forma solubile, localizzata nel IMS. Il processamento di OPA1 è strettamente regolato, in quanto il rapporto tra le due forme è importante per le funzioni della stessa. Numerose proteasi sono state indicate come coinvolte in tale processo. Per caratterizzare questo meccanismo e per comprendere il ruolo specifico di ciascuna delle isoforme di splicing, abbiamo deciso di impiegare un modello di S. cerevisiae deleto per Mgm1, l'omologo di OPA1. L’espressione delle singole varianti di splicing non è in grado di ripristinare la crescita del ceppo deleto mentre una forma ibrida della proteina, contenente la sequenza di import mitocondriale e di processamento di Mgm1, permette il recupero del fenotipo di ΔMgm1. Questi dati indicano che la funzione di OPA1 è conservata e la mancanza di complementazione di OPA1 è probabilmente dovuta ad un differente meccanismo di processamento nel lievito rispetto all’uomo. Il gene ibrido rappresenterà un semplice strumento per studiare la patogenicità di missenso OPA1 mutazioni identificate nei pazienti con ADOA e ADOA plus. Nel complesso questi dati dimostrano che il lievito rappresenta un sistema semplice ed efficace per caratterizzare la funzione e per studiare la patogenicità di un ampio spettro di proteine coinvolte nei processi di respirazione, morfologia mitocondriale e in altre vie metaboliche.
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Marakis, Georgios. "Natural therapy for insulin-resistance syndrome and type II diabetes." Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340013.
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Hagström, Emil. "Metabolic disturbances in relation to serum calcium and primary hyperparathyroidism /." Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6893.
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Witek, Rafal Piotr. "Novel application of gene therapy and somatic stem cells in treating metabolic liver disorders." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0009820.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 127 pages. Includes Vita. Includes bibliographical references.
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Everdell, N. "A mechatronic haemodialysis system for the treatment of acute renal failure and metabolic disorders." Thesis, Middlesex University, 2001. http://eprints.mdx.ac.uk/13400/.
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The aim of this project was to produce a fully automated prototype system for the treatment of premature babies who are suffering from renal failure or metabolic disorders. These patients are difficult or impossible to treat conventionally, due to their very small total blood volume and their intolerance to donated blood. There was a strong case for developing a dialysis system specifically designed for the treatment of such patients. The system is based on a manually operated device developed at the Royal Victoria Infirmary, Newcastle Upon Tyne. It differs from conventional dialysis methods in several ways. Blood access to the patient is via a single venous catheter. Only a very small amount of blood is needed to prime the extracorporeal circuit - this can be as little as 6.8 ml in the smallest patients. This compares very favourably with the volumes needed in conventional circuits, which are in the range of 15 - 40 ml. This small priming volume means that donated blood is not needed to prime the circuit. The clearance and ultrafiltration rates that can be achieved are independent of the rate that blood can be accessed from the patient, since the same blood passes back and forth through the haemofilter several times. The clearances that have been obtained experimentally are consistently above 40% of the mean blood flow rate through the system. The largest mean blood flow rate available is 5 ml/min, so the maximum clearance is approximately 2 ml/min. The maximum ultrafiltration rate that can be obtained is 50 ml/h. The new system is more effective at treating premature babies than conventional dialysis circuits. The hand driven system was tested in vivo and found to work well, so the automated system was developed on a solid foundation. A prototype system has been successfully developed and tested. This thesis details both the development and the testing. The new system uses stepper motors and DC servo motors for actuation, and is controlled by Labwindows/CVI and NIDAQ software running on a standard PC platform. The interface between the PC and the machine is provided by a National Instruments data acquisition board. A comprehensive single fault analysis of the safety of the system was undertaken, including both software and hardware. In vitro testing covered several areas of operation. The accuracy of the ultrafiltration process was established. The clearance rates that could be achieved were determined. The amount of damage caused to the blood by the system was also tested. This was found to be well within acceptable clinical limits. In vivo testing established the feasibility of using a computer algorithm to control the withdrawal of blood from the patient. Finally, the system was successfully used to treat a patient with an in-born metabolic disorder. In summary, a new system has been developed that is superior to any other treatment method currently available for neonates with these types of disorders.
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Henriques, Bárbara J. "Defective protein folding and function in metabolic disorders: studies on the mitochondrial flavoenzyme ETF." Doctoral thesis, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2010. http://hdl.handle.net/10362/5150.
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Dissertation presented to obtain the PhD degree in Biochemistry at the Instituto de Tecnologia Química e Biológica, Universidade Nova de LisboaThe work presented in this dissertation concerns the study of the electron transfer flavoprotein (ETF), a protein involved in mitochondrial β-oxidation whose deficiency is associated to multiple acyl-CoA dehydrogenase deficiency (MADD). The thesis will focus on establishing the functional, cellular and molecular consequences of the genetic variability in ETF, and in particular it aims to clarify the basis for the effect of heat stress on disease progression. Moreover, the beneficial effects of vitamin B2 supplementation will be addressed.(...)
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Maripuu, Martin. "Hypocortisolism in recurrent affective disorders." Doctoral thesis, Umeå universitet, Psykiatri, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-112824.
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Bipolar disorders and recurrent depressions are two common psychiatric disorders with a life time prevalence of approximately 1% and 8%, respectively. Despite treatment these patients suffer from affective symptoms up to 50% of the time, resulting in lower well-being. The average life length is also reduced with 10-15 years, mainly attributable to suicide and cardiovascular disease. Increased stress is one of many factors that have been shown to be linked to an increased risk for developing affective disorders and some comorbid somatic conditions such as metabolic disturbances and cardiovascular disease. An increased stress level is known to cause hyperactivity of the hypothalamic-pituitary-adrenal-axis (HPA-axis) with increased cortisol secretion. Hyperactivity of the HPA-axis (or hypercortisolism) is one of the most replicated neurobiological finding in depression. In other stress related disorders it has however been shown that prolonged stress over long periods of time can lead to a state of low HPA-axis activity, hypocortisolism. Since persons with recurrent affective disorders such as bipolar disorder and recurrent depression are exposed to a high degree of recurrent and chronic stress it could be expected that in addition to hypercortisolism, a state of hypocortisolism could also develop in these disorders, potentially exerting an influence upon the psychological and somatic wellbeing among these patients. The major aim of this thesis was to evaluate whether hypocortisolism is related to relevant psychiatric and somatic phenotypes in recurrent affective disorders. In bipolar disorder, individuals with hypocortisolism exhibited a higher degree of depression and low quality of life compared to patients with normal HPA-axis activity. In recurrent depression, individuals with hypocortisolism exhibited shorter leukocyte telomere length than patients with normal or high HPA-axis activity, which is an indication of an accelerated aging process. In a sample of both bipolar and recurrent depression patients, hypocortisolism was associated with an increased proportion of obesity, dyslipidemia and metabolic syndrome compared with patients with normal or high HPA-axis activity. Patients with recurrent depression showed a higher occurrence of hypocortisolism than the control sample representative of the general population. Patients with bipolar disorder showed a similar occurrence of hypocortisolism as the control sample. Among bipolar disorder patients with a low degree of lifetime with lithium prophylaxis, there was an inverse correlation between age and HPA-axis activity. In contrast, among patients with a higher degree of lifetime with lithium prophylaxis as well as among the controls, there was no correlation between age and HPA-axis activity. Accordingly, hypocortisolism was most common among older patients with a low degree of lifetime with lithium prophylaxis. In conclusion, hypocortisolism in both recurrent depression and bipolar disorder was associated with multiple clinically-relevant phenotypes. Additionally it was shown for bipolar disorder patients that increasing age was a risk factor for hypocortisolism and that prophylactic lithium treatment was a protective factor. It is argued that the protective effect of lithium towards the HPA-axis is attributable to its mood-stabilizing effect, which in turn reduces the chronic stress level. These results provide new insight into the role of hypocortisolism and chronic stress in recurrent affective disorders warranting further studies and hopefully providing clues to improved treatment strategies.
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Wesley, Katherine L. "Perceptions of Quality of Life, Peer Relationships, and Health Literacy in Adolescents with Phenylketonuria (PKU)." Scholar Commons, 2018. https://scholarcommons.usf.edu/etd/7381.
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Phenylketonuria (PKU) is a rare inborn error of metabolism that can be managed through lifelong treatment adherence to a restricted diet and supplemental medical formula (Vockley et al., 2014). Untreated PKU can result in severe intellectual disability, anxiety, depression, executive functioning deficits, and seizures (Cappelletti et al., 2013; Moyle et al., 2007). Even individuals who are continuously treated for PKU can experience high rates of anxiety and depression, executive functioning deficits, social difficulties, and lower full-scale IQ scores than their siblings and parents (Bosch et al., 2015; Manti et al., 2016; Waisbren et al., 2007). Additionally, adolescents are at risk for social difficulties due to the restricted diet and treatment of PKU (Bosch et al., 2015). Quality of life is just beginning to be studied in individuals with PKU. Most studies have focused on adults or on parent or clinician ratings of children and adolescents’ quality of life. Results of these studies have been varied with some individuals with PKU and their parents reporting normal quality of life compared to peers (Cazzorla et al., 2014; Thimm, Schmidt, Heldt, & Spiekerkoetter, 2013) and others showing parents rate their children with PKU as being less happy, confident, and joyful than healthy peers (Landolt, Nuoffer, Steinmann, & Superti-Furga, 2002).
A qualitative interview study was conducted with five adolescents with PKU between the ages of 14 and 18 years. The purpose of this study was to gain an in-depth awareness of the beliefs and perceptions of these adolescents with PKU on how they understand and conceptualize their condition, the impact it has on their life, factors that influence their quality of life, and perceptions of their peer relationships in regard to their illness. A romantic conceptualization of interviewing was used to build rapport and trust between the interviewer and interviewee in order to access the authentic self of each participant (Roulston, 2010a). Each adolescent participated in a series of four semi-structured individual interviews. Data were analyzed using thematic analysis (Braun & Clarke, 2006).
Results indicated adolescents with PKU describe their overall quality of life in positive terms and report similar influences on their life satisfaction and quality of life as other adolescents. Adolescents with PKU identified relationships with family and friends as the most salient influence on their life satisfaction. They largely perceive their social lives to be similar to their peers and believe they are more similar to their peers than different. Adolescents with PKU describe few challenges in social settings and view these challenges as simply inconveniences. However, adolescents with PKU minimize their condition and the impact it has on their life. When talking about PKU, sharing it with others, or when it comes up in social situations they use words that describe it as minor in consequence and significance. The majority of participants had a general understanding and knowledge of how they got PKU, their treatment, and potential consequences. Nevertheless, adolescents also reported a number of incorrect consequences, a lack of awareness of consequences, and misconceptions about PKU and the impact it can have on their life. Implications for medical providers and behavioral health professionals who work with adolescents with PKU include the importance of monitoring and providing extra support during natural transition times, such as moving from elementary school to middle school and then to high school. Current findings also indicate there is room for improvement in health literacy among adolescents with PKU and specific strategies are discussed. Future research should continue to explore the experiences of individuals with PKU during late childhood and early adolescence, the time frame identified as most difficult in the current study. Another direction for future research is further exploration of how PKU influences the idea of self-concept and self-image.
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Rickenlund, Anette. "Hormonal mechanisms of menstrual disturbances, metabolic disorders and effects of oral contraceptives in female athletes /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-148-2/.
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Hontsariuk, D. A. "Correction of metabolic disorders in patients with chronic pancreatitis combined with chronic obstructive pulmonary disease." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18086.
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Mai, Knut [Verfasser]. "Endocrine effects of free fatty acids : relevance in the pathogenesis of complex metabolic disorders / Knut Mai." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1028496613/34.
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Hryniuk, O. Ye. "Correction of metabolic disorders in non-alcoholic steatohepatitis and chronic obstructive pulmonary disease, efficiency of antral." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18589.
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Cubberley, Rebecca Sue. "Evaluating the Reliability and Validity of the Muscle Dysmorphia Inventory." TopSCHOLAR®, 2009. http://digitalcommons.wku.edu/theses/121.
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