A distinct metabolic signature predicts development of fasting plasma glucose

ABSTRACT: BACKGROUND: High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called `omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. METHODS: We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. RESULTS: We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. CONCLUSIONS: We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods

In progress : see inside a lettering artist's sketchbook and process, from pencil to vector

176 p. ; col. ill. ; 26 cm

Investigation of the therapy concept ‘damage control orthopaedics’ at upper extremity injuries of polytraumatised patients

Die vorliegende Arbeit untersucht die Therapiekonzepte „early total care“ (ETC) und „damage control orthopaedics“ (DCO) bei der Behandlung 90 polytraumatisierter Patienten mit Verletzungen an der oberen Extremität in der Universitätsklinik Würzburg. Nach dem „first hit“ im Rahmen des Polytraumas kann der Organismus und das Immunsystem durch eine aufwendige Operation im Sinne eines „second hit“ überfordert werden. Ziel des DCO ist es den „second hit“ zu minimieren, indem initial nur die notwendigsten Behandlungen durchgeführt werden und keine vollständige Ausversorgung entsprechend ETC durchgeführt wird. Es werden Kriterien herausgearbeitet, welche relevant für die initiale Therapieentscheidung sind. Liegen eine hohe Verletzungsschwere (ISS), Kreislaufkomplikationen und eine niedrige Überlebensprognose nach dem RISC II sowie schwere begleitende Kopf-, Abdomen-, Becken- oder Wirbelsäulenverletzungen vor, werden die Verletzungen an der oberen Extremität nach DCO therapiert. Zudem wird für komplexe Verletzungen der oberen Extremität mit Gelenkbeteiligung, Bandschäden oder schwerem Weichteilschaden, welche zeitaufwendige und planungsintensive Operationsverfahren bedürfen, die DCO-Strategie favorisiert. Wenn die notwendige Lagerung des Patienten auf dem Operationstisch für die Ausversorgung der Verletzung an der oberen Extremität initial möglich ist, wird die obere Extremitätenverletzung nach ETC therapiert, insbesondere wenn eine schwere Verletzung an der oberen Extremität vorliegt. In der ETC-Kohorte ist kein Patient verstorben. Das schlechtere Outcome in der DCO-Kohorte liegt vor allem an der initial höheren Verletzungsschwere. Auf Grund der besseren tatsächlichen als erwarteten Mortalität kann DCO als eine erfolgreiche Therapiestrategie bei schwerverletzten Patienten angesehen werden. Jedoch kann die vorliegende Arbeit keinen Nachteil für die Patienten durch die ETC-Behandlung feststellen.The following thesis is analysing the concepts „early total care“ (ETC) and „damage control orthopeadics“ (DCO) treating 90 polytraumatised patients with upper extremity injuries of the university hospital of Würzburg. Following the first hit (trauma), a second hit (prolonged operation) can overwhelm the compensatory mechanisms of the immune system. Therefore, the principle of DCO is to reduce the impact of the second hit by minimal initial procedures. Several criteria relevant to the initial decision between the two therapy concepts are analysed. In case of high injury severity (ISS), cardio-pulmonary deficiencies, low RISC II survival prognosis and a more severe head, abdomen, hip and spine injury, the upper extremity injury is mostly treated by DCO. In addition, DCO is favoured for complex injuries of the upper limb with joint and band damages or severe tissue damage requiring prolonged procedures with intensive preparing and planning . When the patient can be positioned favourably during the initial treatment, the upper limb extremity is treated by ETC, especially in case of a severe upper limb injury. The negative outcome of the DCO patients is primarily due to the higher ISS in this cohort. By showing that the real mortality rate is lower than its prognosis, DCO can be considered as a successful concept. However, this thesis cannot find prove that ETC shows any disadvantages as the results also show positive outcomes for ETC-patients

On Fano arrangement varieties

This thesis contributes to the study of projective varieties with torus action. At first, we present an explicit approach to algebraic varieties with torus action by constructing them suitably embedded inside toric varieties. This extends existing constructions of rational varieties with a torus action of complexity one and delivers i.a. all Mori dream spaces with torus action. Our major example class are the (general/special) arrangement varieties, for which the torus action gives rise to a specific rational quotient to a projective space having as critical values a hyperplane arrangement in (general/special) position. This class comprises i.a. all toric varieties and all rational varieties with a torus action of complexity one. We present an explicit description of their Cox rings, which we use to obtain access to the geometry of these varieties, and give classification results in the smooth case. Then, we turn to singular Fano varieties. For these varieties the anticanonical complex has been introduced as a natural generalization of the toric Fano polytope and so far has been successfully used for the study of varieties with a torus action of complexity one. Using our explicit approach, we enlarge the area of application of the anticanonical complex to varieties with a torus action of higher complexity, for example, the arrangement varieties. As an application, we obtain several classification results. At first we consider intrinsinc quadrics, which are easily verified to be general arrangement varieties. We classify all Q-factorial Fano intrinsic quadrics of dimension three and Picard number one with at most canonical singularities. Moreover, considering the case of complexity two, we obtain the full classification of all Q-factorial canonical Fano intrinsic quadrics of dimension three without restrictions on the Picard number. Finally, we give classification results in the three-dimensional canonical case, where the maximal orbit quotient is the projective plane having a line arrangement of five lines in special position as its critical values