eine Analyse des Deutschen Drug Eluting Stent-Registers (DES.DE)

Hintergrund: Die Koronare Herzkrankheit (KHK) stellt die häufigste Todesursache in den Industrienationen dar. Wichtigste interventionelle Therapieoption ist neben der Koronararterien-Bypass Operation (CABG) die Perkutane Koronarintervention (PCI), bei der das betroffene Gefäß mittels Ballonkatheter dilatiert wird. Für einen nachhaltigen Therapieerfolg kann in selber Prozedur die Implantation von Stents erfolgen. Diese können unbeschichtet (bare metal stents = BMS) oder antiproliferativ beschichtet sein (drug eluting stents = DES). In folgender Arbeit steht die Evaluation der Lebensqualität (LQ) je nach implantiertem Stent im Vordergrund. Ziele: 1. Gibt es gesundheitsbezogene Lebensqualitätsunterschiede in Abhängigkeit des gewählten Stenttyps (DES vs. BMS) zu Studienbeginn (baseline), nach 6 und 12 Monaten? 2. Wie verändert sich im Zeitverlauf nach der Stentimplantation die gesundheitsbezogene Lebensqualität ja nach implantiertem Stent-Typ? 3. Wird die Lebensqualität aufgrund der Reduktion kardialer Ereignisse/ major adverse cardiac events (MACE) verbessert? 4. Lassen sich weitere sozioökonomische oder klinische Einflussfaktoren auf die Lebensqualität identifizieren? Methoden: Das Deutsche Drug Eluting Stent-Register (DES.DE) ist eine vergleichende, multizentrische, prospektive Registerstudie, bei der alle in Deutschland und von der FDA zugelassenen Stents unter Alltagsbedingungen auf ihre Wirksamkeit überprüft werden sollen. Die Rekrutierung, mit Erhebung der LQ, erfolgte in 98 teilnehmenden Zentren. Mittels zweier Fragebögen wurden die allgemein-gesundheitsspezifischen (SF-36) und die krankheitsspezifischen (MACNEW) Lebensqualitätsparameter zu Baseline, 6 und 12 Monaten nach Implantation der jeweiligen Stents erhoben. Die klinischen Zielparameter umfassen u.a. Revaskularisationen jeglicher Art und MACE. Ergebnisse: 3.930 Registerpatienten konnten im Register aufgenommen werden, 458 Patienten mit BMS, 3.472 Patienten mit DES (BMS 11,7% vs. DES 88,3%). Die LQ beider Gruppen unterscheiden sich nicht zu baseline, nach 6 und nach 12 Monaten (SF-36 und MACNEW). Die LQ wird durch Reduktion kardialer Ereignisse nur tendenziell verbessert. Nach Stratifizierung der Lebensqualitätsunterschiede für vermutete Einflussfaktoren, können die Variablen Alter, Geschlecht, Events, Anzahl der Begleiterkrankungen und Anzahl der Vorerkrankungen als relevant für den weiteren Verlauf der Lebensqualität angesehen werden. Nach Adjustierung der Mittelwerte für o.g. Variablen, unterscheiden sich die Gruppenergebnisse in allen Skalen und Dimensionen, mit einer Überlegenheit für die DES-Gruppe zu beiden Nachbeobachtungszeitpunkten. Der Gruppenunterschied wird durch die Adjustierung deutlicher. Schlussfolgerung: DES-Patienten haben bis 12 Monate nach PCI eine bessere Lebensqualität als BMS-Patienten. Lebensqualitätsanalysen sollten für Einflussfaktoren adjustiert werden. Der Nachbeobachtungszeitraum sollte für Lebensqualitätsstudien > 1 Jahr betragen.Background: Coronary heart disease (CHD) is the most common cause of death in the industrial nations. In addition to coronary artery bypass surgery (CABG), the most important interventional therapy option is percutaneous coronary intervention (PCI), in which the affected vessel is dilated using a balloon catheter. Stents can be implanted in the same procedure to ensure sustained therapeutic success. These can be uncoated (bare metal stents = BMS) or antiproliferative coated (drug eluting stents = DES). The following work focuses on the evaluation of quality of life (QoL) depending on the implanted stent. Goals: 1. Are there health-related differences in quality of life depending on the selected stent type (DES vs. BMS) at baseline, after 6 and 12 months? 2. How does the health-related quality of life change over time after stent implantation according to the type of stent implanted? 3. Is the quality of life improved due to the reduction of cardiac events / major adverse cardiac events (MACE)? 4. Can further socio-economic or clinical factors of influence on quality of life be identified? Methods: The German Drug Eluting Stent-Registry (DES.DE) is a comparative, multicenter, prospective registry study in which all stents approved in Germany and by the FDA are to be tested for their efficacy under everyday conditions. Recruitment, including QoL survey, took place in 98 participating centres. Using two questionnaires, the general health-specific (SF-36) and disease-specific (MACNEW) quality of life parameters for baseline, 6 and 12 months after implantation of the respective stents were collected. The clinical target parameters include revascularization of all types and MACE. Results: 3,930 registry patients were enrolled, 458 patients with BMS, 3,472 patients with DES (BMS 11.7% vs. DES 88.3%). The QoL of both groups does not differ to baseline, after 6 and after 12 months (SF-36 and MACNEW). The QoL is only tended to improve by reduction of cardiac events. After stratification of the differences in quality of life for assumed influencing factors, the variables age, gender, events, number of concomitant diseases and number of previous diseases can be regarded as relevant for the further course of quality of life. After adjusting the mean values for the above variables, the group results differ in all scales and dimensions, with a superiority for the DES group at both follow-up times. The group difference becomes clearer by the adjustment. Conclusion: DES patients have a better quality of life up to 12 months after PCI than BMS patients. Quality of life analyses should be adjusted for influencing factors. The follow-up period for quality of life studies should be > 1 year

Massendurchfluss- und Dichtemessung mit einer resonanten Messzelle in Volumenmikromechanik: Massendurchfluss- und Dichtemessungmit einerresonanten Messzelle in Volumenmikromechanik

Die vorliegende Arbeit stellt einen Beitrag zur kontinuierlichen Bestimmung von Massendurchfluss sowie Dichte für den Bereich der Mikroverfahrenstechnik dar. Verschiedene Messverfahren und Sensoren werden vorgestellt und diskutiert. Die fest eingespannte durchflossene Messröhre in resonanter Schwingung kann zum einen zur Dichtebestimmung genutzt werden, da die Dichte des Fluids die bewegte Masse des Sensors und daher dessen Eigenfrequenz beeinflusst. Beim Biegeschwinger erfährt das strömende Fluid zusätzlich eine Winkelgeschwindigkeit, die die Corioliskraft als Maß für die bewegte Masse zur Folge hat. Verschiedene konstruktive Varianten der resonanten Messröhre werden vorgestellt, dabei wird auf analytische Berechnungsverfahren ebenso eingegangen wie auf die Bestimmung der statischen und dynamischen Parameter mit rechnergestützter Simulation (Finite Elemente Methode). Ebenso wird der Einsatz von gekoppelten Mehrfachschwingern erörtert und es werden Schwingungsformen sowie Vor- und Nachteile des Doppelresonators erörtert. Im technologischen Teil wird die Herstellung mechanischer Resonatoren in Volumenmikromechanik vorgestellt. Dabei wird besonders auf das anisotrope Ätzen von einkristallinem Silizium in Kalilauge sowie auf das Silizium-Direktbonden eingegangen. Der Aufbau von Doppelresonatoren durch mehrfaches Bonden wird ebenfalls untersucht und die gefertigten Sensoren werden vorgestellt. Varianten der messtechnischen Auswertung resonanter Sensoren werden bezüglich des Nutzens für die Massendurchfluss- und Dichtemessung untersucht. Dabei werden besonders zwei entwickelte kapazitive Messverfahren näher vorgestellt, mit deren Hilfe die Sensorstrukturen untersucht werden. Es wird die Funktion der Dichtemessung mit einer Auflösung von 0,01 g/cm³ bei Flüssigkeiten und Gasen nachgewiesen und der Massenfluss bis 2 g/s bei einer Auflösung von 0,1 g/s.This thesis represents a contribution to the continuous measurement of mass flow and density for the field of micro process engineering. Different measuring principles and sensors are introduced and discussed. The clamped fluid-filled measuring tube in resonant oscillation can be used on the one hand for density determination, since the density of the fluid influences the moving mass of the sensor and therefore its eigenfrequency. Inside an oscillating U-tube the fluid will additionally be exposed to an angular velocity, which leads to the Coriolis force as a quantity for the moving mass. Different design variants of the resonant measuring tube are presented. Analytical methods are introduced as well as techniques to determine the static and dynamic parameters by computer-aided simulation (finite element method). Furthermore the usage of coupled oscillators is discussed, possible modes of vibration are determined and the pros and cons of the double resonator are estimated. In the technological part the fabrication of mechanical resonators using bulk micromachining is presented. Special attention is drawn to anisotropic etching of monocrystal silicon in a potassium hydroxide solution as well as to silicon fusion bonding. The forming of double resonators by multiple wafer bonding is also examined and the manufactured sensors are shown. Methods of Variants of metrological evaluation of resonant sensors are examined concerning their usability for the mass flow and density measurement. Particularly two developed capacitive measuring techniques are discussed in detail and the sensor structures are examined with their help. The performance of the density measurement with a resolution down to 0,01 g/cm³ is proven with liquids and gases as well as the mass flow measurement up to 2 g/s with a resolution of 0,1 g/s

High‐Saturated‐Fat Diet Increases Circulating Angiotensin‐Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient‐Dependent Increases of Blood Pressure

Background Angiotensin‐converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high‐saturated‐fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study. Methods and Results Forty‐six healthy and nonobese twin pairs initially consumed a carbohydrate‐rich, low‐fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6×10−30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8×10−6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5×10−8) and additionally showed a 2‐fold increase in ACE concentrations in response to the HF diet as compared to non‐ or heterozygous carriers (AA/AG, P=2×10−6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene‐diet interaction was confirmed in a second independent, cross‐sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. Conclusions The HF‐diet‐induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high‐saturated‐fat diets. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins

Background: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Methods: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Results: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. Conclusion: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT

IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling

Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.</p

Bioinformatische Analyse der NUGAT-Studie (NUtriGenomic Analysis in Twins)

Frahnow T. Bioinformatische Analyse der NUGAT-Studie (NUtriGenomic Analysis in Twins). Potsdam: Universität Potsdam; 2016.Dissertation der Universität Potsdam, 201

Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins

Engstler AJ, Frahnow T, Kruse M, Pfeiffer AFH, Bergheim I. Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins. Twin Research and Human Genetics. 2017;20(04):338-348

Island Models Meet Rumor Spreading

International audienc

Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache.

International audienceBACKGROUND: Triptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved. METHODS: Genetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models. RESULTS: Mean age at study entry among patients was 44.6 ± 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype-reference; L*S* genotype-1.33 [0.53-3.32]; S*S* genotype-1.46 [0.54-3.98]), the results were not statistically significant. CONCLUSIONS: Data from our study do not indicate a role of bi-allelic and tri-allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins

Background: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Methods: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Results: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. Conclusion: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT