Es lässt sich feststellen, dass in der vorliegenden Untersuchung eine nichtchirurgische systemische Parodontaltherapie mit und ohne adjuvante Antibiose die beobachteten Keimzahlen der parodontitisassoziierten Keime Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis und Tannerella forsythia signifikant reduzieren konnte. Es konnte jedoch kein direkter Zusammenhang zwischen der beobachteten Keimreduktion des subgingivalen Mikrobioms und der Veränderung der erfassten Parameter der arteriellen Gefäßsteifigkeit festgestellt werden. Weitere Interventionsstudien mit höheren Patientenzahlen und einer hierdurch möglichen differenzierteren Subanalyse des Patientenguts bezüglich Risikofaktoren wie Tabakkonsum, Medikation oder Lebensalter, sowie der Unterscheidung zwischen aggressiver und chronischer Parodontitis sind erforderlich, um die mögliche Existenz eines kausalen Zusammenhangs beider Erkrankungen definitiv abklären zu können. / The purpose of this study was to determine an association between periodontitis and cardiovascular disease. Therefore we analysed the subgingival microbiom of 73 study subjects with periodontitis before and after systematic periodontal therapy and the effect of periodontal therapy on arterial stiffness parameters e.g. pulse-wave velocity and augmentation index, which are indicators for cardiocascular risks. It can be concluded that after periodontal therapy numbers of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythia in the subgingival microbiom have been significantly decreased. There was no significant correlation between the observed reduction of the periodontal pathogens and the changes of the arterial stiffness parameters.

Metabolic syndrome is defined as a combination of obesity, elevated triglycerides, decreased high-density lipoproteins, hypertension and insulin resistance. It is at least partially caused by sedentary life style and unhealthy dietary habits and is a major risk factor for development and progression of cardiovascular disease and type 2 diabetes. Growing medical and socioeconomic impact of the metabolic syndrome warrants further active search for novel risk markers and therapeutic targets. Recent experimental and epidemiological studies have demonstrated the multiple roles of the endogenous methylarginines, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) as wells as the enzymes, which are involved in their catabolism, dimethyarginine dimethylaminohydrolases (DDAHs) and alanine:glyoxylate aminotransferase 2 (AGXT2) in the pathogenesis of metabolic syndrome and its complications. ADMA is thought to exhibit its pathological effects by inhibiting and uncoupling nitric oxide synthases (NOS), while SDMA can inhibit transport of L-arginine. DDAHs, namely DDAH1 and DDAH2, have been thought as the major enzymes metabolizing ADMA to citrulline, while being inactive towards SDMA. Experimental studies with upregulation of DDAH1 in animal models showed that lowering ADMA results in protection against endothelial dysfunction, atherosclerosis, ischemia/reperfusion injury and vascular remodeling, acceleration of angiogenesis in the settings of ischemia and improvement of insulin sensitivity. Unfortunately, all the attempts to upregulate DDAH1 using small drugs have not been successful. The data regarding the role of DDAH2 are contradictory, with some studies showing that it can metabolize ADMA under certain conditions and other studies questioning its enzymatic activity towards ADMA. AGXT2 is a mitochondrial aminotransferase, which can metabolize, among its other substrates, both ADMA and SDMA. It is a large protein with possible allosteric regulatory sites, suggesting that, in contrast to DDAH1, it could be upregulated by small molecules. The role of AGXT2 in different pathophysiological processes involving ADMA and SDMA is poorly understood. It has been recently discovered in the offspring cohort of the Framingham Heart Study participants that a composite compound, consisting of the products of metabolism of ADMA and SDMA by AGXT2 (asymmetric dimethylguanidino valeric acid (ADGV) and symmetric dimethylguanidino valeric acid (SDGV), correspondingly) is an independent biomarker of CT (computed tomography)-defined NAFLD (non-alcoholic fatty liver disease) and a predictor of future diabetes up to 12 years before disease, suggesting that AGXT2 may play a key role in development of metabolic disease and its progression. We and other have recently identified several other metabolically active substrates of AGXT2, such as a marker of cardiovascular and overall mortality homoarginine and a regulator of fatty acid oxidation and browning of adipose tissue beta-amino-isobutyric acid (BAIBA), which further supports the importance of AGXT2 in pathogenesis of cardiovascular and metabolic diseases. The data presented in the current thesis enable answering the two research aims: 1) Identification of the tissue and intracellular expression pattern of human AGXT2 and 2) Testing the hypothesis that ubiquitous transgenic overexpression of AGXT2 protects from ADMA-induced vascular damage in vivo. The first research aim provided a thorough characterization of AGXT2 expression in humans using multiple complimentary techniques and addressed the current discrepancy in the literature with previous demonstration of comparable levels of Agxt2 expression by RT-PCR and Western Blot in the kidneys and liver in mice, and previous reports on detection of predominant Agxt2 expression in the kidneys by Northern Blot and in-situ RNA-hybridization in rats. In our current study we analyzed AGXT2 expression in human tissues from a normal tissue bank by RT-PCR and further validated the results by Western Blot. We also performed immunohistochemical staining for AGXT2 and double fluorescent staining with an anti-AGXT2 antibody and a monoclonal anti-mitochondrial antibody. We saw the strongest expression of AGXT2 in the kidney and liver both on the mRNA and protein levels. Our immunohistochemistry stainings showed that AGXT2 is present in the convoluted tubule in the kidney and in the liver hepatocytes. The double fluorescent staining revealed the intracellular localization of AGXT2 in mitochondria. In the second research aim we investigated whether long-term upregulation of AGXT2 is safe and can protect from ADMA- mediated vascular damage in the setting of DDAH1 deficiency, which is commonly observed in cardiovascular pathologies. We generated AGXT2 transgenic (TG) mice with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of ADGV, the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. The work, included into this thesis demonstrates that both hepatocytes and kidney tubular epithelial cells are the major sources of AGXT2 in humans, where the enzyme is localized in mitochondria. The expression of AGXT2 in the liver is consistent with the proposed role of AGXT2 in development and progression of NAFLD and is consistent with our previous discovery of hepatocyte nuclear factor 4 alpha (HNF4α) as the major regulator of Agxt2 expression in the mouse liver. Chronic upregulation of AGXT2 in mice lowered systemic ADMA levels without any obvious effects on viability, development, growth and fertility, suggesting potential safety of this ADMA-lowering approach. Overexpression of AGXT2 protected from ADMA-induced vascular damage in the highly clinically relevant settings of DDAH1 deficiency, suggesting that the observed vascular damage was indeed caused by ADMA itself, rather than by some ADMA-independent effects of DDAH1 deficiency. The observed protective effects of AGXT2 upregulation are especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful. The current study, therefore, provides the basis for the future screens to identify small molecules, which would upregulate AGXT2 activity.

Innerhalb von Deutschland gibt es erhebliche Unterschiede in der kardiovaskulären Mortalität mit einer erhöhten Mortalität in den ostdeutschen im Vergleich zu den westdeutschen Bundesländern. Das Risiko, an einer koronaren Herzkrankheit oder einem Schlaganfall zu sterben, ist in Ostdeutschland etwa 50% höher als in Westdeutschland. Damit hat sich das Risikoverhältnis seit der Wiedervereinigung insgesamt wenig verändert, obwohl sowohl in Ost- als auch in Westdeutschland die kardiovaskuläre Mortalität abgenommen hat. Mögliche Ursachen für die regionale Variation sind Unterschiede bei kardiovaskulären Risikofaktoren, soziodemographischen Faktoren, Lebensstilfaktoren, Umwelteinflüssen und in der medizinischen Versorgung. In ganz Deutschland wird ein hoher Prozentsatz von Patienten mit kardiovaskulären Erkrankungen nicht entsprechend den aktuellen Leitlinien europäischer Fachgesellschaften behandelt. Eine inadäquate Einstellung von Risikofaktoren kann neben einer erhöhten Morbidität auch über den Verlust an Produktivität zu hohen indirekten Kosten für die Gesellschaft führen, ebenso wie zu einer Einschränkung der Lebensqualität für die Patienten. Neben einer adäquaten Prävention ist auch das „richtige“ Verhalten bei Auftreten von kardiovaskulären Symptomen wesentlich (Notrufnummer „112“), da sich ein hoher Prozentsatz der Todesfälle bereits vor Erreichen des Krankenhauses ereignet. Insgesamt zeigt sich eine deutliche Diskrepanz zwischen den Ergebnissen der klinischen Forschung und der Versorgungssituation im Alltag. Um längerfristig die Versorgung der Patienten zu verbessern, sind gezielte Interventionen erforderlich, um die Einhaltung der Leitlinien durch die Ärzte zu fördern und die Compliance der Patienten mit Lebensstilmaßnahmen und medikamentöser Therapie zu verbessern. Längerfristige Ziele sind die Verringerung der Kluft in der kardiovaskulären Mortalität zwischen Ost- und Westdeutschland und eine weitere Reduktion der Mortalität durch eine verbesserte Prävention. / Within Germany, there is a considerable regional variation in cardiovascular mortality with an increased mortality in the East compared to the West. The relative risk of cardiovascular death due to coronary heart disease or stroke is about 50% higher in East compared to West Germany. Despite an overall decrease in cardiovascular mortality in both East and West Germany, the risk ratio has remained largely constant since reunification. Possible explanations for the regional variation include differences in cardiovascular risk factors, socio-demographic factors, lifestyle, environmental conditions, and medical care. In addition, a high percentage of patients with cardiovascular diseases in Germany are not treated according to current international guidelines. Apart from an increased morbidity, inadequate treatment of risk factors may lead to a high amount of indirect costs due to productivity loss. Also, health-related quality of life is reduced in patients with cardiovascular diseases. As a high percentage of cardiovascular deaths occur prior to the arrival at the hospital, it is also important to educate people at risk about an appropriate help seeking behaviour in the case of an acute event (e. g. emergency number “112”). To conclude, research results are not sufficiently translated into routine medical care. Interventions are, therefore, needed to improve both compliance of physicians with current guidelines and compliance of patients with lifestyle measures and medication. In the long term, the gap in cardiovascular mortality between East and West Germany should be narrowed and preventive measures should be improved to further reduce cardiovascular mortality in Germany

Phytoöstrogene sind in den vergangenen Jahren zunehmend in den Fokus der Wissenschaft gerückt, weil sie eine potentielle Alternative zur klassischen Hormonersatztherapie darstellen. Diese ist aufgrund von zum Teil drastischen Nebenwirkungen für den Einsatz von klimakterischen Beschwerden umstritten. In dieser Arbeit wird die dosisabhängige Wirkung des Phytoöstrogens Genistein an ausgewählten östrogenselektiven Organen näher untersucht. Die Versuche wurden am Modell der langzeitovarektomierten Maus durchgeführt. Es wurden 70 ovarektomierte Tiere in sieben Gruppen aufgeteilt und untersucht. Fünf der sieben Gruppen erhielten genisteinhaltiges Futter in verschiedenen Konzentrationen. Die anderen beiden Gruppen erhielten Estradiol als Zusatz oder sojafreie Diät und dienten jeweils als Positiv- und Negativkontrollgruppe. Zusätzlich gab es eine nicht ovarektomierte intakte Kontrollgruppe, die ebenfalls sojafreies Futter erhielt. Während des dreimonatigen Versuchszeitraums wurden regelmäßig Gewicht und Futterverbrauch der Tiere gemessen. Nach Ende des Versuchs wurden die Feuchtgewichte von Uterus und Herz bestimmt sowie die Genexpression am linken Ventrikel von IGF-1, ERα und Myocardin mittels PCR analysiert. Darüber hinaus wurde am Tibia-Knochen per pQCT die Messung der Spongiosadichte, des polaren Widerstandsmoments und des prozentualen Anteils der Trabekel an der Spongiosaquerschnittsfläche durchgeführt. Die Ergebnisse zeigen, dass Genistein direkt am Herz wirkt, indem es das relative Herzgewicht und die Genexpression am Herz erhöht. Genistein beeinflusst auch das Körpergewicht und das relative Gewicht des Uterus und die untersuchten Knochenparameter dosisabhängig. Genistein kann in höherer Dosierung am Uterus proliferierend wirken, jedoch nach derzeitigem Kenntnisstand weniger stark als der klassische Hormonersatztherapie-Wirkstoff E2. Genistein kann zukünftig nur dann eine Therapiealternative zur klassischen Hormonersatztherapie darstellen, wenn es gelingt, eine Dosis zu finden, bei der Genistein die gewünschten Wirkungen entfaltet, gleichzeitig aber die unerwünschte proliferierende Wirkung an Brust und Uterus sicher ausgeschlossen werden kann. Im Modell der ovarektomierten Maus scheint eine Dosis von 1 g/kg Genistein im Futter ein vielversprechender Ansatzpunkt für weitere Untersuchungen zu sein.

No description available.

Abstract Background: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifes Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Objective: Cardiovascular diseases are the leading cause of death. The gold standard for their diagnosis and treatment are angiographic procedures. Clinicians rely on dedicated and specialized equipment for these interventions, e.g. angiography systems. The speed of the associated development is important as better technology enables progress in treatment methods and clinical outcomes. The goal of this article is to show how to optimize the innovation and development process such that it takes minimal time. Methods: 672 data sets on 302 topics were collected over 47 months during a long-term observation of the innovation and development process of angiographic systems. The total data collected is equivalent to efforts worth 30 man-years. This input was used to calculate key process parameters, analyse key process roles, evaluate the use of problem-solving methods and identify key technologies. We also developed a process model comprising the primary innovation sources, important input providers and key processes. This model is characterized by a continuous loop for the innovation and development process. Results: The conducted literature research identifies this closed loop process model as being unique in comparison to the well-established models proposed by Brockhoff, Cooper, Crawford, Durfee, Ebert, Eppinger, Hughes, Pleschak, Thom, Ulrich, Vahs and Witt. According to the best knowledge of the authors no comparable data collection has been performed and presented anywhere else yet. When analysing our 672 data sets, we found that the median process time ( in this data pool (n=672) was to be 10 weeks (p<0,05). The median number of task owners (xPA) per task across all topics was 2. Our data revealed that the number of task owners had a direct impact on the process time. For data sets with up to eight task owners the relationship between process time and task owners can be described as tPd=3.6*xPA^1.4. The median time of owning a topic was determined for Sales (7 weeks), Service (11 weeks), Customer Relationship Management (6 weeks), Product Lifecycle Management (10 weeks) and Research & Development (11 weeks). Main input providers were Sales (53%) and customers (28%). Sales (42%) and PLM (37%) are significant connectors. Problem solvers are PLM (35%), CRM (27%) and R&D (27%). The problem-solving methods were analysed and it was found that clarification (77%) as well as dialog and variation method (both 50%) were used most often. We found that changes to the application software (33%), mechanics, device interfaces and user interface (all 21%) are the four out of six components that were involved in most often. In the analysed datasets a potential of an up to 20% shorter process time was identified. Conclusion: This article proposes a new model for the innovation and development process. Based on our data, we recommend to apply a continuous loop process in the context of innovation and development of medical devices. Our results can, for example, be used for Activity Based Costing Approach or be applied to bring new or upgraded angiography systems faster to market benefitting patient outcome due to improved diagnosis and treatment of cardiovascular diseases.