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We consider Iterated Function Systems (IFS) on the real line and on the complex plane. Every IFS defines a self-similar measure supported on a self-similar set. We study the transfer operator (which acts on the space of continuous functions on the self-similar set) and the Hutchinson operator (which acts on the space of Borel regular measures on the self-similar set). We show that the transfer operator has an infinitely countable set of polynomial eigenfunctions. These eigenfunctions can be regarded as generalized Bernoulli polynomials. The polynomial eigenfuctions define a polynomial approximation of the self-similar measure. We also study the moments of the self-similar measure and give recursions for computing them. Further, we develop a numerical method based on Markov chains to study the spectrum of the Hutchinson and transfer operators. This method provides numerical approximations of the invariant measure for which we give error bounds in terms of the Wasserstein-distance. The standard example in this thesis is the parametric family of Bernoulli convolutions.
Alcohol dehydrogenases as biocatalysts for the production of enantiomerically pure chiral alcohols
(2016)
Summary Enantiomerically pure chiral alcohols are key compounds in the production of certain chemicals including pharmaceuticals. Chemical synthesis allows to obtain maximal yield of 50% for one enantiomer ( >50% yield is achievable with chiral catalysts used in chemical synthesis), whereas biosynthesis leads to nearly 100% yield. Hence, expensive and time consuming resolution of racemic mixture can be avoided. Alcohol dehydrogenases are the most popular enzymes used in the chiral alcohols synthesis due to high activity with appropriate aldehydes or ketones. ADHs require a cofactor which has to be regenerated after the conversion of aldehyde/ketone to the respective alcohol. Thereby, different regeneration methods were used in the practical work to compare and choose the better one. R. erythropolis and C. hydrogenoformans alcohol dehydrogenases were chosen based on the literature screening. Each gene was cloned into Xplor2 vector and pFPMT vector. Xplor2 vector was used for the transformation of A. adeninivorans and pFPMT vector was used for the transformation of H. polymorpha. Chemically synthesized alcohol dehydrogenase sequences from R. erythropolis (ReADH) and C. hydrogenoformans (ChADH) were cloned between TEF1 promoter and PHO5 terminator which are components of Xplor2 vector or between FMD promoter and MOX terminator which are genetic elements of pFPMT vector. Moreover, ChADH and ReADH sequences with His-tag encoding sequence at the 5’ or 3’ end were constructed and the most active form of the protein was selected for further studies. ReADH-6H was used for the synthesis of 1-(S)-phenylethanol and ethyl (R)-4-chloro-3-hydroxybutanoate whereas ChADH-6H was used for the production of ethyl (R)-mandelate. ReADH-6H synthesized in A. adeninivorans and H. polymorpha was fully biochemically characterized. The enzymes from the two yeast species showed some differences in their pH and temperature optima, thermostability and activity levels. A-ReADH (A. adeninivorans) and H-ReADH (H. polymorpha) were highly active with the same substrates which were: acetophenone, 4-hydroxy-3-butanone and ethyl 4-chloroacetoacetate for reduction reaction along with 1-phenylethanol and 1,6-hexanediol for oxidation reaction. Recombinant A-ReADH-6H and H-ReADH-6H were synthesized in A. adeninivorans and H. polymorpha, respectively. Both enzymes were used for the synthesis of 1-(S)-phenylethanol and ethyl (R)-4-chloro-3-hydroxybutanoate with the use of substrate-coupled cofactor regeneration system. The enantiopurity of the products was >99%. Moreover, A. adeninivorans whole cell catalyst was also used for the synthesis of both chiral alcohols. BmGDH (Bacillus megaterium glucose dehydrogenase) was co-expressed with ReADH-6H for NADH cofactor regeneration. Comparison between isolated enzymes and permeabilized whole cell catalysts indicate that cell biocatalysts are more suitable for the production of 1-(S)-phenylethanol with 92% of acetophenone being converted in 60 min. However, cells did not show any significant advantage over isolated enzymes in the synthesis of ethyl (R)-4-chloro-3-hydroxybutanoate although the velocity of the synthesis of ethyl (R)-4-chloro-3-hydroxybutanoate was slightly improved using whole-cell catalysts, giving an 80% substrate conversion in 120 min. Recombinant C. hydrogenoformans alcohol dehydrogenase was synthesized in A. adeninivorans and biochemically characterized. Enzyme showed high activity only with one substrate, ethyl benzoylformate. The A. adeninivorans and H. polymorpha cell catalysts synthesizing ChADH and BmGDH (Bacillus megaterium glucose dehydrogenase) were constructed and used in the synthesis of ethyl (R)-mandelate (reduction product of ethyl benzoylformate) with the enantiopurity of the reaction product being >98%. H. polymorpha catalysts were more effective in the synthesis than A. adeninivorans cells. The first were able to convert 93% of ethyl benzoylformate within 180 min and the latter were converting 94% of the substrate within 360 min. Re-use of non-immobilized cells and catalysts entrapped in Lentikat® was performed and the improvement of the stability of immobilized catalysts was reported. Space time yield of 3.07 mmol l-1 h-1 and 6.07 mmol l-1 h-1 was achieved with A. adeninivorans and H. polymorpha cell catalysts, respectively. Alcohol dehydrogenase 1 from A. adeninivorans was analyzed concerning the synthesis of enantiomerically pure chiral alcohols. The enzyme did not synthesize industrially attractive products. However, based on biochemical characterization enzyme plays a role in the synthesis of 1-butanol or ethanol and thereby it is of biotechnological interest.
Protamine is administered as protamine sulfate to reverse the anticoagulant effect of heparin following cardiopulmonary bypass surgery. Immunogenicity of protamine has been recognized for decades in several patient groups including vasectomized men, diabetic patients on protamine-containing insulin and patients undergoing cardiopulmonary bypass surgery. Anti-protamine/heparin antibodies are a newly described class of heparin-dependent antibodies found in about 30% of patients exposed to protamine and heparin during cardiac surgery. A subset of seropositive patients especially who tested positive for platelet-activating anti-protamine/heparin immunoglobulin G (IgG) antibodies before surgery have prolonged postoperative thrombocytopenia with an increased risk for arterial occlusions. Studies presented in this thesis shed light on potential approaches that may prevent antibody-mediated platelet activation by anti-protamine/heparin antibodies. Two approaches are presented in this thesis, partially desulfated heparin (ODSH) and low molecular weight protamine (LMWP). Our studies demonstrated the ability of ODSH to inhibit anti-protamine/heparin antibody-mediated platelet destruction in the NOD/SCID mouse model by: i) reduction of antibody binding to preformed protamine/heparin complexes, as shown by enzyme immunoassay, ii) interfering with the binding of protamine/heparin complexes to platelets as shown by flow cytometry and fluorescence microscopy, and iii) inhibition of antibody-mediated platelet activation. Interestingly, ODSH was also able to block ongoing platelet destruction by displacing pre-bound complexes from the platelet surface. In addition, our data suggest the use of synthesized LMWP as a substitute for protamine in heparin reversal. The in vitro investigations showed that synthesized LMWP efficiently neutralizes heparin using the activated partial thromboplastin time. Anti-protamine/heparin antibodies have low binding properties to LMWP/heparin complexes as indicated in enzyme immunoassay. The ability of platelet-activating anti-protamine/heparin antibodies to induce platelet activation in the functional assay was significantly reduced in the presence of LMWP/heparin compared to protamine/heparin complexes. Owing to findings obtained in our studies, both approaches might be a promising future option to reduce anti-protamine/heparin antibody-mediated adverse effects.
Previous studies on the antimicrobial activity of cold atmospheric pressure argon plasma showed varying effects against mecA<sup>+</sup> or mecA<sup>-</sup>Staphylococcus aureus strains. This observation may have important clinical and epidemiological implications. Here, the antibacterial activity of argon plasma was investigated against 78 genetically different S. aureus strains, stratified by mecA, luk-P, agr1-4, or the cell wall capsule polysaccharide types 5 and 8. kINPen09® served as the plasma source for all experiments. On agar plates, mecA<sup>+</sup>luk-P<sup>-</sup>S. aureus strains showed a decreased susceptibility against plasma compared to other S. aureus strains. This study underlines the high complexity of microbial defence against antimicrobial treatment and confirms a previously reported strain-dependent susceptibility of S. aureus to plasma treatment.
Protamine (PRT) is a positively charged protein, which is widely used in medicine as an adjunct to certain preparations of insulin and as a rapidly-acting antidote for heparin, particularly to neutralize the effects of high heparin concentrations needed for anticoagulation during cardiac surgical procedures using cardiopulmonary bypass. It has been demonstrated that PRT and heparin form multimolecular complexes and that these complexes have high immunogenicity in a mouse model. Studies in this thesis provide new insights into the pathophysiology of anti-PRT/heparin antibodies. The results of study I showed that the administration of PRT combined with heparin is responsible for high immunoglobulin G (IgG) immunization after cardiac surgery. A subset of these antibodies was able to induce platelet activation in a way similar to that observed by heparin-induced thrombocytopenia (HIT). Using an animal model, we demonstrated that anti-PRT/heparin antibodies are capable of platelet destruction in the presence of PRT and heparin. Moreover, our data suggests that platelet-activating anti-PRT/heparin antibodies at surgery are potentially associated with postoperative thrombocytopenia and an increased risk for thromboembolic events. In study II, the immune response against PRT/heparin complexes was investigated. This study showed a relatively fast development of IgG with no general preceding IgM formation. In addition, patients undergoing liver transplantation developed anti-PRT/heparin antibodies without previous exposure to PRT. These results suggest that a previous contact with the antigen(s) itself or other antigens with molecular mimicry induced this immune response. In fact, we were able to identify Neutral Protamine Hagedorn (NPH) insulin and core histones (DNA-binding proteins) as potentially antigenic candidates for a previous immunization. Furthermore, the findings of study III demonstrate the ability of anti-PRT/heparin antibodies to activate platelets in the presence of NPH insulin in a heparin-dependent way suggesting that diabetic patients may have an enhanced risk for thromboembolic complications if treated with NPH insulin and possibly while receiving prophylactic heparin. These observations justify further clinical investigations to assess the impact of the interaction between anti-PRT/heparin antibodies and PRT-mimicking antigens, such as NPH insulin or histones.
Decades after international guidelines to approach Universal Health Coverage and Access for All to essential health care services have been formulated by the global community, social protection in health remains a major global challenge. This implies the devastating situation of having less than 15% of the global population benefiting of any kind of social protection in health, while more than 70% of the world population lacks any type of social protection coverage. 36 years after the famous and often-cited Alma-Ata Declaration proclaimed that „the promotion and protection of the health of the people is essential to sustained economic and social development and contributes to a better quality of life and to world peace”, people of the informal sector – which forms up to 90% of the population in many countries of sub-Saharan Africa – are still forced to take out loans or sell their assets to settle their hospital bills and in the end fall into poverty because of unbearable health care costs. While private health insurance schemes are mainly serving people living in urban areas and offer products and services that are not tailored to the needs of people of low-income from rural and/or remote areas, public social health insurance schemes are usually designed to serve the formal sector or are exclusively catering for public servants. At the same time, social protection in health is increasingly regarded to be a guarantor for development and economic growth of the national economy. In this context, some authors are convinced that community-based health financing is to be seen as a promising approach to insure parts of the population, which are normally excluded from any type of social protection in health, against catastrophic health care costs. With a focus on low-income people, Community-based Health Financing (CBHF) schemes offer products, processes and institutions that are tailored to the specific needs of their low-income target group, usually situated in the informal sector. In the aim to meet international standards and comply with the global development agenda, governments in sub-Saharan Africa are increasingly acknowledging the need to include the informal sector and people of low-income into their public health financing systems. As a result, innovative health systems evolved, which often comprise of hybrid sub-systems to cover various target groups of the society. While some governments – such as the governments of Rwanda, Ghana and Tanzania – have already implemented integrated national Social Health Insurance (SHI) systems that consider CBHF schemes to cover the informal sector, others are aiming at implementing this innovative idea in the near future, e.g. Burkina Faso and Togo. Given the above-illustrated situation, the overall research objective of this thesis is to explore the potential contribution of CBHF schemes towards Universal Health Coverage (UHC) in low- income countries of sub-Saharan Africa. Furthermore, the specific research objectives are set as follows; (1) To establish common lessons learnt from low-income countries in sub-Saharan Africa which implemented integrative SHI systems by combining efforts of national SHI schemes and CBHF schemes, or which are in an advanced stage of designing and implementing the same. (2) To comprehensively analyze the Kenyan health financing system and design adequate interventions towards the design and implementation of an integrative national SHI scheme in Kenya which is favoring UHC. (3) To develop a standard model for implementing integrative SHI systems in low-income countries of sub-Saharan Africa and the world. This thesis will at first provide a comprehensive topical background containing evidence about different relevant concepts such as Development, Universal Health Coverage, Social Protection, Health Financing and Micro Health Insurance. On this basis, the potential of combining community-based and national efforts towards tailored health care financing at national level will be explored by analyzing strengths and weaknesses of both approaches and providing brief insights from low-income countries of sub-Sahara Africa in this area. Furthermore, a comprehensive background to common development initiatives as well as the social protection and health care financing sectors in Kenya is provided to introduce the case study of chapter four. In the third chapter, common efforts of governments and other stakeholders involved in health care financing in sub-Saharan African countries to integrate CBHI schemes into public SHI schemes will be reviewed and analyzed. In the scope of this review, Tanzania, Rwanda, Burkina Faso and Ghana will serve as practical country case examples. Based on this extensive cross-country analysis, common lessons learnt regarding the complex process of designing integrative SHI systems in low-income countries of sub-Saharan Africa will be presented. In chapter four, through a comprehensive country case study, the Kenyan health and health financing sector and its stakeholders will be analyzed regarding its potential towards UHC, aiming at the development of most promising interventions towards the design and implementation of an integrated SHI scheme in Kenya, considering CBHF schemes as one building block of the system. A multi-stage model as well as a multi-level structure of a national SHI system to approach UHC in Kenya will be outlined and presented. The thesis will be concluded in chapter five by transferring the Kenyan experience to a global level and suggesting a standard model for implementing integrated SHI schemes in similar contexts as given in Kenya and the presented case examples. In the conclusion, common opportunities and limitations of community-based approaches towards UHC are highlighted and a way forward for the Kenyan context is suggested.
Background: Cardiovascular disease (CVD) remains the major cause of mortality and morbidity worldwide and produces large productivity loss. The majority of CVD mortality could be prevented with changes in modifiable risk factors including tobacco use, physical inactivity, unhealthy diet and harmful use of alcohol. Successful behavioral prevention of CVD requires the identification of relevant target behaviors and reach of populations at risk. Presenteeism i.e. attending work while ill is discussed as a work-related risk factor for CVD. However, little is known about the interplay of presenteeism with established health risk behaviors. The first aim of this dissertation was to examine the association of presenteeism with health behaviors (study 1). The second aim was to examine factors that can enhance the public health impact of CVD prevention efforts. Therefore, the effect of recruitment strategy used on reach (study 2) and of communication channel used on intervention usage (study 3) was examined. Methods: Study 1 comprised data from 710 Australian employees aged 18 years and older who completed an online-survey. Linear regression analysis was used to examine the association of health behaviors (physical activity, work and non-work-related sitting time, sleep duration and sleep quality) with presenteeism. For study 2 individuals aged 40-65 years were invited to a two-stage cardio-preventive program including an on-site health screening and a cardiovascular examination program (CEP) using face-to-face recruitment in general practices (n = 671) and job centers (n = 1,049), and mail invitations from a health insurance company (n = 894). Recruitment strategies were compared regarding three aspects of reach: (1) participation rate, (2) participants’ characteristics i.e. socio-demographics, self-reported health and CVD risk factors, and (3) predictors of program participation. Study 3 compromised 16,948 users (aged 18 years and older) of the feely available physical activity promotion program 10,000 Steps. Users were grouped based on which platform (website, app) they logged their physical activity: Web-only, App-only, or Web-and-app. Groups were compared on socio-demographics, engagement parameters and logged physical activity. Non-usage attrition i.e. discontinued program usage over the first three months was examined using Kaplan-Meier survival curves. A Cox regression model was used to determine predictors of non-usage attrition. Results: Analyses from study 1 revealed that presenteeism was associated with poor sleep quality and suboptimal sleep duration after controlling for socio-demographics, work and health-related variables. Engaging in three health risk behaviors was associated with higher presenteeism compared with engaging in none or one. Study 2 showed screening participation rates of 56.0%, 32.8%, 23.5% for general practices, job centers and the health insurance company, respectively. Participation rate for the CEP among eligible individuals was 80.3%, 65.5%, and 96.1%, respectively. Job center clients showed the lowest socio-economic status and the most adverse CVD risk pattern. Whereas being female predicted screening participation across all strategies, higher age predicted screening participation only within individuals recruited via the health insurance company. Within general practices and job centers CEP participants were less likely to be smokers than non-participants. Study 3 revealed that engagement with the program was highest for Web-and-app users. Cox regression showed that user group predicted non-usage attrition: Web-and-app users (hazard ratio = 0.86; P < .001) and App-only users (hazard ratio = 0.63; P < .001) showed a reduced attrition risk compared to Web-only users. Further, older age, being male, being non-Australian, higher program engagement and higher number of steps logged were associated with reduced non-usage attrition risk. Conclusion: The results of this dissertation have three implications for designing CVD behavioral interventions with a high public health impact. First, employees suffering from presenteeism may require interventions addressing health risk behaviors including suboptimal sleep behaviors. Second, implementing prevention efforts in job centers may be especially useful to reduce health inequalities induced by social gradient. Third, the population impact of web-based interventions may be increased when using mobile delivery channels.
Background: Abdominal obesity is a major driver for adverse medical conditions. While an interaction between adipose tissue and thyroid function is thought to exist, to our knowledge, no study has examined the effect of thyroid-stimulating hormone (TSH) on visceral adipose tissue (VAT) in a population-based context. Objective: We determined an association between serum TSH levels and VAT. Methods: A sample of 1,021 female and 956 male adults aged 20-79 years was drawn from registry offices in the cross-sectional, population-based Study of Health in Pomerania Trend (SHIP Trend) in Northeast Germany from 2008 to 2012. Our main exposure was serum TSH levels. Our main outcome was VAT measured using magnetic resonance imaging. The possibly mediating role of leptin on the TSH-VAT association was also assessed. Results: A total of 1,719 participants (87.9%) had serum TSH levels within the reference range. The mean volume of VAT was 5.33 liters for men and 2.83 liters for women. No association between TSH and VAT (β = 0.06, 95% CI: -0.02, 0.14) was observed, and there were no differences detected between sexes. VAT was strongly associated with leptin with a greater effect in women than in men. Leptin was strongly associated with TSH. Conclusions: No association between TSH and VAT was observed. Other biomarkers such as leptin may play a role in the relationship between thyroid function and metabolic risk.
Ausbildung des Charakters
(2016)