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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)
The antigen in heparin-induced thrombocytopenia (HIT) is expressed on platelet factor 4 (PF4) when PF4 complexes with polyanions. In recent years, biophysical tools (e.g. circular dichroism spectroscopy, atomic force microscopy, isothermal titration calorimetry, x-ray crystallography, electron microscopy) have gained an important role to complement immunological and functional assays for better understanding the interaction of heparin with PF4. This allowed identification of those features that make PF4 immunogenic (e.g. a certain conformational change induced by the polyanion, a threshold energy of the complexes, the existence of multimeric complexes, a certain number of bonds formed by PF4 with the polyanion) and to characterize the morphology and thermal stability of complexes formed by the protein with polyanions. These findings and methods can now be applied to test new drugs for their potential to induce the HIT-like adverse drug effect by preclinical in vitro testing. The methods and techniques applied to characterize the antigen in HIT may also be helpful to better understand the mechanisms underlying other antibody-mediated disorders in thrombosis and hemostasis (e.g. acquired hemophilia, thrombotic thrombocytopenic purpura). Furthermore, understanding the mechanisms making the endogenous protein PF4 immunogenic may help to understand the mechanisms underlying other autoimmune disorders.
All types of muscles use Ca2+ as their main intracellular messenger. In skeletal muscle fibers abnormal levels of intracellular calcium result in altered contractile properties, altered energy metabolism, and altered gene expression. Moreover, long term failure of normal Ca2+ homeostasis can lead to cell death of muscle fibers by necrosis and apoptosis. Elevations of intracellular Ca2+ levels are more and more regarded as the reason for pathological changes and muscle fiber damage in Duchenne Muscular Dystrophy (DMD). DMD is a severe recessive x-linked muscle disease caused by mutations in the dystrophin gene. The characteristics of DMD are muscle tissue wasting and fibrosis. Both muscle wasting and intracellular Ca2+ are to be reflected in changes of muscle force. Several Ca2+ conducting channels including transient receptor potential (TRP) channels are supposed to account for the abnormal Ca2+ homeostasis in DMD. Gene expressions of TRP channels have been studied in human and mouse skeletal muscle and among others TRPC3, TRPC6 and TRPV4 channels were found to occur in skeletal muscles. The present study followed the hypothesis that TRPC3, TRPC6 and TRPV4 are functional in skeletal muscle fibers and that they contribute to muscular Ca2+ homeostasis. Further, it was assumed that dysfunction of the mentioned TRP channels contributes to abnormal contractile properties and pathology and of dystrophin-deficient muscle. To study Ca2+ changes in mouse skeletal muscle fibers the fluorescent calcium indicator Fura-2 was used. Further, the technique of Mn2+ quench of Fura-2 fluorescence was applied. Muscle force measurements of mouse soleus and diaphragm strips were performed. To elucidate abnormalities of TRP channel function in dystrophin-deficient muscle, muscles and muscle fibers of mdx mice were studied. Hyperforin, an activator of TRPC6 channels elicited increases of calcium levels in wildtype muscle fibers. These increases were partly inhibited by the TRPC6 inhibitor 1-(5-chloronaphthalenesulfonyl) homopiperazine hydrochloride (ML-9). The TRPC3/TPRC6 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) resulted in increased calcium entry, which was attenuated by ML-9. 2-aminoethoxydiphenylborane (2-APB), an unspecific TRP channel inhibitor, suppressed calcium entry in muscle fibers under basal conditions. In addition, the specific TRPC3 inhibitor Pyr3, strongly inhibited background calcium entry. The TRPV4 activator 4α-phorbol 12,13-didecanoate (4α-PDD) induced significant increased calcium entry and this increase could be inhibited by the TRPV4 inhibitor HC 067047. During muscle force recordings ML-9 significantly inhibited twitches and tetani and accelerated muscle fatigue during sustained repetitive stimulation. The results indicate that TRPC3, TRPC6 and TRPV4 are functionally expressed in mouse muscle fibers. TRPC3 stays active under the basal conditions and contributes to background calcium entry. In contrast, TRPC6 and TRPV4 did not seem to be active at resting conditions, but could be pharmacologically activated. TRPC6 may play a role to counteract the calcium loss under long-term muscle fatigue. Though TRPC3 and C6 play a role for muscular Ca2+ homeostasis, it is unclear whether and how the two channels associate and cross-talk with each other in skeletal muscle cells. In mdx fibers Pyr3 inhibited background calcium influx stronger that in WT fibers, implying a possible over-activation of TRPC3 channels in mdx muscle fibers. At later stages mdx muscle showed marked decrease in force reflecting muscle wasting. Soleus showed moderate decrease and diaphragm showed severe decrease (more than 60%) in force. Resistance to muscle fatigue was shown in mdx soleus muscle when compared with WT soleus muscle. Diaphragm segments of mdx mice showed very strong resistance to muscle fatigue. The results indicate a substantial loss of muscle mass, an increase in oxidative fiber types and a reduction of fast fatigable muscle fibers. It is concluded that the hypothesis of functional expression of TRPC3, TRPC6 and TRPV4 in mouse skeletal muscle has been confirmed. The results give improved knowledge about the relation of Ca2+ homeostasis, mdx pathology and TRP channels. Diaphragms of old mdx mice show severe muscle weakness but the remaining fibers of the diaphragm showed strong fatigue-resistance. The application of a TRPC3 inhibitor may be a promising treatment to prevent high Ca2+ mediated muscle damage in muscular dystrophy.
This paper reviews the first part of the outcomes of the ORCA Saturday Afternoon Symposium 2014 dealing with ‘caries epidemiology and community dentistry: chances for future improvements in caries risk groups'. After the caries decline in many countries, there are remaining pockets of higher caries levels, mostly in the primary dentition and/or linked to a low socio-economic status (SES). The review into the evidence of caries-preventive measures clearly points to the use of fluorides, especially toothbrushing with fluoridated toothpaste and collective measures such as water fluoridation. In contrast to several unsuccessful high-risk approaches, community and public health programmes seem to be able to ensure a population-wide access and compliance in risk groups. Their simple and evidence-based measures mostly combine regular plaque removal and fluoride applications via toothbrushing, at least for children and adolescents. For the future, the common risk factor approach which addresses associations between oral health, social deprivation, diet, hygiene, smoking, alcohol use and stress should lead to combined efforts with other community health and education specialists. Further engagement with public policy, community leaders and administration is needed in order to strengthen healthy choices and behaviour, e.g. in ‘healthy' schools and kindergartens. It seems advisable that these population programmes also aim at improving upstream factors.
Background: Despite of the remarkable caries reduction in permanent dentition, caries levels of primary teeth has stagnated in Germany. Early Childhood Caries (ECC) or also known as baby bottle tooth decay is the most vulnerable form of caries in young children, but minimal data and information from different German states are available to determine the appropriate preventive programs. Aim: The purpose of the current study is to find the prevalence of ECC among young children in the state of Mecklenburg-Vorpommern (North-East Germany) and to optimize an intervention on ECC prevention in a community setting. In addition to education, fluoride varnish is evaluated on young children with active ECC. Design: In this cross-sectional study, a total of 4283 children living in the state of Mecklenburg-Vorpommern were examined. Four age groups - with an accuracy of one day - were formed as follows: less than one year (n=8), one year (n=293), two years (n=1618) and three years (n=1888). The examination was carried out by community dental service’s examiners whom are calibrated to ECC diagnostic criteria of Robke and Buitkamp (2002), and dmf-t values for caries diagnosis. These data are compared by those of children (n=5355) of same age group for the year 2011-2012. In addition, a structured questionnaire on the starting preventive programme on ECC was filled out by the community dentists and for the city of Greifswald, fluoride varnish (Duraphat®, 5% NaF = 2.26%F, Colgate-Palmolive, Germany) was applied for 32 children previously diagnosed with active ECC (ECC1: n=15, ECC2: n=17). Lesions are identified as active or non active according to texture and luminosity, and oral hygiene index (OHI-S) is measured and re-evaluated at three months follow up. Results: The percentage of children under three years old in 2012-2013 with ECC was comparatively low (4%) which possibly reflects the very young age of the children and a restriction for ECC on the upper incisors. The overall caries prevalence in Mecklenburg-Vorpommern varied from 9% to 15%. Most cavitated lesions are untreated. These results are comparable with the results from other German counties. The interventions of the ECC programme vary considerably among the different counties. There was no significant difference in the oral hygiene index (OHI-S) prior and post fluoride varnish application (p-value = 0.25). The use of fluoride varnish resulted in an 81%, statistically significant decrease of active ECC lesions in Greifswald (p < 0.001). Conclusion: The prevalence of caries among young children was considerable in Mecklenburg-Vorpommern. A preventive intervention in nurseries and fluoride varnish applications for active ECC lesions seems to be a feasible approach in controlling caries in early childhood. However, further quality management and standardization of the program should be reinforced.
Heart Failure is currently the most common cardiac disorder and a major public health concern worldwide. The adult mammalian heart harbors a subpopulation of cardiac progenitor cells (CPC) that are capable of improving cardiac function. The scope of this study was to delineate the molecular phenotype of a subpopulation of CPCs characterized by the expression of the stem cells antigen-1 surface marker (Sca-1+) and to further identify molecular alterations occurring under heart failure conditions. In order to understand the underlying cellular mechanisms an integrated approach of proteomics and transcriptomics-based techniques were employed. The first step towards achieving this goal was to unravel the native Sca-1+ cell characteristics of freshly isolated progenitor cells derived from healthy adult murine hearts. The proteome map of Sca-1 cells was established using a gel-based mass-spectrometry (gel LC-MS/MS) approach. For better interpretation, a comparison with the protein profiles of cardiomyocytes and Sca-1- cells obtained under similar experimental conditions was performed. All three cell-types were morphologically different in size and structure, which was also evident from their protein expression profiles. We observed that Sca-1+ cells lack endothelial-like and cardiac contractile phenotypes, unlike Sca-1- cells and cardiomyocytes, respectively. Functional assessment of both protein and gene expression profiles revealed a possible role of Sca-1+ cells in cell adhesion, migration, and proliferation. CPC remain in a dormant state under physiological condition unless challenged by myocardial injury. Previous studies revealed that resident Sca-1+ cells home to the injured myocardium but not to the healthy heart and further differentiate into functional cardiomyocytes. We investigated the molecular background of this behavior of adult Sca-1+ cells under heart failure condition which might provide a better insight into their cardiogenic potential in a pathological milieu. The double transgenic α-myosin heavy chain (MHC)-cyclin T1/Gαq overexpressing mouse was chosen as a model for heart failure. Using the comparative gene expression profiling we could detect the differential regulation of 197 genes with at least a 2-fold difference. Among these BDNF mRNA levels were 5-fold higher in the Sca-1+ cells derived from transgenic mice (Cyc+) in comparison to that of wild-type controls (Wt+). This difference was also observed at protein level. The substantially higher expression of BDNF during heart failure prompted us to investigate its regulatory effect on Sca1+ cells. In this current study we were able to show that small amounts of exogenous BDNF stimulated the migratory potential of Cyc+ cells. This effect was not seen in treated Wt+ cells. Furthermore, pulsed SILAC was employed to monitor BDNF mediated changes following treatment. After BDNF treatment, 58 proteins were differentially regulated of which proteins related to cell proliferation were reduced in level in Cyc+ cells while they displayed increased levels in Wt+ cells. Findings from bromodeoxyuridine (BrdU) assays and immunoblotting indicated that BDNF might initiate a differentiation program by repressing cell proliferation in Cyc+ cells. Taken together, it could be shown that the BDNF effect on protein synthesis of Cyc+ and Wt+ cells varied considerably, suggesting an improvement of the cardiogenic potential of Sca-1+ cells under pathological conditions. Aldosterone levels are known to be elevated during heart failure. In this part of study it was hypothesized that endocrine factors associated with heart failure might influence the migration of CPC, thereby possibly restoring the cardiac function of diseased hearts. It could be shown that high concentrations of aldosterone, similar to those found in the plasma of heart failure patients, induced the migration of Sca-1+ cells by up to 60% when compared to control, while physiological levels had no significant influence. In addition, it could be demonstrated that the aldosterone stimulus led to the activation of the mineralocorticoid receptor (MR) expressed on Sca1+ cells, which in turn facilitated migration. This was supported by application of MR antagonist eplerenone, which significantly reduced the aldosterone-induced increase in cell migration while a glucocorticoid antagonist exhibited no inhibitory effect. Hence, the results support the potential role of aldosterone in the mobilization of CPC. It is currently believed that the beneficial effects of cell-based therapies on cardiac repair are imparted to a large degree via paracrine mechanisms. We therefore focused on understanding the influence of pathophysiological levels of aldosterone on the extracellular environment of Sca-1+ cells. MS-based secretome profiling of cells treated for 24h with aldosterone treatment revealed higher levels of proteins associated with extracellular matrix remodeling and IGF signaling. Additionally, galectin-1 and gelsolin were significantly increased in level under pathological conditions indicating a possible paracrine tissue repair of Sca-1+ cells. To conclude, the global proteome and transcriptome profiles generated here revealed the molecular phenotype of Sca-1+ cells which may be used for future reference. The comparative microarray study provided deeper insight into the endogenous changes in mRNA expression during heart failure and delineated the cardiogenic characteristics of Sca-1+ cells. Moreover, the data presented here shed new light on the potential role of BDNF in regulating the mobilization and proliferation of CPCs. Our study on the influence of aldosterone on the migration and the extracellular proteome of CPCs provided new insights on the beneficial effects of this mineralocorticoid on cardiac cells.
The aim of this retrospective observational study is to describe and discuss various complications that can arise after insertion of alloplastic materials in the field of urogynecology that require further surgical interventions in order to manage them or to at least improve the quality of life in those women. We were able to collect data on 77 patients who fulfilled the criteria. Medical history, data of clinical findings, and outcomes were collected and analyzed. The most common complication seen as an indication for resecting slings or meshes was de novo overactive bladder syndrome (40%). Other indications seen were lower urinary tract obstruction or obstructive voiding symptoms (21%), chronic pain (21%), and de novo dyspareunia (13%). 36% of the patients had recurrent symptoms (failure) after insertion of alloplastic materials in the form of urinary incontinence or prolapse, 32% presented with vaginal erosions, 2 women had severe signs of infection with abscess formation, another 3 women had urogenital fistulae. Other rare complications after mesh or sling insertion are perforations of the urinary bladder or urethra. Proper case selection is the key factor. The use of meshes and slings seems justified only in patients with known connective tissue weakness and recurrences after native tissue repair. Otherwise, patients will be exposed to unnecessary risk without any expectable improvement to their quality of life. Most of the complications are mainly caused by wrong and inadequate surgical techniques, wrong indications, or missed diagnosis of the underlying problem. In addition, lack of long-term follow-up is usually the cause behind the negligence towards many complications. Therefore, only experienced physicians should be allowed to perform such procedures, and long-term postoperative follow-up is strongly recommended. As slings and meshes are used for procedures of choice as means to improve quality of life, and not for life threatening situations, there is a need for intensive informed consent. All possible alternatives have to be discussed, as do the pros and cons of selected procedures, even the rare complications. Mesh or sling resection is considered to be an effective solution for the management of such complications. It has shown a high success rate in comparison to conservative treatment, and the majority of patients were satisfied and experienced a big improvement in their quality of life. The most common complication after resection is the recurrence of primary symptoms, either urinary incontinence or prolapse. Major or serious intra- or postoperative complications are very rare. All complications were classified and given a code according to the classification system of the international urogynecological association and the international continence society (IUGA/ICS) on 2011. The applicability and practicability of this code were evaluated, looking for ways to possibly improve it or to identify missing parameters. Many patients had more than one code, a problem that entirely torpedoed the idea of “simple” classification. Some complications are not covered individually in the classification, such as failure and recurrence or overactive bladder syndrome. These complications should be included. Many cases began with the same code, despite having different complications. Further sub-classifications should be considered to enable the reader to easily recognize the complication at hand. Patients who came with complications more than one year after mesh or sling insertion were categorized as (T4), regardless of whether the complication arose after 1 year of after 10. Therefore, sub-classifications in the (T4) category are recommended. The “site” category was not applicable in many cases. Furthermore, it is necessary that the severity of a complication is discernible, and should be mentioned in the code. We did not find any correlation between the code given and patient satisfaction. After re-modification and completion, the IUGA/ICS code could be more practical for clinical use, which would allow for the comparison of complications and make the assessment of adverse effects easier for research purposes.
Comprehensive study of the discharge mode transition in inductively coupled radio frequency plasmas
(2016)
In this contribution, the mode transition of an inductively coupled radio frequency plasma at low pressure is investigated. Therefore, a comprehensive set of plasma diagnostics were applied to determine plasma and processing parameters. Therewith, the plasma kinetics and especially the important elementary processes were studied. Hence, the reason for the mode transition was identified.
Abstract
Nanoscale multilayer thin films of W and PC (Polycarbonate) show, due to the great difference of the components’ characteristics, fascinating properties for a variety of possible applications and provide an interesting research field, but are hard to fabricate with low layer thicknesses. Because of the great acoustic mismatch between the two materials, such nanoscale structures are promising candidates for new phononic materials, where phonon propagation is strongly reduced. In this article we show for the first time that W/PC-multilayers can indeed be grown with high quality by pulsed laser deposition. We analyzed the polymer properties depending on the laser fluence used for deposition, which enabled us to find best experimental conditions for the fabrication of high-acoustic-mismatch W/PC multilayers. The multilayers were analyzed by fs pump-probe spectroscopy showing that phonon dynamics on the ps time-scale can strongly be tailored by structural design. While already periodic multilayers exhibit strong phonon localization, especially aperiodic structures present outstandingly low phonon propagation properties making such 1D-layered W/PC nano-structures interesting for new phononic applications.
Connectivity-Based Predictions of Hand Motor Outcome for Patients at the Subacute Stage After Stroke
(2016)
Background: Connectivity-based predictions of hand motor outcome have been proposed to be useful in stroke patients. We intended to assess the prognostic value of different imaging methods on short-term (3 months) and long-term (6 months) motor outcome after stroke.
Methods: We measured resting state functional connectivity (rsFC), diffusion weighted imaging (DWI) and grip strength in 19 stroke patients within the first days (5–9 days) after stroke. Outcome measurements for short-term (3 months) and long-term (6 months) motor function was assessed by the Motricity Index (MI) of the upper limb and the box and block test (BB). Patients were predominantly mildly affected since signed consent was necessary at inclusion. We performed a multiple stepwise regression analysis to compare the predictive value of rsFC, DWI and clinical measurements.
Results: Patients showed relevant improvement in both motor outcome tests. As expected grip strength at inclusion was a predictor for short- and long-term motor outcome as assessed by MI. Diffusion-based tract volume (DTV) of the tracts between ipsilesional primary motor cortex and contralesional anterior cerebellar hemisphere showed a strong trend (p = 0.05) for a predictive power for long-term motor outcome as measured by MI. DTV of the interhemispheric tracts between both primary motor cortices was predictive for both short- and long-term motor outcome in BB. rsFC was not associated with motor outcome.
Conclusions: Grip strength is a good predictor of hand motor outcome concerning strength-related measurements (MI) for mildly affected subacute patients. Therefore additional connectivity measurements seem to be redundant in this group. Using more complex movement recruiting bilateral motor areas as an outcome parameter, DTV and in particular interhemispheric pathways might enhance predictive value of hand motor outcome.
The thesis deals with ions stored in an electrostatic ion beam trap. In the first part of the thesis the so-called self-synchronization effect is discussed. It is demonstrated that the time a bunch of injected ions is conserved by the self-synchronization effect depends on the number of injected ions. In the second part of the thesis the cooling of small anionic cobalt and copper clusters is addressed. Measurements on anionic copper clusters consisting of four to seven atoms are presented and the decay of hot clusters is observed in order to draw conclusions on the internal temperature and the cooling process itself. Afterwards measurements on Co4- are discussed and a measurement scheme based on laser induced delayed electron emission is presented enabling to monitor the internal energy distribution of the clusters over storage time in a temperature-controlled environment. The cooling of initially hot clusters as well as the heating of initially cold clusters were observed.