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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.
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.
Little is known about mechanics underlying the interaction among platelets during activation and aggregation. Although the strength of a blood thrombus has likely major biological importance, no
previous study has measured directly the adhesion forces of single platelet-platelet interaction at different activation states. Here, we filled this void first, by minimizing surface mediated plateletactivation and second, by generating a strong adhesion force between a single platelet and an AFM cantilever, preventing early platelet detachment. We applied our setup to measure rupture forces between two platelets using different platelet activation states, and blockade of platelet receptors. The rupture force was found to increase proportionally to the degree of platelet activation, but reduced with blockade of specific platelet receptors. Quantification of single platelet-platelet interaction provides major perspectives for testing and improving biocompatibility of new materials; quantifying the effect of drugs on platelet function; and assessing the mechanical characteristics of acquired/inherited platelet
defects.
Ausbildung des Charakters
(2016)
High-Frequency Binaural Beats Increase Cognitive Flexibility: Evidence from Dual-Task Crosstalk
(2016)
Increasing evidence suggests that cognitive-control processes can be configured to optimize either persistence of information processing (by amplifying competition between decision-making alternatives and top-down biasing of this competition) or flexibility (by dampening competition and biasing). We investigated whether high-frequency binaural beats, an auditory illusion suspected to act as a cognitive enhancer, have an impact on cognitive-control configuration. We hypothesized that binaural beats in the gamma range bias the cognitive-control style toward flexibility, which in turn should increase the crosstalk between tasks in a dual-task paradigm. We replicated earlier findings that the reaction time in the first-performed task is sensitive to the compatibility between the responses in the first and the second task—an indication of crosstalk. As predicted, exposing participants to binaural beats in the gamma range increased this effect as compared to a control condition in which participants were exposed to a continuous tone of 340 Hz. These findings provide converging evidence that the cognitive-control style can be systematically biased by inducing particular internal states; that high-frequency binaural beats bias the control style toward more flexibility; and that different styles are implemented by changing the strength of local competition and top-down bias.
This multi-methodological study applied functional magnetic resonance imaging to investigate neural activation in a group of adolescent students (N = 88) during a probabilistic reinforcement learning task. We related patterns of emerging brain activity and individual learning rates to socio-motivational (in-)dependence manifested in four different motivation types (MTs): (1) peer-dependent MT, (2) teacher-dependent MT, (3) peer-and-teacher-dependent MT, (4) peer-and-teacher-independent MT. A multinomial regression analysis revealed that the individual learning rate predicts students’ membership to the independent MT, or the peer-and-teacher-dependent MT. Additionally, the striatum, a brain region associated with behavioral adaptation and flexibility, showed increased learning-related activation in students with motivational independence. Moreover, the prefrontal cortex, which is involved in behavioral control, was more active in students of the peer-and-teacher-dependent MT. Overall, this study offers new insights into the interplay of motivation and learning with (1) a focus on inter-individual differences in the role of peers and teachers as source of students’ individual motivation and (2) its potential neurobiological basis.
Observed recent and expected future increases in frequency and intensity of climatic extremes in central Europe may pose critical challenges for domestic tree species. Continuous dendrometer recordings provide a valuable source of information on tree stem radius variations, offering the possibility to study a tree's response to environmental influences at a high temporal resolution. In this study, we analyze stem radius variations (SRV) of three domestic tree species (beech, oak, and pine) from 2012 to 2014. We use the novel statistical approach of event coincidence analysis (ECA) to investigate the simultaneous occurrence of extreme daily weather conditions and extreme SRVs, where extremes are defined with respect to the common values at a given phase of the annual growth period. Besides defining extreme events based on individual meteorological variables, we additionally introduce conditional and joint ECA as new multivariate extensions of the original methodology and apply them for testing 105 different combinations of variables regarding their impact on SRV extremes. Our results reveal a strong susceptibility of all three species to the extremes of several meteorological variables. Yet, the inter-species differences regarding their response to the meteorological extremes are comparatively low. The obtained results provide a thorough extension of previous correlation-based studies by emphasizing on the timings of climatic extremes only. We suggest that the employed methodological approach should be further promoted in forest research regarding the investigation of tree responses to changing environmental conditions.
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.
Induction of Central Host Signaling Kinases during Pneumococcal Infection of Human THP-1 Cells
(2016)
Streptococcus pneumoniae is a widespread colonizer of the mucosal epithelia of the upper respiratory tract of human. However, pneumococci are also responsible for numerous local as well as severe systemic infections, especially in children under the age of five and the elderly. Under certain conditions, pneumococci are able to conquer the epithelial barrier, which can lead to a dissemination of the bacteria into underlying tissues and the bloodstream. Here, specialized macrophages represent an essential part of the innate immune system against bacterial intruders. Recognition of the bacteria through different receptors on the surface of macrophages leads thereby to an uptake and elimination of bacteria. Accompanied cytokine release triggers the migration of leukocytes from peripheral blood to the site of infection, where monocytes differentiate into mature macrophages. The rearrangement of the actin cytoskeleton during phagocytosis, resulting in the engulfment of bacteria, is thereby tightly regulated by receptor-mediated phosphorylation cascades of different protein kinases. The molecular cellular processes including the modulation of central protein kinases are only partially solved. In this study, the human monocytic THP-1 cell line was used as a model system to examine the activation of Fcγ and complement receptor-independent signal cascades during infection with S. pneumoniae. Pneumococci cultured either in chemically defined or complex medium showed no significant differences in pneumococcal phagocytosis by phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells. Double immuno-fluorescence microscopy and antibiotic protection assays demonstrated a time-dependent uptake and killing of S. pneumoniae 35A inside of macrophages. Infections of THP-1 cells in the presence of specific pharmacological inhibitors revealed a crucial role of actin polymerization and importance of the phosphoinositide 3-kinase (PI3K) and Protein kinase B (Akt) as well during bacterial uptake. The participation of essential host cell signaling kinases in pneumococcal phagocytosis was deciphered for the kinase Akt, ERK1/2, and p38 and phosphoimmunoblots showed an increased phosphorylation and thus activation upon infection with pneumococci. Taken together, this study deciphers host cell kinases in innate immune cells that are induced upon infection with pneumococci and interfere with bacterial clearance after phagocytosis.
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: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. Key Messages: Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. Conclusions: Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized.
Introduction: Recently, FOLFIRINOX and gemcitabine + nab-paclitaxel have been introduced as a novel intensified chemotherapy regimen for patients with metastasized pancreatic cancer. This study aims to analyze the real-world clinical practice with FOLFIRINOX and gemcitabine + nab-paclitaxel across Europe. Methods: Invitations to participate in an anonymous web-based questionnaire were sent via e-mail to 5,420 doctors in 19 European countries through the network of national gastroenterological, oncological, surgical and pancreatic societies as well as the European Pancreatic Club. The questionnaire consisted of 20 questions, 14 regarding the use of intensified chemotherapy, 4 regarding demographics of the participants, and 1 to verify the active involvement in the management of metastatic pancreatic cancer. Results: Two hundred and thirteen responses were received and 153 entries were valid for analysis. Of those, 63.4% came from an academic institution, 51% were oncologists, and 52% treated more than 25 cases per year. A majority of responses (71%) were from Italy (40%), Germany (23%), and Spain (8%). As first-line therapy, 11% used gemcitabine +/- erlotinib, 42% used FOLFIRINOX, and 47% used gemcitabine + nab-paclitaxel. Of the intensified regimens, both were applied to equal parts, but the likelihood of protocol deviation was higher when using FOLFIRINOX (p < 0.01). FOLFIRINOX was considered more toxic than gemcitabine + nab-paclitaxel (neutropenia 88 vs. 68%; polyneuropathy 42 vs. 41%; rapid deterioration 42 vs. 31%). FOLFIRINOX was rated to achieve longer survival with an acceptable quality of life (52 vs. 44%). Moreover, 57% of participants thought that gemcitabine + nab-paclitaxel should be the backbone for further clinical trials in pancreatic cancer. Conclusion: Intensified chemotherapy is widely used in pancreatic cancer patients in Europe following its recent clinical approval. Interestingly, nab-paclitaxel and FOLFIRINOX were used at comparable frequency although the latter had to be de-escalated more often.
Complement resistance is an important virulence trait of Yersinia enterocolitica (Ye). The predominant virulence factor expressed by Ye is Yersinia adhesin A (YadA), which enables bacterial attachment to host cells and extracellular matrix and additionally allows the acquisition of soluble serum factors. The serum glycoprotein vitronectin (Vn) acts as an inhibitory regulator of the terminal complement complex by inhibiting the lytic pore formation. Here, we show YadA-mediated direct interaction of Ye with Vn and investigated the role of this Vn binding during mouse infection in vivo. Using different Yersinia strains, we identified a short stretch in the YadA head domain of Ye O:9 E40, similar to the ‘uptake region' of Y. pseudotuberculosis YPIII YadA, as crucial for efficient Vn binding. Using recombinant fragments of Vn, we found the C-terminal part of Vn, including heparin-binding domain 3, to be responsible for binding to YadA. Moreover, we found that Vn bound to the bacterial surface is still functionally active and thus inhibits C5b-9 formation. In a mouse infection model, we demonstrate that Vn reduces complement-mediated killing of Ye O:9 E40 and, thus, improved bacterial survival. Taken together, these findings show that YadA-mediated Vn binding influences Ye pathogenesis.
Background: Pancreatic cancer is the fourth leading cause of cancer-related mortality in both genders. More than 80% of patients suffer from significant weight loss at diagnosis and over time develop severe cachexia. Early nutritional support is therefore essential. Summary: This review evaluates the different nutritional therapies, such as enteral nutrition, parenteral nutrition and special nutritional supplements, on nutritional status, quality of life and survival. Key Message: Due to the high prevalence of malnutrition and the rapid development of anorexia-cachexia-syndrome, early nutritional intervention is crucial and supported by clinical data. Practical Implications: Enteral nutrition should be preferred over parenteral nutrition. Omega-3 fatty acids and <smlcap>L</smlcap>-carnitine are promising substances for the prevention of severe cachexia, but further randomized controlled trials are needed to establish generally accepted guidelines on nutrition in pancreatic cancer.
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.
Glucocorticoid Receptor Gene Variants and Neonatal Outcome in Very-Low-Birth-Weight Preterm Infants
(2016)
Background: Induction of lung maturation by prenatal steroid treatment has become the standard of care for pregnant women at risk for preterm birth. In addition to the beneficial effects on lung maturation, prenatal steroids have been shown to reduce the incidence of neonatal death, necrotizing enterocolitis, sepsis, and intraventricular hemorrhage. However, little is known about the role of interindividual differences in corticoid sensitivity arising from polymorphisms in the glucocorticoid receptor (GR) gene. Objectives: To assess the impact of GR polymorphisms N363S (rs56149945), R23K (rs6190), and BclI (rs41423247) on neonatal outcome. Methods: The GR polymorphisms N363S, R23K, and BclI were examined in 10,490 very-low-birth-weight (VLBW) preterm infants from 49 German tertiary level neonatal units (German Neonatal Network, GNN) with respect to neonatal outcome. Results: Infants carrying the BclI genotype were at higher risk to develop bronchopulmonary dysplasia (BPD) (OR 1.12 per BclI allele, 95% CI: 1.02-1.23, p = 0.013) in a logistic regression model adjusted for gestational age, mechanical ventilation, and small for gestational age status. A similar relative risk was seen in the children (89.4%) who received antenatal betamethasone treatment (OR 1.16, 95% CI: 1.05-1.27, p = 0.003), whereas no such effect was detectable in infants without antenatal steroids. N363S and R23K did not show any stable association with neonatal outcome parameters. Conclusion: Except for a slightly higher risk of BPD in carriers of the GRBclI variant, the GR gene polymorphisms BclI, N363S, and R23K did not affect neonatal outcome parameters in this large multicenter cohort of VLBW preterm infants.
Cerebral cavernous malformations (CCMs) are prevalent slow-flow vascular lesions which harbour the risk to develop intracranial haemorrhages, focal neurological deficits, and epileptic seizures. Autosomal dominantly inherited CCMs were found to be associated with heterozygous inactivating mutations in 3 genes, CCM1(KRIT1), CCM2(MGC4607), and CCM3(PDCD10) in 1999, 2003 and 2005, respectively. Despite the availability of high-throughput sequencing techniques, no further CCM gene has been published since. Here, we report on the identification of an autosomal dominantly inherited frameshift mutation in a gene of thus far unknown function, FAM222B(C17orf63), through exome sequencing of CCM patients mutation-negative for CCM1-3. A yeast 2-hybrid screen revealed interactions of FAM222B with the tubulin cytoskeleton and STAMBP which is known to be associated with microcephaly-capillary malformation syndrome. However, a phenotype similar to existing models was not found, neither in fam222bb/fam222ba double mutant zebrafish generated by transcription activator-like effector nucleases nor in an in vitro sprouting assay using human umbilical vein endothelial cells transfected with siRNA against FAM222B. These observations led to the assumption that aberrant FAM222B is not involved in the formation of CCMs.
Background: Newborns are prone to infections, which are independent predictors of neonatal mortality and morbidity. Neutrophil extracellular traps (NETs) are structures composed of chromatin and antimicrobial molecules that capture and kill pathogens. NETs may play an important role in the innate immune system and, thus, might be associated with impaired neonatal immune function. Objectives: This study aimed to compare NET formation between term neonates and healthy adults. We additionally investigated the effects of gestational age, birth weight, mode of delivery, gender, and perinatal infections. Methods: We collected cord blood from 57 term infants (mean gestational age, 39.1 weeks) and 9 late preterm infants (35 weeks), and peripheral blood from 18 healthy adult donors. Neutrophils were isolated, and then NET formation was induced using three different stimulants: N-formylmethionine-leucyl-phenylalanine, phorbol 12-myristate 13-acetate (PMA), or lipopolysaccharide. NETs were immunohistochemically stained and analyzed with regard to NET percentage and NET area. Results: With all three stimuli, healthy term infants showed a lower NET percentage than the adult control group (p < 0.0001 each). The groups also differed in NET area, but the significance level was lower. Following PMA stimulation, we observed greater reductions in NET percentage and NET area in preterm than term infants. Conclusions: The lower NET formation observed in term infants compared to adults likely contributes to the reduced neonatal immune response. NET formation appeared to be even further decreased in late preterm neonates. There remains a need for further investigations of NET formation in more immature preterm infants.
Background: The mechanism of how childhood trauma leads to increased risk for adult dissociation is not sufficiently understood. We sought to investigate the predicting effects and the putatively mediating roles of PTSD and alexithymia on the path from childhood trauma to adult dissociation. Methods: A total of 666 day-clinic outpatients were administered the Childhood Trauma Questionnaire (CTQ), the Toronto Alexithymia Scale (TAS-20), the Posttraumatic Diagnostic Scale (PDS), and the Dissociative Experiences Scale (DES) and controlled for sex, age, and the Global Symptom Index (GSI). Linear regression analyses and mediation analyses were applied. Results: Independent predictive effects on dissociation were found for childhood trauma, alexithymia and PDS, even after adjusting for GSI. Effects of childhood neglect on dissociation were slightly stronger than of abuse. Alexithymia did not mediate the path from childhood trauma to dissociation. Mediation by PDS was specific for childhood abuse, with all PTSD symptom clusters being significantly involved. Conclusions: Childhood abuse and neglect are important predictors of dissociation. While the effects of abuse are mediated by PTSD, the mechanism of how neglect leads to dissociation remains unclear. The results further support the predictive value of alexithymia for adult dissociation above and beyond the effects of childhood trauma, PTSD, and GSI scores.
Background: Strategies to improve the life of patients suffering from recurrent major depression have a high relevance. This study examined the efficacy of 2 Internet-delivered augmentation strategies that aim to prolong symptom-free intervals. Methods: Efficacy was tested in a 3-arm, multicenter, open-label, evaluator-blind, randomized controlled trial. Upon discharge from inpatient mental health care, 232 adults with 3 or more major depressive episodes were randomized to 1 of 2 intervention groups (SUMMIT or SUMMIT-PERSON) or to treatment as usual (TAU) alone. Over 12 months, participants in both intervention arms received, in addition to TAU, intense monitoring via e-mail or a smartphone, including signaling of upcoming crises, assistance with personal crisis management, and facilitation of early intervention. SUMMIT-PERSON additionally offered regular expert chats. The primary outcome was ‘well weeks', i.e. weeks with at most mild symptoms assessed by the Longitudinal Interval Follow-Up Evaluation, during 24 months after the index treatment. Results: SUMMIT compared to TAU reduced the time with an unwell status (OR 0.48; 95% CI 0.23-0.98) through faster transitions from unwell to well (OR 1.44; 95% CI 0.83-2.50) and slower transitions from well to unwell (OR 0.69; 95% CI 0.44-1.09). Contrary to the hypothesis, SUMMIT-PERSON was not superior to either SUMMIT (OR 0.77; 95% CI 0.38-1.56) or TAU (OR 0.62; 95% CI 0.31-1.24). The efficacy of SUMMIT was strongest 8 months after the intervention. Conclusions: The fully automated Internet-delivered augmentation strategy SUMMIT has the potential to improve TAU by reducing the lifelong burden of patients with recurrent depression. The fact that the effects wear off suggests a time-unlimited extension.
Background: Stereotactic electroencephalography (SEEG) is an invasive diagnostic tool for localizing the epileptic zone in patients with medically refractory focal epilepsy. Despite technical and imaging advances in guiding the electrode placement, vascular injury is still one of its most serious complications. Object: To investigate the usefulness of intraoperative cerebral C-arm CT angiogram (CCTA) in avoiding intracranial hemorrhagic complications during SEEG electrode implantation. Methods: Trajectory data from 12 patients who underwent SEEG electrode implantation were studied in detail. This included an analysis of the implantation of 146 SEEG electrodes, which were guided by intraoperative CCTA, as well as the standard planning based on preoperative contrast-enhanced MRI. In addition, a prospective analysis of SEEG hemorrhagic complications using the studied methodology was performed in a total of 87 patients receiving 1,310 electrodes. Results: There was no complication related to the CCTA itself. Intraoperative CCTA entailed modification of the original trajectory based on the preoperative MRI in 27 of 146 electrode implantations (18.5%). In 10 of them, a severe vascular complication was adverted by intraoperative CCTA. The safety of this new approach was also confirmed by the analysis of postinterventional CT, which revealed a symptomatic hematoma caused by 1 single electrode out of the 1,310 implanted. Conclusions: This study showed that intraoperative CCTA in addition to preoperative MRI is useful in guiding a safer SEEG electrode implantation. The combination of both imaging modalities essentially minimizes the risk of serious hemorrhagic complications.
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.
Urological Complications and BK Virus-Associated Diseases Under Allogenic Stem Cell Transplantation
(2016)
Every year 50,000 patients receive a stem cell transplantation worldwide, but there is lack of data pertaining to urological complications. Methods: We performed a retrospective analysis of all adult patients undergoing their first allogenic stem cell transplantation from January 2011 to June 2013 in our institution. Statistical tests performed were Pearson's correlation, chi-square testing and logistic regression using SPSS 22.0. Results: We identified 39 patients (22 males, 17 females). Twenty four patients (61.5%) had a urological complication. Most frequent urologic complications were bacterial urinary tract infection (n = 13; 33.3%), acute renal failure (n = 6; 15.4%) and BK virus-associated haemorrhagic cystitis (n = 5; 12.8%). BK viruria was detected in 12 patients (30.8%). We observed an association of creatinine increase (about 20 µmol/l at time of onset of BK viruria) with BK viruria (Pearson's correlation 0.64; p = 0.01), and BK viruria is significantly linked to acute renal failure (Pearson's correlation 0.35; p = 0.029). In univariate regression, BK viruria is significantly linked to urological complication (p = 0.025). Conclusions: We suggest that BK virus infection during stem cell transplantation can lead to BK virus associated nephropathy, which is so far only known from patients after kidney transplantation.
Introduction: Inhibition of androgen synthesis by abiraterone acetate (AA) entails enhanced overall survival rates and clinical benefit for patients with locally advanced and metastasized prostate cancer (PC). The expression of heat shock protein 27 (HSP27) is generally associated with cytoprotection and was demonstrated to mediate chemoresistance under cytostatic therapy, for instance, docetaxel treatment. In this study, we investigated the impact of AA treatment on HSP27 expression and PC cell growth. Materials and Methods: HSP27 expression levels in docetaxel and AA-treated PC cell lines LNCaP and PC-3 were determined by SDS PAGE and Western blot analysis. Proliferation assays were performed using a CASY Cell Counter and Analyzer Model TT (Roche Applied Science). Results: Despite significantly increased HSP27 expression in PC cells incubated with docetaxel, Western blot analysis implicated a significant reduction of the cytoprotective HSP27 in AA-treated PC cells. Notably, HSP27 stably overexpressed in PC-3-HSP27 cells did not appear as an HSP27-mediated proliferation benefit in the presence of AA as shown in docetaxel incubation studies. Conclusion: In contrast to repeatedly demonstrated HSP27-driven chemoresistance related to chemotherapeutics, our results may constitute a broader molecular mode of action of AA chemotherapy. AA efficacy may exert an HSP27 suppressive role that goes beyond the primarily assumed inhibition of androgen biosynthesis.
The role of uptake and efflux transporters in the pharmacokinetics of ß1-receptor blocker talinolol
(2016)
Introduction: The β1-adrenergic receptor antagonist talinolol is a probe drug for P-glycoprotein (P-gp). It is absorbed erratically and incompletely from the gastrointestinal tract. However, its pharmacokinetics might also be influenced by further uptake and efflux transporters as concluded from interaction studies with naringin and verapamil in human. Additionally, the transcellular transport through the different tissues, including enterocytes, hepatocytes and kidney tubular cells, is not completely understood so far. Therefore, we aimed to measure the affinity of talinolol to drug transporting proteins (OCT1-3, PEPT1, OCTN2, ASBT, NTCP, MRP 1-3 and P-gp as well as OATP 1B1, 1B3, 2B1 and 1A2) and some of their genetic variants known to be of pharmacokinetic relevance (OATP1A2 *2 and*3 as well as OATP2B1 V201M, R312Q and S486F). In a further step, we retrospectively evaluated the impact of clinically relevant genetic polymorphisms of transporters on the pharmacokinetics of talinolol in healthy subjects. Materials and Methods: Time and concentration-dependent uptake assays with [3H]-talinolol were performed either in stable transfected HEK293 or MDCKII cells expressing OATP1A2 *1, *2 and *3, OATP1B1, OATP1B3, OATP2B1 (and its genetic variants p.V201M, p.R312Q and p.S486F), NTCP, ASBT, PEPT1, OCTN2, OCT 1-3 and the respective vector control or in inside-out lipovesicles expressing the efflux transporters MRP1-3 and P-gp. Talinolol was quantified by liquid scintillation counting. The transport rates were then corrected by the transporter proteomics measured in the cellular membrane. Regarding the pharmacogenomic evaluation, it was carried out retrospectively in 39 healthy subjects who had participated in former pharmacokinetic studies with talinolol. This evaluation included a variety of transporter related genetic variants, known to be of a clinical meaning for their substrates. Results: Among the uptake transporters, talinolol was shown to be a substrate of OATP1B3 (Km= 153 ± 137 μmol/l; Vmax= 168 ± 30.3 μmol/mgxmin), OATP1B1 (Km= 301 ± 133 μmol/l; Vmax= 1135 ± 348 μmol/mgxmin), OATP2B1 (Km= 459 ± 260 μmol/l; Vmax= 4.32 ± 1.33 μmol/mgxmin), OATP1A2 (Km= 477 ± 158 μmol/l; Vmax= 0.61 ± 0.1 μmol/mgxmin) and NTCP (Km= 2560 ± 781 μmol/l; Vmax= 15944 ± 3741 μmol/mgxmin) but not a substrate of OCT1-3, OCTN2, PEPT1 or ASBT. When it comes to the efflux transporters, talinolol was transported by both P-gp (Km = 175 ± 206 mol/l; Vmax = 14 ± 10.8 nmol/mgxmin) and MRP3 (Km= 86.8 ± 62.8 μmol/l; Vmax= 133 ± 51.5 μmol/mgxmin) but not by MRP2. The pharmacogenomic analysis supported the in-vitro results, as it showed a significant decrease in talinolol absorption (AUC and Cmax) in subjects with the loss of function variant MRP3 211C>T and in those with a decreased P-gp function due to having less than 5 T-allels in the haplotype P-gp 1236-2677-3435-TTT. No significant changes were found associated with other transporters’ genetic variants. Conclusion: Our in-vitro results suggested the vectorial transport of talinolol through the enterocytes to consist mainly of apical OATP2B1 and P-gp and basolateral MRP3. Additionally in the hepatocytes, apical OATP1B1, OATP1B3 and NTCP seem to be involved as well. This vectorial transport was demonstrated in-vivo for the first time by our pharmacogenomic analysis, where talinolol absorption was significantly influenced by both P-gp and MRP3 genetic variants.
Bacterial infections represent an increasing threat in human health and hospital- acquired infections meanwhile account for 99,000 deaths every year in the United States (Ventola, 2015). Live-threating bacterial infections will certainly emerge to an even more serious concern in future, essentially by accelerated development of antibiotic resistance. Only recently, the discovery of plasmid-encoded mcr-1, that confers resistance against colistin, marks the point where this highly transmissible resistance mechanism is now reported for every so far developed antibiotic (Liu et al., 2016). Staphylococcus aureus is a Gram-positive bacterium and well-known for its ability to quickly acquire resistance toward antibiotics either by chromosomal mutations and/or horizontal gene transfer (Pantosti et al., 2007). Although approximately 30% of the population is colonized with S. aureus (Kluytmans et al., 1997), it can transform to an invasive pathogen that causes a wide range of severe infections including pneumonia. The success of S. aureus as opportunistic pathogen can be attributed to combinations of several beneficial properties and capabilities including the expression of an arsenal of virulence factors (Archer, 1998), intracellular persistence (Garzoni & Kelley, 2009) and subversion of host cell defense mechanisms (Schnaith et al., 2007). The airway epithelium is the first line of defense against bacterial pathogens by forming a relative impermeable physical barrier composed of epithelial cells that are linked by tight junctions, desmosomes and adherence junctions (Davies & Garrod, 1997). Additionally, the airway epithelium mediates the detection of bacterial pathogens via toll-like receptors (TLRs) that recognize a variety of bacterial molecular patterns such as lipopolysaccharide (LPS), peptidoglycan and flaggelin (Sha et al., 2012). This interaction is transduced via protein phosphorylations into the cell in order to promote adaptation to the infection by initiation of the adaptive and innate immune defense. Although few insights where obtained of the signaling host responses towards staphylococcal infections (Agerer et al., 2003; 2005; Ellington et al., 2001), a comprehensive description of the host signaling network is largely missing. Thus, this dissertation thesis focuses on the decipherment of phosphorylation-mediated signaling responses towards S. aureus infections in non- professional and professional phagocytes by mass spectrometry-based phosphoproteomic techniques. The results of this thesis are summarized in the four chapters. Chapter I introduces to recent advances in the development of methodologies applied in the field of phosphoproteomics, including quantification strategies, peptide fractionation techniques and phosphopeptide enrichment methods applied for the system-wide characterization of protein phosphorylations by mass spectrometry. Additionally, publications reporting phosphorylation-based host signaling responses towards bacterial pathogens or their molecular patterns that applied mass spectrometry-based phosphoproteomics are discussed. In chapter II, the responses of the human bronchial epithelial cell lines 16HBE14o- and S9 following challenge with staphylococcal alpha- toxin at the level of proteome and phosphoproteome are summarized. General and cell type-specific signaling events are highlighted and evidences linking the activity of the epidermal growth factor receptor (EGFR) with differences in tolerance toward alpha-toxin are provided. Chapter III describes the modulation of the host signaling network of 16HBE14o- airway epithelial cells triggered by infection with S. aureus including temporal dissection of signaling events. Several protein kinases were identified as important signaling hubs mediating the host response. Targeted pharmaceutical inhibition of these kinases was probed and resulted in reduction of intracellular bacterial load. Chapter IV describes the rearrangement of the kinome by the differentiation of THP-1 monocytes to macrophage-like cells by application of quantitative kinomics. This approach identified the kinase MAP3K7 (TAK1) as key mediator of bacterial clearance, chemokine secretion and the differentiation process itself.
The focus of this study is on the geochronological and paleo-climatic characterization of late Pleistocene glaciations in Turgen and the Khangai Mountains located in central and western Mongolia. These two mountain ranges form a 700 km long NW-SE transect through Mongolia and allow assumptions of the temporal and causal dynamics of the regional late Quaternary glaciations and their correlation to other mountain glacier records from Central and High Asia. In order to evaluate extent and timing of the Pleistocene glaciations in Mongolia, geomorphological mapping and cosmogenic radionuclide (CRN) surface exposure dating (10Be) were carried out in four valley systems located in the Khangai and Turgen Mountains. Additionally, a coupled 2-D surface energy balance and ice flow model was used to determine steady-state conditions for glaciers under various climatic scenarios. With this model it is possible to test combinations of temperature and precipitation settings, which would produce glacier configurations that fit the field-mapped ice extent. In total, 47 glacial boulders and roche moutonnées were sampled, prepared and AMS measured to determine the absolute timing of moraine formation and ice retreat based on 10Be surface exposure dating. Of these, 27 samples were obtained from the Khangai Mountains (three separate moraine sequences) and 20 samples were taken from the Turgen Mountains (two moraine sequences). The dating results (presented as minimum ages) give evidence for a late Pleistocene maximum ice expansion during late MIS 5 (81−78 ka) and major ice advances during MIS 2 (26−20 ka) in both mountain ranges. Only in the Khangai Mountains (central Mongolia) very significant glacier advances also occurred during mid-MIS 3 (49−35 ka), which exceeded the ice limits set during the MIS 2 glaciation. A final ice position, constructed shortly before the onset of full ice retreat was formed between 19-16 ka, and is likely to represent a recessional ice stillstand, or alternatively a final ice readvance during the early part of the last-glacial-interglacial-transition (LGIT) in both mountain ranges. Energy/mass balance and ice flow modeling results suggest that climatic conditions during the MIS 5 and MIS 3 maximum advances in the Khangai Mountains were depressed between a ∆T of -6.0 to -5.2 °C with a precipitation factor of 1.25-1.75 (P = 125-175 %, compared to modern conditions), and a ∆T of -5.3 to -4.4 °C (P = 75-125 %), respectively. For the MIS 2 ice advances modeling results from the Turgen and Khangai Mountains suggest a temperature depression ∆T of -5.7 to -4.6 °C (at 22 ka; P = 25-50 %) in the East-Turgen, and a ∆T of -7.5 to -6.6 °C (at 20 ka; P = 25-50 %) in the Chulut area (Khangai Mountains). These results document a 1.8 - 2 °C difference of the modeled temperatures required to expand the studied paleo-glaciers in the Turgen and Khangai mountains to their field-mapped MIS 2 ice limits, highlighting a spatially differentiated pattern of paleo-temperature lowering across the studied 700 km NW-SE transect. Taken together, the presented record indicates that the largest ice advance in both investigated mountain ranges occurred during the MIS 5 / MIS 4 transition, despite earlier suggestions by previous studies that the local glacial maximum would be associated with the coldest periods of the last glacial cycle (i.e. MIS 4 or MIS 2). Glacier systems in the Khangai Mountains also increased substantially during MIS 3 (local LGM) in response to cool but comparable wet conditions, probably with a greater-than-today input from winter precipitation and an additional input of recycled moisture from expanded paleo-lakes in the Valley of the Great Lakes. The lack of a severe cooling during the MIS 3 ice advances, and probably also during the late MIS 5 ice expansion, suggests that variations in atmospheric circulation patterns, with its significance for controlling the regional precipitation/moisture supply, was a key driver for these late Pleistocene ice advances in Mongolia. This notwithstanding, there is also clear evidence for the development of an extensive glaciation during MIS 2, coinciding with a period of severe cooling and hyperarid conditions. This highlights that glacier systems in Mongolia responded sensitively, both, to variations in moisture supply and its seasonal distribution, and to the marked insolation minima during the last glacial cycle.
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.
Ischemic stroke is the second leading cause of death worldwide and a disease with a variety of risk factors including hypotension, nutrition/obesity, and smoking but also increased age. In an ageing society stroke is a great challenge and leaves the survivors with disabilities. The aim of this dissertation was to investigate the immunologic changes post ischemic stroke, in order to use a better understanding for new therapeutic approaches as well as for improvement of translation of results from bench to bedside. Ischemic stroke leads to a local and peripheral immune activation. On the other side an immune dysfunction/suppression occurs, that leads to a higher risk of stroke-associated infections. In this dissertation, a long-lasting elevation of HMGB1 after stroke and a correlation with blood leukocyte numbers could be shown. HMGB1 seems to be an important mediator of an endogenous inflammation and an interesting target for post-stroke immunomodulation. In a further study we showed that the quality of the immune response of infiltrating T cells has an impact on the neurologic outcome and functional recovery after experimental stroke. Importantly, a mechanism of how infections, mimicked by LPS injections, could worsen the outcome of stroke patients was revealed. In the context of stroke-induced immunosuppression regulatory T cells as an immunosuppressive T cells subset seem to not play a role as their suppressive capacity is reduced after stroke. Interestingly, the CD39 expression on Tregs is similarly increasing with age in humans and mice. This shows the importance of an age equivalent in experimental studies. In search of predictors for the outcome after stroke as well as the risk of infections, we performed single nucleotide polymorphism genotyping in the IL-1RN and TLR4 gene of stroke patients. Functional significant variants in the IL-1RN and TLR4 genes may have an impact on outcome and systemic markers of inflammation post stroke but these findings need to be replicated in studies with much larger cohorts.
In this Ph.D. project a method is developed to measure the magnetic field and to derive variations in the total plasma pressure due to (dia-) magnetic effects. For this purpose a plasma diagnostic has been set up at the fusion experiment ASDEX Upgrade to measure spectroscopically polarized light. The light is emitted from fast beam-particles excited by the plasma. Since the fast atoms travel through a magnetic field at high velocity, a strong Lorentz field is seen in the moving frame. This electric field gives rise to the so-called motional Stark-effect (MSE) and it is possible to conclude from the Stark-spectrum on the magnetic field.
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.
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.
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.
The presented study was dedicated to outstanding issues in regard to the safety and efficacy of the LAV “CP7_E2alf”, during the final licensing process and towards its putative implementation in outbreak scenarios as emergency vaccine. (I) For application of a genetically engineered virus under field conditions, knowledge about its genetic stability is mandatory. Therefore, the genetic stability of “CP7_E2alf” needed to be assessed in vivo and in vitro. Mutation rates were compared to the parental pestivirus strains (BVDV-1 “CP7” and CSFV “Alfort/187”), and BVDV or CSFV field-strains. There was no indication that “CP7_E2alf” could be more prone to mutational events than its parental viruses or representative field-strains. Moreover, no recombination events were observed in in vitro experiments. In conclusion, the data obtained in this study confirm a strong genetic stability of “CP7_E2alf” as an important safety component. (II) Since vaccination of breeding animals is often discussed, this study was conducted to assess the safety of “CP7_E2alf” vaccination of breeding male pigs. The study with “CP7_E2alf” vaccinated boar demonstrated that the new CSFV marker vaccine is suitable for application in reproductive boar. Neither in organs of the uro-genital tract related to sperm production nor in urine or feces, vaccine virus genome was detectable. Dissemination of “CP7_E2alf” through semen, and shedding with urine and feces, is therefore highly unlikely. (III) In order to investigate the influence of pre-existing pestivirus antibodies of the efficacy of “CP7_E2alf”, a vaccination-challenge-trial was conducted with “CP7_E2alf” (Suvaxyn® CSF Marker) and the “gold-standard” of live-modified CSFV vaccines, the C-strain (RIEMSER® Schweinepestvakzine). Pre-existing antibodies against BVDV-1 were provoked through intramuscular inoculation of a recent field isolate from Germany. Seven days after the vaccination, all animals were challenged with highly virulent CSFV strain “Koslov”. It was demonstrated that pre-existing anti- BVDV-1 antibodies do not impact the efficacy of both live attenuated vaccines against CSFV. Both C-strain “Riems” and marker vaccine “CP7_E2alf” were able to confer full protection against the highly virulent challenge. However, slight interference was seen with serological DIVA diagnostics accompanying “CP7_E2alf”. Amended sample preparation and combination of test systems was able to resolve most cases of false positive reactions. However, in such a coinfection scenario, optimization and embedding in a well-defined surveillance strategy is clearly needed for marker vaccination scenarios. (IV) To supplement the data about the kinetic of maternally derived antibodies in piglets from sows vaccinated during outbreaks, a single “emergency-type” vaccination of two pregnant sows was done. Focus was laid on the kinetics of maternally derived antibodies (MDA) in the screening assays of their offspring with screening assays that would be used in case of CSFV outbreaks, i.e. CSFV E2 and Erns antibody ELISA. Upon vaccination with “CP7_E2alf” 21 days before farrowing, MDAs were measurable in all piglets born to vaccinated sows. The E2- ELISA reactivities showed an almost linear decrease over ten weeks after which all piglets were tested negative in the ELISA. Future studies should investigate, if MDA are able to protect offspring of vaccinated sows or whether the piglets should also be vaccinated.
Psychiatric disorders are highly heritable. But the underlying molecular mechanisms are largely unknown or not understood. For many disorders, candidate genes have been proposed which are biologically driven or based on large GWAS studies. In this work different approaches were shown to investigate the impact of genetic risk factors for major psychiatric disorders in the general population. These genetic risk variants include single nucleotide polymorphisms associated with schizophrenia or major depression and were analyzed using the whole-genome information in polygenic scores or candidate marker analysis in GxE studies. Genetic data from SHIP-0 and SHIP-TREND have been used to calculate a polygenic risk score for schizophrenia. Here, the association between this genetic score and brain alterations is shown in three independent samples (SHIP-2, SHIP-TREND and BIG) which revealed no hint of a common genetic basis for schizophrenia and brain structure. These results are in line with other studies that also failed to find a genetic overlap. The same polygenic scores had been used in a PHEWAS analysis in SHIP-0 where an inverse association to migraine was found. This association could be attributed to the NMDA receptor activation via D-serine at the glutamatergic synapse. To assess the impact of environmental factors on the path from genes to phenotype, gene-environment interactions were applied. A significant interaction could be observed between rs7305115 (TPH2) and rs25531 (5-HTTLPR) and childhood abuse on current depression score in SHIP-LEGEND and SHIP-TREND. In summary, genetic variants associated with major psychiatric disorders can exhibit pleiotropic effects on common phenotypes in the general population.
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.
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.
Nanoengineering and laser optics allow for the fabrication of a wide range of systems that subject fermionic particles to geometric restrictions. In addition to strong correlations, the fermions may couple to internal or external bosonic fields, such as quantized lattice vibrations or light fields. This thesis considers the theoretical description of two such systems. One is a molecular junction, i.e., a small organic molecule contacted by metallic electrodes or leads. Itinerant electrons induce molecular vibrations and deformations, corresponding to phonon modes of considerable energy. The thesis investigates the effects of this local electron-phonon interaction on the electric and thermoelectric transport through the junction. Starting with an Anderson-Holstein quantum dot model, our ansatz is based on the application of a variational Lang-Firsov transformation that accounts for the polaronic character of the dot state. We solve the steady-state Kadanoff-Baym equations and derive a self-consistent approximation to the polaronic self-energy that accounts for finite densities and multi-phonon scattering processes. The optimal variational parameter is determined numerically by minimizing the thermodynamical potential. This allows a detailed study of the electronic dot spectral function for all interaction strengths and adiabaticity regimes. For instance, we discuss how a voltage dependent polaronic renormalization of the dot-lead coupling and the dot level causes negative differential conductance and novel conductance features. The investigation of the second system is motivated by recent experiments on the Bose-Einstein condensation of excitons in small semiconducting cuprous oxide crystals. At ultra cold temperatures three species of para- and orthoexcitons are caught in stress induced potential traps. Their decay luminescence is the primary method of detection. This thesis considers the thermodynamics of this system in terms of a multicomponent gas of weakly interacting bosons in external potentials. The coupled equations of motion are solved within a Hartree-Fock-Bogoliubov-Popov approximation. For typical experimental parameters the density distributions of the interacting species are calculated numerically. Based on the luminescence formula by Shi and Verechaka we discuss, e.g., how the spectrum of the direct decay of thermal paraexcitons may reveal the formation of a nonluminescent paraexciton condensate as well as the spatial separation of strongly repulsive orthocondensates. First results for an extended luminescence theory are presented, which takes into account the polariton effect.
This thesis draws a comprehensive picture about the radiation and diversification of truncatelloidean gastropods across the south pacific. It covers three more specifc studies focussing on the Truncelloideans from Fiji, Vanuatu and New Caledonia, respectively. And a conclusive analysis that combines the results of the three more specific studies and enhances them using species from the Austral Islands, Lord Howe Island, the Indonesian island Sulawesi as well as several species from New Zealand and Australia. Molecular phylogenies were calculated using four nuclear gene fragments (ITS2; 18S rRNA; 28S rRNA and Histone 3) besides the mitochondrial COI and 16S rRNA. Further molecuular data was used to calculate dated phylogenies, perform ancestral range reconstructions and develop a modified molecular barcoding approach.
In this thesis, rates and extend as well as the ecological implications of electron exchange reactions that involve redox-active moieties in organic matter (OM) were explored. The research builds on earlier findings that confirmed that OM may act as terminal electron acceptor (TEA) for electrons released in microbial respiration. This property was associated with quinone moieties that are ubiquitously found in OM from terrestrial and aquatic environments and that may undergo reversible reduction to the respective hydroquinone. Earlier methodological advances allowed for a rapid, direct and precise quantification of the electron accepting and donating properties of quinones in dissolved OM (DOM) by mediated electrochemical analysis. In this work, the previously established mediated electrochemical analysis was adapted and used in the characterization of redox properties of particulate natural samples that contain redox active iron and organic matter ("geochemical phases"). For the first time, direct measurements confirmed that microorganisms transferred electrons (e) from microbial respiration to the organic and inorganic electron acceptors in the particulate phase. Particulate OM in the sediments was found to provide a capacity to accept or donate e of 650 µmol e/gC. An incubation experiment resolved the spatiotemporal dynamics of organic and inorganic TEA species (i.e., nitrate, sulfate, Fe- and Mn oxyhydroxides) in sediments upon changes in oxygen availability and hence redox conditions. Oxygen is consumed when the reduced species are oxidized and, by this means, re-generate their electron-accepting capacity. The use of mediated electrochemical analysis allowed for the quantification of the redox state of the geochemical phases during their reduction and re-oxidation. The electron fluxes initiated by the oxic re generation of the TEAs nitrate, sulfate, Fe(III), Mn(IV) and quinoid moieties in OM were therefore directly monitored instead of modeled from the species’ distribution profiles in interstitial waters. The cyclic reduction and re-oxidation of redox species exposed to oxygen fluctuations was suspected to be a critical component of many aquatic ecosystems. In stratified lakes, extended sediment volumes are exposed to oxygen only upon lake overturn. Lake oxygen budgets are therefore influenced by benthic redox processes. The combined field and laboratory study showed that lake overturn seasonally introduces a finite amount of oxygen to the hypolimnion and that about 50% of the subsequent sediment oxygen consumption is exclusively associated with the re-generation of TEA species. These species previously formed in the sediment when organic matter was microbially decomposed during anaerobia. While lake overturn can completely mix epi- and hypolimnetic waters, small-scaled dynamics in temperature and oxygen availability may confine discrete parts of the water column with oscillations in physicochemical conditions. In the studied lake, a transient thermocline cyclically introduces oxygen to hypoxic hyplimnetic waters close to the pelagic redox interface. In the lake, organic TEAs may represent an important component of the total pelagic electron acceptor capacity. Due to the rapid and reversible redox reactions of DOM, reduced organic TEAs are re-generated upon dislocation to oxic parts of the water column. Results show that diurnal fluctuations of oxycline depth shape a micro-environment selecting for microbial species that are released from TEA limitations by OM in oxidized state. Pelagic microbial communities subjected to the same amount of OM in different oxidation states differed by more than 50% after one day. This work substantiates earlier findings that suggested that OM may be an important TEA species in many aquatic and terrestrial ecosystems. OM reduction in microbial respiration was shown to directly affect critical system parameters as bacterial activity, oxygen budgets and aquatic biodiversity. Both the microbial reduction and subsequent abiotic oxidation of OM are sufficiently fast for relevant interaction with oxycline fluctuation on different timescales. Given that organic TEAs are cyclically regenerated, a significant share of ecosystem respiration could be linked to OM reduction. This thesis demonstrated the new and important role electron exchange reactions in OM-rich environments play and explored the mechanism of this previously neglected part of lake functioning. As of today, linking the chemistry of aquatic turnover processes with the microbiological and physical conditions at redox interfaces remains challenging. In conclusions, by providing several cases from aquatic environments, this thesis contributes to the mechanistic understanding of OM reduction in microbial respiration. The results prompt for further research regarding the competitive inhibition of other respiration pathways, including the reductive production of the potent greenhouse gas methane.
Background: Microvascular Decompression represents an effective treatment for hemifacial spasm. The use of lateral spread responses (LSRs) monitoring remains a useful intraoperative tool to ensure adequate decompression of the facial nerve. Objective: To assess the value of LSRs intraoperative monitoring as a prognostic indicator for the outcome of microvascular decompression in hemifacial spasm. Methods: Our study included 100 patients prospectively. The patients were classified into 4 groups whether LSRs were totally, partially, not relieved or not detected from the start. According to clinical outcome, the patients were classified into 4 groups depending on the clinical course after surgery and the residual symptoms if any. Then, correlations were made between LSRs events and treatment outcome to detect its reliability as a prognostic indicator. Results: LSRs were relieved totally in 56% of the patients, partially relieved in 14%, not relieved in 10% and were not detected in 20% of the patients from the start. HFS was relieved directly after operation in 62% with clinical improvement of 90-100%. 31% described 50-90% improvement over the next 3 months after surgery. Almost all of these 31% (28 out of 31 patients) reported further clinical improvement of 90-100% within one year after surgery. 3% suffered from a relapse after a HFS-free period and 4% reported minimal or no improvement describing 0-50% of the preoperative state. The percentage of the satisfied patients with the clinical outcome who reported after one year a clinical improvement of 90-100% was 90%. Statistical analysis did not find a significant correlation between the relief of LSRs and clinical outcome. Conclusion: LSRs may only represent an intraoperative tool to guide for an adequate decompression but failed to represent a reliable prognostic indicator for treatment outcome.
Dilated cardiomyopathy (DCM) is a myocardial disorder characterised by ventricular dilation with reduced left ventricular ejection fraction (LVEF). Immunoadsorption (IA) followed by immunoglobulin (IgG) substitution (IA/IgG) has been shown to be a promising therapeutic intervention to recover myocardial functions in DCM patients. The beneficial effects of IA/IgG therapy are associated with increased LVEF, decreased left ventricular inner diameter at diastole (LVIDd) and reduced myocardial inflammation. Despite knowing the cardiac benefits of IA/IgG, the precise molecular mechanism induced by therapy is still elusive. Additionally, only ≈60 % DCM patients treated with IA/IgG demonstrated improved heart function. Moreover, the reasons for this differential outcome among DCM patients after treatment have not been clearly understood. In this study, efforts were made to uncover the therapy induced proteomic changes in the heart of responders (relative change in LVEF ≤ 20%, LVEF < 5% absolute value) and non-responders using a global proteomic approach. Apart from it, proteomic profiling of endomyocardial biopsies and plasma was performed to find protein biomarker candidates which might be useful to distinguish responder and non-responder DCM patients before immunoadsorption therapy and support a selective and individualized treatment. To reveal therapy induced myocardial proteomic changes, endomyocardial biopsies of DCM patients before and after therapy were compared. LVEF increased (32 ± 8 to 45±7, p<0.002) and LVIDd decreased (66 ± 6 to 60±6, p<0.040) after therapy in responders, whereas non-responders did not show any significant changes in these clinical parameters. To address the changes in the myocardial proteome induced by therapy, a label-free proteomic approach was applied. The most prominent proteomic differences between both subgroups were observed in cytoskeletal, fibrosis, and extracellular matrix proteins. Therapy linked benefit in responders seems to be highly associated with the lower abundance of fibrotic and extracellular matrix proteins which seems to reflect a lower activity of transforming growth factor-β signaling. To elucidate proteomic differences between responders and non-responders at baseline, endomyocardial biopsies and plasma proteome profiling were performed. Responder and non-responder DCM patients did not show any significant differences in the clinical parameters (LVEF, LVIDd, age, inflammation, etc.) before IA/IgG therapy except for disease duration that was in tendency higher among non-responders. Proteomics profiling of endomyocardial biopsies revealed 54 differentially abundant proteins between responders and non-responders. Among those proteins, Protein S100-A8 and kininogen-1 was found higher whereas perilipin-4 was found lower abundant in responders. Plasma profiling of these subgroups revealed five proteins (S100-A8, S100-A9, C-Reactive protein, lipopolysaccharide-binding protein, and cysteine-rich secretory protein) displaying strong discriminative power between responders and non-responders. Higher abundance of Protein S100-A8 was observed in myocardium as well as in plasma among responders. Protein S100-A8 might be a potential candidate to distinguish responders and non-responders at baseline, and its potential utility at clinical levels must be evaluated. The last objective of the thesis was to establish a workflow for the relative quantitation of phosphopeptides for samples generally obtained in small amounts like myocardial biopsies. To address this question, optimization was performed with HL-1 cardiomyocytes using a PolyMAC phosphopeptide enrichment kit and the effect of TGF-β1 on the phosphoproteome was evaluated as a proof-of-principle study. Using only 200µg protein of each sample up to 2000 phosphopeptides with an efficiency of >90 percent could be covered. In total, upon TGF-β1 incubation alterations of 214, 92, and 53 phosphopeptides were observed after 1, 6 and 24 hours, respectively. Differentially altered phosphopeptides belonged to many signaling pathways including the ubiquitin-proteasome pathway, cytoskeletal regulation by Rho GTPase, calcium signaling, and TGF-β signaling. Thus, in this study a workflow for relative quantitation of phosphopeptides was established that may be later applied to precious biopsy samples. Along with this, TGF- β1 induced phosphoproteome was analysed in HL-1 cardiomyocytes.
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.
Background: Referral to specialized pediatric treatment seems to rise in Germany, especially for children under 5 years of age and mostly due to behaviour management problems, rampant caries and the need for comprehensive dental treatments. There are indications that more dental treatments under general anesthesia were needed in last decade, but there are very few studies on this topic in Germany. Aim: The objectives of this research were to investigate the characteristics and dental features of referred children to Greifswald university dental clinic in 2008 and 2011 as well as to assess dental treatment and characteristics of the children who underwent general anesthesia in 2011 at Greifswald University Clinic in comparison with three specialized pediatric private practices in Germany. Materials and methods: This retrospective analytical comparative study examined the records of all children younger than 18 years of age, whose were referred to the university dental clinic in Greifswald between 2008 and 2011. In addition, all cases that underwent general anesthesia at the university dental clinic and three other private practices in 2011 were analyzed anonymously. All data including age, gender, dental status and caries levels (dmft/DMFT), as well as diagnosis, referral/GA reasons and the dental treatments were collected and then analyzed using the Statistical Package for the Social Sciences program (SPSS, Ver. 16 for Windows). Descriptive analysis was performed, along with univariate analysis of variance (ANOVA) and Chi square tests. Differences between groups were tested through Mann-Whitney U test and Student’s t-test as appropriate. Results: The final study sample for children and adolescents referred to the university consisted of 389 under 18 years old (205 males and 184 females) with a mean age of 8.75 years in 2008 and 7.38 years in 2011. In addition, 297 children (160 males and 137 females) with a mean age of 4.77 years had been treated under general anesthesia in the three specialized private practices (n= 219, age: 4.81±2.06 years) and in the university (n=78, age: 4.65±2.59 years). More patients of age group 1 (5 yrs or younger), as well as, patients residing within a distance of 31-40 km away from the clinic were referred in 2011 (47.2% and 35.9% resp.) in comparison with 2008 (37.1% and 22.7% resp.) Panoramic and intraoral dental x-rays (46.7%, 11.8% resp.) have been widely carried out in 2011 compared to 2008 (29.9%, 6.5% resp. P = 0.002). Statistical analyses have shown that, younger children with higher values of dental caries indices (dmft, DMFT) were referred in 2011 (5.4 and 2.15 resp.) than in 2008 (5.16 and 1.57 resp.) with increasing demand for comprehensive dental treatment under GA. Whereas, more patients were diagnosed to have rampant caries (42.1%) in 2011 followed by orthodontic/oral surgery problems (16.9%) in comparison with 2008 (29.3%, 10.1% resp. P < 0.001). Non-invasive treatment was much more delivered (63%) in first dental visit for referred patients in 2011 followed by dental consultation (23.6%) compared to 2008 (53.6% and 21.3% resp.). While, on the other hand, considerably more fillings were supplied in 2008 (11.5%) compared to 2011 (2.6%). Further dental treatment pattern revealed more treatment under GA (27%) and a slightly more extractions (16.1%) were done in 2011 compared to 2008 (20.9%, 15.5% resp.). On the contrary, less fillings and preventive procedures were performed in 2011 (26.3% and 4.4% resp.) in comparison with 2008. Sixty-one percent of children were referred back to their family dentists in 2011 which was more than it in 2008. Indeed, about a half of children aged 5 years or younger preferred to stay at the University Clinics in 2011, while, the vast majority of children older than 12 years continued their dental care outside the University Clinics. About eighty percent and seventy percent of children underwent GA at both the university clinics and private practices respectively were under five years old. In total 7.1% mental disabilities and 2.4% preterm birth were detected in children treated under GA, as well as, dental caries were mostly diagnosed (37%) among them followed by irreversible pulpitis (21.5%) and Early Childhood Caries (ECC) (18.5%), where only 4.38% of all examined children had no carious lesions. More panoramic radiographs (41%) and less dental films (26.9%) were conducted at the university clinics as in the private practices (15.1% and 52.1% respectively) with a significant reduction in using x-rays at the university (69.2%) compared to private practices (94.1%). Dental extractions were often performed at university clinic (40.2%, 3.14±2.4) followed by fillings (33.9%, 2.65±2.7), while, more restorations and less extractions were supplied at private practices (47.8%, 5.47±3.1 and 16.3%, 1.86±2 resp.). Both of long (106-120 Min) and short (0-15 Min) treatment’s durations were needed in the university clinics to carried out the adequate dental therapy under GA, while, most of the GAs at private practices have lasted between 45 and 90 minutes. Conclusion: There is a growing definite need for specialized pediatric dentistry in Germany, especially for children under 5 years of age being referred with rampant caries and behaviour management problems to specialized pediatric dentistry. This results in a high number of extensive treatment performed under GA. In contrast to other countries, this seems to be a singular event for most children in Germany indicating a solid treatment under GA and possibly also improvements in the caries activity of the affected children afterwards. The range of dental treatment and its outcome at Greifswald University and in the examined three specialized private practices is very similar reflecting in both the profile of the children a valid indication for GA and the subsequent treatment up to date approaches in pediatric dentistry. Thus, the very professional treatment and effective secondary preventive strategies achieve better oral health and reestablished quality of life for these children, but a primary preventive approach would be preferable decreasing the number of children in need of dental treatment under general anaesthesia.
This thesis is about the establishment and the application of novel methods and tools that are re-lated to the most widely used enzyme class: hydrolases. It covers all fields from the identification to the application of these valuable enzymes with particular focus on lactonases, acylases and proteases. The activity assay introduced in Article I substantially extends the method toolbox for studies on lactonases and acylases that interfere with the bacterial cell-cell communication system. Article II describes a fully automatized robotic platform that represents the next-level tool for the high-throughput enzyme screening in the microtiter plate format. It was used, for instance, for the screening for improved porcine aminoacylase I variants. Diverse aspects of the protease-mediated hydrolysis of non-resistant proteins for the purification of resistant target proteins are highlighted in Article III.
Hantaviruses are enveloped viruses with a single-stranded RNA genome of negative polarity. The genome consists of three segments: small (S), medium (M) and large (L). As zoonotic pathogen, hantaviruses are worldwide responsible for 150,000 to 200,000 human disease cases per year. Two forms of human disease are currently distinguished: In the Americas the hantavirus cardiopulmonary syndrome (HCPS) and in Europe and Asia the hemorrhagic fever with renal syndrome (HFRS). Since the introduction of the German Protection against Infection Act in 2001 until now a total of 10,082 disease cases have been reported. As a result, hantavirus infections currently rank as the fifth frequent notifiable disease in Germany. More than 80% of these infections were caused by the hantavirus species Puumala virus (PUUV), transmitted by the bank vole Myodes glareolus. Besides temporal oscillations, an unequal geographical distribution of human PUUV cases was noticed in Germany and in other countries of Central Europe. This is reflected in the presence of endemic and non-endemic regions as well as of so-called outbreak years. Therefore, the overall objective of this study was to find out possible reasons for the inhomogeneous distribution of PUUV in Central Europe, in particular in Poland, Germany and certain districts of Baden-Wuerttemberg. The basic working hypothesis was that PUUV spread in Central Europe after the last glaciation with different evolutionary lineages of the bank vole and that the current emergence of PUUV in bank vole populations is determined by local geographical and ecological factors. Very little was known about the presence of PUUV in Poland. Earlier studies were based exclusively on serological detection of PUUV, but a molecular detection with subsequent phylogenetic investigation was missing so far. Therefore, 45 bank voles from the northeastern part of Poland were investigated by serological and molecular assays. In three animals from a forest region close to the city of Miko³ajki PUUV-reactive antibodies and/or PUUV RNA were detected. Phylogenetic analysis indicated the presence of a Latvian (LAT) PUUV strain. Viral RNA was detected in one bank vole of the Eastern evolutionary lineage and two animals of the Carpathian lineage. Thereby it could be demonstrated for the first time that the distribution of the LAT PUUV lineage ranges from Latvia south-west to the northeastern part of Poland. An inhomogeneous spatial distribution of human disease cases has been observed even for Baden-Wuerttemberg, a long time known endemic federal state of Germany. Therefore 660 bank voles were trapped during the outbreak and non-outbreak years 2012 and 2013 in four districts with high incidences (H) and in four districts with low incidences or lacking PUUV cases (L). During the outbreak year 2012 PUUV-positive bank voles were detected by serological and molecular investigations in seven of eight districts. In contrast, in the following year only in one district PUUV infected bank voles were detected. Furthermore, it was demonstrated that after a beech mast, i.e., a massive fructification of beech trees, in H districts with a higher percentage of beech forest coverage a higher number of human cases was notified, but not in L districts with a lower percentage of beech forest coverage. For the future development of early warning modules it is therefore necessary to have a long-term bank vole monitoring established that incorporates beech mast data and information on beech forest coverage. High endemic regions for PUUV are mainly located in the southern and western parts of Germany, whereas in the eastern and northern parts only low numbers or even no human cases are recorded. To find out possible reasons for this inhomogeneous distribution, 1,774 bank voles from different regions of Germany were investigated for PUUV infections and in parallel for the corresponding bank vole evolutionary lineage (Western, Eastern, Carpathian). The PUUV investigations indicated positive voles in the known endemic regions with an easternmost and northernmost occurrence in western Saxony-Anhalt, western Thuringia and in Osnabrück. In the northern and eastern part of Germany none of the 1,210 investigated bank voles showed a PUUV infection. In the southern and western parts of Germany only the Western bank vole lineage was identified, whereas the Eastern lineage was exclusively found in the eastern and northern part and the Carpathian lineage in the South-East and North-East of Germany. PUUV infections were found almost exclusively in bank voles of the Western lineage. Individuals of the other two vole lineages were found to be PUUV infected only in regions with sympatric occurrence of the Western lineage. The previously described contact zone of the different bank vole phylogroups ranges from Poland to the entire northern part of Germany. In conclusion, the results of this investigation indicate two potential major reasons for the inhomogeneous distribution of PUUV in Germany: First, PUUV of the CE lineage seems to be associated with the Western bank vole lineage. The current geographical distribution of virus and host might be explained by a post-glacial northern expansion of the bank vole starting at the western refuge. Second, the missing detection of PUUV in bank voles of the Western lineage in areas close to high endemic regions might be explained by the extinction of the virus due to a limited winter survival of infected animals during long and harsh winters. The virus stability outside the host or ecological barriers, such as isolated forest areas or broad rivers, might also influence the distribution of PUUV in bank vole populations.
The history of Mathematics has been lead in part by the desire for generalization: once an object was given and had been understood, there was the desire to find a more general version of it, to fit it into a broader framework. Noncommutative Mathematics fits into this description, as its interests are objects analoguous to vector spaces, or probability spaces, etc., but without the commonsense interpretation that those latter objects possess. Indeed, a space can be described by its points, but also and equivalently, by the set of functions on this space. This set is actually a commutative algebra, sometimes equipped with some more structure: *-algebra, C*-algebra, von Neumann algebras, Hopf algebras, etc. The idea that lies at the basis of noncommutative Mathematics is to replace such algebras by algebras that are not necessarily commutative any more and to interpret them as "algebras of functions on noncommutative spaces". Of course, these spaces do not exist independently from their defining algebras, but facts show that a lot of the results holding in (classical) probability or (classical) group theory can be extended to their noncommutative counterparts, or find therein powerful analogues. The extensions of group theory into the realm of noncommutative Mathematics has long been studied and has yielded the various quantum groups. The easiest version of them, the compact quantum groups, consist of C*-algebras equipped with a *-homomorphism &Delta with values in the tensor product of the algebra with itself and verifying some coassociativity condition. It is also required that the compact quantum group verifies what is known as quantum cancellation property. It can be shown that (classical) compact groups are indeed a particular case of compact quantum groups. The area of compact quantum groups, and of quantum groups at large, is a fruitful area of research. Nevertheless, another generalization of group theory could be envisioned, namely by taking a comultiplication &Delta taking values not in the tensor product but rather in the free product (in the category of unital *-algebras). This leads to the theory of dual groups in the sense of Voiculescu, also called H-algebras by Zhang. These objects have not been so thoroughly studied as their quantum counterparts. It is true that they are not so flexible and that we therefore do not know many examples of them and showing that some relations cannot exist in the dual group case because they do not pass the coproduct. Nevertheless, I have been interested during a great part of my PhD work by these objects and I have made some progress towards their understanding, especially regarding quantum Lévy processes defined on them and Haar states.