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Aktive Immunisierung mit GD2-Peptidmimotopen und anti-Idiotypen zur Immuntherapie beim Neuroblastom
(2013)
Das Neuroblastom ist der häufigste solide, extrakranielle Tumor des Kindesalters. Die schlechte Prognose von Patienten mit fortgeschrittener Erkrankung macht die Entwicklung neuer Therapiemodalitäten zu einem der wichtigsten Forschungsziele auf dem Gebiet der pädiatrischen Onkologie. Durch die passive Immuntherapie mit Antikörpern gegen das Glykolipidantigen Disialogangliosid GD2, welches von Neuroblastomen hoch exprimiert wird, konnte die Überlebensrate von Hochrisiko-Neuroblastompatienten zuletzt deutlich verbessert werden. Dennoch ist die passive Immuntherapie mit Nachteilen verbunden: Das Ausbleiben einer langfristigen Immunität erfordert repetitive Antikörpergaben mit akuten antikörperbezogenen Nebenwirkungen und dem Risiko, eine humorale Immunreaktion gegen den applizierten Antikörper zu entwickeln. Eine aktive GD2-gerichtete Immunisierung erscheint daher vorteilhaft. Die schwache Immunogenität des Glykolipids ist hierbei ein wesentliches Hindernis bei der Induktion einer effektiven GD2-gerichteten Immunität. Dieses Problem kann durch die Verwendung von Proteinantigenen wie GD2-Peptidmimotopen oder anti-Idiotyp-Antikörpern umgangen werden. Zunächst beschreibt diese Arbeit die Charakterisierung von zwei GD2-Peptidmimotopen („MA“ und „MD“), welche durch Screening von Phagenbibliotheken identifiziert wurden, sowie den Nachweis der erfolgreichen Induktion einer neuroblastomspezifischen Immunität im syngenen Mausmodell. In einem zweiten Schritt wurden die Peptidmimotope durch Austausch einzelner Aminosäuren in ihrer Affinität zu GD2-Antikörpern optimiert und das so geschaffene neue Peptidmimotop („C3“) im Hinblick auf die Induktion einer humoralen GD2-spezifischen Immunität erfolgreich im Mausmodell getestet. Zudem gelang es, einen neuen monoklonalen GD2-anti-Idiotyp-Antikörper („Ganglidiomab“) zu erzeugen. Ganglidiomab weist typische Eigenschaften eines anti-Idiotypen wie die kompetitive Inhibition der Bindung von GD2 an GD2-Antikörper auf und erwies sich im Mausmodell als wirksam bei der Induktion einer GD2-spezifischen humoralen Immunantwort. Das optimierte GD2-Peptidmimotop C3 und der neue monoklonale GD2-Anti-Idiotyp Ganglidiomab bilden somit eine Basis zur weiteren Entwicklung einer wirksamen und sicheren Vakzine zur Behandlung von Hochrisiko-Neuroblastompatienten.
Viele hämatologische Neoplasien treten vornehmlich in einem Lebensalter deutlich jenseits des 50. Lebensjahres auf. Gleichzeitig sind viele dieser Erkrankungen derzeit nur durch eine allogene Stammzelltransplantation mit kurativem Ansatz behandelbar. Durch die Einführung von intensitätsreduzierten Konditionierungen und der Verbesserung der supportiven Therapie, besonders der antibiotischen und immunsuppressiven Behandlung, wird diese Behandlungsoption für ältere Patienten zunehmend eingesetzt. Im Zeitraum von 1999 und 2011 wurden an der Klinik für Innere Medizin C der Universitätsmedizin Greifswald 91 allogene Stammzelltransplantationen an 86 Patienten durchgeführt, die zum Zeitpunkt der Transplantation 55 Jahre oder älter waren. 85 Patienten bzw. 90 Transplantationen konnten in die Auswertung eingehen. Das mediane Alter lag bei 61 Lebensjahren. Die nach Sorror et al eingestufte Komorbidität erbrachte einen medianen Wert von 3, wobei 50,6% einen Wert von 3 oder höher aufwiesen und damit in die Hochrisikogruppe einzuordnen waren. Das Spektrum der Grunderkrankungen war, einem unselektierten Patientengut entsprechend, heterogen. In 91,1% wurden im Rahmen des Engraftments Leukozyten über 1 Gpt/l und Thrombozyten über 20 Gpt/l erreicht. Eine akute GvHD wurde in einem Drittel der Fälle beobachtet, und zwar in 27,8% nach der Transplantation und 5,6% nach einer DLI-Gabe. Eine chronische GvHD ließ sich in 21,1% der Fälle diagnostizieren, wobei mehr als die Hälfte im Stadium der Limited Disease blieben. Im Beobachtungszeitraum sind 58 Patienten [68,2%] verstorben. 26 dieser Patienten [44,8% der Todesfälle] verstarben aufgrund der Wiederkehr oder Progression der malignen Grunderkrankung. 32 Todesfälle [55,2% der Todesfälle] ereigneten sich in einem erkrankungsfreien Intervall [NRM]. Die Analyse der erhobenen Daten zeigte, dass eine genaue Erhebung des Sorror-Scores über einen Wert von 3 hinaus sinnvoll ist, da auch in diesen Bereichen statistisch signifikante Unterschiede bei Gesamtüberleben und erkrankungs- bzw. progressionsfreiem Überleben zu erhalten sind. Auch bei einem Punktewert von über 3 hinaus sank das Gesamtüberleben und das erkrankungs- bzw. progressionsfreie Überleben statistisch signifikant mit ansteigendem Komorbiditäts-Score. Darüber hinaus konnte ein signifikant längeres Gesamt- und erkrankungs- bzw. progressionsfreies Überleben in Verbindung mit einer chronischen GvHD gezeigt werden. Dies belegt eindrucksvoll die Rolle eines Graft-versus-tumor-Effektes in der Kontrolle der Grunderkrankung. Die Daten zeigen, dass die allogene Stammzelltransplantation für ältere Patienten einsetzbar ist.
Der Schlaganfall ist nach Herz- und Krebsleiden die dritthäufigste Todesursache in den westlichen Industrieländern und einer der Hauptgründe für eine permanente Behinderung. Ein entscheidender Faktor in der Therapie des akuten ischämischen Schlaganfalls ist die Rekanalisation des Gefäßverschlusses. Endovaskuläre Therapieverfahren, sowohl medikamentöse als auch mechanische, spielen eine immer bedeutendere Rolle. Es gibt keinen Konsens darüber, ob für solche Intervention eine Intubationsnarkose (ITN) notwendig ist oder eine lokale Anästhesie (LA) im Zugangsbereich erfolgen sollte. Ziel der Studie war es, die Durchführbarkeit der lokalen Schlaganfalltherapie unter lokaler Anästhesie zu evaluieren. Über einen Zeitraum von fünf Jahren wurden 131 Patienten mit einem akut ischämischen Schlaganfall eingeschlossen. Die endovaskuläre Therapie erfolgte als lokale intraarterielle Thrombolyse, als primäre mechanische Rekanalisation oder als Kombinationstherapie. Die systematische Auswertung erfolgte retrospektiv hinsichtlich Rekanalisationsrate, primärem anästhesiologischem Vorgehen, Konversion von lokaler Anästhesie zu Intubationsnarkose, neurologischem Outcome sowie postinterventionellen Komplikationen. Von den 124 Patienten (mittleres Alter 68,8 ± 14,6) waren 65 weiblich (52,4 %) und 59 (47,6 %) männlich. Der Verschluss lag bei 94 Patienten (75,8 %) im vorderen, bei 30 Patienten (24,4 %) im hinteren Stromgebiet. 105 Patienten (84,7 %) wurden in lokaler Anästhesie, 16 Patienten (12,9 %) primär in ITN behandelt. In 3 Fällen (2,4 %) erfolgte eine Konversion von LA in ITN. Eine primäre Lyse bzw. mechanische Rekanalisation erfolgte bei 60 (48,4 %) bzw. 27 (21,8 %) Patienten, in 37 Fällen (29,8 %) erfolgte eine Kombination beider Verfahren. Zwischen der LA- und ITN-Gruppe bestand weder hinsichtlich Rekanalisationsrate noch peri- oder postinterventionellen Komplikationen ein statistisch signifikanter Unterschied. Das finale Infarktvolumen war bei Behandlung in Lokalanästhesie signifikant kleiner (p = 0.024). Lokal rekanalisierende Verfahren in der Therapie des akut ischämischen Schlaganfalls sind unter lokaler Anästhesie und bedarfsweiser Analgosedierung mit niedrigem Risikoprofil möglich und scheinen zu einem geringeren Infarktvolumen und besserem klinischen und radiologischem Outcome zu führen.
Analyse der Hygienekosten in einer Zahnklinik am Beispiel der AOK Rheinland/Hamburg in Düsseldorf
(2013)
Die Umsetzung gesetzlicher Anforderungen sowie der Richtlinien des RKI und des DAHZ tragen wesentlich zur Erhaltung der Hygiene in der zahnärztlichen Praxis bei. Das erhöht die Qualität der zahnärztlichen Behandlung und minimiert die Risiken, die hygienebedingt die Gesundheit des behandelnden zahnärztlichen Teams und des Patienten gefährden können. Andererseits stellt ein kontinuierliches Schritthalten mit den technologischen Fortschritten und Vorgaben der Hygienemaßnahmen ein betriebswirtschaftliches Thema für die Zahnarztpraxis dar, weil zwischen der Qualität der Leistungen einer Zahnarztpraxis und den Aufwendungen zur Gewährleistung der Qualität eine ökonomisch vertretbare Relation bestehen muss, wenn die Zahnarztpraxis langfristig erhalten bleiben soll. Die Analyse der Hygienekosten der Zahnklinik der AOK im Jahr 2010 zeigte, dass die wesentlichen angefallenen Kosten für die Unterbindung der Infektionsverbreitung auf den Wegen aufgewendet worden sind, die in dieser Arbeit unter Hygienesachkosten zusammengefasst wurden. Sie ergaben in der Summe 66.721,22 €. Gemäß der Analysenergebnisse stellen die Kostenarten Personalkosten (PK) und Medizinprodukte (G1) die zwei wesentlichen Anteile der Kosten der Zahnklinik der AOK mit einem Anteil von ca. 72 % Kosten dar (entsprach 92.061,07 €). Die Verwendungszwecke der Personalkosten umfassen arbeitsmedizinische Untersuchungen, Schutzimpfungen, Reinigungskraft und Sterilisationsdienst, wobei Schutzimpfungen den niedrigsten und der Sterilisationsdienst den höchsten Kostenanteil verursachten. Die übrigen Kosten verteilten sich wie folgt: Berufs- und Schutzkleidung 14.892,00 €, Antiseptika 1.216,18 €, Zertifizierung und Qualitätsmanagement 7.667,00 €, Geräte 12.411,74 €. Damit ergibt sich ein Gesamtbetrag für die Hygienekosten für das Jahr 2010 von 128.247,99 €. Eine Prognose der Hygienekosten auf Grund der Kostenerfassung für vier Quartale eines Jahres ist nicht möglich, da dieses Vorgehen unrealistische Ergebnisse liefert. Es wird daher empfohlen, für eine Prognose die Daten von mindestens drei aufeinander folgenden Jahren zu verwenden.
Sowohl Kaubewegungen als auch deren Kaumuster erweisen sich als sehr komplexe und variantenreiche Vorgänge, welche durch zahlreiche Faktoren beeinflusst werden können. Bei 271 vollbezahnten Probanden, davon 109 männliche und 162 weibliche, aus der bevölkerungsrepräsentativen Basisstudie SHIP-0 wurden die Kaubewegungen mit dem Jaw Motion Analyser (JMA) der Firma Zebris Medical (D-Isny) aufgezeichnet. Als viskoelastisches Kaugut wurde jeweils ein Gummibärchen der Firma Haribo (D-Bonn) verwendet. Die Ergebnisse dieser Studie zeigen keine eindeutigen Unterschiede der Variabilität der Öffnungs- und Schließbewegungen des Inzisalpunktes in okklusaler Nähe in Bezug auf Geschlecht, Alter, bevorzugter Kauseite oder Dysfunktionsgrad. Lediglich die Schließbewegungen weisen eine tendenzielle Abnahme der Variabilität bei steigendem Dysfunktionsgrad auf. Wie auch bei den Kaubewegungen besteht bei den Kaumusterfeldverteilungen eine hohe Ähnlichkeit zwischen angewiesenem Rechts- und Linkskauen. Die Auswertung zeigt, dass weder die Bevorzugung einer Kauseite noch das Geschlecht einen erkennbaren Einfluss haben. In Abhängigkeit vom Alter hingegen nimmt tendenziell mit steigendem Alter die relative Anzahl der Fälle mit zahngeführten Anteilen (KMF A) zu. Die Auswertung der Kaumusterfeldverteilung nach allgemeinen Dysfunktionsgraden lässt keine eindeutige Zuordnung einzelner Kaumusterfelder (KMF) zu. Das tropfenförmige KMF C tritt bei allen Schweregraden verhältnismäßig am häufigsten auf. Lediglich im konkreten Fall der Gelenkdysfunktion ließ sich für beide angewiesenen Kauseiten eine charakteristische Zunahme der prozentualen Anzahl der Fälle mit Dysfunktionen im KMF D feststellen. Im Einzelfall hat eine Kaumusterklassifizierung somit keine gesicherte Aussagekraft über das Vorhandensein oder gar die Art einer Dysfunktion.
Genomics is the field of modern biology that studies the genome as the sum of all genes of a given organism. Genomics includes the analysis of genomic variations in order to identify genetic susceptibility loci for various human diseases. Besides genomics, there are related fields summarized by the term "Omics" such as transcriptomics and proteomics, studying the sum of all transcripts and proteins in a defined biological system, respectively. Genetic variants, namely single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) are used to identify genomic loci associated with human traits and diseases. Genome-wide association studies (GWASs) based on SNP data have been performed for a wide range of human traits and diseases. In the population-based Study of Health in Pomerania (SHIP) and the independent SHIP-TREND study, whole-genome genotyping data were available for 4081 and 986 individuals, respectively. In contrast to the widely used GWAS based on SNPs, association studies using CNV data are difficult to implement and thus less common. Therefore, one aim of this work was to detect CNVs using the whole-genome genotyping data available for 4081 individuals from SHIP. Another aim was to develop an efficient workflow for the analysis of these CNVs. As most common genetic variants exhibit only relatively small effects on phenotypic variability, large sample sizes are needed to maximize the statistical power to detect such effects. Therefore, the integration of data from multiple collaborating studies is indispensable. In this context, several CNV studies with the SHIP data have been performed and published, for example on body mass index (BMI) phenotypes where the SHIP cohort was used as a population-based control. Trait-associated genetic markers identified through GWASs are often intergenic or synonymous coding, and those loci identified through whole-genome CNV analyses often contain multiple genes, making it difficult to identify the causal variants. In this context, the functional analysis of identified loci aids in determining causal variant(s). One possibility to conduct functional analysis is the expression quantitative trait loci (eQTL) analysis, defined as the association of genome-wide genotyping data with genome-wide gene expression data based on measured transcriptomes. This allows the identification of genetic variants influencing the expression levels of defined genes. A further example are transcriptome-wide association analysis (TWAS), defined as the association of phenotype data with whole-genome expression data. Thus, another aim of this work was to establish an analysis pipeline for processing such expression data, which were available for about 1000 individuals from the SHIP-TREND study. Here, array-based gene expression data were generated using RNA prepared from whole-blood. Interpretation of TWAS results is often difficult, because of possible reverse causation on gene expression data. Furthermore, technical errors of measurement may bias the results. In a comprehensive work, biological and technical factors influencing measured gene expression data have been identified and were subsequently taken into account to improve the association analyses. To further elucidate the molecular mechanisms underlying the relationship of gene expression levels with human traits or diseases, pathway analyses using the Ingenuity Pathway Analysis (IPA) tool have been performed in connection with the TWAS. As for GWASs, the associations identified in TWAS usually exhibit only small effect sizes, highlighting the need for larger studies or meta-analysis to identify all susceptibility variants. In this context several eQTL- and TWAS meta-analyses using the SHIP-TREND data have been performed, for example on the phenotypes age, sex, BMI, smoking status and serum lipid traits. The results of these analyses are in preparation for publication and the most advanced example, the correlation of expression data with BMI, is presented here. The integration of whole-genome genotyping and expression data provides new functional information of the underlying biological mechanisms of complex human traits and diseases. Within the frame of this work, this could be demonstrated for the example of susceptibility to Helicobacter pylori infection.
Betrachtet werden Optimalsteuerungsaufgaben der dreidimensionalen Fischpopulationsmodelle. Solche Modelle gehören zu der Klasse der sogenannten Lotka-Volterra-Modelle. Fischerei-Probleme mit Steuerungen werden für Steuerungsfunktionen verschiedener Klassen gelöst. Der Schwerpunkt der Arbeit liegt auf den notwendigen Optimalitätsbedingungen, die mit Hilfe des Bellman-Prinzips hergeleitet werden.
The focus of the first two articles was the engineering and application of enzymes for the conversion of the bio-based resources glycerol and its oxidation product glyceraldehyde for the production of the value added product glyceric acid. Article III focuses on the cloning, exploration and engineering of a polyol dehydrogenase, which later on was used as cofactor recycling system in order to produce ε-caprolactone from cyclohexanol as presented in arti-cle IV. The following paragraphs will give a short outline of each article. ARTICLE I: ASYMMETRIC SYNTHESIS OF D-GLYCERIC ACID BY AN ALDITOL OXIDASE AND DIRECTED EVOLUTION FOR ENHANCED OXIDATIVE ACTIVITY TOWARDS GLYCEROL. GERSTENBRUCH, S., WULF, H., MUßMANN, N., O’CONNELL, T., MAURER, K.-H. & BORNSCHEUER, U. T. (2012). Appl. Microbiol. Biotechnol. 96, 1243-1252. The alditol oxidase of Streptomyces coelicolor A3(2) (AldO) was used to catalyze the oxida-tion of glycerol to glyceraldehyde and glyceric acid. The enantioselectivity for the FAD-de-pendent glycerol oxidation was elucidated and different strategies were used to enhance the substrate specificity towards glycerol. Directed evolution by error-prone PCR led to an AldO double mutant with 1.5-fold improved activity for glycerol. Further improvement of activity was achieved by combination of mutations, leading to a quadruple mutant with 2.4-fold higher specific activity towards glycerol compared to the wild-type enzyme. In small-scale biotransformation concentrations up to 2.0 g•l-1 D-glyceric acid could be reached using whole cells. Investi¬gation of the effects of the introduced mutations led to a further identification of es¬sential amino acids with respect to enzyme functionality and structural stability. ARTICLE II: KINETIC RESOLUTION OF GLYCERALDEHYDE USING AN ALDEHYDE DEHYDROGENASE FROM DEINOCOCCUS GEOTHERMALIS DSM 11300 COMBINED WITH ELECTROCHEMICAL COFACTOR RECYCLING. WULF, H., PERZBORN, M., SIEVERS, G., SCHOLZ, F. & BORNSCHEUER, U. T. (2012). J. Mol. Catal. B Enzym. 74, 144-150. Two aldehyde dehydrogenases (ALDH) from Escherichia coli BL21 and Deinococcus geother-malis were cloned, characterized and evaluated according to their applicability for a bio-catalysis setup with electrolytic cofactor recycling. Both ALDHs turned out to have a sim¬ilar substrate scope and favor short to medium chain aldehydes and both oxidize glyceralde¬hyde to D-glyceric acid. The ALDH variant of D. geothermalis shows higher specific activity towards glyceraldehyde and has an elevated optimum temperature compared to the BL21 enzyme. Due to the higher specific activity of the ALDH of D. geothermalis, this enzyme was used to conduct a kinetic resolution of glyceraldehyde with electrolytic NAD+ recycling at a glassy carbon foam electrode with ABTS as redox mediator yielding in 1.8 g•l-1 glyceric acid. ARTICLE III: PROTEIN ENGINEERING OF A THERMOSTABLE POLYOL DEHYDROGENASE. WULF, H.*, MALLIN, H.*, BORNSCHEUER U.T. (2012). Enzyme Microb. Technol. 51, 217-224 (*equally contributed). The new enzyme polyol dehydrogenase PDH-11300 from D. geothermalis was extensively characterized regarding its temperature optimum and thermostability. A peptide stretch responsible for substrate recognition from the PDH-11300 was substituted by this particular stretch of a homolog enzyme, the galactitol dehydrogenase from Rhodobacter sphaeroides (PDH-158), resulting in a chimeric enzyme (PDH-loop). The substrate scopes were deter-mined and basically the chimeric enzyme represented the average of both wild-type en-zymes. A rather unexpected finding was the notably increased T5060, by 7°C to 55.3°C, and an increased specific activity against cyclohexanol. Finally, the cofactor specificity was suc¬cess-fully altered from NADH to NADPH by an Asp55Asn mutation, which is located at the NAD+ binding cleft, without influencing the catalytic properties of the dehydrogenase. ARTICLE IV: A SELF-SUFFICIENT BAEYER-VILLIGER BIOCATALYSIS SYSTEM FOR THE SYNTHESIS OF Ɛ-CAPROLACTONE FROM CYCLOHEXANOL. MALLIN, H. *, WULF, H. *, BORNSCHEUER U.T. (2013). Enzyme Microb. Technol., online, DOI: 10.1016/j.enzmictec.2013.01.007 (*equally contributed). The application of the engineered PDH-loopN mutant [1] (Article III) for the production of ε-caprolactone from cyclohexanol was investigated in a co-immobilization approach with the cyclohexanone monooxygenase from Acinetobacter calcoaceticus. Biotransformation with solubilized enzymes led to an isolated yield of 55% pure ε-caprolactone with no residual cy-clohexanol to be detected. During the immobilization experiments a higher enzyme ratio in favor of the CHMO led to higher reaction velocities. Similarly, the addition of soluble fresh CHMO during reuse of co-immobilization batches significantly increased the activity identi-fying the CHMO as the bottleneck in this reaction setup.
Metabolomics is the scientific study of metabolites of an organism, cell, or tissue. Metabolomics makes use of different analytical approaches. In this thesis, an analytical platform consisting of proton nuclear magnetic resonance spectroscopy (1H-NMR), gas chromatography-mass spectrometry (GC-MS, EI/quadrupol) and liquid chromatography-mass spectrometry (LC-MS, ESI/TOF) was used for metabolite analysis. Due to the high physicochemical diversity of metabolites, the usage of different analytics is profitable. Focusing on metabolome analysis of microorganisms, the development of viable protocols was prerequisite. To ensure metabolome samples of best possible quality, particularly the sampling procedure has to be optimized for each microorganism to be analyzed individually. In microbial metabolomics, the energy charge value is a commonly used parameter to assure high sample quality (Atkinson 1968). The pathogenic bacterium Staphylococcus aureus and the biotechnical relevant bacterium Bacillus subtilis were main target of research. The sampling protocol development “A protocol for the investigation of the intracellular Staphylococcus aureus metabolome” (Meyer et al. 2010) and “Methodological approaches to help unravel the intracellular metabolome of Bacillus subtilis”s (Meyer et al. 2013) confirmed the need for development and verification of viable protocols. It was observed, that minor differences in the sampling procedure can cause major differences in sample quality. Using the validated analytical platform and the optimized protocols, we were able to investigate the metabolome of S. aureus and B. subtilis under different conditions. Investigations of the pathogenic bacterium S. aureus are of major interest due to its increasing resistance to antibiotics. Methicillin (multi)-resistant S. aureus (MRSA) strains are responsible for several difficult-to-treat infections. The cell wall of bacteria is the target of an array of antibiotics, like the beta-lactam antibiotics. Our study “A metabolomic view of Staphylococcus aureus and Its Ser/Thr kinase and phosphatase deletion mutants: Involvement in cell wall biosynthesis” (Liebeke et al. 2010) revealed the influence of the serine-threonine kinase on cell wall biosynthesis of S. aureus. LC-MS based metabolome data uncovered prevalent wall teichoic acid precursors in the serine-threonine kinase deletion mutant (ΔpknB), and predominantly peptidoglycan precursors in the phosphatase deletion mutant (Δstp), compared to the S. aureus wild type strain 8325. This uncovered a so far undescribed importance of the serine-threonine kinase on the cell wall metabolism and provides new insights into its regulation. The nasopharynx and the human skin are often the ecological niche of S. aureus. Furthermore, S. aureus exists outside its host, for example on catheters. Depending on its niche, S. aureus is exposed to several stress factors and limitation conditions, such as carbon source limitation and starvation. To cope with the latter, a number of regulatory cellular processes take place. In “Life and death of proteins: a case study of glucose-starved Staphylococcus aureus” (Michalik et al. 2012) protein degradation during glucose starvation was monitored. An intriguing observation was that proteins involved in branch chain amino acid biosynthesis and purine nucleotide biosynthesis were distinctly down-regulated in the clpP mutant. This lead to the assumption of a stronger repression of CodY-dependent genes in the clpP mutant. Intracellular metabolome data revealed higher GTP concentrations in the clpP mutant. This may explain the higher CodY activity and thereby stronger repression of CodY-dependent genes in the clpP mutant. Since different S. aureus strains are known to colonize different niches, global carbon source (glucose, glucose 6-phosphate, glycerol, lactate, lactose and a mixture of all) and carbon source limitation dependent exo-metabolome analyses were performed using three different S. aureus strains (HG001: laboratory strain, EN493: human endocarditis isolate and RF122: bovine mastitis strain). The most apparent observation was that RF122 can utilize lactose best, while EN493 and HG001 are better at utilizing glucose-6-phosphate compared to the bovine RF122 strain. Bacillus subtilis is an extensively studied Gram-positive and non-pathogenic bacterium. In the functional genomics approach “System-wide temporal proteomics profiling in glucose-starved Bacillus subtilis” (Otto et al. 2010) growth phase dependent changes in the proteome, transcriptome and extracellular metabolome were monitored. By mass spectrometric analysis of five different cellular subfractions, ~ 52% of the predicted proteins could be identified. To confirm and complete the proteomic data transcriptome and extracellular metabolome analyses were performed. The extracellular metabolome data ensured that cells were glucose-starved and revealed growth phase dependent metabolic footprints. In “A time resolved metabolomics study: The influence of different carbon sources during growth and starvation of Bacillus subtilis” ((Meyer et al. 2013) submitted) four different compounded cultivation media were investigated as only glucose, glucose and malate, glucose and fumarate and glucose and citrate as carbon source. It could be shown, that B. subtilis is able to maintain an intracellular metabolite homeostasis independent of the available carbon source. On the other hand, in the exo-metabolome, carbon source as well as growth phase dependent differences were detected. Furthermore, in this study the influence of ATP and GTP on the activation of the alternative RNA polymerase sigma factor B (σB) was discussed. The concentration of ATP and GTP decreased for all conditions, as cells entered the stationary growth phase. While cell growth on solely glucose and during growth on glucose and additional malate, the ATP and GTP concentrations increased slightly when the consumption of the second carbon source was initiated. Only under these conditions, a considerable σB activity increase during the transition from exponential to stationary growth phase was observed. Furthermore, the developed sampling protocol for metabolome analysis of B. subtilis enabled us to be part of a “multi omics” system biological approach to study the physiological adjustment of B. subtilis to cope with osmotic stress under chemostat conditions.
Hyperuricemia and its symptoms are becoming increasingly common worldwide. Elevated serum uric acid levels are caused by increased uric acid synthesis from food constituents and reduced renal excretion. Treatment in most cases involves reducing alcohol intake and consumption of meat and fish or treatment with pharmaceuticals. Another approach could be to reduce uric acid level in food, either during production or consumption. This work reports the production of recombinant urate oxidase by Arxula adeninivorans and its application to reduce uric acid in a food product. The A. adeninivorans urate oxidase amino acid sequence was found to be similar to urate oxidases from other fungi (61-65% identity). In media supplemented with adenine, hypoxanthine or uric acid, induction of the urate oxidase (AUOX) gene and intracellular accumulation of urate oxidase (Auoxp) was observed. The enzyme characteristics were analyzed from isolates of the wild-type strain A. adeninivorans LS3, as well as from those of transgenic strains expressing the AUOX gene under control of the strong constitutive TEF1 promoter or the inducible AYNI1 promoter. The enzyme showed high substrate specificity for uric acid, a broad temperature and pH range, high thermostability and the ability to reduce uric acid content in food.
This thesis aims at improving the current representation of adaptation in economic frameworks of climate change by a) accounting for the time-dependent evolution of the adaptive capacities of countries and b) quantifying unwelcome feedbacks of the adaptation process. In this context, it is proposed that economic assessments of climate change incorporate adaptation as a cyclic and phase-dependent process while devising their cost methodologies. A phase-dependent process acknowledges the existence of adaptation barriers while a cyclic process accounts for potential unwanted feedbacks of adaptation. By analyzing economic assessments against this framework, it is shown that dependencies between phases of adaptation and phases altogether are often disregarded. Furthermore, potential negative consequences associated with adaptation are rarely considered and adaptation is generally assumed to be unconstrained. The assumption of unconstrained adaptation is only acceptable in the context of high adaptive capacity. This concept was further investigated through a review of vulnerability assessments regarding their operation of the adaptive capacity component. It was found that adaptive capacity is mostly equated to proxies that reflect the knowledge, financial and livelihood capacities of the system under analysis. With this theoretical considerations in mind, a dynamic representation of adaptive capacity was elaborated at a country-level. The Human Development Index (HDI) was used as a proxy of the adaptive capacity of countries and its evolution in time extrapolated. The time required for countries to achieve developed world standards of human development was then estimated. The results indicate that between 2005 and 2020, half of the world population will live in countries with low adaptive capacity. This percentage is then progressively reduced to 15% in the year 2050, with marked regional differences. The time required for a country to achieve an appropriate level of development sets a clear constraint on when, and to what extent, the country can engage on climate change adaptation. This does not imply that adaptation will not take place before development occurs. Rather, it calls for adaptation options to be tailored in order to t the current and future adaptive capacities of countries. Obtaining higher levels of adaptive capacity is likely to be associated with negative consequences for the climatic system. The statistical relation between HDI and per-capita emissions of countries was established and future projections made. Between 2010 and 2050 approx. 300 Gt of CO2 are estimated to be associated with the increase of adaptive capacities of current developing countries. This value represents about 30% of the allowed CO2-budgets to restrict global temperatures to an increase of 2 degrees by 2100 compared to pre-industrial times - conditional to a 25% risk of failing to meet the target. For the case of sea-level rise, the modelling framework DIVA (Dynamic Interactive Vulnerability Assessment) was used in order to illustrate the drawbacks of a simplistic representation of adaptation. The results show that adaptation via the construction of protective infrastructure might be economically feasible for particular countries. For others, modeled results fail to provide a clear choice between adaptation or inaction. The assumption of unconstrained adaptation resulted in the valuation of costly protection options whose financial and knowledge requirements can be at odds with the capacities of some coastal countries - namely developing countries. Further, infrastructural protection as adaptive measure to prevent coastal damages can have the counter-productive effect of raising the amount and value of assets at risk. This is a direct result of DIVA disregarding the potential unwelcome feedbacks of adaptation itself. In conclusion, the full potential of economic assessments of climate adaptation is likely to remain unlocked as long as adaptation continues to be misrepresented. The methodologies discussed in this work provide a way forward to alleviate this deficiency in forthcoming assessments. For the case of sea-level rise, the modeling framework DIVA (Dynamic Interactive Vulnerability Assessment) was used in order to illustrate the drawbacks of a simplistic representation of adaptation. The results show that adaptation via the construction of protective infrastructure might be economically feasible for particular countries. For others, modeled results fail to provide a clear choice between adaptation or inaction. The assumption of unconstrained adaptation resulted in the valuation of costly protection options whose financial and knowledge requirements can be at odds with the capacities of some coastal countries - namely developing countries. Further, infrastructural protection as adaptive measure to prevent coastal damages can have the counter-productive effect of raising the amount and value of assets at risk. This is a direct result of DIVA disregarding the potential unwelcome feedbacks of adaptation itself. In conclusion, the full potential of economic assessments of climate adaptation is likely to remain unlocked as long as adaptation continues to be misrepresented. The methodologies discussed in this work provide a way forward to alleviate this deficiency in forthcoming assessments.
In terms of climate change and climate change mitigation, the quantitative knowledge of global carbon pools is important information. On the one hand, knowledge on the amount of carbon cycling among – and stored in – global pools (i.e. Atmosphere, Biosphere, Cryosphere, Hydrosphere, and Lithosphere) may improve the reliability of models predicting atmospheric CO2 concentrations in terms of fossil fuel combustion. On the other hand, the carbon sequestration potential of specific ecosystems allows for estimating their feasibility regarding carbon trade mechanisms such as the Clean Development Mechanism or the Reducing Emissions from Deforestation and Degradation Program (REDD+). However, up to date, the majority of terrestrial carbon assessments have focused on forests and peatlands, leaving a data gap open regarding the remaining ecosystems. This data gap is likely to be explained by the relatively high carbon densities and/or productivities of forests and peatlands. Nevertheless, to get a precise as possible global picture, information on carbon pools and sequestration of other ecosystems is needed. Although desert ecosystems generally express low carbon densities, they may absolutely store a remarkable amount of carbon due to their large areal extent. In this context, Central Asian Deserts (in particular within the Turanian Deserts, i.e. Karakum, Kysylkum, Muyunkum) likely inhibit comparably high carbon pools as they express a sparse vegetation cover due to an exceptionally high annual precipitation if compared to the World’s deserts. In this dissertation, three important woody plant species – Populus euphratica and Haloxylon aphyllum and Haloxylon persicum – of Central Asian Deserts were investigated for their carbon pools and carbon sequestration potential. These species were chosen as they I) locally express high carbon densities, II) are dominant species, III) have a rather large spatial distribution, and IV) have experienced a strong degradation throughout the 20th century. Thus, they likely show a remarkable potential for carbon re-sequestration through restoration and thus for an application of carbon trade mechanisms (CHAPTER I). P. euphratica was investigated in the nature reserve Kabakly at the Amu Darya, Turkmenistan and in Iminqak at the Tarim He, Xinjiang, China. The assessment of Haloxylon species was restricted to the Turanian deserts west of the Tain Shan. To achieve a first scientific basis for large scale estimates, different methodologies, ranging from allometric formulas, over dendrochronology to remote sensing were combined (CHAPTERS II-V). In CHAPTER II allometric formulas were successfully developed for Haloxylon aphyllum and Haloxylon persicum and applied to six study sites distributed over the Turanian Deserts to represent the allometric variability of Haloxylon species in Central Asia. CHAPTER III derives another allometric formula (only based on canopy area) for H. aphyllum and combines it with a remote sensing analysis from the nature reserve Repetek. Thereby, a first large scale estimate covering the Northeastern Karakum Desert of carbon pools related to mono specific H. aphyllum stands is achieved. CHAPTER IV describes the wood structure of Populus euphratica forests in the nature reserve Kabakly (Turkmenistan) and in Iminqak (Xinjiang, China). In CHAPTER V a dendrochronological approach derives models for predicting the Net Primary Productivity (NPP) and the age of P. euphratica in the nature reserve Kabakly. Thereby, a first feasibility assessment regarding remote sensing analyses and the upscaling of the obtained NPP results is carried out. First estimates based on these local studies (CHAPTER VI), reveal carbon densities ranging from 0.1 – 26.3 t C ha 1 for the three investigated species. Highest maximum and median carbon densities were found for P. euphratica, but Haloxylon aphyllum expressed remarkable maximum carbon densities (13.1 t C ha-1), too. The total carbon pools were estimated at 6480 kt C for P. euphratica, 520 kt C for H. aphyllum stands and 6900 kt C for Haloxylon persicum shrubland. Accounting for the extent of degraded areas, the total re-sequestration potentials of the respective species were estimated at 4320 kt C, 1620 kt C and 21900 kt C, this highlighting the remarkable absolute re-sequestration potential of H. persicum shrubland despite its low average carbon densities. In the end, the main results were put into a broader context (CHAPTER VI), discussing the general feasibility of reforestations both in ecological terms as well as in terms of carbon trade mechanisms. A short example highlights the strong connection between the feasibility of reforestations and the global carbon market. Finally, open research questions are brought forth revealing the yet large research potential of Central Asian Desert ecosystems in general and in terms of carbon sequestration.
Objective: The purpose of this study was to determine the accuracy and reliability of Frankfort horizontal plane identification using displays of multi-planar reconstructed MRI images, and propose it as a sufficiently stable and standardized reference plane for craniofacial structures Materials and Methods: MRI images of 43 adolescent randomly selected subjects were obtained from the longitudinal population based cohort study SHIP-2 using a T1-weighted 3D sequence. Five examiners independently identified the three landmarks that form FH plane. Intra-examiner reproducibility and inter-examiner reliability, correlation coefficients (ICC), coefficient of variability and Bland-Altman plots were obtained for all landmarks coordinates to assess reproducibility. Intra-examiner reproducibility and inter-examiner reliability in terms of location and plane angulation were also assessed. Results: Intra- and inter-examiner reliabilities for X, Y and Z coordinates of all three landmarks were excellent with ICC values ranging from 0.914 to 0.998. Differences among examiners were more in X and Z than in Y dimensions. The Bland–Altman analysis demonstrated excellent intra- as well as inter-examiner agreement between examiners in all coordinates for all landmarks. Intra-examiner reproducibility and inter-examiner reliability of the three landmarks in terms of distance showed mean differences between 1.3 to 2.9 mm, Mean differences in plane angulation were between 1.0° to 1.5° among examiners. Conclusion: This study revealed excellent intra-examiner and inter-examiner reproducibility of Frankfort Horizontal plane through 3D landmark identification in MRI. Sufficiently stable landmark-based reference plane could be used for different treatments and studies.
This study aims to analyze psychometric properties and validity of the Compulsive Internet Use Scale (CIUS) and the Internet Addiction Test (IAT) and, second, to determine a threshold for the CIUS which matches the IAT cut-off for detecting problematic Internet use. A total of 292 subjects with problematic or pathological gambling (237 men, 55 women) aged 14-63 years and with private Internet use for at least 1 h per working or weekend day were recruited via different recruitment channels. Results include that both scales were internally consistent (Cronbach's α = 0.9) and had satisfactory convergent validity (r = 0.75; 95% CI 0.70-0.80). The correlation with duration of private Internet use per week was significantly higher for the CIUS (r = 0.54) compared to the IAT (r = 0.40). Among all participants, 25.3% were classified as problematic Internet users based on the IAT with a cut-off ≥40. The highest proportion of congruent classified cases results from a CIUS cut-off ≥18 (sensitivity 79.7%, specificity 79.4%). However, a higher cut-off (≥21) seems to be more appropriate for prevalence estimation of problematic Internet use.
Background: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. Patients and Methods: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARγ and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. Results: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARγ and MAPK1. One SNP remained significant after Bonferroni's correction: IGF1R SNP rs4966035's minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. Conclusion:IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS.
Aim: To evaluate the association of Insulin-like Growth Factor (IGF) I related variables with periodontitis in the population-based Study of Health in Pomerania (SHIP). Material and Methods: From the cross-sectional SHIP, 2293 subjects with clinical attachment loss (CAL) data and 2398 subjects with tooth count data aged 20-59 years were analysed. Serum IGF-I and IGF binding protein (BP)-3 levels were determined by chemiluminescence immunoassays. Linear and logistic regressions with fractional polynomials were used to study associations between IGF-related variables and mean CAL or high tooth loss. For non-linear relations between IGFBP-3 and mean CAL, graphical presentations of fractional polynomials were used to deduce knots for linear splines. Results: In fully adjusted models, for serum IGFBP-3 values ≤1200 ng/mL, mean CAL increased significantly for decreasing serum IGFBP-3 levels (B=-0.027 (95% CI, -0.049; -0.005), p=0.02). The odds for high tooth loss decreased significantly for high serum IGFBP-3 values (OR=0.97 (0.95; 0.99), p=0.02). Serum IGF-I levels and the IGF-I/IGFBP-3 ratio were not related to mean CAL or tooth loss after full adjustment. Conclusions: Low serum IGFBP-3 levels might be associated with higher levels of periodontal disease. Neither serum IGF-I nor IGF-I/IGFBP-3 ratios were associated with periodontitis.
Background/Aims: Only a small percentage of pathological gamblers utilizes professional treatment for gambling problems. Little is known about which social and gambling-related factors are associated with treatment utilization. The aim of this study was to look for factors associated with treatment utilization for pathological gambling. Methods: The study followed a sampling design with 3 different recruitment channels, namely (1) a general population-based telephone sample, (2) a gambling location sample and (3) a project telephone hotline. Pathological gambling was diagnosed in a telephone interview. Participants with pathological gambling (n = 395) received an in-depth clinical interview concerning treatment utilization, comorbid psychiatric disorders and social characteristics. Results: Variables associated with treatment were higher age [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03-1.08], an increased number of DSM-IV criteria for pathological gambling (OR 1.34, 95% CI 1.06-1.70), more adverse consequences from gambling (OR 1.10, 95% CI 1.03-1.16) and more social pressure from significant others (OR 1.17, 95% CI 1.07-1.27). Affective disorders were associated with treatment utilization in the univariate analysis (OR 1.81, 95% CI 1.19-2.73), but multivariate analysis showed that comorbid psychiatric disorders were not independently associated. Conclusion: These results indicate that individuals with more severe gambling problems utilize treatment at an older age when more adverse consequences have occurred. Further research should focus on proactive early interventions.
Die dentale Plaque beeinflusst entscheidend die Ätiologie von Karies, Parodontitis und Periimplantitis. Die Plaque stellt nach wie vor eine therapeutische Herausforderung dar, weil ihre Eliminierung durch mechanische Reinigung aufgrund der schweren Zugänglichkeit nur unvollständig gelingt. Antiseptische Mundspülungen können zwar über die Senkung der Bakterienzahl das Plaquewachstum hemmen, allerdings ohne dabei die Plaque selbst zu eliminieren. Darüber hinaus sind nur wenige antiseptische Wirkstoffe aufgrund möglicher Nebenwirkung für die Daueranwendung geeignet. Als mögliche Option zur Inaktivierung der Mikroorganismen in der Plaque bei gleichzeitiger Plaqueelimination wurde die Anwendung von Argonplasma, erzeugt mit dem kinpen09, an S. sanguinis Biofilmen, kultiviert im Europäischen Biofilmreaktor (EUREBI) bzw. in der 24-Well-Platte, untersucht. In beiden Modellen konnte auf Titanplättchen innerhalb von 72 h ein homogener, stabiler, gut analysierbarer Biofilm (>6,9 log10 KbE/ml) erzeugt werden. Trotz der signifikant stärkeren Biofilmbildung im EUREBI war die erzielte Differenz von 0,4 log10 KbE/ml ohne praktische Relevanz, so dass beide Prüfmodelle gleichermaßen zur Erprobung der Wirksamkeit von Plasmaquellen geeignet sind. Verglichen mit der Kontrolle war in beiden Biofilmmodellen nach der längsten gewählten Einwirkungszeit von 180 s eine signifikante Reduktion des Biofilms um 0,6 log10 KbE/ml bzw. 0,5 log10 KbE/ml erreichbar. Im Vergleich zur Wirksamkeit des kinpen09 in anderen Studien bildet S. sanguinis offensichtlich einen schwierig eliminierbaren Biofilm aus, wobei die Reifungszeit des Biofilms sowie andere Plasmazusammensetzungen und Behandlungseinstellungen die vergleichsweise geringe Effektivität beeinflusst haben dürften. Um die Wirksamkeit gegen S. sanguinis Biofilme zu verbessern, sind weitere Untersuchungen mit reduziertem Abstand zwischen Plasmaquelle und Biofilm, veränderter Zusammensetzung des Plasmas sowie mit anderen Plasmaquellen erforderlich. Schlüsselwörter: S. sanguinis Biofilm, Biofilmreaktor, Mikrotiterplattenbiofilmmodell, kaltes Atmosphärendruckplasma, Argonplasma, kinpen09
Hintergrund: Psychiatrische Institutsambulanzen (PIA) sind in Deutschland inzwischen weit verbreitet, deren Nutzen für gerontopsychiatrische Patienten jedoch wenig untersucht. Methoden: In einem Prä-Post-Studiendesign werden Effekte durch die PIA-Behandlung hinsichtlich Hospitalisierung, Polypharmazie und Effizienz analysiert. Datengrundlage sind retrospektiv erhobene Routinedaten der Jahre 2003 bis 2006 von 114 im Jahr 2006 durch die PIA Stralsund behandelten Altenheimbewohnern. Ergebnisse: Für Patienten ohne stationäre Voraufenthalte während der dreijährigen Präphase vor Behandlung durch die PIA und Heimbewohner mit geringem stationärem Behandlungsbedarf finden sich keine signifikanten Ergebnisse. Bei Patienten mit hohem Behandlungsbedarf (heavy-user) ist hinsichtlich der Hospitalisierungsdauer- und Häufigkeit eine Reduktion um durchschnittlich 50 Tage (83%) bzw. 2 Aufenthalte (69%) festzustellen. Auch ist für diese Patientengruppe eine Effizienzsteigerung in Höhe von mehr als 10.000€ pro Patient und Jahr nachweisbar. Es wird für keine der drei Patientengruppen eine Abschwächung des zuvor beobachteten Trends zunehmender Verschreibung somatischer und psychiatrischer Arzneimittel gefunden. Diskussion und Schlussfolgerung: Heavy user profitieren von der aufsuchenden und multiprofessionellen Behandlung der PIA, für weitere Heimbewohner deutet sich die Behebung einer bisherigen Unterversorgung an. Insbesondere für jüngere Patienten und langjährige Heimbewohner scheint eine Reduktion der Polypharmazie möglich. Für beide Aspekte sind weiterführende Untersuchungen notwendig.
Die häufigste Erblindungsursache weltweit ist die Katarakt. Etwa 85% der betroffenen Menschen leben in den Ländern der Dritten Welt. Durch eine zunehmende Trübung der Augenlinse verlieren die Patienten ständig an Sehkraft bis sie vollständig erblinden. Die Möglichkeit zur Behandlung der Katarakt besteht in einer Operation, bei der die eigene trübe Linse entfernt und an deren Stelle eine Kunstlinse implantiert wird. In dieser Studie wurden zwei etablierte OP Verfahren, die Small Incision Cataract Surgery und die Phakoemulsifikation unter den Bedingungen eines ambulanten EyeCamps evaluiert. Die SICS stellt derzeit den besten Kompromiss der Kataraktchirurgie in der Dritten Welt dar, da sie ohne komplizierte technische Hilfsmittel auskommt, kostengünstig in der Durchführung ist und sehr gute postoperative Ergebnisse bietet. Die Phakoemulsifikation ist die verbreiteteste Methode in den Industrienationen. Sie bietet ebenfalls sehr gute postoperative Ergebnisse, ist aber auch technisch sehr anspruchsvoll und in den OP Kosten deutlich teurer als die anderen OP Techniken. Im Zeitraum von vier Tagen wurden 117 Patienten am Grauen Star operiert. Das Geschlechterverhältnis lag bei 57 Frauen (48,7%) zu 60 Männern (51,3%). Das Durchschnittsalter der Patienten betrug 69,84 Jahre. Es wurde an 72 rechten Augen (61,5%) und 45 linken Augen (38,5%) operiert. Mit SICS Technik wurden 65 Patienten (55,6%) behandelt. Eine Phakoemulsifikation erfolgte bei 52 Patienten (44,4%). Beide OP Verfahren waren bezüglich des postoperativen Sehvermögens gleich. Bei der Phakoemulsifikation betrug der gemittelte Durchschnittsvisus 0,37, bei der SICS 0,32. Statistisch bestand kein signifikanter Unterschied p=0,196. Im Bezug auf intra- und postoperative Komplikationen traten bei der Phakoemulsifikation vermehrt Zonulolysen (n=6:1) auf, was jedoch auch auf den höheren Anteil an Patienten mit Pseudoexfoliationssyndrom (n=5:1) zurückzuführen sein könnte. Weiterhin wurden mehr postoperative Keratopathien bei der Phakoemulsifikation beobachtet (n=14:5). Kapselrupturen traten in beiden Gruppen etwa gleich häufig auf (n=3:2). Insgesamt konnte gezeigt werden, dass durch die technische Weiterentwicklung in der Phakoemulsifikation ( Oertli Catarhex© Phakomaschine und die EasyPhaco© Tips) auch unter den Bedingungen der Dritten Welt gleichwertige Ergebnisse erzielt werden können wie mit der Small Incision Cataract Surgery.