OPUS 4 | Universitätspublikationen

Dynamic nuclear polarization for magnetic resonance imaging : an in-bore approach (2012)

Jan G. Krummenacker

Nuclear Magnetic Resonance ("NMR") is a powerful and versatile technique relying on nuclei that posses a spin. Since its discovery more than 6 decades ago, NMR and related techniques has become a tool with innumerable applications throughout the fields of Physics, Chemistry, Biology and Medicine. Numerous Nobel Prizes have been awarded for work in the field and a multi billion dollar industry has developed on its basis. One of NMR's major shortcomings is its inherent lack of sensitivity. Because it relies on the Boltzmann populations of spin states with a minuscule Zeeman splitting, this is particularly true for room temperature experiments. As a result, in an enormous technological effort to enlarge the Zeeman splitting NMR magnets have been moving to higher and higher magnetic fields. However, even for proton spins possessing the largest magnetic moment of all nuclei, the degree of polarization that can be achieved in the strongest spectroscopic magnets available today (~24 T) at room temperature is merely ~ 8*(10 exp (-5)). In other words, this low polarization theoretically allows a sensitivity enhancement of 104 towards full polarization. Since Magnetic Resonance Imaging ("MRI") is based on the same principle, it shares this problem with NMR. Furthermore, for technical and physiological reasons full body MRI tomographs do not reach the magnetic field strengths of spectroscopic NMR magnets, making this even more of an issue for MRI. In consequence, MRI is chiefly restricted to detecting protons, while both MRI and NMR detection of 13C (or other low nuclei) under physiological conditions, i.e. low natural abundance of 13C and a low concentration of the respective substance, suffer from long acquisitions times that are necessary to obtain adequate signal to noise ratios ("SNR"). However, this drawback of NMR can be overcome. The enormous potential sensitivity increase of four orders of magnitude can - at least partially - be exploited by several hyperpolarization techniques, creating entirely new applications and fields of research. These hyperpolarization techniques comprise chemical approaches like Parahydrogen Induced Polarization ("PHIP") or Photochemically Induced Dynamic Nuclear Polarization ("Photo-CIDNP"), as well as physical techniques like optically pumped (noble) gases13, 14 or Dynamic Nuclear Polarization ("DNP"), which will be the focus of this work. A hyperpolarized substance will render a larger signal without being physically or chemically altered in any other way. It is therefore "marked" without any marker, making it an agent free contrast agent for MRI. DNP is a technique, in which hyperpolarization of nuclear spins is achieved by microwave (\MW") irradiation of unpaired electron spins in radicals, which are coupled to these nuclei, e.g. 1H, 13C or 15N. The electron spin population is perturbed if the microwave irradiation is resonant with the electron spin transition, which affects the polarization of hyperfine-coupled close nuclei. For large microwave power (i.e. saturating the electron spin transition) the orders of magnitude larger thermal electron spin polarization is effectively transferred to these nuclear spins in the sample. For proton spins the maximum polarization gain amounts to 660, whereas for 13C the sensitivity gain can be as large as 2600. In contrast to e.g. PHIP, which is restricted to specific reaction precursors, DNP is not limited to specific nuclei or hyperpolarization target molecules, making it a very versatile technique. DNP has been first proposed by Overhauser in 1953,15 and experimentally observed shortly thereafter in metals16 and liquids,17 both being systems with mobile electrons. In the 1960s and 70s, DNP was used as a spectroscopic tool in liquids, thoroughly mapping the effect in the low field regime. As well, several other transfer mechanisms were discovered, which are active in the solid state with localized electrons, namely the solid effect the cross effect and thermal mixing. The theory for all three of these mechanisms predicts reduced transfer efficiencies at higher magnetic fields. This fact and the lack of high frequency microwave sources to excite electron spins at magnetic field strengths above 1 T, effectively relegated DNP to a position of an interesting scientifi curiosity. In the early 1990s, DNP came to a renaissance, when DNP was performed at high field in solid state magic angle spinning ("MAS") experiments using high power gyrotron microwave sources. This pioneering work sparked a surge of new developments and applications. As well, this success triggered attempts to investigate also the potential of DNP in the liquid state at high magnetic fields, e.g. at 3.4 T35{38 and 9.2 T. To date, DNP can be considered one of the "hot topics" in the field of magnetic resonance, bringing about special issue in magnetic resonance journals and DNP sections on magnetic resonance conferences. This thesis deals with the development of an in-bore liquid state DNP polarizer for MRI applications operating in ow through mode at a magnetic field strength of 1.5 T. Following this introductory chapter, the theoretical background necessary to understand and interpret the experimental results is explained in chapter 2. Subsequently, chapter 3 deals with the issue of performing liquid state DNP at high magnetic fields and its challenges. The chapter comprises a quick overview of the necessary hardware, the experimental findings for various samples and the interpretation of these findings. along with the ramifications for the aim of this work. Chapter 4 deals with the issue of increasing sensitivity and contrast in MRI, in particular by means of DNP. The chapter illustrates the development of our polarizer by presenting the hardware that was developed and demonstrating its performance under various conditions. As well, several alternative approaches are introduced and compared to our approach. Finally, chapter 5 summarizes the findings and gives an outlook on further developments.

Von Sklavenhändlern zu Seelenfängern: Afrikanische Studenten in Großbritannien 1750 - 1830 (2012)

Esther Mirjam Ries

Die Geschichte von Sklavenhandel und Sklaverei im britischen Einflussgebiet ist in den letzten Jahrzehnten intensiv behandelt worden. Dabei ging es in der öffentlichen Wahrnehmung um das – nicht zuletzt ‚erinnerungspolitische‘ – Problem der Verstrickung britischer Kaufleute und Politiker in den Sklavenhandel, um die Bedeutung der Sklaverei für die britische Wirtschaft und den britischen Aufstieg zur Weltmacht, schließlich um die Motive der Pionierrolle, welche die britische Öffentlichkeit und die britische Regierung für die Kritik an und die Abschaffung von Sklavenhandel und Sklaverei einnahmen. Die vorliegende Dissertation nimmt sich vor, das Bild zu ergänzen, in dem sie nach einer nur auf den ersten Blick marginalen Gruppe fragt: Afrikanerinnen und Afrikanern, die sich weder auf ‚Staatsbesuch‘ noch als Arbeitskräfte in Großbritannien aufhielten, sondern die danach strebten, in England eine britische bzw. europäische Bildung zu erhalten. Die Gruppe erscheint Ries aus zwei Gründen besonders signifikant: Zum einen, weil sie eine entscheidende Funktion für ‚Kulturkontakte‘ zwischen Großbritannien und Afrika hatte, da sie möglicherweise dazu beitragen konnte, britische Bilder und Perzeptionen von Afrika und Afrikanern in anderer Weise zu prägen, als Sklaven oder lokale Potentaten; zum anderen, weil sie die Möglichkeit bietet, die Veränderungen der Haltung(en) der britischen Öffentlichkeit im Allgemeinen und besonders an Afrika interessierter Gruppen im Besonderen abseits der (bereits hinreichend erforschten) Debatten zum Sklavenhandel genauer zu untersuchen.

Hindu class and Hindu education system in Bali: Emergence, organization, and conception in the context of Indonesian educational and religious policies (2012)

Alexandra Landmann

The present study focuses on specific aspects in the organization of teaching religion in Indonesia. It analyses the position of religion within the Indonesian Basic Law, consequential legislation, and educational policies. How does this framework translate into national and regional policies pertaining to the emergence, institutionalization, and organization of the Hindu class and the Hindu education system in Bali from 1945 to 2008? Muslim majority Indonesia constitutes an interesting laboratory for doing fundamental research on religious plurality and transformations of religion. The model of organizing the religion class in Indonesia is rooted in a specific historical, socio-cultural, political, and legal context, which is fundamentally different to European models of religious education. In addition, in contrast to classical Islam and modern Islamic states, Indonesia recognizes Asian religions as equal in status with the religions of the book. Besides Islam and Christianity, Hindu Dharma and Buddhism were recognized as state funded religions in 1965. This recognition had important consequences for the Indonesian model of organizing five confessional religion classes and faith-based education systems. The Balinese are a rare case of a religious and ethnic minority being simultaneously an ethnic and religious majority. Therefore, the Balinese provide an outstanding case to analyze how Indonesia’s religious and educational policies do deal with that particular ethnic and religious minority. In addition, how do the Balinese themselves use the constitutional and legal framework to establish the Hindu religion class in public schools and a private Hindu education system from the level of pre-school to higher education? A qualitative examination was conducted basing on a combination of theoretical and empirical investigations. The province of Bali and three educational institutions were chosen, because the Balinese were the reformers of Indonesian Hindu Dharma and the inventors of the Hindu education system. As the study focuses on constitutional and legal contexts of the Hindu class and the Hindu education system, teachers’ professional education, and composition of curricula and textbooks, a qualitative approach was applied combining ethnographic fieldwork and case study research. In consequence, the subject positions the study in the academic disciplines of Religious Studies and Area Studies. Data were collected through bibliographical surveys and fieldwork. The amended 1945 Basic Law and consequential legislation give the same right to state sanctioned religions. The state is based on “One Supreme Lordship” prescribing national monotheism or monism. Indonesia’s spirited statehood is based on a religious, but not confessional interpretation. In addition, the strategy to manage religious plurality is authoritarian, as positive freedom of religion is limited to six state-funded religions, whereas negative religious freedom is not provided for. Despite the equal status of the six state funded religions, discriminative practices prevail with regard to funding those Asian religions. Notwithstanding, the Muslim majority Pancasila state can serve a model function for countries with illiberal politics in the Muslim world. The first objective of strategic and educational policies is to mould a citizen who has faith in God, follows the commands of God, and has morals. The dimension of spiritual intelligence in education is a particular Indonesian dimension of education, which Indonesian educational planners added to the UNESCO standards of student-centered learning throughout life. Indonesia organizes the religion class and faith-based education systems in a confessional but pluralistic style. The citizens are required to attend the religious class in the religion they adhere to instructed by a teacher of the same belief from elementary to higher education. In addition, the religious mark is a compulsory item in the school report, and whether a pupil/student stays back or is promoted to the next level depends, amongst other factors, on how the religion teacher grades the student. Unlike the Muslim or Christian based education systems, the Hindu education system is still marginal and minuscule. Its funding is discriminative. Funding and expansion are linked to national policies, and the personal networks of Hindu agents are given the mandate to organize the Hindu administration and education system.

Konsumentinnen illegaler Drogen in Deutschland und den USA : eine explorative Vergleichsstudie zur Wirkung von Drogenpolitiken auf die Lage drogenkonsumierender Frauen (2012)

Christiane Bernard

Als Unterzeichnerstaaten der internationalen Drogenabkommen, deren Ausgestaltung maßgeblich durch die Vereinigten Staaten bestimmt wurde, ist die Drogenpolitik in Deutschland und den USA als Prohibitionspolitik verfasst. Dennoch bestehen zwischen beiden Ländern drogenpolitische Unterschiede, die aus einer tendenziellen „Emanzipierung“ Deutschlands vom US-amerikanischen Modell seit den 1990er Jahren resultieren: Während die USA weiterhin vor allem auf Punitivität setzen, wird in Deutschland verstärkt ein medizinischer und schadensreduzierender Ansatz verfolgt. Gegenstand der vorliegenden Studie ist eine komparative Analyse der Drogengebrauchssituation und Drogenkontrollpolitik in Deutschland und den USA, mit der genderbezogene Einblicke in die Wirkung differenter drogenpolitischer Ansätze gewonnen werden sollten. Das Erkenntnisinteresse richtete sich einerseits auf die sozialstrukturellen und drogenpolitischen Bedingungen und deren Auswirkungen auf den Umgang mit illegalen Substanzen und die hiermit assoziierten gesundheitlichen und sozialen Begleitfolgen. Andererseits sollten die Spezifika der in diese Strukturen eingebetteten Alltagswelten von kompulsiven Drogenkonsumentinnen der Straßenszenen in Frankfurt und New York untersucht werden. Das Forschungsdesign der Studie war methodenplural angelegt. Der quantitative Zugang erfolgte über eine Sekundäranalyse nationaler statistischer Daten, mit der soziale Indikatoren des Drogengebrauchs länder- und geschlechtervergleichend betrachtet wurden. Zudem wurden standardisierte Fragebogeninterviews mit Drogenkonsumierenden der Frankfurter Straßenszene geführt. Qualitative Ergebnisse wurden durch Leitfadeninterviews mit Heroinund/ oder Crackkonsumentinnen und eine Metaanalyse ethnographischer Forschungsarbeiten gewonnen. Ein zentrales Ergebnis der Untersuchung ist, dass sich der Drogengebrauch offenbar relativ unabhängig von der Drogenpolitik bzw. der Intensität der Repression entwickelt. Trotz der punitiveren Ausrichtung der US-amerikanischen Drogenpolitik ist der illegale Substanzkonsum dort wesentlich stärker verbreitet als in Deutschland. Gleichzeitig erzeugt die Prohibitionspolitik zahlreiche Problemlagen, die in den USA erneut gravierender ausfallen und sich in höheren Morbiditäts- und Mortalitätsraten und einer stärkeren Kriminalisierung von Drogenkonsumentinnen niederschlagen. Trotz der stärkeren Hinwendung zu einem gesundheitspolitischen Ansatz ist jedoch auch in Deutschland keine Entpönalisierung des Drogengebrauchs erkennbar. Eine verstärkt dem gesundheitspolitischen Ansatz folgende Drogenpolitik, die weiterhin unter dem Drogenverbot operiert, kann den durch die Prohibition entstehenden Schaden allenfalls mildern. So hat sich in Deutschland durch die modifizierte drogenpolitische Richtung zwar die gesundheitliche Situation von Drogenkonsumentinnen in Teilbereichen (v.a. rückläufige HIV- und Drogentodeszahlen) verbessert, das Grundproblem ihrer Kriminalisierung, sozialen Marginalisierung und Etikettierung aber bleibt. Konzepte einer Legalisierung und deren Begründungszusammenhänge müssen daher zukünftig verstärkt im gesellschaftlichen Diskurs platziert werden, um so eine Politik der Integration initiieren zu können.

Volumetric assessment of the therapeutic response of pediatric neuroblastoma (2012)

Ola Abdelmonem Hassan Ahmed

1 Purpose of the Study: The purpose of this retrospective study was to assess the volumetric changes of our institutional pediatric neuroblastoma in response to various therapeutic protocols. 2 Materials and Methods: A retrospective study was conducted on children with neuroblastoma from different anatomical locations including suprarenal, paraspinal, pelvic, mediastinal and cervical neuroblastoma primaries. These children underwent tumor-stage based therapeutic protocols in Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany, between January 1996 and July 2008. The study included 72 patients (44 males and 28 females). Patient demographics (age and gender), disease-related symptoms, laboratory results (tumor biomarkers including ferritin, neuron specific enolase, and urine catecholamine) and histopathological reports were collected from the electronic medical archiving system and subsequently analyzed. Patients were classified into following groups according the anatomical origin of the primary neuroblastoma into: 1) Suprarenal neuroblastoma Group: This group included patients with neuroblastoma arising from the suprarenal gland. This group composed of 54 patients with male to female ratio (32:22). 2) Paravertebral neuroblastoma Group: This group composed of 6 male patients. 3) Mediastinal neuroblastoma Group: This group included patients with mediastinal neuroblastoma and composed of 3 patients (1 male and 2 females). 4) Pelvic neuroblastoma Group: This group included patients with pelvic neuroblastoma and composed of 6 patients (3 males and 3 females). 5) Cervical neuroblastoma Group: This group included patients with cervical neuroblastoma and composed of 2 male patients. 3 Results: The mean volume of all suprarenal neuroblastoma group involved in the study before therapy was 176.62 cm3 (SD: 234.15) range: 239.4-968.9cm3. The mean initial volume of all suprarenal neuroblastoma group who underwent observation protocol was 86.0378 cm3 (SD: 114.44) range: 5.2-347.94cm3. Volumetric evaluation of suprarenal neuroblastoma following observation (Wait and See) protocol revealed continuous reduction of the tumor volumes in a statistically significant manner during the follow up periods up to 12 months with p value of less than 0.05. The volumetric changes afterwards were statistically insignificant. The mean initial volume of all suprarenal neuroblastoma group who underwent primary surgery protocol was 42.4 cm3 (SD: 28.5) range: 7.5-90cm3. Complete surgical resection of the tumor was not feasible in all lesions due to local tumor extension and / or infiltration with the associated risk of injury of nearby organs or structures. However statistical analysis of the volumetric changes in the successive follow up periods did not reveal statistical significance. Volumetric estimation of the tumor in the subsequent follow up periods revealed significant changes within the period first (3-9 month periods). The changes afterwards were statistically non significant. On the other hand, the mean initial volume of all suprarenal neuroblastoma group who underwent combined chemotherapy and Stem cell transplantation protocol only without surgical interference was 99.98cm3 (SD:46.2) range: 48.48-160.48 cm3. In this group the volumetric changes were variable and difference in volumes in follow up was statistically non significant during the follow up period. The mean initial volume of all abdominal paravertebral neuroblastoma group was 249.197cm3 (SD: 249.63) range: 9.6-934cm3. The mean initial volume of all pelvic neuroblastoma group was 118.88cm3 (SD: 50.61) range: 73.4-173.4cm3. The mean initial volume of all mediastinal neuroblastoma group was 189.7cm3 (SD: 139.057) range: 10.7-415 cm3. The mean initial volume of all cervical neuroblastoma group was 189.7cm3 (SD: 139.057) range: 10.7-415 cm3. The volumetric measurements in the corresponding follow up periods according to the therapeutic protocol of abdominal paravertebral neuroblastoma, pelvic neuroblastoma, mediastinal and cervical neuroblastoma revealed significant change in the tumor volume within the early 3-6 months from the initial therapy while subsequently the tumor volumetric changes were statistically non significant. 4 Conclusion: In conclusion, the role of MRI volumetry in the evaluation of tumor response is dependent on the risk adapted concept of neuroblastoma with the combination of different imaging modalities as well the therapeutic protocol. MRI Volumetry in addition to new protocols such as Whole-body imaging and 3D visualization techniques are gaining more importance and acceptance.

T cell receptor diversity prevents T cell leukemia, lymphoma development / von Nabil Saleh Ahmed Al-Ghaili (2010)

Nabil al- Ghaili

Gene therapy is a promising therapeutic strategy that emerged from the attractive idea of targeting therapy at the molecular level. For many patients who suffer from genetic and acquired diseases that cannot be effectively treated by conventional treatment approaches gene therapy remains a huge hope of cure in spite of the hurdles regarding efficacy and safety that need to be overcome. The development of efficient gene transfer vehicles, mainly retroviral vectors, led to the first successful gene therapy trial, to treat patients suffering from X-linked severe combined immunodeficiency syndrome (X-SCID) using gene modified stem cells (Hacein-Bey-Abina, Le Deist et al. 2002). Despite the success of this trial, it revealed the danger of retroviral insertional mutagenesis as a major adverse event of gene therapy using gene-modified stem cells (Hacein-Bey-Abina, von Kalle et al. 2003). In contrast to stem cells, T cells are relatively resistant to insertional mutagenesis and transformation even after transduction with potent oncogenes using retroviral vectors (Newrzela, Cornils et al. 2008). However, mature T cells can self-renew, proliferate and survive for long periods. These criteria are supposed to render T cells prone to transformation. Therefore, the questions of mature T cells transformability and the control mechanism limiting their transformation are still elusive.

Functional characterization of NOSTRIN in signal transduction and vascular development (2011)

Igor Kovačević

NOSTRIN belongs to the recently defined F-BAR protein family. F-BAR proteins are multi-domain proteins, which serve as adaptors between plasma membrane and cytoskeleton components in processes such as membrane protrusion formation, endocytosis and migration. NOSTRIN encompasses a F-BAR domain at the N-terminus, which mediates membrane association, followed by a HR1 motif and an intermediate domain (ID) domain in the middle, and a SH3 domain at the C-terminus. The domain architecture and ability to form oligomers enable NOSTRIN to coordinate several interaction partners namely dynamin, caveolin, N-WASP and endothelial nitric oxide synthase (eNOS) in the process of eNOS trafficking. In this context NOSTRIN was originally identified and hence termed eNOS traffick inducer. NOSTRIN is expressed in vascularized tissues (e.g. liver and lung) and in primary endothelial cells. Aims of the present work were (1) to investigate if NOSTRIN is involved in other processes besides eNOS trafficking, (2) to analyse the function of NOSTRIN in vivo through knockdown of NOSTRIN in developing zebrafish and (3) to study the consequences of the loss of NOSTRIN on signal transduction in a primary cell culture model derived from NOSTRIN knockout mice. To study the possible involvement of NOSTRIN in other processes besides eNOS trafficking a yeast two-hybrid screen was performed in which fibroblast growth factor receptor 1 (FGFR1) was identified as a putative novel interaction partner of NOSTRIN. In a series of yeast two-hybrid, pulldown and co-immunoprecipitation experiments the interaction between NOSTRIN and FGFR1 was confirmed to occur between endogenously expressed proteins and determined to be direct and to depend on the ID domain of NOSTRIN and the 130 C-terminal amino acid residues of FGFR1. FGFR1 is activated by binding of fibroblast growth factors (FGFs) and induces several different signal transduction pathways (e.g. MAPK and Akt pathway). Overexpression of NOSTRIN in HeLa cells specifically enhanced FGF2-dependent MAPK activation. Accordingly, depletion of NOSTRIN attenuated FGF2-dependent MAPK activation and did not affect FGF2-induced Akt activation. In summary, NOSTRIN has been identified as a novel interaction partner of FGFR1 involved in FGF2-dependent signal transduction. The morpholino oligonucleotide-mediated knockdown of NOSTRIN in developing zebrafish caused vascular leakage and irregular vascular patterning e.g. a loss of the proper trajectory of intersegmental vessel and interruptions of the dorsal longitudinal anastomotic vessel. The vascular phenotype was consistent upon use of two different morpholinos and could be rescued in a dose dependent manner by the injection of zebrafish NOSTRIN mRNA. Detailed analysis involving confocal and time lapse microscopy in zebrafish with endothelial specific expression of EGFP revealed that the knockdown of NOSTRIN impacts in vivo on the migration and morphology of endothelial tip cells and leads to a reduction of filopodia number and length. Additionally a NOSTRIN knockout mouse was generated. The analysis of FGFR1 signal transduction in primary mouse lung endothelial cells (MLECs) from NOSTRIN knockout and wild type mice revealed that FGF2-dependent MAPK activation was attenuated in MLECs isolated from NOSTRIN knockout mice when compared to MLECs isolated from wild type mice. The effect of NOSTRIN on FGF2-dependent signal transduction seems to be specific, since VEGF-induced MAPK activation was not affected in NOSTRIN knockout MLECs. The importance of NOSTRIN for FGF2 signal transduction in vivo is demonstrated by the greatly impaired angiogenic response to FGF2 in NOSTRIN knockout mice in matrigel plug assay. In a detailed biochemical analysis it was discovered that NOSTRIN interacts with the activated small GTPase Rac1 and that overexpression of NOSTRIN enhances Rac1 activation. Furthermore, the interactions of NOSTRIN with both Rac1 and its GEF Sos1 are required for NOSTRIN-mediated activation of Rac1. In accordance, activation of Rac1 was not detected upon FGF2 stimulation in NOSTRIN knockout MLECs. In conclusion, the present work describes a novel function of the F-BAR protein NOSTRIN in FGFR1 signal transduction. Data presented in this work demonstrate that NOSTRIN is required for the assembly of a complex consisting of FGFR1, Sos1 and Rac1 and subsequently for the FGF2-dependent activation of Rac1 in endothelial cells.

Islamischer Fundamentalismus in der Migration : eine biographie-analytische Untersuchung über die adoleszente Hinwendung türkisch-männlicher Migranten zum Islamismus in Deutschland (2011)

Erdem Özbek

Diversity, biogeography and conservation status of the Bromeliaceae in Panama and Costa Rica (2012)

Daniel Cáceres González

Religiöse Triebfedern des Rationalisierungsprozesses : individuelles und gemeinschaftliches Leben in einer hugenottischen Neusiedlung des 18. Jahrhunderts (2010)

Gudrun Petasch

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