Telomeres and telomerase in haematopoietic progenitors and bone marrow endothelial cells

In normal human somatic cells, the length of telomeres (chromosomal end structures) decreases with each cell division until reaching a critically short length, which halts cell proliferation and induces senescence. The enzyme telomerase, which functions to maintain telomeres at a length that is permissive for cell division, is expressed in approximately 85% of cancer cells and some stem and progenitor cells, including haematopoietic progenitor cells (HPCs), but not most other normal somatic cells. Previous investigations have demonstrated that ectopic expression of telomerase reverse transcriptase (hTERT) reconstitutes telomerase activity, resulting in telomere elongation in some normal human cell types. However, similar experiments performed in HPCs and endothelial cells have demonstrated a dissociation between the expression of telomerase activity and telomere lengthening. This thesis is focussed on further investigating telomerase-mediated telomere length regulation in HPCs and endothelial cells. Short telomeres in bone marrow and blood leukocytes are associated with the development of disorders linked to bone marrow failure. However, to date a relationship between telomere length and myeloid cell proliferative potential has not been demonstrated. In the current investigations, the telomere length and proliferative potential of 31 cord blood-derived HPCs was determined. Regression analysis revealed a significant correlation between mean telomere length and erythroid cell expansion, but not expansion of other myeloid lineage cells. Another novel finding was that telomerase activity was upregulated in lineage-committed CD34- erythroid cells that were positive for the erythroid-specific lineage marker glycophorin A. It was also functionally demonstrated that telomerase activity facilitates the maximum expansion of erythroid cells. To address the dissociation between telomerase activity and telomere maintenance in BMECs, a dominant negative mutant of the telomere binding protein TRF1, which functions to regulate telomere accessibility, was over-expressed in hTERT-transduced BMECs. These studies showed that telomere access, as well as oncogene expression and exposure to oxidative stress, contribute to telomere length regulation in BMECs. Overall, the results from these investigations demonstrate for the first time the functional significance of telomere length and telomerase activity in ex vivo expansion of erythroid cells, and provide novel insight to the molecular complexity of telomere length maintenance in endothelial cells

Safety and efficacy of high-dose intravenous iron carboxymaltose vs. iron sucrose for treatment of postpartum anemia

Objective: The purpose of this study is to compare the safety and efficacy of intravenous (IV) high-dose iron carboxymaltose (ICM) with iron sucrose (IS) for the treatment of postpartum anemia. Study design: We performed a retrospective cohort study with 210 anemic inpatient women in the postpartum period who received IV high-dose ICM (15 mg/kg; maximum, 1000 mg) or IS (2×200 mg), respectively. Safety and tolerability of both groups were compared on the basis of reported systemic and local adverse events. The cohorts were matched for baseline characteristics and their initial hemoglobin (Hb) values. The secondary endpoint included drug efficacy assessment by measurement of Hb level increase up to 8 days after treatment. Results: Rapid administration of high ICM doses was as well tolerated as IS with overall adverse events of 5% (ICM) vs. 6% (IS). The most common complaint was burning and pain at the injection site. ICM was as effective as IS in changing Hb levels from the baseline. There was no difference in the mean daily Hb increase between the groups. Women with severe anemia showed the most effective responsiveness. Conclusions: IV ICM is as safe as IS in the management of postpartum (IDA) iron deficiency anemia despite five times of higher dosage. Both drugs are effective and offer a rapid normalization of Hb after delivery. The single application of ICM shows advantages of lower incidence of side effects at the injection site, a shorter treatment period, and better patient complianc

Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose

Objective: Oral iron substitution has shown to be insufficient for treatment of severe iron deficiency anemia in pregnancy. Ferric carboxymaltose is a new intravenous (i.v.) iron formulation promising to be more effective and as safe as iron sucrose. We aimed to assess side effects and tolerance of ferric carboxymaltose compared to i.v. iron sucrose in pregnant women. Methods: We performed a retrospective analysis of 206 pregnant women who were treated either with ferric carboxymaltose or iron sucrose for iron-deficiency anemia with intolerability to oral iron substitution, or insufficient hemoglobin increase after oral iron treatment, or need for rapid hemoglobin reconstitution. Primary endpoint was to evaluate the maternal safety and tolerability. Secondary endpoint was to assess efficacy of the treatment and exclude safety concerns for the fetus. Results: The incidence of drug-related adverse events was low and mostly mild in both groups. Mild adverse events occurred in 7.8% for ferric carboxymaltose and in 10.7% for iron sucrose. The mean rise of hemoglobin value was 15.4 g/L for ferric carboxymaltose and 11.7 g/L for iron sucrose. Conclusion: Ferric carboxymaltose administration in pregnant women is well tolerated and is not associated with any relevant clinical safety concerns. Ferric carboxymaltose has a comparable safety profile to iron sucrose but offers the advantage of a much higher iron dosage at a time reducing the need for repeated applications and increasing patients' comfort. Ferric carboxymaltose is the drug of choice, if i.v. iron treatment becomes necessary in the second or third trimester of pregnanc

Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative

Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases

Social capital, social inclusion and changing school contexts: a Scottish perspective

This paper synthesises a collaborative review of social capital theory, with particular regard for its relevance to the changing educational landscape within Scotland. The review considers the common and distinctive elements of social capital, developed by the founding fathers – Putnam, Bourdieu and Coleman – and explores how these might help to understand the changing contexts and pursue opportunities for growth

Beyond outputs: pathways to symmetrical evaluations of university sustainable development partnerships

As the United Nations Decade of Education for Sustainable Development (2005–2014) draws to a close, it is timely to review ways in which the sustainable development initiatives of higher education institutions have been, and can be, evaluated. In their efforts to document and assess collaborative sustainable development program outcomes and impacts, universities in the North and South are challenged by similar conundrums that confront development agencies. This article explores pathways to symmetrical evaluations of transnationally partnered research, curricula, and public-outreach initiatives specifically devoted to sustainable development. Drawing on extensive literature and informed by international development experience, the authors present a novel framework for evaluating transnational higher education partnerships devoted to sustainable development that addresses design, management, capacity building, and institutional outreach. The framework is applied by assessing several full-term African higher education evaluation case studies with a view toward identifying key limitations and suggesting useful future symmetrical evaluation pathways. University participants in transnational sustainable development initiatives, and their supporting donors, would be well-served by utilizing an inclusive evaluation framework that is infused with principles of symmetry

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future

Szenarienbasierte Bewertung von Data Warehouses in der Cloud

Data Warehouses bieten Unternehmen Einblicke aus verschiedenen Perspektiven und Zeithorizonten für die Analyse ihrer Daten. Dies soll datengetriebene Entscheidungsfindung ermöglichen. Solche Systeme sind strukturelle Datenlager, welche bestimmte Richtlinien befolgen. Sie ermöglichen flexible und schnelle Auswertung von großen Datenmengen ermöglichen. Es gibt eine Menge DataWarehouse Systeme, die sich in allen möglichen Formen unterscheiden. Angefangen bei unterschiedlichen Architekturen bis hin zur Infrastruktur. Unternehmen stehen vor einer wichtigen Entscheidung, welches Data Warehouse am Besten zu ihnen passt. Zur begründeten Entscheidungsfindung wird in dieser Arbeit geforscht. Es wird ein Überblick über bestehende Data Warehouses verschafft und zwei cloudbasierte Lösungen ausgewählt. Es folgt ein konzeptueller Vergleich, zwischen der traditionellen und der cloudbasierten Lösung. Anschließend folgt ein Vergleich zweier cloudbasierter Lösungen. Beide Lösungen werden aufgesetzt und im Anschluss wird eine Nutzwertanalyse durchgeführt. Abschließend wird ein Experteninterview gehalten, welches Ergebnisse bestätigen oder widersprechen soll. Als Ergebnis können bestimmte Data Warehouses bestimmten Unternehmen begründet empfohlen werden.Data warehouses provide companies with insights from different perspectives and time horizons for analyzing their data. This is to enable data-driven decision making. Such systems are structural data storages that follow specific guidelines. They enable flexible and fast analysis of large amounts of data. There are a lot of data warehouse systems, which differ in all possible forms. Starting with different architectures and ending with infrastructure. Companies are faced with an important decision, which data warehouse suits them best. To make a well-founded decision, research is done in this thesis. An overview of existing data warehouses is provided and two cloud-based solutions are selected. This is followed by a conceptual comparison, between the traditional and cloud-based solution. Right after, a comparison of two cloud-based solutions is conducted. Both solutions are set up and then a utility analysis is performed. Finally, an expert interview is held to confirm or contradict results. As a result, certain data warehouses can be justifiably recommended to certain companies

Sectio caesarea: Aktuelle Kontroversen

Caesarean section is one of the most frequently performed operations in human medicine. It has become a routine procedure with a very low morbidity and mortality. Over the centuries, it has emerged an essential achievement in obstetric medicine. In the presence of cephalo-pelvic-disproportion, cervical dystocia, malpresentation, preterm birth, macrosomia, placental insufficiency, placenta praevia or fetal distress it is crucial to improve the perinatal morbiditiy and mortality of mother and child. The procedure has become much more frequent over the past 20 years for multiple reasons. There is variety in incidence between countries but also regional differences. It's occurrence is being influenced by level of education and socio-economic status of the pregnant woman. In the meantime, also the longterm consequences of cesarean section are well known. The potential hazards for future pregnancies and deliveries are well described. Actual controversy addresses cesarean section on demand without any medical indication, which in fact is only seldom performed in Switzerland. The ethical justification of this procedure needs to be discussed in view of the current tendency towards autonomy and self-determination of the pregnant woman.Der Kaiserschnitt zählt zu den häufigsten Eingriffen in der Humanmedizin und ist zu einer „Routineoperation“ mit sehr geringer Morbidität und Mortalität geworden. Er zählt zu den zentralen Errungenschaften der modernen Geburtsmedizin. Bei medizinischen Indikationen wie Lageanomalien, Planzenta prävia, Kopf-Becken-Missverhältnis mit oder ohne Wehenschwäche in der Eröffnungsperiode oder „fetal distress“ ist er eine unverzichtbare Maßnahme zur Verbesserung des perinatalen outcome von Mutter und Kind. Die Häufigkeit der Sectio-Entbindung ist in den letzten 20 Jahren weltweit deutlich angestiegen, was vielfältige Ursachen hat. Es bestehen Unterschiede zwischen Ländern, aber auch zwischen verschiedenen Regionen, insbesondere im Sinne eines Stadt-Land-Gefälles. Die Sectio-Häufigkeit wird wesentlich beeinflusst durch den Bildungsgrad und den sozioökonomischen Status der Frau. Inzwischen sind auch mögliche nachteiligen Folgen der Kaiserschnittentbindung und ihre potentiellen Auswirkungen auf Folgeschwangerschaften und Folgegeburten bestens bekannt und untersucht. Aktuelle Kontroversen drehen sich insbesondere um den Kaiserschnitt auf Wunsch ohne medizinische Indikation, welcher allerdings in der Schweiz eher selten durchgeführt wird und dessen ethische Berechtigung im Rahmen der Selbstbestimmung und Autonomie der schwangeren Frau diskutiert werden muss