Multi-Parameter Analysis of Biobanked Human Bone Marrow Stromal Cells Shows Little Influence for Donor Age and Mild Comorbidities on Phenotypic and Functional Properties

Heterogeneous populations of human bone marrow-derived stromal cells (BMSC) are among the most frequently tested cellular therapeutics for treating degenerative and immune disorders, which occur predominantly in the aging population. Currently, it is unclear whether advanced donor age and commonly associated comorbidities affect the properties of ex vivo-expanded BMSCs. Thus, we stratified cells from adult and elderly donors from our biobank (n = 10 and n = 13, mean age 38 and 72 years, respectively) and compared their phenotypic and functional performance, using multiple assays typically employed as minimal criteria for defining multipotent mesenchymal stromal cells (MSCs). We found that BMSCs from both cohorts meet the standard criteria for MSC, exhibiting similar morphology, growth kinetics, gene expression profiles, and pro-angiogenic and immunosuppressive potential and the capacity to differentiate toward adipogenic, chondrogenic, and osteogenic lineages. We found no substantial differences between cells from the adult and elderly cohorts. As positive controls, we studied the impact of in vitro aging and inflammatory cytokine stimulation. Both conditions clearly affected the cellular properties, independent of donor age. We conclude that in vitro aging rather than in vivo donor aging influences BMSC characteristics

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Search for anomalous production of events with three or more leptons in pp collisions at √s = 8TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.A search for physics beyond the standard model in events with at least three leptons is presented. The data sample, corresponding to an integrated luminosity of 19.5fb-1 of proton-proton collisions with center-of-mass energy s=8TeV, was collected by the CMS experiment at the LHC during 2012. The data are divided into exclusive categories based on the number of leptons and their flavor, the presence or absence of an opposite-sign, same-flavor lepton pair (OSSF), the invariant mass of the OSSF pair, the presence or absence of a tagged bottom-quark jet, the number of identified hadronically decaying τ leptons, and the magnitude of the missing transverse energy and of the scalar sum of jet transverse momenta. The numbers of observed events are found to be consistent with the expected numbers from standard model processes, and limits are placed on new-physics scenarios that yield multilepton final states. In particular, scenarios that predict Higgs boson production in the context of supersymmetric decay chains are examined. We also place a 95% confidence level upper limit of 1.3% on the branching fraction for the decay of a top quark to a charm quark and a Higgs boson (t→cH), which translates to a bound on the left- and right-handed top-charm flavor-violating Higgs Yukawa couplings, λtcH and λctH, respectively, of |λtcH|2+|λctH|2<0.21

Measurement of associated W plus charm production in pp collisions at √s=7 TeV

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Synthetische Biomaterial-Mikroumgebungen zur Modulation von parakrinen Wirkungen von mesenchymalen Stromazellen zur Skelettmuskelregeneration

While skeletal muscles can recover from minor injuries, severe trauma can often induce irreversible structural damage such as extensive scar tissue formation and damaged muscle fibers. This leads to functional deficits and loss in the quality of life of patients. Effective treatment of severe muscle injuries is currently an unmet clinical need. In such cases, a therapeutic intervention such as cell transplantation can be beneficial. Mesenchymal stromal cells (MSCs) have gained wide attention in regenerative medicine, and have recently been explored in the context of muscle repair. The hypothesis guiding this thesis was that the paracrine effects of MSCs, by which they can influence the biological function of progenitor cells, can be enhanced by providing MSCs with appropriate microenvironments during transplantation. In this way, the paracrine function of MSCs can be harnessed to stimulate muscle progenitor cells function leading to muscle regeneration. Comparison of a series of substrates that differed in dimensionality and microstructure revealed that MSCs enhanced their secretion pattern after culture on 3D macroporous scaffolds. In response to MSC conditioned medium, muscle progenitor cells displayed improved proliferation, survival, migration, and differentiation behaviors. Interestingly, MSCs encapsulated in 3D nanoporous hydrogels elicited significantly weaker functional response in myoblasts. MSC paracrine effects depended on the establishment of N-cadherin mediated cell-cell contacts which was facilitated by the macroporous structure of 3D scaffolds, but inhibited by the nanoporous structure of 3D hydrogels. The ability of MSCs to respond to soluble cues was investigated via transient exposure to recombinant growth factors. MSCs in macroporous scaffolds upregulated their secretion pattern in response to growth factor stimulation. As a result, pro-regenerative myoblast functions were further enhanced. In comparison, encapsulated MSCs showed a much weaker response to growth factor stimulation. Thus, macroporous scaffolds constituted optimal microenvironments that could increase the ability of MSCs to induce muscle regeneration in a paracrine manner. Autologous MSCs were transplanted near severely injured muscle tissues using porous scaffolds that could provide a sustained, local release of stimulatory factors. From this synthetic niche, the MSCs stimulated muscle regeneration by promoting re-vascularization, muscle fiber formation, and remodeling scar tissue over time. These positive effects on structural regeneration led to restoration of functional strength in the treated muscles. This approach is an important example of enabling endogenous tissue regeneration without physical engraftment of transplanted cells, and can likely be adapted for the treatment of other injuries and diseases.Während minderschwere Verletzungen der Skelettmuskulatur sehr heilen, führen schwere Traumata zu irreversiblen strukturellen Beschädigungen, wie beispielsweise ausgedehnte Narbengewebsbildung und zerstörte Muskelfasern. Dies führt zu funktionellen Defiziten, welche die Lebensqualität des Patienten stark einschränken. Eine effektive Behandlung solcher schweren Muskelverletzungen ist gegenwertig enormer klinischer Bedarf. Mesenchymale Stromazellen (MSCs) haben große Aufmerksamkeit im Bereich der regenerativen Medizin geweckt und werden seit kurzem im Kontext der Muskelregeneration untersucht. Die Grundhypothese dieser Arbeit ist die Annahme, dass die parakrinen Effekte, über welche MSCs die biologischen Funktionen anderer Vorläuferzellen beeinflussen, durch eine geeignete Mikroumgebung während bzw. nach ihrer Translation verbessert werden kann. Dementsprechend könnte die parakrine Funktion von MSCs dazu genutzt werden Muskelvorläuferzellen zu stimulieren und so Muskelregeneration zu ermöglichen. Der Vergleich verschiedener Kultivierungsumgebungen, welche sich sowohl in ihrer Dimensionalität als auch in ihrer Mikrostruktur unterscheiden, zeigte dass die Kultivierung in einem 3D makroporösen Trägermaterial die Proteinsekretion von MSCs erhöht. Muskelvorläuferzellen zeigten eine verbesserte Proliferation, Vitalität, Migration und Differenzierung nach der Exposition zu konditioniertem Medium von MSCs. Interessanterweise, führte die Verkapselung von MSCs in einem 3D (nanoporösen) Hydrogel zu einer signifikant geringeren funktionellen Antwort der Myoblasten. Die parakrinen Effekte der MSCs hängen von der Ausbildung von N-Cadherin-vermittelten Zell-Zell-Kontakten ab, was durch die makroporöse Struktur der 3D Trägermaterialen ermöglicht wird, jedoch durch die nanoporöse Struktur der 3D Hydrogele unterbunden wird. Die Fähigkeit der MSCs auf lösliche Signale zu antworten, wurde mittels kurzzeitiger Exposition zu rekombinanten Wachstumsfaktoren untersucht. MSCs im makroporösen Trägermaterial erhöhten ihr allgemeines Sekretionsmuster in Folge dieser Stimulation und verbesserten dementsprechend auch die pro-regenerativen Funktionen der Myoblasten. Im Vergleich dazu zeigten MSCs im Hydrogel eine wesentlich geringere Antwort auf die Stimulation mit Wachstumsfaktoren. Folglich stellt das makroporöse Trägermaterial eine optimale Mikroumgebung dar, welche durch eine anhaltende Freisetzung von stimulierenden Wachstumsfaktoren, die Fähigkeit der MSCs erhöht die Muskelregeneration parakrin zu induzieren. Autologe MSCs in einem makroporösen Trägermaterial, welches die stimulierenden Wachstumsfaktoren konstant freisetzt, wurden anschließend in die Nähe von schwerverletztem Muskelgewebe transplantiert. Aus dieser synthetischen Nische heraus, stimulierten die MSCs die Muskelregeneration durch die Förderung der (Re-)Vaskularisation, der Bildung neuer Muskelfasern und dem Umbau von Narbengewebe. Diese positiven Effekte auf die strukturelle Regeneration führten zu einer Wiederherstellung der funktionellen Kraft der so behandelten Muskeln. Der beschriebene Ansatz ist ein wichtiges Beispiel für die Aktivierung endogener Geweberegeneration ohne die Notwendigkeit des physischen Einwachsens der transplantierten Zellen und kann sehr wahrscheinlich auch auf die Behandlung anderer Verletzungen und Krankheiten übertragen werden

Measurement of the tt¯ production cross section in the dilepton channel in pp collisions at s√ = 8 TeV

The top-antitop quark ( tt¯ ) production cross section is measured in proton-proton collisions at s√ = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb−1. The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 ± 2 (stat.) ± 11 (syst.) ± 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model