Preparation, Characterisation and Measurement of the in vitro Cytotoxicity of Mesoporous Silica Nanoparticles Loaded with Cytotoxic Pt(II) Oxadiazoline Complexes

Cytotoxic platinum compounds play a major role in the chemotherapy of a large number of human cancers. However, due to the severe side effects for the patient and other problems associated with their use, there is a need for the development of more efficient drugs and new methods for their selective delivery to the tumours. One way to achieve the latter could be in the use of nanoparticular carrier materials that can adsorb or chemically bind the drug. In the cell, the drug is supposed to be slowly released, either by physical desorption or by dissolution of the particle framework. Ideally, the cytotoxic properties of the platinum drug unfold only then, in the cancer cell and over a longer period of time due to the gradual release. In this paper, we report on our first steps in this direction. The binding properties of a series of cytotoxic Pt(II) oxadiazoline compounds to mesoporous silica particles has been studied by NMR and UV/vis spectroscopy. High loadings were achieved when the Pt(II) compound was relatively polar, and has been dissolved in a relatively unpolar solvent before the silica was added. Typically, 6-10 hours were required for complete equilibration, suggesting the adsorption did not only occur to the outer surface but also to the interior of the pores. The untreated and Pt(II) loaded particles were characterised by C,H,N combustion analysis, BET/BJH nitrogen sorption, electron microscopy (REM and TEM) and EDX. With the latter methods we were able to demonstrate the homogenous distribution of the Pt(II) compound on and in the silica particles, and no Pt(II) bulk precipitate had formed. The in vitro cytotoxicity in a human cancer cell line (HeLa) has been determined for one of the new platinum compounds adsorbed to mesoporous silica particles of different size, and compared with the corresponding compound in solution. The IC50 data are similar in all cases, suggesting that the release of the Pt(II) compound was relatively fast and possibly occurred before the particles reached the cells. Overall, the platinum drug is chemically stable on silica and retained its activity upon prolonged storage

Bio-psycho-social aspects of severe multiple trauma

Subjects with severe multiple trauma present great challenges in rehabilitation, and investigations with a holistic bio-psycho-social point of view have been scarce. In the main part of this investigation all 146 patients with severe multiple trauma (ISS 16) admitted to a regional hospital in 1990. were target. Ten years survival probability for those discharged alive from the Department of Surgery (fl: 91) was 82%. Mortality rates were significantly higher than those of the general population, particularly during the first year after discharge, during which the main cause of death was traumatic brain injury. Later, overuse of alcohol and drugs, were the main causes of death. A principal aim was to analyse the relations between impairments/ functions. disabilities/ abilities and psychological and social well-being. In a three year follow-up investigation of 69 subjects (84% of those available), 80% had one or more residual impairments: 74% had physical and 32°/g cognitive impairment. Very few subjects (n=4) were ADL-dependent. Vocational disability was present in 19% and leisure disability in 76%. Vocational disability was associated with higher age, blue collar work and cognitive impairment. Leisure disability was most prevalent in those with severe physical impairments and residual pain. Cognitive performance was significantly related both to the severity of traumatic brain injury and to degree of psychological distress. A consecutive series of subjects with severe multiple trauma without brain injury (n:26), were investigated at admission to the rehabilitation hospital, at discharge and at follow-up 1- 3.5 year following trauma. Both retrospectively and prospectively, the subjects experienced significant decreases in satisfaction with life as a whole from before to after trauma. Furthermore, compared to before trauma, significantly fewer subjects reported to be satisfied (5-6) with life as a whole, and with the domains: Sexual life. ADL, contact with friends, leisure, vocational situation and financial situation. Among the life satisfaction domains, the most important contributors for global life satisfaction after trauma. were satisfaction with leisure, family life and vocation. In multiple regression analyses, having a sufficient social network, and also a strong sense of coherence, could buffer the negative influence of disabilities on life satisfaction following trauma. Though level of sense of coherence was closely related to simultaneously measured social well-being, the SOC was not stable over time, and the hypothesis about a strong sense of coherence as protective against future distress and reduced satisfaction after stressful life events could not be confirmed, at least not the first years after multiple trauma

Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction

Substrates in large numbers are removed from the blood by the kidney in linear relationship to their arterial concentrations [1, 2]. At normal arterial blood levels, the kidney utilizes significant amounts of free fatty acids, lactate, glutamine, 3-hydroxybutyrate, and citrate. Furthermore, the kidney removes substrates like pyruvate, α-ketoglutarate, glycerol, proline, and some other amino acids of low arterial concentrations. However, when blood levels of these substances increase, their renal uptake rates likewise increase [1, 2]. Metabolic fates of these substrates in the kidney are related intimately to major functions of the kidney including excretion of waste materials, reabsorption of life conserving substances and water, and other important endocrine and metabolic functions.When studied in vitro, the capacity of renal tissue to take up substrates was shown to be far in excess of the rates occurring under in vivo conditions [2]. This indicates that saturation is not reached in vivo due to suboptimal substrate concentrations. For lactate, pyruvate, glutamine, proline, fatty acids, and ketone bodies, normal arterial levels are below or around the half-maximal concentration kinetically determined in in vitro uptake studies [3–8]. However, even under this nonsaturating condition, the rates of substrate uptake in vivo exceed the quantities of fuel needed to meet the energy demands of the kidney as calculated from oxygen uptake [1, 9]. Table 1 summarizes the calculated oxygen uptake and ATP formation rates for some substrates. From the theoretical and the experimental data on substrate uptake rates and measurements of oxygen consumption [1, 2], it becomes clear that the kidney takes up more substrates than could be accounted for by oxidation.The term “incomplete oxidation” was introduced by Cohen [1] to explain this phenomenon. For example, 3-hydroxybutyrate taken up by the kidney is partially released as acetoacetate [8]. On the other hand, no net product release was found for other substrates taken up in excess. From recent in vitro studies, it was concluded that the kidney can utilize substrates by metabolic pathways that do not lead to their oxidation [2–7]. Thus, lactate, glycerol, glutamine, and other substrates are in part converted to glucose through the gluconeogenic pathway, whereas fatty acids which cannot be converted to glucose are recovered mainly as triacylglycerol [5, 10].Two major questions may be raised at this point: (1) What nephron cells are responsible for the substrate uptake rates observed? (2) What are the mechanisms regulating intracellular interactions of various substrates?This review will briefly summarize some recent findings on intercellular heterogeneity and intracellular regulatory mechanisms that may help explain the metabolic balances observed in vivo

Understanding Project Survival In An Es Environment: A Practice Perspective

Modern organizations are increasingly choosing to adopt off-the-shelf software applications (e.g., Enterprise Systems, ES) rather than develop tailor-made solutions. However, many studies have shown that adopting prepackaged software is difficult with these large scale, highly integrated ES, amplifying the potential for organizational conflict – in part due to their embedding of external ‘best practices.’ Research has begun investigating the process by which these best practice designs are eventually resolved within the implementing organization. We contribute to this emerging literature by seeking to explore project survival – the turnaround process by which a troubled project at go-live becomes a working information system. Using data from an intensive qualitative field study, we argue that practices are negotiated through processes of use rather than being permanently and systematically selected during a particular moment in time. Thus, we find that project survival is achieved as an outcome of a continued process of negotiation in the post-implementation period

Einbindung Privater in den öffentlich-rechtlichen Abwägungsprozess bei Straßenprojekten

Diese Arbeit stellt im Zuge von Privatisierungsüberlegungen eine interdisziplinäre Verknüpfung öffentlicher und privater Leistungserbringung vor. Sie wählt ausgehend von öffentlicher Aufgabenerfüllung Abgrenzungen auf die Erarbeitung von Infrastruktur, auf die Erarbeitung von Bundesfernstraßen und beantwortet folgende Fragen anhand der Projektplanungsphase von Bundesfernstraßenprojekten: Wann darf privatisiert werden? Was wird privatisiert? Wie muss privatisiert werden? Die Vorgabe einer optimalen Entwicklungsrichtung für Privatisierung unter Beachtung der Fragestellung ‚von wem für wen vollzieht sich öffentliche Aufgabenerfüllung' durchdringt diese Untersuchung ebenso wie die scharfe Trennung von Wirtschaftlichkeit aus öffentlichem Betreiberinteresse und Wirtschaftlichkeit aus privatem Eigeninteresse. Der eingebundene Private wird auf der Grundlage interdisziplinärer Forschungsmethodik in Aneinanderreihung strikt aufeinander aufbauender Verfahren in die öffentliche Ausrichtung der Leistungserbringung bewegt. Dies erfolgt über die Zwischenschritte Eingrenzung der Vergabequantität, theoretische Normung der zu vergebenden Leistung und deren Komplexitätsbewertung, sowie ein auf systematische Beachtung aller betroffenen öffentlichen und privaten Interessen anreizendes Vergabeverfahren. Es entsteht eine Modellierung, die sich als Teil des Sozialkapitals auf eine von Gemeinwohlorientierung, Eigeninteressenfreiheit, Objektivität, Sparsamkeit und Wirtschaftlichkeit (§ 7 Abs. 1 BHO) geprägte Art und Weise für den Nutzer und Steuerzahler einsetzt. Diese Modellierung führt folgender Forschungsfrage einer Lösung zu: „Wie muss die Öffentliche Verwaltung vorgehen, um von einem egoistisch denkenden Privaten eine umfassend, eigeninteressenfrei, objektiv abgewogene Projektplanungsleistung unter gleichzeitiger Optimierung des wirtschaftlichen, öffentlichen Betreiberinteresses zu beschaffen?“ Den Erkenntnisfortschritt dieser Untersuchung schließt eine Stärken-Schwächen-Analyse ohne Anspruch auf exakte Beweisführung. Es werden sowohl Forschungsmethodik als auch erhaltene Ergebnisse innerhalb der vorab getroffenen Abgrenzungen Bundesfernstraßenprojekte, Infrastrukturprojekte sowie öffentlicher Aufgabenerfüllung auf ihre Übertragbarkeit jenseits des Untersuchungsgegenstandes angedacht. In Folge des interdisziplinären Blickwinkels dieser Arbeit entwickeln sich einhergehend vielfältige und sehr interessante Weiter-entwicklungsmöglichkeiten

Mononuclear Transition Metal Complexes of 7-Nitro-1,3,5-Triazaadamantane

This is the peer reviewed version of the following article: Wagner, G., Horton, P. N., & Coles, S. J. (2016). Mononuclear Transition Metal Complexes of 7-Nitro-1,3,5-Triazaadamantane. ChemistrySelect, 1(8), 1548-1555. DOI: 10.1002/slct.201600502, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/slct.201600502/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingComplexes of the type [MCl2(7-nitro-1,3,5-triaza-adamantane)2] (M = Zn(II), Pd(II), Pt(II)) and [MCl2(H2O)2(7-nitro-1,3,5-triazaadamantane) 2] (M = Mn (II), Co(II), Ni(II)) have been prepared and their structures have been analysed by X-ray crystallography, elemental analysis, IR and solid state 13C and 15N NMR spectroscopy, supported by density functional theory/ gauge independent atomic orbital (DFT/GIAO) calculations. In each case, 7-nitro-1,3,5-triazaadamantane acts as a mono-dentate ligand and binds to one metal centre only, in spite of the presence of three equivalent amino nitrogens. In the Co(II) and Ni(II) complexes, a two-dimensional intermolecular hydrogen bonding network between the aqua- and the chloro ligands is established. The uncoordinated amines of the 7-nitro-1,3,5-triaza- adamantane are not involved in any H-bonding, as a result of the exceptionally low basicity of this compound