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Utrecht, Netherlands

Pouwels S.,University Utrecht | De Boer A.,University Utrecht | Javaid M.K.,University of Oxford | Hilton-Jones D.,University of Oxford | And 8 more authors.
Osteoporosis International

The aim of this study was to evaluate fracture risk after onset of myasthenia gravis using the UK General Practice Research Database. Overall fracture risk is not statistically increased compared with age- and gender-matched controls irrespective of glucocorticoid use, but was increased in those using antidepressants, anxiolytics or anticonvulsants. Introduction: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. The aim of this study was to evaluate the risk of fracture after onset of MG. Methods: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2009). Each MG patient was matched by age, sex, calendar time and practice to up to six patients without a history of MG and we identified all fractures and those associated with osteoporosis. Results: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure. However, fracture risk was higher in patients with MG prescribed antidepressants (AHR 3.27 [95 % CI, 1.63-6.55]), anxiolytics (AHR 2.18 [95 % CI, 1.04-4.57]) and anticonvulsants (AHR 6.88 [95 % CI, 2.91-16.27]). Conclusion: Overall risk of fracture in patients with MG is not statistically increased compared with age- and gender-matched controls irrespective of glucocorticoid use but was increased in those using antidepressants, anxiolytics or anticonvulsants. These findings have implications in strategies preserving bone health in patients with MG. © 2012 The Author(s). Source

Vader P.,University Utrecht | Vader P.,Universiteitsweg 99 | Van Der Aa L.J.,University of Twente | Engbersen J.F.J.,University of Twente | And 2 more authors.
Pharmaceutical Research

Purpose: Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity. Methods: We report the synthesis of a new PEGylated polymer based on biodegradable poly(amido amine)s with disulfide linkages in the backbone. Various amounts of PEGylated polymers were mixed with their unPEGylated counterparts prior to polyplex formation to alter PEG content in the final complex. Results: PEGylation effectively decreased polyplex surface charge, salt- or serum-induced aggregation and interaction with erythrocytes. Increasing amount of PEG in formulation also reduced its stability against heparin displacement, cellular uptake and subsequent silencing efficiency. Yet, for polyplexes with high PEG content, significant gene silencing efficacy was found, which was combined with almost no toxicity. Conclusions: PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery in vivo. © The Author(s) 2011. Source

Fong H.,California Institute of Technology | Moret M.-E.,California Institute of Technology | Moret M.-E.,Universiteitsweg 99 | Lee Y.,California Institute of Technology | And 2 more authors.

Reversible, heterolytic addition of H2 across an iron-boron bond in a ferraboratrane with formal hydride transfer to the boron gives iron-borohydrido-hydride complexes. These compounds catalyze the hydrogenation of alkenes and alkynes to the respective alkanes. Notably, the boron is capable of acting as a shuttle for hydride transfer to substrates. The results are interesting in the context of heterolytic substrate addition across metal-boron bonds in metallaboratranes and related systems, as well as metal-ligand bifunctional catalysis. © 2013 American Chemical Society. Source

Huis In 'T Veld R.,Universiteitsweg 99 | Huis In 'T Veld R.,University Utrecht | Storm G.,Universiteitsweg 99 | Hennink W.E.,Universiteitsweg 99 | And 3 more authors.

Macromolecular carrier materials based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized drug delivery systems that have been extensively evaluated in the past two decades, both at the preclinical and at the clinical level. Using several different imaging agents and techniques, HPMA copolymers have been shown to circulate for prolonged periods of time, and to accumulate in tumors both effectively and selectively by means of the Enhanced Permeability and Retention (EPR) effect. Because of this, HPMA-based macromolecular nanotheranostics, i.e. formulations containing both drug and imaging agents within a single formulation, have been shown to be highly effective in inducing tumor growth inhibition in animal models. In patients, however, as essentially all other tumor-targeted nanomedicines, they are generally only able to improve the therapeutic index of the attached active agent by lowering its toxicity, and they fail to improve the efficacy of the intervention. Bearing this in mind, we have recently reasoned that because of their biocompatibility and their beneficial biodistribution, nanomedicine formulations might be highly suitable systems for combination therapies. In the present manuscript, we briefly summarize several exemplary efforts undertaken in this regard in our labs in the past couple of years, and we show that long-circulating and passively tumor-targeted macromolecular nanotheranostics can be used to improve the efficacy of radiochemotherapy and of chemotherapy combinations. © 2011 The Royal Society of Chemistry. Source

Yousefi A.,Universiteitsweg 99 | Storm G.,Universiteitsweg 99 | Schiffelers R.,University Utrecht | Mastrobattista E.,Universiteitsweg 99
Journal of Controlled Release

Delivery of nucleic acids to tumors has received extensive attention in the past few decades since these molecules are capable of treating disease by modulating the source of abnormalities. Although high efficiency and low toxicity of numerous delivery systems for nucleic acids have been approved frequently with in vitro assays, contradictions have been observed in many cases between these results and what has occurred in the dynamic in vivo situation. Filling this gap seems to be crucial for further preclinical development of such systems. In this paper, we discuss various barriers which polymeric DNA or siRNA nanoparticles encounter upon systemic administration with an aim to assist in designing more relevant in vitro assays. Furthermore, individual considerations concerning delivery of DNA and siRNA have been addressed. © 2013 Published by Elsevier B.V. Source

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