101,473 research outputs found
Selbstregulierung und Fremdsteuerung in Medienkommunikation sowie subjektiver und sozialer Medienaneignung
No full textSutter T. Selbstregulierung und Fremdsteuerung in Medienkommunikation sowie subjektiver und sozialer Medienaneignung. In: Allmendinger J, ed. Entstaatlichung und soziale Sicherheit. Verhandlungen des 31. Kongresses der Deutschen Gesellschaft für Soziologie in Leipzig 2002. Verhandlungen des .. Kongresses der Deutschen Gesellschaft für Soziologie. Vol 31. Opladen: Leske + Budrich; 2003
Rheological investigation of manufacturability and injectability of highly concentrated monoclonal antibody formulations
No full textHighly concentrated protein therapeutics offer a convenient way for subcutaneous (sc) drug administration by the patient him-/herself or a healthcare professional. As the therapy e.g. with monoclonal antibodies requires quite high doses in the range of mg per kg body weight, the development of highly concentrated protein formulations is needed due to the limited injection volume, generally considered being 1 - 2 mL for sc administration. The development of highly concentrated formulations exceeding 50 - 100 mg/mL poses several challenges including chemical and physical stability (e.g. aggregation) as well as solution viscosity. Thereby, the increase in viscosity observed with higher protein concentration may cause severe limitations during product development as well as processing and drug administration. These limitations are defined by the flow rate/injection rate depending on the applied pressure which is needed during manufacture (fill-finish), in particular during filtration, and drug administration.
The focus of this work was to investigate the rheological behavior of protein solutions at high protein concentrations. The main objective was to obtain a profound understanding of two critical, hydrodynamic processes for highly concentrated protein solutions, which were drug administration and filtration, and to elucidate the role of viscosity with regard to potential limitations.
The current work provides a detailed overview on product characteristics of ten commercially available, highly concentrated protein therapeutics (Chapter 1). This technical overview summarizes formulation properties like viscosity and number of visible and sub-visible particles, physico-chemical properties like pH and osmolality as well as injection device characteristics, such as device dimensions. The analysis of marketed products revealed significant differences between the products. The current benchmark for maximum protein concentration and of viscosity was identified as a liquid formulation at a protein concentration of 200 mg/mL with a dynamic viscosity of 102 mPas (20? C). This product, which is provided in a pre-filled syringe, also exhibits the largest inner needle diameter of 25 G compared to other commercial products using 27 G needle for the injection device.
In the following (Chapter 2), advantages and limitations of different methods for viscosity determination of protein formulations are discussed. Moreover, a high-throughput method to measure viscosity was established. This method uses a capillary electrophoresis instrumentation without operation of the electrical field. The established method has the advantage of being automated offering the possibility for high-throughput by use of low sample amounts in the microliter range at the same time. (Allmendinger et al., J Pharm Biomed Anal, 99 (2014) 51-58)
Based on these studies, the present work investigated and characterized the subcutaneous drug administration process of highly concentrated protein formulations providing quantitative in vitro (Chapter 3) and in vivo data (G¨ottingen minipigs) of injection forces (Chapter 4).
Chapter 3 describes in detail the establishment of an in silico model to predict injection forces depending on syringe and needle dimensions, solution viscosity, and injection rate. Importantly, this model accounts for shear thinning behavior (non-Newtonian flow behavior) of highly concentrated protein olutions, which leads to lower effective injection forces than expected from current literature models. (Allmendinger et al., Eu J Pharm Biopharm, 87 (2014) 318-328)
To address the in vivo situation, Chapter 4 investigates and quantifies the contribution of the subcutaneous tissue backpressure and specifically reports the additional influence of body temperature on injection forces, which was found to compensate the tissue backpressure to some parts. Overall, an extended model, which addresses the injection force as a function of viscosity, volumetric flow/injection rate, needle/device dimensions, shear-thinning behavior, sc backpressure, and body temperature, was developed to predict injection forces representative for the in vivo situation. This knowledge is of key importance for the development of combination products (e.g. autoinjectors or pre-filled syringes) as a detailed understanding of injection forces depending on various parameters is required. It may be also supportive for the definition of limits during the evaluation, planning, and design phase during the development of injection devices. (Allmendinger et al., submitted to Pharm Research, 2014)
Besides drug administration, filtration was investigated as another critical hydrodynamic process for highly concentrated protein formulations, depending on formulation composition and filter material (Chapter 5). For both processes, filtration and drug administration, shear thinning behavior was found for some of the products depending on viscosity and protein concentration, shear rate, and formulation composition.
Within the present work it was shown, that the two investigated hydrodynamic processes, filtration and drug administration by injection, are two highly complex processes which are influenced by various factors. Thereby, the final limiting parameter for the injection process is given by the user capability of the patient population. However, the needle inner diameter was shown to have major influence on injection forces. It is related to injection forces by the power of four compared to other parameters like viscosity, injection rate, and contribution of sc backpressure being directly proportional. For the filtration process, the final limiting parameter may be discussed controversially. The study showed that the filtration pressure is mainly defined by the pore size distribution of the filter material, which was furthermore found to trigger the rheological behavior at high protein concentrations dependent on filtration rate. Moreover, literature data reported that the influence of filtration pressure on product quality might not be the limiting parameter during filtration. For the formulations previously tested, the shear stress exposure during manufacture was not considered important for final product quality, however only tested up to a protein concentration of 100 mg/mL. More important causes of aggregation were suggested to be the presence of air-bubbles, adsorption to solid surfaces, or contamination by particulates. Nevertheless, the stability of formulations showing pronounced shear-thinning behavior at high shear rates, which is most likely only the case for higher protein concentrations than previously tested, needs further experiments and has to be evaluated on a case-by-case basis dependent on product and process characteristics. (Allmendinger et al., submitted to J Pharm Sci, 2014)
With respect to viscosity, the current work has demonstrated for both processes, drug administration and filtration, that the potential limitation defined by the proportional increase in pressure based on Newtonian flow behavior was overestimated due to the presence of shear-thinning behavior which was shown for highly concentrated protein formulations
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Pelevin’s Trinity in the novel “t”: author – protagonist – reader
No full textThe article attempts to interpret Pelevin's artistic strategy in the novel "T" by exploring its subject organization and addressing the key problems of the author, the protagonist, and the reader as they are seen by the researcher. The article analyzes the peculiarities of constructing the narrative reality in the novel "T", and goes on to discuss Pelevin's philosophic models of the development of the humankind, and the emergence of his new anthropology
Measuring industry-science links through inventor-author relations: A profiling method
No full textIn this pilot study we examine the performance of text-based profiling in recovering a set of validated inventor-author links. In a first step we match patents and publications solely based on their similarity in content. Next, we compare inventor and author names on the highest ranked matches for the occurrence of name matches. Finally, we compare these candidate matches with the names listed in a validated set of inventor-author names. Our text-based profile methodology performs significantly better than a random matching of patents and publications, suggesting that text-based profiling is a valuable complementary tool to the name searches used in previous studies.innovation; industry-science links; text-based profiling;
Wave turbulence of a rotating array of quantized vortices in the T → 0 temperature limit
No full textThe dynamics of quantized vortices in the zero temperature limit is currently of great interest, particularly in the case of the Fermi superfluid He-B. Here we study wave turbulence, generated by the librating motion of a rotating cylindrical container filled with He-B, in the limit of vanishing viscous forces at temperatures . The polarization of the quantized vortices with respect to the axis of rotation is measured using non-invasive NMR techniques. We observe a decrease of the polarization when the librating motion is started, and a two-stage relaxation process when the modulation of the rotation velocity is stopped. The first relaxation process is associated with the dissipation of large-scale flow stored in inertial waves and the solid body rotation of the vortex array. From the decay of these energy reservoirs we determine the rate of energy dissipation of large-scale flow. The later second process is related to the relaxation of Kelvin waves on individual vortices. This process is monitored by the recovery of the polarization. The existence of a Kelvin wave cascade at the lowest temperatures is currently a central open question. We supply some evidence for the cascade
Change, Rigidity & Delay in the UK System of Land-use Development Control
No full textThe British system of development control is time-consuming and uncertain in outcome. Moreover, it is becoming increasingly overloaded as it has gradually switched away from being centred on a traditional ‘is it an appropriate land-use?’ type approach to one based on multi-faceted inspections of projects and negotiations over the distribution of the potential financial gains arising from them. Recent policy developments have centred on improving the operation of development control. This paper argues that more fundamental issues may be a stake as well. Important market changes have increased workloads. Furthermore, the UK planning system's institutional framework encourages change to move in specific directions, which is not always helpful. If expectations of increased long-term housing supply are to be met more substantial changes to development control may be essential but hard to achieve.
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