11 research outputs found

    Heparan sulphate mimetics as a therapeutic for central nervous system repair

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    The central nervous system (CNS) is composed of the brain, optic nerve and spinal cord and is responsible for most of the body’s functions and processing external environmental information. Damage to the CNS can develop in different pathological conditions ranging from infection, traumatic injury of the spinal cord (SCI), traumatic brain injury (TBI), and degenerative disorders such as multiple sclerosis (MS). Neural degeneration and demyelination of axons are hallmarks of CNS injury. Demyelination in the CNS occurs due to a variety of pathophysiological conditions, therefore, any repair strategies for demyelination must consider multifactorial pathways including promotion of axonal outgrowth, and remyelination. Previously, we have demonstrated that low sulphated modified heparin mimetics (LSmHeps) enhance neurite outgrowth and myelination in vitro. Heparin mimetics (mHeps) are a class of glycomolecules with structural similarities to resident heparan sulphates (HS) and are made up of repeating disaccharide units with variable sulphation groups. They are thought to modulate cell signalling by both sequestering ligands and acting as a cofactor in the formation of ligand-receptor complexes. Thus, LS-mHeps have the capacity to represent novel candidates as therapeutics for CNS damage. However, a major hurdle for CNS therapeutics is for molecules and compounds to cross the blood brain barrier (BBB). Large molecular weight is known to prevent molecules crossing the BBB; therefore, we have developed a low molecular weight form of our lead compound LS-mHep7. This thesis aimed to validate the ability of this low molecular weight form (LS-mHep7L) to maintain the ability to enhance repair in several CNS injury models including in vitro myelinating cultures, during both myelin development (MC-Dev) and demyelination (MCDeMy), and astrocyte injury assays. Additionally, this thesis aimed to optimise an ex vivo slice culture model to further validate LS-mHeps and found that spinal cords from C57BL/6 P1 mice produced healthy myelinating axons for remyelination studies. It was found that LS-mHep7L enhanced neurite outgrowth in vitro and remyelination both in vitro and ex vivo. LS-mHep7L was found to sequester CCL5 – a negative regulator of myelination both in vitro and ex vivo, and restored CCL5 induced hypomyelination in developing cultures. LS-mHeps also reduced signs of reactive astrocytes with a decrease in nestin expression and appeared to enhance gap closure in the injury model. Finally, we investigated the use of recombinant heparin mimetics (rHS) as an alternative source for heparin derived therapeutics. Currently 80% of the world’s heparin supply is sourced from China from porcine intestines and having such a reliance on a specific animal source for any new therapeutic comes with an elevated risk. Here we demonstrated that low sulphated recombinant heparan sulphate (rHS10) enhance remyelination in MC-DeMy and SC-DeMy, while rHS09 enhance neurite outgrowth in MC-Inj. In summary, the results of this thesis demonstrated that low sulphated heparin mimetics have the potential to become novel therapeutics for remyelination and neurite outgrowth for diseases and injury of the CNS. Additionally, low molecular weight LS-mHeps show the same bioactivity as the high molecular weight form, by demonstrating neurite outgrowth in vitro, enhanced remyelination and sequestration of negative regulators of repair both in vitro and ex vivo cultures

    Communication Technology and Governance: The Case of Nigeria

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    Considering its level of sophistication and complexity communication can be understood as a fundamental characteristic of humankind. Since early times humanity has continued to devise novel techniques and tools to enhance the process of communication and governance procedures. This study explores and analyses developments in internet and communication technology (ICT) in relation to governance procedures in Nigeria. It looks at the rapid expansion of ICT and examines levels of assimilation by the population. This study includes an investigation of the challenges and impediments encountered in the process of the integration of ICT into the fabric of Nigeria’s governance. The data and information gained about ICT is then employed towards the development of a theoretical framework to identify and assess good governance. A mixed method and hermeneutical approach were used in the collection and analysis of data. A survey questionnaire was distributed to 100 selected professionals with varied backgrounds as users or experts regarding communication. Those chosen to receive questionnaires were members of the public and individuals from professional and stakeholder groups in the communication industry. Survey questions addressed the frequency of use of ICT in Nigeria in commonly-cited activities as well as areas of success where future improvement may be identified. The questionnaires provided an overview of the benefits of ICT regarding the developments and challenges confronting the communication industry and governance. This overview formed the basis for semi-structured interview questions and focus group sessions. This thesis demonstrates the interconnectivity between communication and governance and how triangulation and hermeneutics were combined to study ICT use in the context of Nigeria. The results also indicated that in certain population groups and in some economic sectors of government ICT use is rapidly growing. However, the study and theoretical framework illustrate that many opportunities and challenges remain for optimal use of ICT for Nigerian governance procedures

    Micro-costing study of rituximab subcutaneous injection versus intravenous infusion in dutch setting

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    Background: Rituximab for subcutaneous (SC) administration has recently been approved for use in common forms of diffuse large B-cell lymphoma (DLBCL). This form of rituximab is supplied in ready-to-use vials that do not require individual dose adjustment. It is expected that SC-injection will shorten the treatment time per administration of rituximab in comparison with currently available intravenous (IV) infusion. Aims: The goal of this study is to identify and compare all direct costs of IV and SC rituximab given to the DLBCL patients in the Netherlands. Methods: Using a prospective, observational, bottom up, micro-costing study we collected primary data on the direct medical costs of the preparation, administration and acquisition of rituximab. Drug costs and spillage, labor costs, material costs and remaining daycare costs were identified using standardized forms, structured using guideline prices and compared for the IV and SC forms of rituximab. Results: Measurements were done on 53 administrations (33 IV and 20 SC). The mean total costs of the IV infusion were €2174, and €1907 for the SC injection. The estimated difference of €267 per administration was mainly due to spillage costs and differences in chair time, related daycare costs and drug costs. Summary and Conclusions: Rituximab administered in the form of SC injection is less costly than its IV form. Taking into account their equal effectiveness, favorable pharmacoeconomic profile of SC rituximab can result in significant savings when transferred to the total DLBCL population in the Netherlands

    Trial efficacy vs real world effectiveness in first line treatment of multiple myeloma

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    Background: Large randomized clinical trials (RCT) are the foundation of the registration of newly developed drugs. A potential problem with RCTs is that the inclusion/exclusion criteria will make the population different from the actual population treated in real life. Hence, it is important to understand how the results from the RCT can be generalized to a general population. Aims: The primary aim of the present study was to assess the generalizability of the large 1st line RCTs in Multiple Myeloma (MM) to the Nordic setting and to understand potential difference and magnitude in outcomes between RCTs and patients treated in standard care in the Nordics. Methods: A retrospective analysis was performed on an incident cohort of 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics, treatments and outcomes. Data from relevant 1st line MM RCTs was selected from the treatment MP (Waage, A., et al., Blood. 2010], MPT (Waage, A., et al., Blood. 2010) and VMP (San Miguel, J.F., et al., N Engl J Med, 2008) and baseline characteristics were compared to newly diagnosed Nordic MM treated patients. Potential difference in response and overall survival (OS) was estimated by adjusting the RWE population to the RCT population using matching adjusted indirect comparisons. Patients were matched on age (median approximated to mean), gender, calcium, beta2-microglobulin and ISS score 3. These variables were selected because they were reported in all trials and have previously been identified as having prognostic value. Results: Patients in the Nordic database treated with MP (n=880) had a response rate of (PD, NR, PR, VGPR, ≥nCR) of (13%, 39%, 38%, 6%, 4%). After matching (n=347), the response rate was slightly worse (12%, 43%, 36%, 6%, 3%). This can be compared to the response rate from the RCT of (7%, 53%, 33%, 3%, 4%). OS for Nordic MP treated patients was 2.67 years (2.25-3.17). After matching the OS was 3.37 years (2.86-3.96) and this can be compared to the trial with OS 2.40 years (2.23-2.66). Patients treated with MPT (n=283) in the Nordic countries had a response rate of (5%, 14%, 52%, 20%, 9%). After matching (n=179) the response rate was slightly changed to (6%, 20%, 50%, 13% 11%). The corresponding RCT response results were 14%, 29%, 34%, 10%, and 13% respectively. OS for Nordic MPT treated patients was 4.15 years (3.73- 4.74). After matching the OS was 4.28 years (3.98-NA) years and compared to 2.42 years (2.08-3.17) OS observed in the corresponding trial. Patients treated with VMP (n=59) in the Nordic countries had a response rate of (4%, 5%, 40%, 18%, 33%). After matching (n=31) the response rate was improved to (8%, 11%, 28%, 8%, 45%). This corresponding response rates shown in the trial are 1%, 23%, 33%, 8%, and 33% respectively. OS for Nordic MP treated patients was 4.86 years (3.79-NA). After matching the OS was 4.86 years (4.86-NA) and this can be compared to the trial with OS 4.70 years. Summary and Conclusions: Surprisingly Nordic treated MM patients do very well compared to, and even better than, patients treated in RCTs. Since the OS for all tested treatments improves after matching to the RCT baseline characteristics, patients recruited to the RCTs seems to be a bit better than ordinary Nordic patents. The database used in the present study, and the used method, can be valuable for generalizing the results to the Nordic setting and estimating potential difference for future RCTs and Nordic MM treated patients. Future research should include different data cuts to see whether the analyses are biased by differences subsequent treatments applied in RCTs and clinical practice

    The application of genomic technologies to cancer and companion diagnostics.

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    This thesis describes work undertaken by the author between 1996 and 2014. Genomics is the study of the genome, although it is also often used as a catchall phrase and applied to the transcriptome (study of RNAs) and methylome (study of DNA methylation). As cancer is a disease of the genome the rapid advances in genomic technology, specifically microarrays and next generation sequencing, are creating a wave of change in our understanding of its molecular pathology. Molecular pathology and personalised medicine are being driven by discoveries in genomics, and genomics is being driven by the development of faster, better and cheaper genome sequencing. The next decade is likely to see significant changes in the way cancer is managed for individual cancer patients as next generation sequencing enters the clinic. In chapter 3 I discuss how ERBB2 amplification testing for breast cancer is currently dominated by immunohistochemistry (a single-gene test); and present the development, by the author, of a semi-quantitative PCR test for ERBB2 amplification. I also show that estimating ERBB2 amplification from microarray copy-number analysis of the genome is possible. In chapter 4 I present a review of microarray comparison studies, and outline the case for careful and considered comparison of technologies when selecting a platform for use in a research study. Similar, indeed more stringent, care needs to be applied when selecting a platform for use in a clinical test. In chapter 5 I present co-authored work on the development of amplicon and exome methods for the detection and quantitation of somatic mutations in circulating tumour DNA, and demonstrate the impact this can have in understanding tumour heterogeneity and evolution during treatment. I also demonstrate how next-generation sequencing technologies may allow multiple genetic abnormalities to be analysed in a single test, and in low cellularity tumours and/or heterogenous cancers. Keywords: Genome, exome, transcriptome, amplicon, next-generation sequencing, differential gene expression, RNA-seq, ChIP-seq, microarray, ERBB2, companion diagnostic

    Nouvelles méthodes de codage vidéo distribué

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    De nos jours certaines applications vidéo de par des limitations de mémoire et de capacités de calculs requièrent un système où l'encodage d'une séquence vidéo doit être le plus simple possible. Le codage vidéo distribué nouveau paradigme de la compression vidéo semble prometteur pour ce genre de demande. Il permet une compression peu complexe de séquences animées. Son principe repose sur les travaux de D. Slepian et J. K. Wolf [1] ainsi que ceux de A. D. Wyner et J. Ziv [2] menés dans les années 70. La présente thèse énonce trois différentes contributions relatives au codage vidéo conventionnel et distribué. La première est un nouveau procédé de filtrage vidéo basé sur l'utilisation d'arbres de décision. Afin de réduire les artefacts visuels issus d'une trop forte compression, les arbres de décision identifient et appliquent les meilleurs coefficients de filtrage en fonction des données à filtrer. La seconde contribution concerne un schéma de codage vidéo distribué où l'on évite de transmettre au décodeur 1 information relative aux blocs de l'image les moins significatifs. De cette manière, on engendre une diminution importante du débit binaire et une réduction de la complexité de décodage. Ce schéma de codage repose sur une séparation en couche des coefficients de transformée en cosinus discret de l'image. Les coefficients DC sont les premiers à être transmis au décodeur. De là, ils sont analysés par ce dernier afin de trouver les blocs les plus significatifs de l'image. Le décodeur indique alors à l'encodeur, via un canal de retour, quels sont les coefficients AC des blocs à transmettre. Enfin, la dernière contribution consiste en une méthode de représentation binaire adaptative des images dans les procédés de codage vidéo distribué. Cette représentation permet de réduire efficacement le débit binaire et tenant compte uniquement de l'information source la plus pertinente. Ici encore cette méthode repose sur une utilisation plus efficace d 'un canal de retour

    Subject Index Volumes 1–200

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    Personen- und Vorlesungsverzeichnis : Wintersemester 2009/10, Stand: 29. September 2009.

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    Retrodigitalisierte Vorlesungsverzeichnisse der Johannes-Gutenberg-Universität. Teilweise auch enthaltend: - Vorlesungsverzeichnis - Personenverzeichnis - Studienverzeichnis - Personalverzeichni

    Conference Proceedings ICD Granada 2016

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