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Background: After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity).
Methods/design: The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs.
Discussion: This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation.
Research information, i.e., data about research projects, organisations, researchers or research outputs such as publications or patents, is spread across the web, usually residing in institutional and personal web pages or in semi-open databases and information systems. While there exists a wealth of unstructured information, structured data is limited and often exposed following proprietary or less-established schemas and interfaces. Therefore, a holistic and consistent view on research information across organisational and national boundaries is not feasible. On the other hand, web crawling and information extraction techniques have matured throughout the last decade, allowing for automated approaches of harvesting, extracting and consolidating research information into a more coherent knowledge graph. In this work, we give an overview of the current state of the art in research information sharing on the web and present initial ideas towards a more holistic approach for boot-strapping research information from available web sources.
Clinical scores and motion-capturing gait analysis are today’s gold standard for outcome measurement after knee arthroplasty, although they are criticized for bias and their ability to reflect patients’ actual quality of life has been questioned. In this context, mobile gait analysis systems have been introduced to overcome some of these limitations. This study used a previously developed mobile gait analysis system comprising three inertial sensor units to evaluate daily activities and sports. The sensors were taped to the lumbosacral junction and the thigh and shank of the affected limb. The annotated raw data was evaluated using our validated proprietary software. Six patients undergoing knee arthroplasty were examined the day before and 12 months after surgery. All patients reported a satisfactory outcome, although four patients still had limitations in their desired activities. In this context, feasible running speed demonstrated a good correlation with reported impairments in sports-related activities. Notably, knee flexion angle while descending stairs and the ability to stop abruptly when running exhibited good correlation with the clinical stability and proprioception of the knee. Moreover, fatigue effects were displayed in some patients. The introduced system appears to be suitable for outcome measurement after knee arthroplasty and has the potential to overcome some of the limitations of stationary gait labs while gathering additional meaningful parameters regarding the force limits of the knee.
Background: Maintenance of metal homeostasis is crucial in bacterial pathogenicity as metal starvation is the most important mechanism in the nutritional immunity strategy of host cells. Thus, pathogenic bacteria have evolved sensitive metal scavenging systems to overcome this particular host defence mechanism. The ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) displays a unique gut tropism and causes a chronic progressive intestinal inflammation. MAP possesses eight conserved lineage specific large sequence polymorphisms (LSP), which distinguish MAP from its ancestral M. avium ssp. hominissuis or other M. avium subspecies. LSP14 and LSP15 harbour many genes proposed to be involved in metal homeostasis and have been suggested to substitute for a MAP specific, impaired mycobactin synthesis.
Results: In the present study, we found that a LSP14 located putative IrtAB-like iron transporter encoded by mptABC was induced by zinc but not by iron starvation. Heterologous reporter gene assays with the lacZ gene under control of the mptABC promoter in M. smegmatis (MSMEG) and in a MSMEGΔfurB deletion mutant revealed a zinc dependent, metalloregulator FurB mediated expression of mptABC via a conserved mycobacterial FurB recognition site. Deep sequencing of RNA from MAP cultures treated with the zinc chelator TPEN revealed that 70 genes responded to zinc limitation. Remarkably, 45 of these genes were located on a large genomic island of approximately 90 kb which harboured LSP14 and LSP15. Thirty-five of these genes were predicted to be controlled by FurB, due to the presence of putative binding sites. This clustering of zinc responsive genes was exclusively found in MAP and not in other mycobacteria.
Conclusions: Our data revealed a particular genomic signature for MAP given by a unique zinc specific locus, thereby suggesting an exceptional relevance of zinc for the metabolism of MAP. MAP seems to be well adapted to maintain zinc homeostasis which might contribute to the peculiarity of MAP pathogenicity.
Background: Epidemiological and experimental studies suggest that exposure to ultrafine particles (UFP) might aggravate the allergic inflammation of the lung in asthmatics.
Methods: We exposed 12 allergic asthmatics in two subgroups in a double-blinded randomized cross-over design, first to freshly generated ultrafine carbon particles (64 μg/m3; 6.1 ± 0.4 × 105 particles/cm3 for 2 h) and then to filtered air or vice versa with a 28-day recovery period in-between. Eighteen hours after each exposure, grass pollen was instilled into a lung lobe via bronchoscopy. Another 24 hours later, inflammatory cells were collected by means of bronchoalveolar lavage (BAL). (Trial registration: NCT00527462)
Results: For the entire study group, inhalation of UFP by itself had no significant effect on the allergen induced
inflammatory response measured with total cell count as compared to exposure with filtered air (p = 0.188). However, the subgroup of subjects, which inhaled UFP during the first exposure, exhibited a significant increase in total BAL cells (p = 0.021), eosinophils (p = 0.031) and monocytes (p = 0.013) after filtered air exposure and subsequent allergen challenge 28 days later. Additionally, the potential of BAL cells to generate oxidant radicals was
significantly elevated at that time point. The subgroup that was exposed first to filtered air and 28 days later to UFP did not reveal differences between sessions.
Conclusions: Our data demonstrate that pre-allergen exposure to UFP had no acute effect on the allergic inflammation. However, the subgroup analysis lead to the speculation that inhaled UFP particles might have a long-term effect on the inflammatory course in asthmatic patients. This should be reconfirmed in further studies with an appropriate study design and sufficient number of subjects.
Nanotechnology is emerging as one of the key technologies of the 21st century and is expected to enable developments across a wide range of sectors that can benefit citizens. Nanomedicine is an application of nanotechnology in the areas of healthcare, disease diagnosis, treatment and prevention of disease. Nanomedicines pose problem of nanotoxicity related to factors like size, shape, specific surface area, surface morphology, and crystallinity. Currently, nanomedicines are regulated as medicinal products or as medical devices and there is no specific regulatory framework for nanotechnology-based products neither in the EU nor in the USA. This review presents a scheme for classification and regulatory approval process for nanotechnology based medicines.
The drugs we use to treat any condition – from an innocuous cough to a life-threatening cancer – are the outcome of painstaking human clinical trials. These trials are the only way to credibly determine the safety and efficacy of drugs. In recent years there has been a clear shift in clinical trial sites from core developed countries like USA, European countries to developing countries like India, China, South American countries. This shift is related to challenges and opportunities like costs of trials, recruitment issues, and regulatory challenges in developed vs. developing countries. Developing countries and developed countries have their unique disease burden patterns based on various parameters like but not limited to age, health care facilities, health insurance, sanitary conditions, environmental issues, education, nutrition
and GDP. Previous studies have reported that many of the important global diseases are not much explored in clinical trials and many published clinical trials have very less international health relevance. This study was aimed at finding the correlation between disease burdens, number of clinical trials done and trial success rates. We compared 2005 - 2010 Global Burden of Disease data for Germany, India and number of clinical trials from clinicaltrials.gov database done in the same period. Our findings indicated that there was a good correlation between the disease burden and clinical trials for Germany in 2005 and 2010. For India in 2005 there was a moderate positive correlation, 2010 data showed the improvement in India in terms of match between disease burden and clinical trials. But careful observation of the data shows still a need for more trials on Communicable, maternal, neonatal and nutritional disorders.
The dependency of word similarity in vector space models on the frequency of words has been noted in a few studies, but has received very little attention. We study the influence of word frequency in a set of 10 000 randomly selected word pairs for a number of different combinations of feature weighting schemes and similarity measures. We find that the similarity of word pairs for all methods, except for the one using singular value decomposition to reduce the dimensionality of the feature space, is determined to a large extent by the frequency of the words. In a binary classification task of pairs of synonyms and unrelated words we find that for all similarity measures the results can be improved when we correct for the frequency bias.
Der Arbeitsalltag von Wissenschaftlerinnen und Wissenschaftlern hat sich in den letzten Jahren dramatisch verändert. Forschen, Schreiben und Publizieren sind mittlerweile stark durch netzbasierte Anwendungen geprägt. Das digitale Zeitalter aber hat nicht nur neue technische Werkzeuge hervorgebracht, sondern auch neue Wege eröffnet, um Wissen zu generieren und zu verbreiten. Dies gilt sowohl innerhalb der akademischen Welt als auch über diese hinaus. Das Arbeiten mit dem Netz stellt unsere bisherigen etablierten wissenschaftlichen Praktiken in Frage. Forschung wird zunehmend vernetzt, kollaborativ, multimedial, trans- bzw. interdisziplinär durchgeführt. Das vorliegende Handbuch beschreibt diese sich herausbildenden wissenschaftlichen Praktiken. Ziel der Autoren war es dabei, ein praxisnahes und leicht verständliches Handbuch zu schreiben.