Glioblastoma Therapy with Cytotoxic Mesenchymal Stromal Cells Optimized by Bioluminescence Imaging of Tumor and Therapeutic Cell Response

Genetically modified adipose tissue derived mesenchymal stromal cells (hAMSCs) with tumor homing capacity have been proposed for localized therapy of chemo- and radiotherapy resistant glioblastomas. We demonstrate an effective procedure to optimize glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo non invasive monitoring of tumor and therapeutic cells. Glioblastoma U87 cells expressing Photinus pyralis luciferase (Pluc) were implanted in combination with hAMSCs expressing a trifunctional Renilla reniformis luciferase-red fluorescent protein-thymidine kinase reporter in the brains of SCID mice that were subsequently treated with ganciclovir (GCV). The resulting optimized therapy was effective and monitoring of tumor cells by bioluminescence imaging (BLI) showed that after 49 days GCV treatment reduced significantly the hAMSC treated tumors; by a factor of 104 relative to controls. Using a Pluc reporter regulated by an endothelial specific promoter and in vivo BLI to image hAMSC differentiation we gained insight on the therapeutic mechanism. Implanted hAMSCs homed to tumor vessels, where they differentiated to endothelial cells. We propose that the tumor killing efficiency of genetically modified hAMSCs results from their association with the tumor vascular system and should be useful vehicles to deliver localized therapy to glioblastoma surgical borders following tumor resection

'The Girl Effect': Exploring Narratives of Gendered Impacts and Opportunities in Neoliberal Development

This paper explores representations of girls in current discourses of neoliberal development through an analysis of a range of texts that promote the global Girl Effect movement. These representations are situated in the context of theoretical debates about gender mainstreaming and policy developments that construct girls and women's 'empowerment' as 'smart economics'. The paper draws on postcolonial and transnational feminist analyses that critique market-led approaches to development and their complicities in the dynamics of neo-colonialism and uneven development, to contextualise the Girl Effect movement. It is argued that the Girl Effect movement draws on colonial stereotypes of girls as sexually and culturally constrained, but reworks these through the discourses of neoliberal development to construct girls as good investment potential. In doing so, it reproduces a dominant narrative that highlights the cultural causes of poverty but obscures structural relations of exploitation and privilege

Habitat heterogeneity enables spatial and temporal coexistence of native and invasive macrophytes in shallow lake landscapes

Macrophyte invasive alien species (IAS) fitness is often hypothesised to be associated with beneficial environmental conditions (environmental matching) or species-poor communities. However, positive correlations between macrophyte IAS abundance and native plant richness can also arise, due to habitat heterogeneity (defined here as variation in abiotic and native biotic conditions over space and time). We analysed survey and palaeoecological data for macrophytes in satellite lakes along the Upper Lough Erne (ULE) system (Northern Ireland, UK), covering a gradient of eutrophication and connectivity to partition how environmental conditions, macrophyte diversity and habitat heterogeneity explained the abundance of Elodea canadensis, a widely distributed non-native macrophyte in Europe. E. canadensis abundance positively correlated with macrophyte richness at both the within- and between-lake scales indicating coexistence of native and invasive species over time. E. canadensis was also more prolific in highly connected and macrophyte-rich lakes, but sparser in the more eutrophic-isolated ones. Partial boosted regression trees revealed that in eutrophic-isolated lakes, E. canadensis abundances correlated with water clarity (negatively), plant diversity (positively), and plant cover (negatively) whereas in diverse-connected lakes, beta diversity (both positively and negatively) related to most greatly E. canadensis abundance. Dense macrophyte cover and unfavourable environmental conditions thus appear to confer invasibility resistance and sufficient habitat heterogeneity to mask any single effect of native biodiversity or environmental matching in controlling E. canadensis abundance. Therefore, in shallow lake landscapes, habitat heterogeneity variously enables the coexistence of native macrophytes and E. canadensis, reducing the often-described homogenisation effects of invasive macrophytes.Output Status: Forthcoming/Available Onlin

Procalcitonin-guided antibiotic use versus a standard approach for acute respiratory tract infections in primary care: study protocol for a randomised controlled trial and baseline characteristics of participating general practitioners [ISRCTN73182671]

BACKGROUND: Acute respiratory tract infections (ARTI) are among the most frequent reasons for consultations in primary care. Although predominantly viral in origin, ARTI often lead to the prescription of antibiotics for ambulatory patients, mainly because it is difficult to distinguish between viral and bacterial infections. Unnecessary antibiotic use, however, is associated with increased drug expenditure, side effects and antibiotic resistance. A novel approach is to guide antibiotic therapy by procalcitonin (ProCT), since serum levels of ProCT are elevated in bacterial infections but remain lower in viral infections and inflammatory diseases. The aim of this trial is to compare a ProCT-guided antibiotic therapy with a standard approach based on evidence-based guidelines for patients with ARTI in primary care. METHODS/DESIGN: This is a randomised controlled trial in primary care with an open intervention. Adult patients judged by their general practitioner (GP) to need antibiotics for ARTI are randomised in equal numbers either to standard antibiotic therapy or to ProCT-guided antibiotic therapy. Patients are followed-up after 1 week by their GP and after 2 and 4 weeks by phone interviews carried out by medical students blinded to the goal of the trial. Exclusion criteria for patients are antibiotic use in the previous 28 days, psychiatric disorders or inability to give written informed consent, not being fluent in German, severe immunosuppression, intravenous drug use, cystic fibrosis, active tuberculosis, or need for immediate hospitalisation. The primary endpoint is days with restrictions from ARTI within 14 days after randomisation. Secondary outcomes are antibiotic use in terms of antibiotic prescription rate and duration of antibiotic treatment in days, days off work and days with side-effects from medication within 14 days, and relapse rate from the infection within 28 days after randomisation. DISCUSSION: We aim to include 600 patients from 50 general practices in the Northwest of Switzerland. Data from the registry of the Swiss Medical Association suggests that our recruited GPs are representative of all eligible GPs with respect to age, proportion of female physicians, specialisation, years of postgraduate training and years in private practice

Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers

Prescribing indicators at primary health care centers within the WHO African region: a systematic analysis (1995-2015)

Abstract Background Rational medicine use is essential to optimize quality of healthcare delivery and resource utilization. We aim to conduct a systematic review of changes in prescribing patterns in the WHO African region and comparison with WHO indicators in two time periods 1995–2005 and 2006–2015. Methods Systematic searches were conducted in PubMed, Scopus, Web of science, Africa-Wide Nipad, Africa Journals Online (AJOL), Google scholar and International Network for Rational Use of Drugs (INRUD) Bibliography databases to identify primary studies reporting prescribing indicators at primary healthcare centres (PHCs) in Africa. This was supplemented by a manual search of retrieved references. We assessed the quality of studies using a 14-point scoring system modified from the Downs and Black checklist with inclusions of recommendations in the WHO guidelines. Results Forty-three studies conducted in 11 African countries were included in the overall analysis. These studies presented prescribing indicators based on a total 141,323 patient encounters across 572 primary care facilities. The results of prescribing indicators were determined as follows; average number of medicines prescribed per patient encounter = 3.1 (IQR 2.3–4.8), percentage of medicines prescribed by generic name =68.0 % (IQR 55.4–80.3), Percentage of encounters with antibiotic prescribed =46.8 % (IQR 33.7–62.8), percentage of encounters with injection prescribed =25.0 % (IQR 18.7–39.5) and the percentage of medicines prescribed from essential medicines list =88.0 % (IQR 76.3–94.1). Prescribing indicators were generally worse in private compared with public facilities. Analysis of prescribing across two time points 1995–2005 and 2006–2015 showed no consistent trends. Conclusions Prescribing indicators for the African region deviate significantly from the WHO reference targets. Increased collaborative efforts are urgently needed to improve medicine prescribing practices in Africa with the aim of enhancing the optimal utilization of scarce resources and averting negative health consequences

Poor adherence to antibiotic prescribing guidelines in acute otitis media—obstacles, implications, and possible solutions

Many countries now have guidelines on the clinical management of acute otitis media. In almost all, the public health goal of containing acquired resistance in bacteria through reduced antibiotic prescribing is the main aim and basis for recommendations. Despite some partial short-term successes, clinical activity databases and opinion surveys suggest that such restrictive guidelines are not followed closely, so this aim is not achieved. Radical new solutions are needed to tackle irrationalities in healthcare systems which set the short-term physician–patient relationship against long-term public health. Resolving this opposition will require comprehensive policy appraisal and co-ordinated actions at many levels, not just dissemination of evidence and promotion of guidelines. The inappropriate clinical rationales that underpin non-compliance with guidelines can be questioned by evidence, but also need specific developments promoting alternative solutions, within a framework of whole-system thinking. Promising developments would be (a) physician training modules on age-appropriate analgesia and on detection plus referral of rare complications like mastoiditis, and (b) vaccination against the most common and serious bacterial pathogens