18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke

PURPOSE: Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer 11C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer 18F-GE-180 in a rat model of stroke. METHODS: Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with 11C-R-PK11195 and 18F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). RESULTS: 18F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of 11C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BPND = 3.5 ± 0.4 and 2.4 ± 0.5 for 18F-GE-180 and 11C-R-PK11195, respectively, with R 1 = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180 significantly displaced 18F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. CONCLUSION: The in vivo binding characteristics of 18F-GE-180 demonstrate a better signal to noise ratio than 11C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that 18F-GE-180 is a strong candidate to replace 11C-R-PK11195

The positions of primary and secondary schools in the English school field: a case of durable inequality

In interviews as part of a research study of structural reform in England, some tension between primary head teachers and their secondary peers was evident. This was symptomatic of a long-standing difference in status between the two phases. At a time when relations between stakeholders in local systems are subject to change, we seek to understand anew why that might be the case and how the tension we found was evidence of a current difference of power within interactions between representatives of the phases. We analyse differences of size, resources, workforce, pedagogy and history, and how they have resulted in different, and differently valued, practices and professional identities. We explore how attributes of the two phases have been counterposed and how, in complex interaction with wider discourses of politics, gender and age, this process has invested the differences with meanings and values that tend to relegate attributes associated with primary school. By focusing on the activation of cumulative inequality in interactions, we contribute a complementary perspective to studies of perceived relative status and highlight the implications for understanding school positioning in local arenas as the role of local authorities is reduced

Pathways to teacher education for intercultural communicative competence: teachers’ perceptions

Intercultural and plurilingual encounters have become increasingly frequent due to Information and Communication Technologies (ICT) developments, mobility (real/ virtual) and migration. To face the challenges inherent in such encounters, the development of intercultural communicative competence (ICC) is crucial. ICC development may start in the home but should also be a commitment in school curricula, in particular in language classrooms. To facilitate this, language teachers require training in order to integrate the intercultural dimension into their professional practice. In such a context, we implemented a training programme entitled The Intercultural Teacher with an experimental group of language teachers from secondary schools in the Aveiro district (Portugal). In this article, we describe teachers’ social perceptions of ICC and explore the following questions: (a) what does ICC mean for language teachers?; and (b) what are teachers’ views on the development of ICC? The findings of this analysis enabled us, firstly, to design a heuristic model of ICC, based on teachers’ views and perceptions. We were then able to identify some pathways for developing ICC through teacher education, which were validated by teachers themselves

Resting-state auditory network in tinnitus: a fMRI study

BACKGROUND AND PURPOSE: Positron emission tomography (PET) has the potential to improve our understanding of the preclinical pharmacokinetics and metabolism of therapeutic agents, and is easily translated to clinical studies in humans. However, studies involving proteins radiolabelled with clinically relevant PET isotopes are currently limited. Here we illustrate the potential of PET imaging in a preclinical study of the biodistribution and metabolism of (18)F-labelled IL-1 receptor antagonist ([(18)F]IL-1RA) using a novel [(18)F]-radiolabelling technique. EXPERIMENTAL APPROACH: IL-1RA was radiolabelled by reductive amination on lysine moieties with [(18)F]fluoroacetaldehyde. Sprague-Dawley rats were injected intravenously with [(18)F]IL-1RA and imaged with a PET camera for 2 h. For the study of IL-1RA metabolites by ex vivoγ-counting of samples, rats were killed 20 min, 1 h or 2 h after injection of [(18)F]IL-1RA. KEY RESULTS: [(18)F]IL-1RA distribution into the major organs of interest was as follows: kidneys >> liver > lungs >> brain. In lungs and liver, [(18)F]IL-1RA uptake peaked within 1 min post-injection then decreased rapidly to reach a plateau from 10 min post-injection. In the brain, the uptake exhibited slower pharmacokinetics with a smaller post-injection peak and a plateau from 6 min onward. IL-1RA was rapidly metabolized and these metabolites represented ∼40% of total activity in plasma and ∼80% in urine, 20 min after injection. CONCLUSIONS AND IMPLICATIONS: Preclinical PET imaging is a feasible method of assessing the biodistribution of new biological compounds of therapeutic interest rapidly. The biodistribution of [(18)F]IL-1RA reported here is in agreement with an earlier study suggesting low uptake in the normal brain, with rapid metabolism and excretion via the kidneys

Maternal-effect loci involved in Drosophila oogenesis and embryogenesis: P element-induced mutations on the third chromosome

A collection of 1609 recessive P-lethal mutations on the third chromosome was tested in germline clones for effects on egg differentiation and embryonic development. In 164 lines, normal differentiation of the egg chamber is prevented and in 841 lines, embryos develop abnormally. This latter group of maternal-effect mutations was subdivided into 23 classes based on the cuticular phenotypes. Our collection comprises new alleles of previously characterized genes (e.g. kayak, punt, string, tramtrack). For some of the genes identified in this screen, a maternal contribution to embryonic development has not been described previously (e.g. extramacrochaete, Trithorax-like, single minded, couch potato, canoe). The genes classified in our study with a dual function during oogenesis and embryogenesis not only substantially extends the existing collection of maternal-effect genes but will also aid further understanding of how patterning of the Drosophila embryo is controlled by the maternal genome

Co-ordination and management of chronic conditions in Europe:The role of primary care - position paper of the European Forum for Primary Care

Healthcare systems in Europe struggle with inadequate co-ordination of care for people with chronic conditions. Moreover, there is a considerable evidence gap in the treatment of chronic conditions, lack of self-management, variation in quality of care, lack of preventive care, increasing costs for chronic care, and inefficient use of resources. In order to overcome these problems, several approaches to improve the management and co-ordination of chronic conditions have been developed in European healthcare systems. These approaches endeavour to improve self-management support for patients, develop clinical information systems and change the organisation of health care. Changes in the delivery system design and the development of decision support systems are less common. Almost as a rule, the link between healthcare services and community resources and policies is missing. Most importantly, the integration between the six components of the chronic care model remains an important challenge for the future. We find that the position of primary care in healthcare systems is an important factor for the development and implementation of new approaches to manage and coordinate chronic conditions. Our analysis supports the notion that countries with a strong primary care system tend to develop more comprehensive models to manage and co-ordinate chronic conditions. (aut. ref.