Transactivation of Sphingosine-1–Phosphate Receptors by FcɛRI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis

Mast cells secrete various substances that initiate and perpetuate allergic responses. Cross-linking of the high-affinity receptor for IgE (FcɛRI) in RBL-2H3 and bone marrow–derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1–phosphate (S1P). In turn, S1P activates its receptors S1P1 and S1P2 that are present in mast cells. Moreover, inhibition of SphK blocks FcɛRI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P1 and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for FcɛRI-triggered degranulation. However, S1P2, whose expression is up-regulated by FcɛRI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by FcɛRI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation

Product Development Partnerships: Case studies of a new mechanism for health technology innovation

There is a continuing need for new health technologies to address the disease burdens of developing countries. In the last decade Product Development Partnerships (PDP) have emerged that are making important contributions to the development of these technologies. PDPs are a form of public private partnerships that focus on health technology development. PDPs reflect the current phase in the history of health technology development: the Era of Partnerships, in which the public and private sectors have found productive ways to collaborate. Successful innovation depends on addressing six determinants of innovation. We examine four case studies of PDPs and show how they have addressed the six determinants to achieve success

'Rumours' and clinical trials: a retrospective examination of a paediatric malnutrition study in Zambia, southern Africa

BACKGROUND: Many public health researchers conducting studies in resource-constrained settings have experienced negative 'rumours' about their work; in some cases they have been reported to create serious challenges and derail studies. However, what may appear superficially as 'gossip' or 'rumours' can also be regarded and understood as metaphors which represent local concerns. For researchers unaccustomed to having concerns expressed from participants in this manner, possible reactions can be to be unduly perturbed or conversely dismissive.This paper represents a retrospective examination of a malnutrition study conducted by an international team of researchers in Zambia, Southern Africa. The fears of mothers whose children were involved in the study and some of the concerns which were expressed as rumours are also presented. This paper argues that there is an underlying logic to these anxieties and to dismiss them simply as 'rumours' or 'gossip' would be to overlook the historic and socio-economic factors which have contributed to their production. METHODS: Qualitative interviews were conducted with the mothers whose children were involved in the study and with the research nurses. Twenty five face-to-face interviews and 2 focus group discussions (FGDs) were conducted with mothers. In addition, face-to-face interviews were conducted with research nurses participating in the trial. RESULTS: A prominent anxiety expressed as rumours by the mothers whose children were involved in the study was that recruitment into the trial was an indicator that the child was HIV-infected. Other anxieties included that the trial was a disguise for witchcraft or Satanism and that the children's body parts would be removed and sold. In addition, the liquid, milk-based food given to the children to improve their nutrition was suspected of being insufficiently nutritious, thus worsening their condition.The form which these anxieties took, such as rumours related to the stealing of body parts and other anxieties about a stigmatised condition, provide an insight into the historical, socio-economic and cultural influences in such settings. CONCLUSIONS: Employing strategies to understand local concerns should accompany research aims to achieve optimal success. The concerns raised by the participants we interviewed are not unique to this study. They are produced in countries where the historic, socio-economic and cultural settings communicate anxieties in this format. By examining this study we have shown that by contextualizing these 'rumours', the concerns they express can be constructively addressed and in turn result in the successful conduct of research aims

Standardising Clinical Caremaps: Model, Method and Graphical Notation for Caremap Specification

Standardising care can improve patient safety and outcomes, and reduce the cost of providing healthcare services. Caremaps were developed to standardise care, but contemporary caremaps are not standardised. Confusion persists in terms of terminology, structure, content and development process. Unlike existing methods in the literature, the approach, model and notation presented in this chapter pays special attention to incorporation of clinical decision points as first-class citizens within the modelling process. The resulting caremap with decision points is evaluated through creation of a caremap for women with gestational diabetes mellitus. The proposed method was found to be an effective way for comprehensively specifying all features of caremaps in a standardised way that can be easily understood by clinicians. This chapter contributes a new standardised method, model and notation for caremap content, structure and development

Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

The Protein Partners of GTP Cyclohydrolase I in Rat Organs

GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin biosynthesis and has been shown to be a promising therapeutic target in ischemic heart disease, hypertension, atherosclerosis and diabetes. The endogenous GCH1-interacting partners have not been identified. Here, we determined endogenous GCH1-interacting proteins in rat.A pulldown and proteomics approach were used to identify GCH1 interacting proteins in rat liver, brain, heart and kidney. We demonstrated that GCH1 interacts with at least 17 proteins including GTP cyclohydrolase I feedback regulatory protein (GFRP) in rat liver by affinity purification followed by proteomics and validated six protein partners in liver, brain, heart and kidney by immunoblotting. GCH1 interacts with GFRP and very long-chain specific acyl-CoA dehydrogenase in the liver, tubulin beta-2A chain in the liver and brain, DnaJ homolog subfamily A member 1 and fatty aldehyde dehydrogenase in the liver, heart and kidney and eukaryotic translation initiation factor 3 subunit I (EIF3I) in all organs tested. Furthermore, GCH1 associates with mitochondrial proteins and GCH1 itself locates in mitochondria.GCH1 interacts with proteins in an organ dependant manner and EIF3I might be a general regulator of GCH1. Our finding indicates GCH1 might have broader functions beyond tetrahydrobiopterin biosynthesis

Simulated Impact of RTS,S/AS01 Vaccination Programs in the Context of Changing Malaria Transmission

INTRODUCTION: The RTS,S/AS01 pre-erythrocytic malaria vaccine is in phase III clinical trials. It is critical to anticipate where and how it should be implemented if trials are successful. Such planning may be complicated by changing levels of malaria transmission. METHODS/RESULTS: Computer simulations were used to examine RTS,S/AS01 impact, using a vaccine profile based on phase II trial results, and assuming that protection decays only slowly. Settings were simulated in which baseline transmission (in the absence of vaccine) was fixed or varied between 2 and 20 infectious mosquito bites per person per annum (ibpa) over ten years. Four delivery strategies were studied: routine infant immunization (EPI), EPI plus infant catch-up, EPI plus school-based campaigns, and EPI plus mass campaigns. Impacts in changing transmission settings were similar to those in fixed settings. Assuming a persistent effect of vaccination, at 2 ibpa, the vaccine averted approximately 5-7 deaths per 1000 doses of vaccine when delivered via mass campaigns, but the benefit was less at higher transmission levels. EPI, catch-up and school-based strategies averted 2-3 deaths per 1000 doses in settings with 2 ibpa. In settings where transmission was decreasing or increasing, EPI, catch-up and school-based strategies averted approximately 3-4 deaths per 1000 doses. DISCUSSION: Where transmission is changing, it appears to be sufficient to consider simulations of pre-erythrocytic vaccine impact at a range of initial transmission levels. At 2 ibpa, mass campaigns averted the most deaths and reduced transmission, but this requires further study. If delivered via EPI, RTS,S/AS01 could avert approximately 6-11 deaths per 1000 vaccinees in all examined settings, similar to estimates for pneumococcal conjugate vaccine in African infants. These results support RTS,S/AS01 implementation via EPI, for example alongside vector control interventions, providing that the phase III trials provide support for our assumptions about efficacy

An Introduction to Sphingolipid Metabolism and Analysis by New Technologies

Sphingolipids (SP) are a complex class of molecules found in essentially all eukaryotes and some prokaryotes and viruses where they influence membrane structure, intracellular signaling, and interactions with the extracellular environment. Because of the combinatorial nature of their biosynthesis, there are thousands of SP subspecies varying in the lipid backbones and complex phospho- and glycoheadgroups. Therefore, comprehensive or “sphingolipidomic” analyses (structure-specific, quantitative analyses of all SP, or at least all members of a critical subset) are needed to know which and how much of these subspecies are present in a system as a step toward understanding their functions. Mass spectrometry and related novel techniques are able to quantify a small fraction, but nonetheless a substantial number, of SP and are beginning to provide information about their localization. This review summarizes the basic metabolism of SP and state-of-art mass spectrometric techniques that are producing insights into SP structure, metabolism, functions, and some of the dysfunctions of relevance to neuromedicine