Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice

OBJECTIVE: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS: Although treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity. CONCLUSIONS: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease

Strategic Planning for Environmental Stewardship at Eastern Kentucky University

The 2006-2010 Strategic Plan for Eastern Kentucky University, under Strategic Direction 5.4, mandates the formulation of a plan to guide the University toward greater environmental stewardship. The creation and implementation of that plan is the charge of the Eastern Committee on Responsible Environmental Stewardship (ECRES), which was formed in September of 2005. On October 27th, 2006, ECRES hosted a Strategic Planning Workshop. This workshop brought together a wide range of paticipants, including elected officials, college and university representatives, and interested citizens. The result was a broad consensus in the identification of environmental goals and objectives toward which EKU should strive

Volcanism and the Greenland ice cores: A new tephrochronological framework for the last glacial-interglacial transition (LGIT) based on cryptotephra deposits in three ice cores

Chemical profiles from Greenland ice cores show that the frequency of volcanism was higher during the last glacial-interglacial transition (LGIT) and early Holocene, (17–9 ka b2k) than in any other period during the last 110 kyr. This increased frequency has partly been linked to climate-driven melting of the Icelandic ice sheet during the last deglaciation, with regional isostatic changes thought to alter mantle viscosity and lead to more eruptions. Our study is the first to construct a comprehensive tephrochronological framework from Greenland ice cores over the LGIT to aid in the reconstruction of volcanic activity over this period. The framework is based on extensive high-resolution sampling of three Greenland ice cores between 17.4 and 11.6 ka b2k and comprises a total of 64 cryptotephra deposits from the NGRIP, GRIP and NEEM ice cores. We show that many of these tephras are preserved within the core without an associated chemical signature in the ice, which implies that reconstructions of volcanism based solely on glacio-chemical indicators might underestimate the number of events. Single glass shards from each deposit were geochemically characterised to trace the volcanic source and many of these deposits could be correlated between cores. We show that the 64 deposits represent tephra deposits from 42 separate volcanic events, and of these, 39 are from Iceland, two from the north Pacific region (Japan and USA) and one has an unknown source. Six deposits can be correlated to terrestrial and/or marine tephra deposits in the Northern Hemisphere and the remaining 36 are unreported in other archives. We did not locate tephra from the compositionally distinctive Laacher See eruption (∼13 ka b2k) in our records. Combining our new discoveries with the previously published tephra framework, raises the number of individual tephra horizons found in Greenland ice over this interval to 50. This significantly improves the regional tephrochronological framework, our knowledge of the eruptive history of Iceland during the LGIT and provides new tephra constraints over key LGIT climate events. Consequentially, this framework can guide sampling strategies of future tephra studies in the terrestrial and marine realms aiming to link these records to the Greenland ice cores to assess regional climate synchroneity

Can patient-reported measurements of pain be used to improve cancer pain management? A systematic review and meta-analysis

PURPOSE: Cancer pain is a distressing and complex experience. It is feasible that the systematic collection and feedback of patient-reported outcome measurements (PROMs) relating to pain could enhance cancer pain management. We aimed to conduct a systematic review of interventions in which patient-reported pain data were collected and fed back to patients and/or professionals in order to improve cancer pain control. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for randomised and non-randomised controlled trials in which patient-reported data were collected and fed back with the intention of improving pain management by adult patients or professionals. We conducted a narrative synthesis. We also conducted a meta-analysis of studies reporting pain intensity. RESULTS: 29 reports from 22 trials of 20 interventions were included. PROM measures were used to alert physicians to poorly controlled pain, to target pain education and to link treatment to management algorithms. Few interventions were underpinned by explicit behavioural theories. Interventions were inconsistently applied or infrequently led to changes in treatment. Narrative synthesis suggested that feedback of PROM data tended to increase discussions between patients and professionals about pain and/or symptoms overall. Meta-analysis of 12 studies showed a reduction in average pain intensity in intervention group participants compared with controls (mean difference=-0.59 (95% CI -0.87 to -0.30)). CONCLUSIONS: Interventions that assess and feedback cancer pain data to patients and/or professionals have so far led to modest reductions in cancer pain intensity. Suggestions are given to inform and enhance future PROM feedback interventions

Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT-treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc

Quality target negotiation in health care : evidence from the English NHS

We examine how public sector third-party purchasers and hospitals negotiate quality targets when a fixed proportion of hospital revenue is required to be linked to quality. We develop a bargaining model linking the number of quality targets to purchaser and hospital characteristics. Using data extracted from 153 contracts for acute hospital services in England in 2010/11, we find that the number of quality targets is associated with the purchaser’s population health and its budget, the hospital type, whether the purchaser delegated negotiation to an agency, and the quality targets imposed by the supervising regional health authority

When serving customers includes correcting them : understanding the ambivalent effects of enforcing service rules

Service employees frequently must enforce rules upon their customers to mitigate dysfunctional customer behavior and ensure proper service delivery (e.g., enforce “fasten seatbelt” signs on flights). However, the consequences of enforcing service rules (ESR) are not well understood. To elucidate the effect of ESR, the authors present seven studies involving > 6800 customers and consisting of cross-sectional and longitudinal data from customer surveys and company records as well as experiments. The results indicate that ESR exerts ambivalent effects: customers who experience ESR directed at other customers perceive service employees as more competent, which increases customer loyalty. However, if ESR is directed at customers themselves, they perceive a self-concept threat, leading them to devalue service employees' warmth and competence and to become less loyal. The effects of ESR hinge on a number of factors, including the harm that dysfunctional behavior potentially causes, the way ESR is communicated, and customers' experience with the service situation. Furthermore, the authors show that service employees can alleviate the negative effects of ESR by communicating service rules in advance and justifying ESR appropriately

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie