Immune Responses Accelerate Ageing: Proof-of-Principle in an Insect Model

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies. Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology. Along with presenting a proof-of-principle study, we discuss a mechanism for the apparently counter-adaptive persistence of immunopathology in natural populations. If immunopathology from early immune response only becomes costly later in life, natural selection on reducing self-harm would be relaxed, which could explain the presence of immune self-harm in nature

The complete connectome of a learning and memory center in an insect brain

Associating stimuli with positive or negative reinforcement is essential for survival, but a complete wiring diagram of a higher-order circuit supporting associative memory has not been previously available. Here we reconstruct one such circuit at synaptic resolution, the $\textit{Drosophila}$ larval mushroom body. We find that most Kenyon cells integrate random combinations of inputs but that a subset receives stereotyped inputs from single projection neurons. This organization maximizes performance of a model output neuron on a stimulus discrimination task. We also report a novel canonical circuit in each mushroom body compartment with previously unidentified connections: reciprocal Kenyon cell to modulatory neuron connections, modulatory neuron to output neuron connections, and a surprisingly high number of recurrent connections between Kenyon cells. Stereotyped connections found between output neurons could enhance the selection of learned behaviours. The complete circuit map of the mushroom body should guide future functional studies of this learning and memory centre.AL-K was supported by NIH grant #F32DC014387. AL-K and LFA were supported by the Simons Collaboration on the Global Brain. LFA was also supported by the Gatsby, Mathers and Kavli Foundations. CEP and YP were supported by the DARPA XDATA program (AFRL contract FA8750-12-2-0303) and the NSF BRAIN EAGER award DBI-1451081. KE and AST thank the Deutsche Forschungsgemeinschaft, TH1584/1-1, TH1584/3- 1; the Swiss National Science Foundation, 31003A 132812/1; the Baden Wurttemberg Stiftung; Zukunftskolleg of the University of ¨ Konstanz and DAAD. BG and TS thank the Deutsche Forschungsgemeinschaft, CRC 779, GE 1091/4-1; the European Commission, FP7-ICT MINIMAL. We thank the Fly EM Project Team at HHMI Janelia for the gift of the EM volume, the Janelia Visiting Scientist program, the HHMI visa office, and HHMI Janelia for funding

Factors that influence nurses' assessment of patient acuity and response to acute deterioration.

BACKGROUND: nurses play a crucial role in the early recognition and management of the deteriorating patient. They are responsible for the care they provide to their patients, part of which is the monitoring of vital signs (blood pressure, pulse, respiratory rate and temperature), which are fundamental in the surveillance of deterioration. The aim of this study was to discover what factors influence how nurses assess patient acuity and their response to acute deterioration. METHODS: a generic qualitative approach was used. Some 10 nurses working in an acute NHS trust were interviewed using a semi- structured approach, with equal representation from medical and surgical inpatient wards. RESULTS: the main themes identified were collegial relationships, intuition, and interpretation of the MEWS system (Modified Early Warning Score). Collegial relationships with the medical staff had some influence on the nurses' assessment, as they tended to accept the medical peers' assessment as absolute, rather than their own assessment. It was also highlighted that nurses relied on the numerical escalation of the MEWS system to identify the deteriorating patient, instead of their own clinical judgement of the situation. Interestingly, the nurses found no difficulty in escalating the patient's care to medical staff when the patient presented with a high MEWS score. The difficulty arose when the MEWS score was low-the participants found it challenging to authenticate their findings. CONCLUSION: this study has identified several confounding factors that influence the ways in which nurses assess patient acuity and their response to acute deterioration. The information provides a crucial step forward in identifying strategies to develop further training

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.100213

A study of plane, axi-symmetric and general three dimensional elastic contacts

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