The MIF antagonist ISO-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of COPD

Copyright © 2016 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods. Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from nonsmokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results. MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD

Excitation of airborne acoustic surface modes driven by a turbulent flow

This is the author accepted manuscript. The final version is available from AIAA via the DOI in this recordThis experiment demonstrated the generation of trapped acoustic surface waves excited by a turbulent flow source through the coupling of pressure fluctuations at the interface between an acoustic metamaterial and a flow environment. The turbulent flow, which behaves as a stochastic pressure source, was produced using a fully developed turbulent wall jet. The plate in the wall jet was perforated with a single cavity. On the flow-side it was capped by a Kevlar weave to ensure the cavity did not significantly disturb the flow, whilst on the adjacent side the cavity was open to the quiescent (static) environment. The through-cavity opening, on the quiescent side, was flush with an acoustic metasurface waveguide, which, through evanescent diffractive coupling of the pressure field, produced an acoustic surface mode. This acoustic mode was trapped at the plate surface, with its mode dispersion determined by the surface geometry. The results of two different metasurface geometries are discussed; (1) a slotted cavity array, and (2) a meander connected cavity array, each demonstrating a different trapped surface wave dispersion behavior. Fourier transform and correlation analyses of spatially-resolved temporal acoustic signals, measured close to the metamaterial surface, were used to construct the frequency and wave vector-dependent acoustic mode dispersion. Results demonstrated the flow can indeed be used to excite these acoustic modes and that their mode dispersion can be tailored towards realizing novel control of turbulent flow through acoustic-flow interactionsDefence Science and Technology Laboratory (DSTL

Empowerment or Engagement? Digital Health Technologies for Mental Healthcare

We argue that while digital health technologies (e.g. artificial intelligence, smartphones, and virtual reality) present significant opportunities for improving the delivery of healthcare, key concepts that are used to evaluate and understand their impact can obscure significant ethical issues related to patient engagement and experience. Specifically, we focus on the concept of empowerment and ask whether it is adequate for addressing some significant ethical concerns that relate to digital health technologies for mental healthcare. We frame these concerns using five key ethical principles for AI ethics (i.e. autonomy, beneficence, non-maleficence, justice, and explicability), which have their roots in the bioethical literature, in order to critically evaluate the role that digital health technologies will have in the future of digital healthcare

Variations in clinical decision-making between cardiologists and cardiac surgeons; a case for management by multidisciplinary teams?

OBJECTIVE: To assess variations in decisions to revascularise patients with coronary heart disease between general cardiologists, interventional cardiologists and cardiac surgeons DESIGN: Six cases of coronary heart disease were presented at an open meeting in a standard format including clinical details which might influence the decision to revascularise. Clinicians (n = 53) were then asked to vote using an anonymous electronic system for one of 5 treatment options: medical, surgical (CABG), percutaneous coronary intervention (PCI) or initially medical proceeding to revascularisation if symptoms dictated. Each case was then discussed in an open forum following which clinicians were asked to revote. Differences in treatment preference were compared by chi squared test and agreement between groups and between voting rounds compared using Kappa. RESULTS: Surgeons were more likely to choose surgery as a form of treatment (p = 0.034) while interventional cardiologists were more likely to choose PCI (p = 0.056). There were no significant differences between non-interventional and interventional cardiologists (p = 0.13) in their choice of treatment. There was poor agreement between all clinicians in the first round of voting (Kappa 0.26) but this improved to a moderate level of agreement after open discussion for the second vote (Kappa 0.44). The level of agreement among surgeons (0.15) was less than that for cardiologists (0.34) in Round 1, but was similar in Round 2 (0.45 and 0.45 respectively) CONCLUSION: In this case series, there was poor agreement between cardiac clinical specialists in the choice of treatment offered to patients. Open discussion appeared to improve agreement. These results would support the need for decisions to revascularise to be made by a multidisciplinary panel

The ‘Biophilic Organization’: An Integrative Metaphor for Corporate Sustainability

This paper proposes a new organizational metaphor, the ‘Biophilic Organization’, which aims to counter the bio-cultural disconnection of many organizations despite their espoused commitment to sustainability. This conceptual research draws on multiple disciplines such as evolutionary psychology and architecture to not only develop a diverse bio-cultural connection but to show how this connection tackles sustainability, in a holistic and systemic sense. Moreover, the paper takes an integrative view of sustainability, which effectively means that it embraces the different emergent tensions. Three specific tensions are explored: efficiency versus resilience, organizational versus personal agendas and isomorphism versus institutional change. In order to illustrate how the Biophilic Organization could potentially provide a synthesis strategy for such tensions, healthcare examples are drawn from the emerging fields of Biophilic Design in Singapore and Generative Design in the U.S.A. Finally, an example is provided which highlights how a Taoist cultural context has impacted on a business leader in China, to illustrative the significance of a transcendent belief system to such a bio-cultural narrative

Small group interventions for children aged 5-9 years old with mathematical learning difficulties

The research related to educational interventions for children with mathematical learning difficulties has been increasing steadily. In this chapter I focus on small group interventions for children aged 5–9 years old with learning difficulties in mathematics. First, I describe the important issues: (1) who are the children having problems in mathematics, (2) what do we mean with (special) education intervention, (3) what does Responsiveness to Intervention mean, and (4) what intervention features have been found effective for children aged 5–9 years with learning difficulties in mathematics. Then, I describe the research and developmental work that has been done in Finland on designing web services which provide evidence-based information and materials for educators. The two web services are LukiMat and ThinkMath. Together, these two web services include the knowledge base, assessment batteries and intervention tools to be used in relation to mathematical learning difficulties in the age group 5–9 years.Peer reviewe

A Global Metabolic Shift Is Linked to Salmonella Multicellular Development

Bacteria can elaborate complex patterns of development that are dictated by temporally ordered patterns of gene expression, typically under the control of a master regulatory pathway. For some processes, such as biofilm development, regulators that initiate the process have been identified but subsequent phenotypic changes such as stress tolerance do not seem to be under the control of these same regulators. A hallmark feature of biofilms is growth within a self-produced extracellular matrix. In this study we used metabolomics to compare Salmonella cells in rdar colony biofilms to isogenic csgD deletion mutants that do not produce an extracellular matrix. The two populations show distinct metabolite profiles. Even though CsgD controls only extracellular matrix production, metabolite signatures associated with cellular adaptations associated with stress tolerances were present in the wild type but not the mutant cells. To further explore these differences we examine the temporal gene expression of genes implicated in biofilm development and stress adaptations. In wild type cells, genes involved in a metabolic shift to gluconeogenesis and various stress-resistance pathways exhibited an ordered expression profile timed with multicellular development even though they are not CsgD regulated. In csgD mutant cells, the ordered expression was lost. We conclude that the induction of these pathways results from production of, and growth within, a self produced matrix rather than elaboration of a defined genetic program. These results predict that common physiological properties of biofilms are induced independently of regulatory pathways that initiate biofilm formation

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases