Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth.

Lung disease and elevation of blood glucose are associated with increased glucose concentration in the airway surface liquid (ASL). Raised ASL glucose is associated with increased susceptibility to infection by respiratory pathogens including Staphylococcus aureus and Pseudomonas aeruginosa. We have previously shown that the anti-diabetes drug, metformin, reduces glucose-induced S. aureus growth across in vitro airway epithelial cultures. The aim of this study was to investigate whether metformin has the potential to reduce glucose-induced P. aeruginosa infections across airway epithelial (Calu-3) cultures by limiting glucose permeability. We also explored the effect of P. aeruginosa and metformin on airway epithelial barrier function by investigating changes in tight junction protein abundance. Apical P. aeruginosa growth increased with basolateral glucose concentration, reduced transepithelial electrical resistance (TEER) and increased paracellular glucose flux. Metformin pre-treatment of the epithelium inhibited the glucose-induced growth of P. aeruginosa, increased TEER and decreased glucose flux. Similar effects on bacterial growth and TEER were observed with the AMP activated protein kinase agonist, 5-aminoimidazole-4-carboxamide ribonucleotide. Interestingly, metformin was able to prevent the P. aeruginosa-induced reduction in the abundance of tight junction proteins, claudin-1 and occludin. Our study highlights the potential of metformin to reduce hyperglycaemia-induced P. aeruginosa growth through airway epithelial tight junction modulation, and that claudin-1 and occludin could be important targets to regulate glucose permeability across airway epithelia and supress bacterial growth. Further investigation into the mechanisms regulating metformin and P. aeruginosa action on airway epithelial tight junctions could yield new therapeutic targets to prevent/suppress hyperglycaemia-induced respiratory infections, avoiding the use of antibiotics

Blow-up profile of rotating 2D focusing Bose gases

We consider the Gross-Pitaevskii equation describing an attractive Bose gas trapped to a quasi 2D layer by means of a purely harmonic potential, and which rotates at a fixed speed of rotation $\Omega$. First we study the behavior of the ground state when the coupling constant approaches $a\_*$ , the critical strength of the cubic nonlinearity for the focusing nonlinear Schr{\"o}dinger equation. We prove that blow-up always happens at the center of the trap, with the blow-up profile given by the Gagliardo-Nirenberg solution. In particular, the blow-up scenario is independent of $\Omega$, to leading order. This generalizes results obtained by Guo and Seiringer (Lett. Math. Phys., 2014, vol. 104, p. 141--156) in the non-rotating case. In a second part we consider the many-particle Hamiltonian for $N$ bosons, interacting with a potential rescaled in the mean-field manner $--a\_N N^{2\beta--1} w(N^{\beta} x), with$w$a positive function such that$\int\_{\mathbb{R}^2} w(x) dx = 1$. Assuming that$\beta < 1/2$and that$a\_N \to a\_*$sufficiently slowly, we prove that the many-body system is fully condensed on the Gross-Pitaevskii ground state in the limit$N \to \infty$

Morality and progress:IR narratives on international revisionism and the status quo

Scholars debate the ambitions and policies of today’s ‘rising powers’ and the extent to which they are revising or upholding the international status quo. While elements of the relevant literature provide valuable insight, this article argues that the concepts of revisionism and the status quo within mainstream International Relations (IR) have always constituted deeply rooted, autobiographical narratives of a traditionally Western-dominated discipline. As ‘ordering narratives’ of morality and progress, they constrain and organize debate so that revisionism is typically conceived not merely as disruption, but as disruption from the non-West amidst a fundamentally moral Western order that represents civilizational progress. This often makes them inherently problematic and unreliable descriptors of the actors and behaviours they are designed to explain. After exploring the formations and development of these concepts throughout the IR tradition, the analysis is directed towards narratives around the contemporary ‘rise’ of China. Both scholarly and wider political narratives typically tell the story of revisionist challenges China presents to a US/Western-led status quo, promoting unduly binary divisions between the West and non-West, and tensions and suspicions in the international realm. The aim must be to develop a new language and logic that recognize the contingent, autobiographical nature of ‘revisionist’ and ‘status quo’ actors and behaviours

The Cold Peace: Russo-Western Relations as a Mimetic Cold War

In 1989–1991 the geo-ideological contestation between two blocs was swept away, together with the ideology of civil war and its concomitant Cold War played out on the larger stage. Paradoxically, while the domestic sources of Cold War confrontation have been transcended, its external manifestations remain in the form of a ‘legacy’ geopolitical contest between the dominant hegemonic power (the United States) and a number of potential rising great powers, of which Russia is one. The post-revolutionary era is thus one of a ‘cold peace’. A cold peace is a mimetic cold war. In other words, while a cold war accepts the logic of conflict in the international system and between certain protagonists in particular, a cold peace reproduces the behavioural patterns of a cold war but suppresses acceptance of the logic of behaviour. A cold peace is accompanied by a singular stress on notions of victimhood for some and undigested and bitter victory for others. The perceived victim status of one set of actors provides the seedbed for renewed conflict, while the ‘victory’ of the others cannot be consolidated in some sort of relatively unchallenged post-conflict order. The ‘universalism’ of the victors is now challenged by Russia's neo-revisionist policy, including not so much the defence of Westphalian notions of sovereignty but the espousal of an international system with room for multiple systems (the Schmittean pluriverse)

A new generic open pit mine planning process with risk assessment ability

Conventionally, mining industry relies on a deterministic view, where a unique mine plan is determined based on a single resource model. A major shortfall of this approach is the inability to assess the risk caused by the well-known geological uncertainty, i.e. the in situ grade and tonnage variability of the mineral deposit. Despite some recent attempts in developing stochastic mine planning models which have demonstrated promising results, the industry still remains sceptical about this innovative idea. With respect to unbiased linear estimation, kriging is the most popular and reliable deterministic interpolation technique for resource estimation and it appears to remain its popularity in the near future. This paper presents a new systematic framework to quantify the risk of kriging-based mining projects due to the geological uncertainties. Firstly, conditional simulation is implemented to generate a series of equally-probable orebody realisations and these realisations are then compared with the kriged resource model to analyse its geological uncertainty. Secondly, a production schedule over the life of mine is determined based on the kriged resource model. Finally, risk profiles of that production schedule, namely ore and waste tonnage production, blending grade and Net Present Value (NPV), are constructed using the orebody realisations. The proposed model was applied on a multi-element deposit and the result demonstrates that that the kriging-based mine plan is unlikely to meet the production targets. Especially, the kriging-based mine plan overestimated the expected NPV at a magnitude of 6.70% to 7.34% (135 M$to 151 M$). A new multivariate conditional simulation framework was also introduced in this paper to cope with the multivariate nature of the deposit. Although an iron ore deposit is used to prove the concepts, the method can easily be adapted to other kinds of mineral deposits, including surface coal mine

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co

Design of the Advance Directives Cohort: a study of end-of-life decision-making focusing on Advance Directives

<p>Abstract</p> <p>Background</p> <p>ADs are documents in which one can state one's preferences concerning end-of-life care, aimed at making someone's wishes known in situations where he/she is not able to do so in another manner. There is still a lot unclear about ADs. We designed a study aimed at investigating the whole process from the formulating of an AD to its actual use at the end of life.</p> <p>Methods/Design</p> <p>The study has mixed methods: it's longitudinal, consisting of a quantitative cohort-study which provides a framework for predominantly qualitative sub-studies. The members of the cohort are persons owning an AD, recruited through two Dutch associations who provide the most common standard ADs in the Netherlands, the NVVE (Right to Die-NL), of which 5561 members participate, and the NPV (Dutch Patient Organisation), of which 1263 members participate. Both groups were compared to a sample of the Dutch general public. NVVE-respondents are more often single, higher educated and non-religious, while amongst NPV-respondents there are more Protestants compared to the Dutch public. They are sent a questionnaire every 1,5 year with a follow-up of at least 7,5 years. The response rate after the second round was 88% respectively 90% for the NVVE and NPV. Participants were asked if we were allowed to approach close-ones after their possible death in the future. In this way we can get insight in the actual use of ADs at the end of life, also by comparing our data to that from the Longitudinal Aging Study Amsterdam, whose respondents generally do not have an AD.</p> <p>Discussion</p> <p>The cohort is representative for people with an AD as is required to study the main research questions. The longitudinal nature of the study as well as the use of qualitative methods makes it has a broad scope, focusing on the whole course of decision-making involving ADs. It is possible to compare the end of life between patients with and without an AD with the use of data from another cohort.</p

Oral vitamin B(12 )therapy in the primary care setting: a qualitative and quantitative study of patient perspectives

BACKGROUND: Although oral replacement with high doses of vitamin B(12 )is both effective and safe for the treatment of B(12 )deficiency, little is known about patients' views concerning the acceptability and effectiveness of oral B(12). We investigated patient perspectives on switching from injection to oral B(12 )therapy. METHODS: This study involved a quantitative arm using questionnaires and a qualitative arm using semi-structured interviews, both to assess patient views on injection and oral therapy. Patients were also offered a six-month trial of oral B(12 )therapy. One hundred and thirty-three patients who receive regular B(12 )injections were included from three family practice units (two hospital-based academic clinics and one community health centre clinic) in Toronto. RESULTS: Seventy-three percent (63/86) of respondents were willing to try oral B(12). In a multivariate analysis, patient factors associated with a "willingness to switch" to oral B(12 )included being able to get to the clinic in less than 30 minutes (OR 9.3, 95% CI 2.2–40.0), and believing that frequent visits to the health care provider (OR 5.4, 95% CI 1.1–26.6) or the increased costs to the health care system (OR 16.7, 95% CI 1.5–184.2) were disadvantages of injection B(12). Fifty-five patients attempted oral therapy and 52 patients returned the final questionnaire. Of those who tried oral therapy, 76% (39/51) were satisfied and 71% (39/55) wished to permanently switch. Factors associated with permanently switching to oral therapy included believing that the frequent visits to the health care provider (OR 35.4, 95% CI 2.9–432.7) and travel/parking costs (OR 8.7, 95% CI 1.2–65.3) were disadvantages of injection B(12). Interview participants consistently cited convenience as an advantage of oral therapy. CONCLUSION: Switching patients from injection to oral B(12 )is both feasible and acceptable to patients. Oral B(12 )supplementation is well received largely due to increased convenience. Clinicians should offer oral B(12 )therapy to their patients who are currently receiving injections, and newly diagnosed B(12)-deficient patients who can tolerate and are compliant with oral medications should be offered oral supplementation

Innovative gait robot for the repetitive practice of floor walking and stair climbing up and down in stroke patients

<p>Abstract</p> <p>Background</p> <p>Stair climbing up and down is an essential part of everyday's mobility. To enable wheelchair-dependent patients the repetitive practice of this task, a novel gait robot, G-EO-Systems (EO, Lat: I walk), based on the end-effector principle, has been designed. The trajectories of the foot plates are freely programmable enabling not only the practice of simulated floor walking but also stair climbing up and down. The article intended to compare lower limb muscle activation patterns of hemiparetic subjects during real floor walking and stairs climbing up, and during the corresponding simulated conditions on the machine, and secondly to demonstrate gait improvement on single case after training on the machine.</p> <p>Methods</p> <p>The muscle activation pattern of seven lower limb muscles of six hemiparetic patients during free and simulated walking on the floor and stair climbing was measured via dynamic electromyography. A non-ambulatory, sub-acute stroke patient additionally trained on the G-EO-Systems every workday for five weeks.</p> <p>Results</p> <p>The muscle activation patterns were comparable during the real and simulated conditions, both on the floor and during stair climbing up. Minor differences, concerning the real and simulated floor walking conditions, were a delayed (prolonged) onset (duration) of the thigh muscle activation on the machine across all subjects. Concerning stair climbing conditions, the shank muscle activation was more phasic and timely correct in selected patients on the device. The severely affected subject regained walking and stair climbing ability.</p> <p>Conclusions</p> <p>The G-EO-Systems is an interesting new option in gait rehabilitation after stroke. The lower limb muscle activation patterns were comparable, a training thus feasible, and the positive case report warrants further clinical studies.</p