Differential Effect of LPS on Glucose, Lactate and Inflammatory Markers in the Lungs of Normal and Diabetic Mice

Elevation of blood glucose results in increased glucose in the fluid that lines the surface of the airways and this is associated with an increased susceptibility to infection with respiratory pathogens. Infection induces an inflammatory response in the lung, but how this is altered by hyperglycemia and how this affects glucose, lactate and cytokine concentrations in the airway surface liquid is not understood. We used Wild Type (WT) and glucokinase heterozygote (GK+/-) mice to investigate the effect of hyperglycemia, with and without LPS-induced inflammatory responses, on airway glucose, lactate, inflammatory cells and cytokines measured in Bronchoalveolar Lavage Fluid (BALF). We found that glucose and lactate concentrations in BALF were elevated in GK+/-compared to WT mice and that there was a direct correlation between blood glucose and BALF glucose concentrations. LPS challenge increased BALF inflammatory cell numbers and this correlated with decreased glucose and increased lactate concentrations although the effect was less in GK+/- compared to WT mice. All cytokines measured (except IL-2) increased in BALF with LPS challenge. However, concentrations of TNFa, INFg, IL-1band IL-2 were less in GK+/- compared to WT mice. This study shows that the normal glucose/lactate environment of the airway surface liquid is altered by hyperglycemia and the inflammatory response. These data indicate that inflammatory cells utilize BALF glucose and that production of lactate and cytokines is compromised in hyperglycemic GK+/-mice

Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

BACKGROUND AND PURPOSE: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. EXPERIMENTAL APPROACH: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. KEY RESULTS: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. CONCLUSION AND IMPLICATIONS: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection

Modelling human performance within manufacturing systems design:from a theoretical towards a practical framework

Computer-based simulation is frequently used to evaluate the capabilities of proposed manufacturing system designs. Unfortunately, the real systems are often found to perform quite differently from simulation predictions and one possible reason for this is an over-simplistic representation of workers' behaviour within current simulation techniques. The accuracy of design predictions could be improved through a modelling tool that integrates with computer-based simulation and incorporates the factors and relationships that determine workers' performance. This paper explores the viability of developing a similar tool based on our previously published theoretical modelling framework. It focuses on evolving this purely theoretical framework towards a practical modelling tool that can actually be used to expand the capabilities of current simulation techniques. Based on an industrial study, the paper investigates how the theoretical framework works in practice, analyses strengths and weaknesses in its formulation, and proposes developments that can contribute towards enabling human performance modelling in a practical way

A modified fluorescent sensor for reporting glucose concentration in the airway lumen.

We have modified the periplasmic Escherichia coli glucose/galactose binding protein (GBP) and labelled with environmentally sensitive fluorophores to further explore its potential as a sensor for the evaluation of glucose concentration in airway surface liquid (ASL). We identified E149C/A213R GBP labelled with N,N'-Dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)ethylenediamine (IANBD, emission wavelength maximum 536nm) with a Kd for D-glucose of 1.02mM and a fluorescence dynamic range of 5.8. This sensor was specific for D-glucose and exhibited fluorescence stability in experiments for several hours. The use of E149C/A213R GBP-IANBD in the ASL of airway cells grown at air-liquid-interface (ALI) detected an increase in glucose concentration 10 minutes after raising basolateral glucose from 5 to 15mM. This sensor also reported a greater change in ASL glucose concentration in response to increased basolateral glucose in H441 airway cells compared to human bronchial epithelial cells (HBEC) and there was less variability with HBEC data than that of H441 indicating that HBEC more effectively regulate glucose movement into the ASL. The sensor detected glucose in bronchoalveolar lavage fluid (BALf) from diabetic db/db mice but not normoglycaemic wildtype mice, indicating limited sensitivity of the sensor at glucose concentrations <50μM. Using nasal inhalation of the sensor and spectral unmixing to generate images, E149C/A213R GBP-IANBD fluorescence was detected in luminal regions of cryosections of the murine distal lung that was greater in db/db than wildtype mice. In conclusion, this sensor provides a useful tool for further development to measure luminal glucose concentration in models of lung/airway to explore how this may change in disease

Cytokinesis in bloodstream stage Trypanosoma brucei requires a family of katanins and spastin

Microtubule severing enzymes regulate microtubule dynamics in a wide range of organisms and are implicated in important cell cycle processes such as mitotic spindle assembly and disassembly, chromosome movement and cytokinesis. Here we explore the function of several microtubule severing enzyme homologues, the katanins (KAT80, KAT60a, KAT60b and KAT60c), spastin (SPA) and fidgetin (FID) in the bloodstream stage of the African trypanosome parasite, Trypanosoma brucei. The trypanosome cytoskeleton is microtubule based and remains assembled throughout the cell cycle, necessitating its remodelling during cytokinesis. Using RNA interference to deplete individual proteins, we show that the trypanosome katanin and spastin homologues are non-redundant and essential for bloodstream form proliferation. Further, cell cycle analysis revealed that these proteins play essential but discrete roles in cytokinesis. The KAT60 proteins each appear to be important during the early stages of cytokinesis, while downregulation of KAT80 specifically inhibited furrow ingression and SPA depletion prevented completion of abscission. In contrast, RNA interference of FID did not result in any discernible effects. We propose that the stable microtubule cytoskeleton of T. brucei necessitates the coordinated action of a family of katanins and spastin to bring about the cytoskeletal remodelling necessary to complete cell divisio

The Expanding Fireball of Nova Delphini 2013

A classical nova occurs when material accreting onto the surface of a white dwarf in a close binary system ignites in a thermonuclear runaway. Complex structures observed in the ejecta at late stages could result from interactions with the companion during the common envelope phase. Alternatively, the explosion could be intrinsically bipolar, resulting from a localized ignition on the surface of the white dwarf or as a consequence of rotational distortion. Studying the structure of novae during the earliest phases is challenging because of the high spatial resolution needed to measure their small sizes. Here we report near-infrared interferometric measurements of the angular size of Nova Delphini 2013, starting from one day after the explosion and continuing with extensive time coverage during the first 43 days. Changes in the apparent expansion rate can be explained by an explosion model consisting of an optically thick core surrounded by a diffuse envelope. The optical depth of the ejected material changes as it expands. We detect an ellipticity in the light distribution, suggesting a prolate or bipolar structure that develops as early as the second day. Combining the angular expansion rate with radial velocity measurements, we derive a geometric distance to the nova of 4.54 +/- 0.59 kpc from the Sun.Comment: Published in Nature. 32 pages. Final version available at http://www.nature.com/nature/journal/v515/n7526/full/nature13834.htm

Anaesthetic considerations of adults with Morquio's syndrome - a case report

<p>Abstract</p> <p>Background</p> <p>The anaesthetic management of patients with Morquio syndrome is complicated by a number of factors including odontoid hypoplasia, atlantoaxial instability, thoracic kyphosis, and deposition of mucopolysaccharides in the soft tissue of the oropharnyx.</p> <p>Case presentation</p> <p>Herein we describe the anaesthetic considerations and management of a 26 year old adult with Morquio syndrome, who presented for an elective hip replacement.</p> <p>Conclusion</p> <p>This report details an awake fiberoptic intubation in an adult with Morquio syndrome. We recommend that this approach be considered in patients with Morquio syndrome undergoing general anaesthesia.</p

What is the point: will screening mammography save my life?

Background: We analyzed the claim mammography saves lives by calculating the life-saving absolute benefit of screening mammography in reducing breast cancer mortality in women ages 40 to 65. Methods: To calculate the absolute benefit, we first estimated the screen-free absolute death risk from breast cancer by adjusting the Surveillance, Epidemiology and End Results Program 15-year cumulative breast cancer mortality to account for the separate effects of screening mammography and improved therapy. We calculated the absolute risk reduction (reduction in absolute death risk), the number needed to screen assuming repeated screening, and the survival percentages without and with screening. We varied the relative risk reduction from 10%–30% based on the randomized trials of screening mammography. We developed additional variations of the absolute risk reduction for a screening intervention, including the average benefit of a single screen, as well as the life-saving proportion among patients with earlier cancer detection. Results: Because the screen-free absolute death risk is approximately 1% overall but rises with age, the relative risk reduction from repeated screening mammography is about 100 times the absolute risk reduction between the starting ages of 50 and 60. Assuming a base case 20% relative risk reduction, repeated screening starting at age 50 saves about 1.8 (overall range, 0.9–2.7) lives over 15 years for every 1000 women screened. The number needed to screen repeatedly is 1000/ 1.8, or 570. The survival percentage is 99.12% without and 99.29% with screening. The average benefit of a single screening mammogram is 0.034%, or 2970 women must be screened once to save one life. Mammography saves 4.3% of screen-detectable cancer patients\u27 lives starting at age 50. This means 23 cancers must be found starting at age 50, or 27 cancers at age 40 and 21 cancers at age 65, to save one life. Conclusion: The life-saving absolute benefit of screening mammography increases with age as the absolute death risk increases. The number of events needed to save one life varies depending on the prospective screening subset or reference class. Less than 5% of women with screen-detectable cancers have their lives saved

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co

Determining solar effects in Neptune’s atmosphere

Long-duration observations of Neptune’s brightness in two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultra-violet (UV) or galactic cosmic ray (GCR) effects on atmospheric particles. Here we use a recently extended brightness dataset (1972-2014), with physically realistic modelling to show that rather than alternatives, UV and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune's atmosphere to an intermittent 1.5 to 1.9 year periodicity, which occurred preferentially in GCR (not UV) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and UV mechanisms may occur more rapidly than the subsequent atmospheric particle transport