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

Assessment of ePrescription quality: an observational study at three mail-order pharmacies

<p>Abstract</p> <p>Background</p> <p>The introduction of electronic transfer of prescriptions (ETP) or ePrescriptions in ambulatory health care has been suggested to have a positive impact on the prescribing and dispensing processes. Thereby, implying that ePrescribing can improve safety, quality, efficiency, and cost-effectiveness. In December 2007, 68% of all new prescriptions were transferred electronically in Sweden. The aim of the present study was to assess the quality of ePrescriptions by comparing the proportions of ePrescriptions and non-electronic prescriptions necessitating a clarification contact (correction, completion or change) with the prescriber at the time of dispensing.</p> <p>Methods</p> <p>A direct observational study was performed at three Swedish mail-order pharmacies which were known to dispense a large proportion of ePrescriptions (38–75%). Data were gathered on all ePrescriptions dispensed at these pharmacies over a three week period in February 2006. All clarification contacts with prescribers were included in the study and were classified and assessed in comparison with all drug prescriptions dispensed at the same pharmacies over the specified period.</p> <p>Results</p> <p>Of the 31225 prescriptions dispensed during the study period, clarification contacts were made for 2.0% (147/7532) of new ePrescriptions and 1.2% (79/6833) of new non-electronic prescriptions. This represented a relative risk (RR) of 1.7 (95% CI 1.3–2.2) for new ePrescriptions compared to new non-electronic prescriptions. The increased RR was mainly due to 'Dosage and directions for use', which had an RR of 7.6 (95% CI 2.8–20.4) when compared to other clarification contacts. In all, 89.5% of the suggested pharmacist interventions were accepted by the prescriber, 77.7% (192/247) as suggested and an additional 11.7% (29/247) after a modification during contact with the prescriber.</p> <p>Conclusion</p> <p>The increased proportion of prescriptions necessitating a clarification contact for new ePrescriptions compared to new non-electronic prescriptions indicates the need for an increased focus on quality aspects in ePrescribing deployment. ETP technology should be developed towards a two-way communication between the prescriber and the pharmacist with automated checks of missing, inaccurate, or ambiguous information. This would enhance safety and quality for the patient and also improve efficiency and cost-effectiveness within the health care system.</p

Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach

The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1−/− and GPR55−/−) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55−/− mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55−/− mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control

Predicting the ligand-binding properties of Borrelia burgdorferi ss Bmp proteins in light of the conserved features of related Borrelia proteins

Bacteria of the genus Borrelia cause vector-borne infections like the most important hard tick-borne disease in the northern hemisphere, Lyme borreliosis (LB), and soft tick or louse transmitted relapsing fevers (RF), prevalent in temperate and tropical areas. Borrelia burgdorferi sensu lato (s.l.) includes several genospecies and causes LB in humans. In infected patients, Borrelia burgdorferi sensu stricto (s.s.) expresses the BmpA, BmpB, BmpC and BmpD proteins. The role of these proteins in the pathogenesis of LB remains incompletely characterized, but they are, however, closely related to Treponema pallidum PnrA (Purine nucleoside receptor A), a substrate-binding lipoprotein of the ATP-binding cassette (ABC) transporter family preferentially binding purine nucleosides. Based on 3D homology modeling, the Bmp proteins share the typical fold of the substrate-binding protein family and the ligand-binding properties of BmpA, BmpB and BmpD are highly similar, whereas those of BmpC differ markedly. Nevertheless, these residues are highly conserved within the genus Borrelia and the inferred phylogenetic tree also reveals that the RF Borrelia lack BmpB proteins but has an additional Bmp protein (BmpA2) missing in LB-causing Borrelia burgdorferi s.l. Our results indicate that the Bmp proteins could bind nucleosides, although BmpC might have a different ligand-binding specificity and, therefore, a distinct function. Furthermore, the work provides a means for classifying the Bmp proteins and supports further elucidation of the roles of these proteins

Molecular Dynamics Simulations of the Interactions between Platinum Clusters and Carbon Platelets

Molecular dynamics simulations have been performed with two reactive force fields to investigate the structure of a Pt_(100) cluster adsorbed on the three distinct sides of a carbon platelet. A revised Reax force field for the carbon−platinum system is presented. In the simulations, carbon platelet edges both with and without hydrogen termination have been studied. It is found that the initial mismatch between the atomic structure of the platelet egde and the adsorbed face of the Pt_(100) cluster leads to a desorption of a few platinum atoms from the cluster and the subsequent restructuring of the cluster. Consequently, the average Pt−Pt bond length is enlarged in agreement with experimental results. This change in the bond length is supposed to play an important role in the enhancement of the catalytic activity, which is demonstrated by studying the changes in the bond order of the platinum atoms. We found an overall shift to lower values as well as a loss of the well-defined peak structure in the bond-order distribution

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

A mathematical modelling study of an athlete's sprint time when towing a weighted sled

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s12283-013-0114-2.This study used a mathematical model to examine the effects of the sled, the running surface, and the athlete on sprint time when towing a weighted sled. Simulations showed that ratio scaling is an appropriate method of normalising the weight of the sled for athletes of different body size. The relationship between sprint time and the weight of the sled was almost linear, as long as the sled was not excessively heavy. The athlete’s sprint time and rate of increase in sprint time were greater on running surfaces with a greater coefficient of friction, and on any given running surface an athlete with a greater power-to-weight ratio had a lower rate of increase in sprint time. The angle of the tow cord did not have a substantial effect on an athlete’s sprint time. This greater understanding should help coaches set the training intensity experienced by an athlete when performing a sled-towing exercise