Peripheral inflammation is associated with remote global gene expression changes in the brain

Background: Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain.<p></p> Methods: Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation.<p></p> Results: Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain.<p></p> Conclusions: These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes.<p></p&gt

Trapline foraging by bumble bees: VII. Adjustments for foraging success following competitor removal

Animals collecting food from renewable resource patches scattered in space often establish small foraging areas to which they return faithfully. Such area fidelity offers foraging advantages through selection of profitable patches route minimization and regular circuit visits to these patches (“trapline foraging”). Resource distribution under field conditions may often vary in time however especially when competitors suddenly vanish and a number of patches become available for their neighbors. Previous studies suggested that site-faithful foragers of bumble bees quickly respond to such unexpected events by readjusting their foraging areas although it is not clear how much their foraging performance was improved beyond the simple relaxation of competitive pressure or how they manifest such flexibility while persistently using certain foraging areas or paths. Here we conducted indoor flight-cage experiments with bumble bees and found that a bee when encountering a loss of its competitor improved its foraging performance to a greater extent than expected from a simple relaxation of competitive pressure by increasing the size of its foraging area. Moreover bees with better-established traplines achieved greater foraging areas after the loss of competitors suggesting that bees do not necessarily need to “sample” neighboring patches to monitor temporal changes in environments. We discuss how periodical returns and route memory associated with accurate reward values could allow inherently conservative trapliners to make flexible adjustments by effectively monitoring their circumstances and quickly readjusting to detected changes.journal articl

The forgotten '45 : Donald Dubh's rebellion in an archipelagic context

The final rebellion of Donald Dubh, heir to the forfeited MacDonald lordship of the Isles, is usually examined within the context of Highland rebellions that occurred in the half century after forfeiture. However, the factors that motivated the Islesmen to rise in rebellion in 1545 are multi-faceted and can only be fully understood by placing the rising in a wider context, which considers national and archipelagic events. The discussion that follows explores the reasons why the Islesmen, almost unanimously, entered into agreement with Henry VIII to attack Scotland from the west and why this endeavour failed. At the same time, the article highlights Henry’s recognition of the strategic importance of the west which led him into alliance with Donald Dubh and his supporters

The use of a thyroid shield for intra-oral anterior oblique occlusal views - a risk based approach

Objectives: To estimate the radiation dose reduction to the thyroid for an anterior oblique occlusal view from the use of a thyroid shield, compare this with the variation in thyroid dose resulting from differences in examination positioning and discuss the additional considerations associated with the use of a thyroid shield before making a recommendation on their routine use for this examination. Methods: Doses to the oral mucosa, the salivary glands, the thyroid, the extrathoracic airways, the oesophagus and the lungs were directly measured for anterior oblique occlusal X-rays of a Rando phantom with and without a thyroid shield using strips of calibrated XRQA Gafchromic film. The examination was also simulated using Monte Carlo software for the without thyroid shield case for a comparison of the dose and to evaluate the dosimetric effect of suboptimal examination positioning.Results: A 36% reduction in thyroid dose was measured as a result of thyroid shield use; the effective dose reduction is of the order of 22%. Suboptimal positioning was found to increase thyroid dose by a far more significant amount. Conclusions: Despite the reduction in thyroid dose, cost-benefit considerations mean that the purchase of a thyroid shield is only recommended where a very high number of anterior oblique occlusal views are undertaken. Optimization efforts for this examination are better focussed on training in examination positioning.</p

Therapeutic drug monitoring in the past 40 years of the JAC

Since the Journal was first published in 1975, papers addressing therapeutic drug monitoring (TDM) have been a regular feature. Initially they focused on laboratory aspects of drug concentration measurement then they changed more to the application of TDM in a clinical setting. Over its history, the Journal has provided its readership with the latest technological and scientific advances in TDM and has helped to drive changes in TDM that have directly impacted on patient care. These have varied from improvement in the quality of antimicrobial measurements through better identification of dosage regimens and TDM targets that help predict outcome and adverse events

Amikacin concentrations and target ranges for mycobacterial infection

The aim of this research is to determine whether amikacin dosage guidelines for multi - drug resistant mycobacterial infections achieve peaks of 35 - 45 mg/L (OD) or 65 - 80 mg/L (TW) and troughs <5 mg/L

Contact-induced apical asymmetry drives the thigmotropic responses of Candida albicans hyphae

Acknowledgements We thank Marco Thiel for assistance with data interpretation, Peter Sudbery for the provision of strains and Jeremy Craven for useful discussions. This work was supported by a BBSRC-DTG to D. D. T., NIH award DK083592 to F. J. B. and P. A. J., and a Royal Society URF UF080611 and MRC NIRG 90671 to A. C. B.Non peer reviewedPublisher PD

Timing of the first vancomycin maintenance dose in an acute hospital setting - room for improvement?

Introduction Intravenous vancomycin therapy typically starts with a loading dose followed by a maintenance dose 12 to 24 hours later. In the acute hospital setting, this often results in doses being administered in the middle of the night, which is impractical for both patients and staff. This audit examined current practice and developed new guidelines to support greater flexibility in the timing of the first maintenance dose. Methods Data recording forms used by pharmacists to support the therapeutic drug monitoring of vancomycin were collected from two hospital sites over six weeks. Forms containing at least two vancomycin concentrations were selected and the time of administration of the first maintenance dose was recorded. Individual vancomycin pharmacokinetic parameter estimates were obtained using MAP Bayesian analysis then used to predict vancomycin concentrations 6, 8, 10, 12 and 14 hours after a banded loading dose and 20 mg/kg (capped at 3000 mg). Predicted concentrations were compared with a target range of 10 – 20 mg/L. Results Data were obtained from 49 patients with a mean (SD) age of 63.1 (16.7) years and weight 80.1 (27.6) kg. In all patients, creatinine clearance estimates were >40 mL/min and, according to current practice guidelines, all patients required 12 hourly maintenance dosing. The time recorded for the administration of the first maintenance dose was between 11 pm and 7 am in 30 (61%) of these patients. In 14 patients (29%), the first maintenance dose was administered >12 hours after loading. The target range was achieved with banded doses (20 mg/kg) in 65% (71%) of concentrations at 6 hours, 74% (84%) at 8 hours, 57% (67%) at 10 hours, 53% (55%) at 12 hours and 39% (43%) at 14 hours. Conclusions This audit has shown that current practice results in a high proportion of vancomycin maintenance doses being administered at impractical times. Allowing a more flexible time window of 6-12 hours after the loading dose for administration of the first vancomycin maintenance dose could help to alleviate this problem and reduce the risk of early subtherapeutic vancomycin trough concentrations