The systemic response to topical Aldara treatment is mediated through direct TLR7 stimulation as Imiquimod enters the circulation

Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use

The Effects of Alcohol on the Protein Profile of Rat Lingual Epithelium

A large volume of epidemiological evidence suggests a strong correlation between chronic alcohol abuse and the development of intra oral squamous cell carcinoma (Rothman & Keller, 1972; Kissin, 1975; Tuyns, 1982). Despite this evidence linking alcohol abuse and oral cancer, there are few properly controlled studies of the effect of alcohol alone on the oral epithelium. Those that have been properly controlled have demonstrated histological effects of alcohol on the epithelium. Structural or morphological changes in the oral epithelium may have a biochemical basis and thus the aim of this study was to investigate any biochemical abnormalities in the oral epithelium of alcoholic animals. The specific approach to the study involved an assessment of the effects of alcohol on the protein profile of rat lingual epithelium. A suitable animal model was required for the study and that chosen was the Isocalorific Matched Pair Feeding Technique of Lieber and DeCarli (1973). This involved maintaining one group of experimental animals on a nutritionally adequate liquid diet with ethanol substituted to provide 36 percent of the daily calorific intake. A second group was maintained on the same liquid diet, but with sucrose substituted to provide 36 percent of the animals' calories. By measuring the volume of diet consumed, each pair of animals had their calorific intake closely monitored and matched exactly. A control group maintained on standard laboratory chow was included in both of the animal studies presented and, in the second study, an additional control group maintained on liquid diet alone was also included. The usefulness of this animal model as a representation of chronic alcohol consumption was demonstrated by assessing liver damage in the alcoholic animals. Liver damage was demonstrated both enzymically, with Gamma-Glutamyl Transferase being of particular use in this respect, and histologically, with centrilobular fatty infiltration being observed in the livers of the alcoholic animals. Unfortunately, two of the liver enzymes that were measured, Aspartate Transaminase and Alanine Transaminase, appeared to be affected by the liquid diet and as a result were of limited use in assessing liver damage. It was as a means of investigating the effects of the liquid diet on these enzymes that the extra control group was included in the second animal study. The initial animal study ran for 102 days at the end of which, the animals were sacrificed and the lingual epithelium was removed and prepared for sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. Results from this protein study revealed, in the alcoholic animals, a reduction in the levels of a high molecular weight (MW) glycoprotein with a molecular weight of c. 160 Kilodaltons (K), and an accompanying increase in the levels of two lower MW proteins (30K and 28K). Visual and densitometric analysis revealed that these protein levels were significantly altered in the alcoholic animals with respect to both the sucrose pair-fed control animals and the animals maintained on standard laboratory chow. A second animal study was set up to investigate the alterations in the levels of these three proteins, in the alcoholic animals, over fractions of the original 102 day study. The results demonstrated that chronic alcohol consumption was required before alterations could be detected in the levels of these proteins. It was postulated that the two lower MW proteins may be breakdown products of the high MW glycoprotein although there was no evidence of such a relationship in this time-course study, with each of the proteins being capable of expressing themselves at altered levels independently of the other two. An alternative approach to investigating a possible relationship between the high MW glycoprotein and the two lower MW proteins involved the use of peptide mapping. Results from these studies were inconclusive as the high MW glycoprotein appeared to be resistant to proteolytic digestion. Characterisation of the two lower MW proteins proved to be difficult as little was known about them, short of their molecular weights. Subcellular localisation studies revealed the 30K protein to be present in the epithelial cells associated with the membrane/microsomal fraction. Unfortunately, the 28K protein was more difficult to study in this respect, as it banded on SDS gels alongside a protein of very similar molecular weight as a closely associated doublet. One member of this doublet was seen to be associated with the membrane/microsomal fraction and the other with the cytoplasmic fraction of the cell. It is not yet clear which member of this doublet is enhanced in the alcoholic animals. Investigation of the solubility of these two proteins showed them to be maximally soluble in distilled water. Given the lack of information on these two proteins, it has not been possible to accurately identify them. It is suggested, however, that they may be members of the heat shock family of proteins. (Abstract shortened by ProQuest.)

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

CCL19-sorted mature dendritic cells have enhanced lymph node migratory capacity and function

No abstract available

A Renormalisation group for TCSA

We discuss the errors introduced by level truncation in the study of boundary renormalisation group flows by the Truncated Conformal Space Approach. We show that the TCSA results can have the qualitative form of a sequence of RG flows between different conformal boundary conditions. In the case of a perturbation by the field phi(13), we propose a renormalisation group equation for the coupling constant which predicts a fixed point at a finite value of the TCSA coupling constant and we compare the predictions with data obtained using TBA equations.Comment: 11 pages, 7 figures, talk presented by G Watts at the workshop "Integrable Models and Applications: from Strings to Condensed Matter", Santiago de Compostela, Spain, 12-16 September 200

Editorial : Launch of the European Journal of Taxonomy (EJT)

We are very pleased and proud to announce the launch of the European Journal of Taxonomy. The EJT is an international, online, fast-track, peer-reviewed, open access journal in descriptive taxonomy,covering subjects in zoology, entomology, botany, and palaeontology, owned and run by a Consortium of European Natural History Institutes. EJT is a collaborative project outcome of the EDIT network

Elevated ACKR2 expression is a common feature of inflammatory arthropathies

Objectives. Chemokines are essential contributors to leucocyte accumulation at sites of inflammatory pathology. Interfering with chemokine or chemokine receptor function therefore represents a plausible therapeutic option. However, our currently limited understanding of chemokine orchestration of inflammatory responses means that such therapies have not yet been fully developed. We have a particular interest in the family of atypical chemokine receptors that fine-tune, or resolve, chemokine-driven responses. In particular we are interested in atypical chemokine receptor 2 (ACKR2), which is a scavenging receptor for inflammatory CC-chemokines and that therefore helps to resolve in vivo inflammatory responses. The objective of the current study was to examine ACKR2 expression in common arthropathies. Methods. ACKR2 expression was measured by a combination of qPCR and immuno-histochemistry. In addition, circulating cytokine and chemokine levels in patient plasma were assessed using multiplexing approaches. Results. Expression of ACKR2 was elevated on peripheral blood cells as well as on leucocytes and stromal cells in synovial tissue. Expression on peripheral blood leucocytes correlated with, and could be regulated by, circulating cytokines with particularly strong associations being seen with IL-6 and hepatocyte growth factor. In addition, expression within the synovium was coincident with aggregates of lymphocytes, potentially atopic follicles and sites of high inflammatory chemokine expression. Similarly increased levels of ACKR2 have been reported in psoriasis and SSc. Conclusion. Our data clearly show increased ACKR2 in a variety of arthropathies and taking into account our, and others’, previous data we now propose that elevated ACKR2 expression is a common feature of inflammatory pathologies

Compatibility of the large quasar groups with the concordance cosmological model

We study the compatibility of large quasar groups with the concordance cosmological model. Large quasar groups are very large spatial associations of quasars in the cosmic web, with sizes of 50–250 h−1 Mpc. In particular, the largest large quasar group known, named Huge-LQG, has a longest axis of ∼860 h−1 Mpc, larger than the scale of homogeneity (∼260 Mpc), which has been noted as a possible violation of the cosmological principle. Using mock catalogues constructed from the Horizon Run 2 cosmological simulation, we found that large quasar groups size, quasar member number and mean overdensity distributions in the mocks agree with observations. The Huge-LQG is found to be a rare group with a probability of 0.3 per cent of finding a group as large or larger than the observed, but an extreme value analysis shows that it is an expected maximum in the sample volume with a probability of 19 per cent of observing a largest quasar group as large or larger than Huge-LQG. The Huge-LQG is expected to be the largest structure in a volume at least 5.3 ± 1 times larger than the one currently studied

Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes

Background: Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication. Methods: Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate Result: Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma. Conclusions: Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities