Heat-kernels and functional determinants on the generalized cone

We consider zeta functions and heat-kernel expansions on the bounded, generalized cone in arbitrary dimensions using an improved calculational technique. The specific case of a global monopole is analysed in detail and some restrictions thereby placed on the $A_{5/2}$ coefficient. The computation of functional determinants is also addressed. General formulas are given and known results are incidentally, and rapidly, reproduced.Comment: 26p,LaTeX.(Cosmetic changes and eqns (9.8),(11.2) corrected.

Early blood stream infection after BMT is associated with cytokine dysregulation and poor overall survival

The key complications of allogeneic bone marrow transplant (BMT) remain graft-versus-host disease (GVHD) and opportunistic infection. We have analyzed the blood stream infections (BSI) occurring between day -7 and day 100 in a cohort of 184 adult patients undergoing allogeneic BMT in our center. 167 of the 184 patients (91%) had blood cultures collected, and 69 (38%) patients had a confirmed BSI. Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp. and viridans Streptococcus spp. were the most commonly isolated organisms. Gender, conditioning (myeloablative vs. reduced intensity) and donor type (sibling vs. unrelated) did not differ significantly between those with and without confirmed BSI. Elevated temperature (>38°C) at the time of culture collection was associated with an almost 2-fold increased likelihood of returning a positive blood culture. The absence of a BSI was associated with a significant improvement in overall survival at 2 years, due to a significant reduction in non-relapse mortality predominantly unrelated to the primary BSI. The presence of a BSI prior to engraftment was associated with the dysregulation of IL-6 and IL-8. Our findings suggest that BSI early after BMT defines a group of high-risk patients with enhanced cytokine dysregulation and poor transplant outcome

Glucocorticoids can activate the α-ENaC gene promoter independently of SGK1

The role of SGK1 (serum- and glucocorticoid-induced protein kinase 1) in the glucocorticoid induction of α-ENaC (epithelial Na+ channel α subunit) gene transcription was explored by monitoring the transcriptional activity of a luciferase-linked, α-ENaC reporter gene construct (pGL3-KR1) expressed in H441 airway epithelial cells. Dexamethasone evoked a concentration-dependent (EC50∼4 μM) increase in transcriptional activity dependent upon a glucocorticoid response element in the α-ENaC sequence. Although dexamethasone also activated endogenous SGK1, artificially increasing cellular SGK1 activity by expressing a constitutively active SGK1 mutant (SGK1-S422D) in hormone-deprived cells did not activate pGL3-KR1. Moreover, expression of catalytically inactive SGK1 (SGK1-K127A) suppressed the activation of endogenous SGK1 without affecting the transcriptional response to dexamethasone. Increasing cellular PI3K (phosphoinositide 3-kinase) activity by expressing a membrane-anchored form of the catalytic PI3K-P110α subunit [CD2 (cluster of differentiation 2)-P110α] also activated endogenous SGK1 without affecting pGL3-KR1activity. A catalytically inactive form of CD2-P110α (R1130P), on the other hand, prevented the dexamethasone-induced activation of SGK1, but did not inhibit the activation of pGL3-KR1. However, expression of SGK1-S422D or CD2-P110α enhanced the transcriptional responses to maximally effective concentrations of dexamethasone and this effect occurred with no change in EC50. Dexamethasone-induced (0.3–300 nM) activation of pGL3-KR1 was unaffected by inhibitors of PI3K (PI-103 and wortmanin) and by rapamycin, a selective inhibitor of the TORC1 (target of rapamycin complex 1) signalling complex. Dexamethasone-induced activation of the α-ENaC gene promoter can thus occur independently of SGK1/PI3K, although this pathway does provide a mechanism that allows this transcriptional response to dexamethasone to be enhanced

Recipient mucosal-associated invariant T cells control GVHD within the colon

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I–like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A–/– and MR1–/– mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A–dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT

CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17–dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS–). Cutaneous cGVHD developed in a CSF-1/CSF-1R–dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r–/– mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti–CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD

Improving risk management for violence in mental health services: a multimethods approach

contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-2015contractual_start_date: 07-2008 editorial_review_begun: 07-2014 accepted_for_publication: 06-201