Reduced ventricular proliferation in the foetal cortex following maternal inflammation in the mouse

It has been well established that maternal inflammation during pregnancy alters neurological function in the offspring, but its impact on cortical development and long-term consequences on the cytoarchitecture is largely unstudied. Here we report that lipopolysaccharide-induced systemic maternal inflammation in C57Bl/6 mice at embryonic Day 13.5 of pregnancy, as early as 8 h after challenge, caused a significant reduction in cell proliferation in the ventricular zone of the developing cerebral cortex, as revealed by quantification of anti-phospho-Histone H3 immunoreactivity and bromodeoxyuridine pulse labelling. The angle of mitotic cleavage, determined from analysis of haematoxylin and eosin staining, cyclin E1 gene expression and the pattern of β-catenin immunoreactivity were also altered by the challenge, which suggests a change from symmetric to asymmetric division in the radial progenitor cells. Modifications of cortical lamination and gene expression patterns were detected at post-natal Day 8 suggesting prolonged consequences of these alterations during embryonic development. Cellular uptake of proteins from the cerebrospinal fluid was observed in brains from lipopolysaccharide-treated animals in radial progenitor cells. However, the foetal blood–brain barrier to plasma proteins remained intact. Together, these results indicate that maternal inflammation can disrupt the ventricular surface and lead to decreased cellular proliferation. Changes in cell density in Layers IV and V at post-natal Day 8 show that these initial changes have prolonged effects on cortical organization. The possible shift in the fate of progeny and the resulting alterations in the relative cell numbers in the cerebral cortex following a maternal inflammatory response shown here will require further investigation to determine the long-term consequences of inflammation on the development of neuronal circuitry and behaviour

The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor

Sanglifehrin A (SFA) is a cyclophilin-binding immunosuppressant but the immunobiology of action is poorly understood. We and others have reported that SFA inhibits IL-12 production and antigen uptake in dendritic cells (DC) and exhibits lower activity against lymphocytes. Here we show that SFA suppresses DC chemokine production and migration. Gene expression analysis and subsequent protein level confirmation revealed that SFA suppressed CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DC (moDC). A systems biology analysis, Onto Express, confirmed that SFA interferes with chemokine-chemokine receptor gene expression with the highest impact. Direct comparison with the related agent cyclosporine A (CsA) and dexamethasone indicated that SFA uniquely suppresses moDC chemokine expression. Competitive experiments with a 100-fold molar excess of CsA and with N-Methyl-Val-4-cyclosporin, representing a nonimmunosuppressive derivative of CsA indicated chemokine suppression through a cyclophilin-A independent pathway. Functional assays confirmed reduced migration of CD4+ Tcells and moDCs to supernatant of SFA-exposed moDCs. Vice versa, SFA-exposed moDC exhibited reduced migration against CCL19. Moreover, SFA suppressed expression of the ectoenzyme CD38 that was reported to regulate DC migration and cytokine production. These results identify SFA as a DC chemokine and migration inhibitor and provide novel insight into the immunobiology of SFA

Living in Living Cities

This paper presents an overview of current and potential applications of living technology to some urban problems. Living technology can be described as technology that exhibits the core features of living systems. These features can be useful to solve dynamic problems. In particular, urban problems concerning mobility, logistics, telecommunications, governance, safety, sustainability, and society and culture are presented, while solutions involving living technology are reviewed. A methodology for developing living technology is mentioned, while supraoptimal public transportation systems are used as a case study to illustrate the benefits of urban living technology. Finally, the usefulness of describing cities as living systems is discussed.Comment: 40 pages, 4 figures, overview pape

IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8α− DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3− expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25− effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity

Disparate Associations of HLA Class I Markers with HIV-1 Acquisition and Control of Viremia in an African Population

BACKGROUND:Acquisition of human immunodeficiency virus type 1 (HIV-1) infection is mediated by a combination of characteristics of the infectious and the susceptible member of a transmission pair, including human behavioral and genetic factors, as well as viral fitness and tropism. Here we report on the impact of established and potential new HLA class I determinants of heterosexual HIV-1 acquisition in the HIV-1-exposed seronegative (HESN) partners of serodiscordant Zambian couples. METHODOLOGY/PRINCIPAL FINDINGS:We assessed the relationships of behavioral and clinically documented risk factors, index partner viral load, and host genetic markers to HIV-1 transmission among 568 cohabiting couples followed for at least nine months. We genotyped subjects for three classical HLA class I genes known to influence immune control of HIV-1 infection. From 1995 to December 2006, 240 HESNs seroconverted and 328 remained seronegative. In Cox proportional hazards models, HLA-A*68:02 and the B*42-C*17 haplotype in HESN partners were significantly and independently associated with faster HIV-1 acquisition (relative hazards = 1.57 and 1.55; p = 0.007 and 0.013, respectively) after controlling for other previously established contributing factors in the index partner (viral load and specific class I alleles), in the HESN partner (age, gender), or in the couple (behavioral and clinical risk score). Few if any previously implicated class I markers were associated here with the rate of acquiring infection. CONCLUSIONS/SIGNIFICANCE:A few HLA class I markers showed modest effects on acquisition of HIV-1 subtype C infection in HESN partners of discordant Zambian couples. However, the striking disparity between those few markers and the more numerous, different markers found to determine HIV-1 disease course makes it highly unlikely that, whatever the influence of class I variation on the rate of infection, the mechanism mediating that phenomenon is identical to that involved in disease control

Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection

Innledning. Trykksår er en kjent komplikasjon ved varig immobilisering av pasienter. Det finnes relativt få europeiske studier om rekonstruktiv behandling av tilstanden. Studiet undersøkte forekomst og ulike kliniske aspekter ved plastisk rekonstruksjon av pasienter med alvorlige trykksår ved Universitetssykehuset i Nord Norge. Materiale og metoder. Retrospektiv studie av trykksår grad 3 og 4, av ulik lokalisasjon, behandlet med plastisk kirurgi ved Universitetssykehuset i Nord-Norge (Tromsø og Harstad) i perioden 01.01.2011-31.12.2015 med innleggelse. Seleksjonskriterier: trykksår grad 3 og 4 og plastisk rekonstruksjon. Statistisk analyse ble gjennomført med bruk av deskriptiv statistikk, Independent samples T-test og Pearson's chi-squared test. Resultater. Det ble gjennomført en omfattende undersøkelse av pasientdata. Studiepopulasjonen består av 29 pasienter, 62 % kvinner, med 38 rekonstruktive inngrep (25 % øyeblikkelig hjelp) med 1,24 rekonstruktive inngrep per pasient. Gjennomsnittlig liggetid var 31,38 dager, med langt sykehusopphold i påvente av inngrepet. 20/29 pasienter (68,96 %) har hatt invalidiserende tilstand, 9/29 pasienter (31,03 %) med dokumentert underernæring. Kvinnelige pasienter var eldre enn mannlige pasienter (gjennomsnittsalder på 75,1 år versus 64,64 år) og hadde kortere innleggelsestid (23,17 dager versus 44,82 dager) og færre inngrep per pasient. Kun 48,28 % av pasientene fikk vurdering av ernæringsstatus, og det ble ikke funnet forbedring i løpet av studieårene. Gjennomsnittslengden per inngrep var 1,99 timer. Det ble brukt ulike lapper ved 63,89 % inngrep. 5/29 pasienter (17,24 %) måtte reopereres. Hyppighet av komplikasjoner var så høy som 41,38 %. Kun 17/29 pasienter (58,62 %) hadde fullstendig sårtilheling ved utskrivelse. Det ble ikke påvist signifikant korrelanse mellom kjønn, lang preoperativ faste, underernæring, lave hemoglobin og albuminnivåer, høyt CRP nivå, multiresistente bakterier i såret eller bein under sårområde og lengre sykehusopphold eller økt antall kirurgiske inngrep, trolig grunnet for lite studieutvalg. Konklusjon. Det ble funnet dårlig etterlevelse av Nasjonal faglig retningslinje for forebygging og behandling av underernæring og stort forbedringspotensial i dokumentføring og bruk av medisinske koder

Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing regulatory macrophages to tolerogenic DCs and MDSCs

Several types of myeloid suppressor cell are currently being developed as cell-based immunosuppressive agents. Despite detailed knowledge about the molecular and cellular functions of these cell types, expert opinions differ on how to best implement such therapies in solid organ transplantation. Efforts in our laboratory to develop a cell-based medicinal product for promoting tolerance in renal transplant patients have focused on a type of suppressor macrophage, which we call the regulatory macrophage (M reg). Our favoured clinical strategy is to administer donor-derived M regs to recipients one week prior to transplantation. In contrast, many groups working with tolerogenic dendritic cells (DCs) advocate post-transplant administration of recipient-derived cells. A third alternative, using myeloid-derived suppressor cells, presumably demands that cells are given around the time of transplantation, so that they can infiltrate the graft to create a suppressive environment. On present evidence, it is not possible to say which cell type and treatment strategy might be clinically superior. This review seeks to position our basic scientific and early-stage clinical studies of human regulatory macrophages within the broader context of myeloid suppressor cell therapy in transplantation