International Consensus Conference on Atopic Dermatitis II (ICCAD II * ): clinical update and current treatment strategies

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74915/1/j.1365-2133.148.s63.1.x.pd

In Vivo Dioxin Favors Interleukin-22 Production by Human CD4+ T Cells in an Aryl Hydrocarbon Receptor (AhR)-Dependent Manner

The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals.This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells

The life cycle impact for platinum group metals and lithium to 2070 via surplus cost potential

© 2017 The Author(s)Purpose: A surplus cost potential (SCP) indicator has been developed as a measure of resource scarcity in the life cycle impact assessment (LCIA) context. To date, quality SCP estimates for other minerals than fossils are either not yet available or suffer methodological and data limitations. This paper overcomes these limitations and demonstrate how SCP estimates for metals can be calculated without the utilisation of ore grade function and by collecting primary economic and geological data. Methods: Data were collected in line with the geographical distribution, mine type, deposit type and production volumes and total production costs in order to construct cost-cumulative availability curves for platinum group metals (PGMs) and lithium. These curves capture the total amount of known mineral resources that can be recovered profitably at various prices from different types of mineral deposits under current conditions (this is, current technology, prevailing labour and other input prices). They served as a basis for modelling the marginal cost increase, a necessary parameter for estimating the SCP indicator. Surplus costs were calculated for different scenario projections for future mineral production considering future market dynamics, recyclability rates, demand-side technological developments and economic growth and by applying declining social discount rate. Results and discussion: Surplus costs were calculated for three mineral production scenarios, ranging from (US$2014/kg) 6545–8354 for platinum, 3583–4573 for palladium, 8281–10,569 for rhodium, 513–655 for ruthenium, 3201–4086 for iridium and 1.70–5.80 for lithium. Compared with the current production costs, the results indicate that problematic price increases of lithium are unlikely if the latest technological trends in the automotive sector will continue up to 2070. Surplus costs for PGMs are approximately one-third of the current production costs in all scenarios; hence, a threat of their price increases by 2070 will largely depend on the discovery of new deposits and the ability of new technologies to push these costs down over time. This also applies to lithium if the increasing electrification of road transport will continue up to 2070. Conclusions: This study provides useful insight into the availability of PGMs and lithium up to 2070. It proves that if time and resources permit, reliable surplus cost estimates can be calculated, at least in the short-run, based on the construction of one’s own curves with the level of quality comparable to expert-driven consulting services. Modelling and incorporating unknown deposits and potential future mineral production costs into these curves is the subject of future work

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma

The Schnitzler syndrome

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections