The transition from pediatric to adult healthcare in individuals with inflammatory bowel disease (IBD) poses significant challenges mainly due to the high burden of IBD during adolescence, a critical ...period of psychosocial development. So far, there are few longitudinal data linking transition readiness to long-term disease outcomes.
We aimed to assess patients' readiness to transition and its impact on clinical outcomes, quality of life, and adherence to therapy.
An observational, prospective study was conducted in a tertiary adult and pediatric center, including adolescents aged ⩾17 years with a diagnosis of IBD, who underwent a 'structured transition' program including two joint adult-pediatric visits.
Transition readiness skills were assessed with the Transition Readiness Assessment Questionnaire (TRAQ). All patients completed the TRAQ at the time of recruitment, which occurred during the initial joint adult-pediatric visit, to determine those deemed ready for transition
those not ready. The Morisky Medication Adherence Scale and the 36-Item Short Form Health Survey Questionnaire (SF-36) were also completed at baseline and after 12 months. Clinical outcomes were collected at the 12-month follow-up.
In all, 80 patients were enrolled who had transitioned through a structured transition clinic and completed 12 months of follow-up. In total, 54 patients were ready for the transition, with a mean TRAQ = 3.2 ± 0.5. The number of clinical relapses and hospitalizations at 12 months was lower in ready compared to not-ready patients (
= 0.004 and
= 0.04, respectively). SF-36 did not differ between ready and not-ready patients and pre- and post-transition clinics (
> 0.05). Based on the receiver operating characteristic curve, a TRAQ cutoff ⩾3.16 could predict medication adherence with a sensibility of 77%, a specificity of 82%, and an AUC of 0.81 (0.71-0.91;
< 0.001).
Patients ready for transition had better outcomes at 12 months compared to those who were not ready. Therefore, readiness assessment tools should be integrated into transition management to ensure that interventions are targeted, patient-centered, and responsive to individuals' changing needs.
The outcome of dendritic cell (DC) presentation of P815AB, a tolerogenic tumor/self peptide, depends on a balance between the respective immunogenic and tolerogenic properties of myeloid (CD8 ...alpha(-)) and lymphoid (CD8 alpha(+)) DC. We have previously shown that CD8(-) DC can be primed by IL-12 to overcome inhibition by the CD8(+) subset and initiate immunogenic presentation in vivo when the two types of peptide-pulsed DC are cotransferred into recipient hosts. IFN-gamma enhances the inhibitory activity of CD8(+) DC on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8(-) DC to overcome suppression. We report here that CD40 ligation on lymphoid DC ablated their inhibitory function on Ag presentation as well as IFN-gamma potentiation of the effect. CD40 modulation of IFN-gamma action on lymphoid DC involved a reduction in IFN-gamma R expression and tryptophan-degrading ability. This effect was accompanied in vitro by an impaired capacity of the CD40-modulated and IFN-gamma-treated DC to initiate T cell apoptosis. In vivo, not only did CD40 triggering on lymphoid DC abrogate their tolerogenic activity, but it also induced the potential for immunogenic presentation of P815AB. Importantly, a pattern similar to P815AB as well as CD40 modulation of lymphoid DC function were observed on testing reactivity to NRP, a synthetic peptide mimotope recognized by diabetogenic CD8(+) T cells in nonobese diabetic mice.
Although much is known about the transcriptional profiles of dendritic cells (DCs) during maturation, the molecular switches critical for the induction of a tolerogenic program in DC subsets are ...still obscure. We examined the gene-expression profiles of murine splenic CD8+ DCs rendered highly tolerogenic by interferon-γ (IFN-γ), which activates the enzyme indoleamine 2,3-dioxygenase (IDO, encoded by Indo) and thus initiates the immunosuppressive pathway of tryptophan catabolism. By examining the expression of a series of relevant genes in IDO+ compared with IDO- DCs, we found consistent and selective association of the IDO-competent phenotype with down-modulation of the Tyrobp gene, encoding the signaling adapter DAP12, which typically associates with activating receptors. Down-modulation of Tyrobp involved IFN consensus sequence binding protein (ICSBP), a transcription factor also known as IRF-8. In murine and human monocyte-derived DCs, silencing DAP12 expression imparted IDO functional competence to IDO- cells, whereas silencing IRF-8 in IDO+ counterparts abolished IDO expression and function. Thus, IRF-8 is required in tolerogenic DCs for the positive regulation of Indo and the negative regulation of Tyrobp. Overall, these studies reveal the occurrence of a simple and evolutionarily conserved code in the control of tolerance by an ancestral metabolic enzyme.
In this study, using a soluble CD200-Ig fusion protein, we provide evidence that murine dendritic cells (DCs) possess a functional CD200R, whose engagement results in the reinforcement or appearance ...of immunosuppressive properties in these cells. In particular, the plasmacytoid subset (CD11c+B220+120G8+) of splenic DCs (pDCs) is induced by CD200-Ig to express the enzyme IDO, which initiates the tolerogenic pathway of tryptophan catabolism. As a result, pDCs are capable of suppressing Ag-specific responses in vivo when transferred into recipient hosts after treatment with CD200-Ig. IDO induction in pDCs through CD200R engagement requires type I IFNR signaling. Although the release of IFN-alpha may contribute to the full expression of CD200-Ig activity, autocrine IFN-alpha is unlikely to mediate alone the effects of CD200R engagement. These data prospect novel functions for both pDCs and the CD200-CD200R pair in the mouse. At the same time, these data underscore the possible unifying role of the IDO mechanism in immune tolerance.
The thermal history of carbon phases, including graphite and diamond, in the ureilite meteorites has implications for the formation, igneous evolution, and impact disruption of their parent body ...early in the history of the Solar System. Geothermometry data were obtained by micro-Raman spectroscopy on graphite in Almahata Sitta (AhS) ureilites AhS 72, AhS 209b and AhS A135A from the University of Khartoum collection. In these samples, graphite shows G-band peak centers between 1578 and 1585 cm
and the full width at half maximum values correspond to a crystallization temperature of 1266 °C for graphite for AhS 209b, 1242 °C for AhS 72, and 1332 °C for AhS A135A. Recent work on AhS 72 and AhS 209b has shown graphite associated with nanodiamonds and argued that this assemblage formed due to an impact-event. Our samples show disordered graphite with a crystalline domain size ranging between about 70 and 140 nm. The nanometric grain-size of the recrystallized graphite indicates that it records a shock event and thus argues that the temperatures we obtained are related to such an event, rather than the primary igneous processing of the ureilite parent body.
Anthracyclines are widely employed in lymphoma's chemotherapy and has been shown to induce heart failure. Echocardiographic parameters of left ventricular (LV) systolic function are usually used to ...monitor the cardiac side effects during and after anthracyclines treatment. The measurement of theTei index could anticipate the onset of LV dysfunction. The aim of this study was to evaluate the performance of the delta Tei index for the early detection of cardiac toxicity in a prospective population of anthracycline-treated lymphoma patients. Our preliminary data suggest that the Tei index may predict the risk for cardiotoxicity in this subset of patients earlier than LV ejection fraction alteration.
Tryptophan catabolism is a tolerogenic effector system in regulatory T cell function, yet the general mechanisms whereby tryptophan catabolism affects T cell responses remain unclear. We provide ...evidence that its effects include the emergence of a regulatory phenotype in
naive CD4
+CD25
− cells via the general control non-depressing 2 (GCN2) protein kinase mediated induction of the forkhead transcription factor Foxp3. These cells are capable of effective control of diabetogenic T cells
in vivo.
DAP12 is an immunoreceptor tyrosine‐based activation motif‐bearing membrane adapter molecule expressed by different cell types. Although several receptors associate with DAP12 in murine dendritic ...cells (DC), the function of these receptors is as yet unknown. Here we report that splenic mature DC with DAP12 overexpression are characterized by an impaired tolerogenic potential. In contrast, inhibition of DAP12 function results in enhanced tolerogenesis and constitutive expression of immunosuppressive tryptophan catabolism mediated by indoleamine 2,3‐dioxygenase (IDO). Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression. Therefore, DAP12‐related receptors act as negative regulators of IDO‐mediated tolerance in vivo.
Tertiary volcanic rocks in northwestern Firoozeh, Iran (the Meshkan triangular structural unit), constitute vast outcrops (up to 250 km
2
) of high-Mg basaltic andesites to dacites that are ...associated with high-Nb hawaiites and mugearites. Whole-rock
40
Ar/
39
Ar ages show a restricted range of 24.1 ± 0.4-22.9 ± 0.5 Ma for the volcanic rocks. The initial ratios of
87
Sr/
86
Sr and
143
Nd/
144
Nd vary from 0.703800 to 0.704256 and 0.512681 to 0.512877, respectively, in the high-Mg basaltic andesites-dacites. High-Th contents (up to 11 ppm) and Sr/Y values (27-100) and the isotopic composition of the subalkaline high-Mg basaltic andesites-dacites indicate derivation from a mantle modified by slab and sediment partial melts. Evidence such as reverse zoning and resorbed textures and high Ni and Cr contents in the evolved samples indicate that magma mixing with mafic melts and concurrent fractional crystallization lead to the compositional evolution of this series. The high-Nb hawaiites and mugearites, by contrast, have a sodic alkaline affinity and are silica undersaturated; they are also enriched in Nb (up to 47 ppm) and a wide range of incompatible trace elements, including LILE, LREE, and HFSE. Geochemistry and Sr-Nd isotopic compositions of the high-Nb hawaiites and mugearites suggest derivation from a mantle source affected by lower degrees of slab melts. Post-orogenic slab break-off is suggested to have prompted the asthenospheric upwelling that triggered partial melting in mantle metasomatized by slab-derived melts.
Tryptophan catabolism occurring in dendritic cells (DCs) and initiated by indoleamine 2,3-dioxygenase (IDO) is an emerging major mechanism of peripheral tolerance. Here we provide evidence that: 1) ...tryptophan conversion to kynurenines is activated in DCs by cytotoxic T lymphocyte antigen 4, both in a soluble form or anchored to the regulatory T cell (Treg) membrane; 2) an increased IDO-dependent tolerogenesis correlates with the inhibition of DAP12 functions, an adapter molecule associated with activating receptors; 3) a tolerogenic phenotype can be acquired by DCs lacking functional IDO through the paracrine production of kynurenines by IDO-competent DCs; 4) the suppressive effect of Treg generated in a microenvironment with low tryptophan concentration and a mixture of kynurenines can protect mice in an experimental model of fulminant diabetes. Altogether, these data indicate that, in addition to tryptophan starvation induced by IDO activity, the paracrine production of kynurenines by enzymes downstream of IDO can also contribute to tolerogenesis in DCs, independently of tryptophan deprivation.
PDF
