Validation of the Human Activity Profile Questionnaire in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Chronic graft-versus-host disease (cGVHD) associated morbidity and mortality remain major barriers for successful allogeneic hematopoietic stem cell transplantation (alloHSCT). Currently, no reliable measures are established to monitor cGVHD activity changes for use in clinical trials. The Human Activity Profile (HAP) patient self-report was proposed by the National Institutes of Health (NIH) cGVHD consensus project as an independent measure of patients' functional status that could also indirectly reflect improvement of cGVHD, but that has not been validated in an alloHSCT patient population. One hundred seventy-six patients (median age 44 years [range: 18-72 years] after alloHSCT were evaluated with a German translation of the HAP, the NIH criteria-based cGVHD activity assessment, the Lee cGVHD Symptom-Scale, FACT-BMT, SF36, Berlin Social Support Scale, 24-Item Adjective Measure (24-AM), Hospital Anxiety and Depression Scale, and the NCCN-Distress-Thermometer. Enrollment occurred a median of 286 (range: 85-4003) days after alloHSCT. Follow-up surveys were conducted at 1, 2, 3, 5, 8, and 12 months after the baseline survey. Although 117 patient had cGVHD at time of enrollment (mild n = 33, moderate n = 50, or severe n = 34), 59 patients were included into the study in the absence of cGVHD between days 85 and 395 after transplantation. The maximum activity score (MAS) and adjusted activity score (AAS) of the HAP correlated inversely with grading of cGVHD severity (mild, moderate, or severe) (r = −0.25 for MAS and −0.24 for AAS). Lung manifestations of cGVHD correlated with AAS (r = 0.17), but not with MAS. HAP scores correlated with subscales from other instruments measuring physical domains, especially the physical functioning scale of the SF36. Performance was improved by use of an HSCT-modified HAP scoring system that excluded activities prohibited within the first year after alloHSCT. No significant correlation of the HAP was found with personality, age, sex, symptom burden, or social functioning or social well-being. Moreover, the HAP displayed a higher sensitivity to change of cGVHD activity compared to the SF36 and the FACT-BMT. In addition, steroid myopathy correlated with both HAP scores, but not the SF36. The HAP is a simple and valid questionnaire for the evaluation of the physical activity in patients after alloHSCT, with the advantage of detecting changes in cGVHD status independently of other quality-of-life measures and with a superior sensitivity compared to the SF36

Antithymocyte Globulin Induces a Tolerogenic Phenotype in Human Dendritic Cells

Antithymocyte globulin (ATG) is used in the prevention of graft-versus-host disease during allogeneic hematopoietic stem cell transplantation. It is generally accepted that ATG mediates its immunosuppressive effect primarily via depletion of T cells. Here, we analyzed the impact of ATG-Fresenius (now Grafalon (R)) on human monocyte-derived dendritic cells (DC). ATG induced a semi-mature phenotype in DC with significantly reduced expression of CD14, increased expression of HLA-DR, and intermediate expression of CD54, CD80, CD83, and CD86. ATG-DC showed an increase in IL-10 secretion but no IL-12 production. In line with this tolerogenic phenotype, ATG caused a significant induction of indoleamine 2,3-dioxygenase expression and a concomitant increase in levels of tryptophan metabolites in the supernatants of DC. Further, ATG-DC did not induce the proliferation of allogeneic T cells in a mixed lymphocyte reaction but actively suppressed the T cell proliferation induced by mature DC. These data suggest that besides its well-known effect on T cells, ATG modulates the phenotype of DC in a tolerogenic way, which might constitute an essential part of its immunosuppressive action in vivo

Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation

Application of anti-thymocyte globulin (ATG) is a widely used strategy for the prevention of graftversus-host disease (GvHD). As vitamin D3 serum levels are also discussed to affect hematopoietic stem cell transplantation (HSCT) outcome and GvHD development, we analysed a possible interplay between ATG treatment and serum levels of 25-hydroxyvitamin D3and 1,25-dihydroxyvitaminD3in 4HSCT cohorts withdifferent vitaminD3supplementation. ATG is significantly associated with higher serum level of 1,25 dihydroxyvitamin D3 around HSCT (day -2 to 7, peri-transplant), however only in patients with adequate levels of its precursor 25-hydroxyvitamin D3. ATG exposure had no impact on overall survival in patients supplemented with high dose vitamin D3, but was associated with higher risk of one-year treatment-related mortality (log rank test p=0.041) in patients with no/low vitamin D3 supplementation. However, the difference failed to reach significance applying a Cox-model regression without and with adjustment for baseline risk factors (unadjusted P=0,058, adjusted p=0,139). To shed some light on underlying mechanisms, we investigated the impact of ATG on 1,25-DihydroxyvitaminD3 production by human dendritic cells (DCs) in vitro.ATGincreased gene expression ofCYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3, which was accompanied by higher 1,25-dihydroxyvitamin D3levels in ATG-treatedDCculture supernatants.Our data demonstrate a cooperative effect of 25-hydroxyvitamin D3 and ATG in the regulation of 1,25-dihydroxyvitamin D3 production. This finding may be of importance in the context of HSCT, where early high levels of 1,25- dihydroxyvitamin D3 levels have been shown to be predictive for lower transplant related mortality and suggest that vitamin D3 supplementation may especially be important in patients receiving ATG for GvHD prophylaxis

Assessment of Physiological Rat Kidney Ageing—Implications for the Evaluation of Allograft Quality Prior to Renal Transplantation

Due to organ shortage and rising life expectancy the age of organ donors and recipients is increasing. Reliable biomarkers of organ quality that predict successful long-term transplantation outcomes are poorly defined. The aim of this study was the identification of age-related markers of kidney function that might accurately reflect donor organ quality. Histomorphometric, biochemical and molecular parameters were measured in young (3-month-old) and old (24-month-old) male Sprague Dawley rats. In addition to conventional methods, we used urine metabolomics by NMR spectroscopy and gene expression analysis by quantitative RT-PCR to identify markers of ageing relevant to allograft survival. Beside known markers of kidney ageing like albuminuria, changes in the concentration of urine metabolites such as trimethylamine-N-oxide, trigonelline, 2-oxoglutarate, citrate, hippurate, glutamine, acetoacetate, valine and 1-methyl-histidine were identified in association with ageing. In addition, expression of several genes of the toll-like receptor (TLR) pathway, known for their implication in inflammaging, were upregulated in the kidneys of old rats. This study led to the identification of age-related markers of biological allograft age potentially relevant for allograft survival in the future. Among those, urine metabolites and markers of immunity and inflammation, which are highly relevant to immunosuppression in transplant recipients, are promising and deserve further investigation in humans

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation

Abstract The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person’s vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day −16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day −2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann–Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients

Strain specific differences in vitamin D3 response: impact on gut homeostasis

Vitamin D3 regulates a variety of biological processes irrespective of its well-known importance for calcium metabolism. Epidemiological and animal studies indicate a role in immune regulation, intestinal barrier function and microbiome diversity. Here, we analyzed the impact of different vitamin D3- containing diets on C57BL/6 and BALB/c mice, with a particular focus on gut homeostasis and also investigated effects on immune cells in vitro. Weak regulatory effects were detected on murine T cells. By trend, the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 suppressed IFN, GM-CSF and IL-10 cytokine secretion in T cells of C57BL/6 but not BALB/c mice, respectively. Using different vitamin D3-fortified diets, we found a tissue–specific enrichment of mainly CD11b+ myeloid cells but not T cells in both mouse strains e.g. in spleen and Peyer’s Patches. Mucin Reg3γ and Batf expression, as well as important proteins for gut homeostasis, were significantly suppressed in the small intestine of C57BL76 but not BALB/c mice fed with a high-vitamin D3 containing diet. Differences between both mouse stains were not completely explained by differences in vitamin D3 receptor expression which was strongly expressed in epithelial cells of both strains. Finally, we analyzed gut microbiome and again an impact of vitamin D3 was detected in C57BL76 but not BALB/c. Our data suggest strain-specific differences in vitamin D3 responsiveness under steady state conditions which may have important implications when choosing a murine disease model to study vitamin D3 effects

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

Das Praxissemester an Grundschulen und an weiterführenden Schulen im Vergleich. Befunde einer Befragung von Studierenden zu ihren Erfahrungen am Lernort Schule: Lerngelegenheiten, subjektiver Nutzen und Belastungserleben

Holler-Nowitzki B. Das Praxissemester an Grundschulen und an weiterführenden Schulen im Vergleich. Befunde einer Befragung von Studierenden zu ihren Erfahrungen am Lernort Schule: Lerngelegenheiten, subjektiver Nutzen und Belastungserleben. In: Klewin G, te Poel K, Heinrich M, eds. Empirische Studien zum Praxissemester. Untersuchungen zum Bielefelder Modell. 1st ed. Münster: Waxmann Verlag GmbH; 2022: 147-170.Befunde einer Befragung von Studierenden zu ihren Erfahrungen am Lernort Schule: Lerngelegenheiten, subjektiver Nutzen und Belastungserleben. Mit der Einführung des Praxissemesters in Nordrhein-Westfalen sind hohe Erwartungen an die Ausbildung der Studierenden hinsichtlich ihrer Professionalisierung verbunden, die insbesondere mit der spezifischen hochschuldidaktischen Rahmung des Forschenden Lernens verknüpft sind (vgl. MSW NRW, 2010). Dieses Konzept ist für alle Praxissemesterstudierenden verpflichtend; in der Ausgestaltung an der Universität Bielefeld müssen die Studierenden neben einer verpflichtenden Unterrichtstätigkeit (unbenotet) auch zwei benotete Studienprojekte1 durchführen (vgl. Universität Bielefeld, ZfsL Bielefeld, ZfsL Minden & ZfsL Paderborn, 2011). Im Austausch der kooperierenden Dozent*innen der vorbereitenden und begleitenden Veranstaltungen in den Bildungswissenschaften entstand schnell der Eindruck, dass die meisten Studierenden der Möglichkeit des frühzeitigen selbständigen Erprobens im Unterrichten eher positiv gegenüberstanden, den Studienprojekten hingegen mit einer skeptischen Haltung begegneten. Die Evaluation des Praxissemesters in Nordrhein-Westfalen (2016) bestätigt, dass „offensichtlich vor allem die Studienprojekte von den Studierenden als sehr herausfordernd wahrgenommen werden“ (MSW NRW, 2016, S. 5). Entsprechend müssen in den universitären Vorbereitungs- und Begleitseminaren u. a. die unterschiedlichen Perspektiven und Wahrnehmungen der Studierenden berücksichtigt werden

A model to reproduce the emission of young pulsar wind nebulae

We present a radially symmetric leptonic model which allows to reproduce the spectral properties of the X-ray emission of several regions inside a young PWN. Using the optimized model parameter values obtained from the X-ray analysis, it is possible to calculate the IC emission of the lepton population and compare it with the data in the very high-energy range (E > 100GeV). This method has been applied to three young PWNe, namely MSH15−52, G0.9+0.1, and G21.5−0.9

Unidentified VHE γ-ray sources and evolved pulsar wind nebulae - A possible connection?

Among Galactic VHE (very high energy, E > 100 GeV) γ-ray sources, pulsar wind nebulae (PWNe) form the most abundant class. At the same time, there are numerous sources of VHE γ-rays which are still unidentified. A firm identification of such objects requires a counterpart at other wavelengths. Middle-aged PWNe may account for many of these unidentified sources. While leptons that have been injected into a PWN a long time ago can still cause the observed VHE γ-ray flux, the present energy output of the pulsar is significantly reduced with respect to former times and powers only a faint synchrotron nebula which is difficult to detect with current X-ray observatories. We present a time-dependent model to study the spectral evolution of PWNe. With this model it is possible to roughly predict the X-ray emission of PWNe based on the VHE γ-ray observations only. These predictions allow to select those unidentified VHE γ-ray sources for which, assuming an evolved PWN scenario, a detection of an X-ray counterpart seems to be feasible