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Purpose Vitamin D (VitD) deficiency is common in patients with hematologic malignancies undergoing allogeneic transplantation (alloSCT), but its prognostic relevance is unclear. Patients and Methods The impact of pretransplant VitD status on overall survival, relapse mortality, and nonrelapse mortality was investigated retrospectively in a cohort of 492 patients undergoing alloSCT at our center from 2002 to 2013. VitD deficiency was defined as a serum level of 25-hydroxyvitamin D3 < 20 ng/mL (equivalent to < 50 nM) before alloSCT and was assessed using accredited laboratory methods and a standard chemiluminescent immunoassay. Results were validated in an independent cohort of 398 patients diagnosed with myeloid malignancies. Results A total of 396 (80%) and 348 (87%) patients had VitD deficiency before alloSCT in the training and validation cohort, respectively. In the training cohort, VitD deficiency was significantly associated with inferior overall survival (hazard ratio [HR], 1.78; P = .007) in multivariable analysis. This was due to a higher risk of relapse (HR, 1.96; P = .006) rather than nonrelapse mortality. A significant association of pretransplant VitD deficiency with higher relapse rates was observed only in patients diagnosed with myeloid (HR, 2.55; P = .014) but not with lymphatic diseases (HR, 1.60; P = .147). A similar impact of pretransplant VitD deficiency on relapse risk in myeloid diseases was also observed in an independent patient cohort (HR, 2.60; P = .017). Validation of the effect of VitD deficiency on relapse in patients with myeloid malignancies was successful. Conclusion Pretransplant VitD deficiency was associated with a higher risk of relapse in patients allografted for myeloid malignancies. Prospective studies on VitD status and correction of VitD deficiency in the setting of alloSCT are highly warranted.

Background: Impaired gastric emptying is common in critically ill patients. Intestinal dysmotility, a major cause of feed intolerance, may foster infectious complications due to mucosal barrier disruption. However, little is known about gut-directed immune activation, intestinal barrier function and its association with impaired gastric emptying in critically ill patients at ICU admission., Methods: We conducted a prospective observational study at two tertiary care medical ICUs. Fifty consecutive patients needing invasive mechanical ventilation were recruited within 24 h of ICU admission, prior to any nutritional support. The acute physiology and chronic health evaluation (APACHE) II score, the sequential organ failure assessment (SOFA) score and the multiple organ dysfunction score (MODS) were used to assess illness severity and multiple organ dysfunction. Gastric emptying was assessed by paracetamol absorption test. Peripheral blood mononuclear cells were freshly isolated and cultured for 24 h, and TNF-α, IL-1β and IL-10 measured in cell culture supernatants and in serum by ELISA. The intestinal epithelial barrier was assessed, quantifying serum concentrations of intestinal fatty acid binding protein (I-FABP), ileal bile-acid binding protein (I-BABP) and zonulin-1 by ELISA. Small bowel homing T lymphocytes (CD4+ α4β7 + CCR9+) were analyzed by flow cytometry. The Mann-Whitney test and Spearman correlation were used in statistical evaluation., Results: CD4 + α4β7 + CCR9+ T lymphocytes were inversely correlated with gastric emptying. Patients with delayed gastric emptying at ICU admission (n = 35) had significantly higher serum and PBMC-induced TNF-α and IL-1β and increased intestinal barrier disruption reflected by higher I-FABP, I-BABP and zonulin-1. Patients who died in the ICU had significantly impaired gastric empting at admission compared to ICU survivors. No differences were observed in APACHE II, SOFA or MODS in patients with delayed gastric emptying compared to patients with normal gastric emptying., Conclusions: Exaggerated CD4 + α4β7 + CCR9+ T lymphocyte homing with increased pro-inflammatory cytokine release and intestinal epithelial barrier disruption are associated with delayed gastric emptying. This is not simply due to differences in overall severity of illness at ICU admission and may represent a pathophysiological mechanism of gut-directed immune activation leading to impaired barrier function in the critically ill.

Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention., Competing Interests: The authors declare no conflict of interest.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

The success of haematopoietic stem cell (HSC) transplantation largely depends on numbers of transplanted HSCs, which reside in the CD34(+) populations of bone marrow (BM), peripheral blood stem cells (PBSC) and umbilical cord blood (UCB). More specifically HSCs reside in the CD38(low/-) subpopulation, which cannot be objectively discriminated from mature CD34(+)  CD38(+) progenitors. Thus, better marker combinations for the quantification of more primitive haematopoietic stem and progenitor cells in transplants are required. Recently, by combining CD34 and CD133 we could clearly distinguish CD133(+)  CD34(+) multipotent and lympho-myeloid from CD133(low)  CD34(+) erythro-myeloid progenitors in UCB samples. To qualify the assessment of CD133 for routine quality control of adult HSC sources, we analysed the developmental potentials of CD133(+) and CD133(low) subpopulations in BM and PBSC. Similar to UCB, CD133 expression objectively discriminated functionally distinct subpopulations in adult HSC sources. By implementing anti-CD45RA staining, which separates multipotent (CD133(+)  CD34(+)  CD45RA(-) ) from lympho-myeloid (CD133(+)  CD34(+)  CD45RA(+) ) progenitor fractions, UCB was found to contain 2-3 times higher multipotent progenitor frequencies than BM and PBSC. To test for the consistency of CD133 expression, we compared CD133(+)  CD34(+) contents of 128 UCB samples with maternal and obstetrical factors and obtained similar correlations to related studies focusing on CD34(+) cell contents. In conclusion, implementation of anti-CD133 staining into existing routine panels will improve the quality control analyses for HSC transplants., (© 2015 John Wiley & Sons Ltd.)

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.

Background and Objective: Resuscitation is the most important emergency action in a life-threatening cardiopulmonary arrest. The organizational, personnel and equipment requirements for an optimal treatment of emergency patients in a university hospital are described, as well as the short- and mid-term results., Patients and Methods: Retrospective analysis of 132 cases of cardiopulmonary resuscitation based on a two-pages reporting form whose completion by the involved physician and intensive care nurse is mandatory after each event., Results: About 65 % of all events were triggered by cardiac and respiratory causes. In 50 % of all cases there was an acute life-threatening situation, requiring an intubation in 46 % and mechanical reventilation in 42 % of all cases. One third of all patients who were successfully reanimated were discharged alive from hospital after the intensive care treatment., Conclusion: A well organized and adequately equipped resuscitation team is the basis for achieving optimal chances of survival in life-threatening emergencies. This is especially so in large university hospitals with often care for patients with multiple morbidities., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell (HSCT) or solid organ transplantation. The majority of PTLD are associated with the Epstein-Barr virus (EBV). PTLD may involve several organs like liver, lungs, kidney, spleen, and small intestine. PTLD with central nervous system (CNS) involvement only has been reported in very few cases so far., Case Reports: We here describe 2 cases who 7 and 12 months after HSCT developed EBV PTLD with CNS lymphomas only. The efficacy of therapy was monitored by magnetic resonance imaging, EBV replication, light chain detection, and the clinical course. Both patients responded very well to the intravenous administration of the monoclonal anti-CD20 antibody rituximab., Conclusion: These 2 case reports illustrate that in EBV PTLD with CNS lymphomas, the systemic administration of rituximab only may prove effective., (Copyright 2008 S. Karger AG, Basel.)

Kant's discussion of the ethical implications of smallpox inoculation is presented here. In four fragments Kant analyzes the moral legitimacy of endangering other people in medical practice and especially endangering people who are incapable of giving consent. In addition, we re-evaluate the alleged "success story" of the development of smallpox prevention and review the technical and theoretical difficulties of smallpox inoculation at the time of Kant.