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Purpose To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. Patients and Methods In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. Results All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positively correlated with the cumulative incidence of relapse (P < .01). A multivariable Cox model was fitted for each time point, which showed that MRD ≥ 10−4 leukemic cells was consistently correlated with inferior EFS (P < .003). The accuracy of MRD measurements in predicting relapse was investigated with time-dependent receiver operating curves at days +30, +60, +90, and +180. From day +60 onward, the discriminatory power of MRD detection to predict the probability of relapse after 1, 3, 6, and 9 months was more than 96%, more than 87%, more than 71%, and more than 61%, respectively. Conclusion MRD after transplantation was a reliable marker for predicting impending relapses and could thus serve as the basis for pre-emptive therapy.

Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (n = 1) and itraconazole (n = 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (n = 4) and itraconazole (n = 5) groups compared to patients receiving posaconazole (n = 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.

Background aims Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regenerative medicine but also for immunomodulatory cell therapies. The application of different MSC culture protocols has significantly hampered the comparability of experimental and clinical data from different laboratories and has posed a major obstacle for multicenter clinical trials. Manufacturing of cell products for clinical application in the European Community must be conducted in compliance with Good Manufacturing Practice and requires a manufacturing license. In Germany, the Paul-Ehrlich-Institut as the Federal Authority for Vaccines and Biomedicines is critically involved in the approval process. Methods This report summarizes a consensus meeting between researchers, clinicians and regulatory experts on standard quality requirements for MSC production. Results The strategy for quality control testing depends on the product's cell composition, the manufacturing process and the indication and target patient population. Important quality criteria in this sense are, among others, the immunophenotype of the cells, composition of the culture medium and the risk for malignant transformation, as well as aging and the immunosuppressive potential of the manufactured MSCs. Conclusions This position paper intends to provide relevant information to interested parties regarding these criteria to foster the development of scientifically valid and harmonized quality standards and to support approval of MSC-based investigational medicinal products.

This research studied the changes in leaf reflectance spectra (350–2500 nm) due to metal phytoextraction into barley plants grown in metal-spiked soils (3 levels of Cd, Pb, As and their metal-mixtu...

Recently H3+ was detected at Saturn’s low- and mid-latitudes for the first time (O’Donoghue et al. [2013]. Nature 496(7444), 193–195), revealing significant latitudinal structure in H3+ emissions, with local extrema in one hemisphere mirrored at magnetically conjugate latitudes in the opposite hemisphere. The observed minima and maxima were shown to map to regions of increased or decreased density in Saturn’s rings, implying a direct ring–atmosphere connection. Here, using the Saturn Thermosphere Ionosphere Model (STIM), we investigate the “ring rain” explanation of the O’Donoghue et al. (O’Donoghue et al. [2013]. Nature 496(7444), 193–195) observations, wherein charged water group particles from the rings are guided by magnetic field lines as they “rain” down upon the atmosphere, altering local ionospheric chemistry. Based on model reproductions of observed H3+ variations, we derive maximum water influxes of (1.6–16) × 105 H2O molecules cm−2 s−1 across ring rain latitudes (∼23–49° in the south, and ∼32–54° in the north), with localized regions of enhanced influx near −48°, −38°, 42°, and 53° latitude. We estimate the globally averaged maximum ring-derived water influx to be (1.6–12) × 105 cm−2 s−1, which represents a maximum total global influx of water from Saturn’s rings to its atmosphere of (1.0–6.8) × 1026 s−1. The wide range of global water influx estimates stems primarily from uncertainties regarding H3+ temperatures (and consequently column densities). Future ring rain observations may therefore be able to reduce these uncertainties by determining H3+ temperatures self consistently.

The first dependable thermodynamic laws -- in the early 19th century -- were those of Fourier and Navier-Stokes for heat conduction and viscous friction. They were purely phenomenological and did not require the understanding of the nature of heat, let alone the concepts of energy and entropy. Those concepts emerged in the works of Mayer, Joule, Helmholtz, Clausius and Boltzmann in the latter half of the 19th century and -- apart from making energy conversion more efficient -- they had a deep impact on natural philosophy: It was recognized that nature is governed by a universal conflict between determinacy, which forces energy into a minimum, and stochasticity, by which entropy tends to a maximum. The outcome of the competition is determined by temperature so that miminal energy requires cold systems and maximal entropy occurs in hot systems. Thus phenomena like phase transitions, planetary atmospheres, osmosis, phase diagrams and chemical reactions were all understood in terms of the universal competition of energy and entropy. Mixtures, alloys and solutions were systematically incorporated into thermodynamics by Gibbs. And so the early 20th century saw the development of a second vast field of industrial application, -- apart from energy conversion --, the rectification of naturally occuring mixtures like natural gas and mineral oil. By the work of Eckart the phenomenological laws of Fourier, Navier-Stokes and Fick -- the latter for diffusion -- received a systematic derivation in terms of the Gibbs equation for the entropy. Thus equilibrium thermodynamics and thermodynamics of irreversible processes had come to a kind of conclusion by the mid 20th century. At the same time the limits of those fields were recognized: They required fairly dense matter which means that they could not describe rapidly changing processes and processes with steep gradients. Some wishful thinking occured concerning stationary processes: The hypothesis of Onsager about the mean regression of fluctuations, and Prigogine´s principle on minimal entropy production.Boltzmann´s kinetic theory of gases provides macroscopic balance laws in its hierarchy of moments of the distribution function. These have furnished the blueprint for extended thermodynamics which is capable of describing rapid changes and steep gradients, if enough moments are taken into account. The theory assumes that all field equations are balance laws with local and instantaneous constitutive relations for fluxes and productions. Thus follows a system of quasi-linear field equations and the entropy principle ensures that the system is symmetric hyperbolic, if written in the proper variables. That property guarantees existence and uniqueness of solutions, continuous dependence of solutions on the initial data and finite speeds of characteristic waves. That is to say: The entropy principle ensures well-posedness of initial value problems. Extended thermodynamics permits the calculation of light scattering spectra down to very rarefied gases. Moreover, it offers a deep insight into the structure of shocks and, above all, it reveals the very narrow limitations of linear irreversible thermodynamics based on the laws of Fourier, Fick and Navier-Stokes. Thus for instance extended thermodynamics shows that a gas in the gap between two cylinders cannot rotate rigidly, if heat conduction occurs between the inner and outer surface. Moreover, the temperature fields in the gap does not obey the Fourier law, even if there is no rotation.

Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34

Inherited forms of epidermolysis bullosa are blistering diseases of the skin and mucosa resulting from various gene mutations. Transplantation of bone marrow-derived stem cells might be a promising systemic treatment for severe dystrophic or junctional epidermolysis bullosa, but many key questions remain unresolved. Two open questions of clinical interest are whether systemically transplanted bone marrow-derived stem cells of mesodermal origin might be able to transdifferentiate into keratinocytes with an ectodermal phenotype and whether these cells are also capable of repairing a specific intraepidermal gene defect. To address these questions, we transplanted bone marrow-derived stem cells into mice with a blistering disease exclusively localized to the epidermis resulting from a functional knockout of desmoglein-3 (Dsg3). We found that Dsg3+ donor-derived cells migrate into the recipient epidermis. However, these cells failed to restore the missing Dsg3 mRNA and DSG3 protein expression in the transplanted Dsg3–/– mice. The donor-derived cells found in the epidermis preserved their CD45+ hematopoietic origin, and no transdifferentiation into integrin α6+ keratinocytes or integrin α6+/CD34+ epidermal stem cells occurred. Our results indicate that bone marrow-derived stem cells preserve their mesodermal fate after systemic transplantation and are not capable of treating patients with epidermolysis bullosa with an intraepidermal skin defect.

A questionnaire survey was carried out in four European countries to gather end-user's perceptions of using plants from phytotechnologies in combustion and anaerobic digestion (AD). Nine actors of the wood energy sector from France, Germany, and Sweden, and eleven AD platform operators from France, Germany, and Austria were interviewed. Questions related to installation, input materials, performed analyses, phytostabilization, and phytoextraction were asked. Although the majority of respondents did not know phytotechnologies, results suggested that plant biomass from phytomanaged areas could be used in AD and combustion, under certain conditions. As a potential benefit, phytomanaged plants would not compete with plants grown on agricultural lands, contaminated lands being not suitable for agriculture production. Main limitations would be related to additional controls in process' inputs and end-products and installations that might generate additional costs. In most cases, the price of phytotechnologies biomass was mentioned as a driver to potentially use plants from metal-contaminated soils. Plants used in phytostabilization or phytoexclusion were thought to be less risky and, consequently, benefited from a better theoretical acceptance than those issued from phytoextraction. Results were discussed according to national regulations. One issue was related to the regulatory gap concerning the status of the plant biomass produced on contaminated land.

Paediatric recipients of haematopoietic stem cell transplantation (HSCT) have a high risk for invasive fungal infections. Posaconazole oral suspension has proven to be effective in antifungal prophylaxis in adult and paediatric patients. A new posaconazole tablet formulation with absorption independent of the gastric conditions was approved by the FDA in 2013. This is the first report on the use of posaconazole tablets in paediatric patients. This single-centre study included 63 paediatric patients with haemato-oncological malignancies who received posaconazole for antifungal prophylaxis after HSCT. They were analysed for efficacy, feasibility and the safety of posaconazole. Out of 63 patients, 31 received posaconazole oral suspension and 32 received posaconazole tablets up to 200 days after transplantation. Analyses of the posaconazole trough levels were determined. No possible, probable or proven invasive fungal infection was observed in either group. Posaconazole trough levels were significantly higher in the tablet group than in the suspension group at all analysed time points. Drug-related adverse events were similarly low in both groups. Posaconazole tablets are effective in preventing invasive fungal infections in paediatric patients. As early as day 3 after starting posaconazole tablets, over 50% of the posaconazole trough levels were >500 ng/mL, while this was observed on day 14 after start with posaconazole suspension. The administration of posaconazole tablets was safe, effective and feasible as antifungal prophylaxis in paediatric patients after HSCT.

Summary Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 109/l leucocytes, >20 × 109/l platelets and >0·1 × 109/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (GvHD) grade II and III-IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality (TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor.

Analysis of the Cassini Ion Neutral Mass Spectrometer data reveals the omnipresence of density waves in various constituents of Titan's upper atmosphere, with quasi-periodical structures visible for N2, CH4,29N2, and some of the minor constituents. The N2 amplitude lies in the range of ≈4%–16%with a mean of ≈8%. Compositional variation is clearly seen as a sequence of decreasing amplitude with increasing scale height. The observed vertical variation of amplitude implies significant wave dissipation in different constituents, possibly contributed by molecular viscosity for N2but by both molecular viscosity and binary diffusion for the others. A wave train with near horizontally propagating wave energy and characterized by a wavelength of ≈730 km and a wave period of ≈10 h is found to best reproduce various aspects of the observations in a globally averaged sense. Some horizontal and seasonal trends in wave activity are identified, suggesting a connection between the mechanism driving the overall variability in the background atmosphere and the mechanism driving the waves. No clear association of wave activity with magnetospheric particle precipitation can be identified from the data.

Gentle remediation options (GRO) are based on the combined use of plants, associated microorganisms and soil amendments, which can potentially restore soil functions and quality. We studied the effects of three GRO (aided-phytostabilisation, in situ stabilisation and phytoexclusion, and aided-phytoextraction) on the soil microbial biomass and respiration, the activities of hydrolase enzymes involved in the biogeochemical cycles of C, N, P, and S, and bacterial community structure of trace element contaminated soils (TECS) from six field trials across Europe. Community structure was studied using denaturing gradient gel electrophoresis (DGGE) fingerprinting of Bacteria, α - and β - Proteobacteria , Actinobacteria and Streptomycetaceae , and sequencing of DGGE bands characteristic of specific treatments. The number of copies of genes involved in ammonia oxidation and denitrification were determined by qPCR. Phytomanagement increased soil microbial biomass at three sites and respiration at the Biogeco site (France). Enzyme activities were consistently higher in treated soils compared to untreated soils at the Biogeco site. At this site, microbial biomass increased from 696 to 2352 mg ATP kg −1 soil, respiration increased from 7.4 to 40.1 mg C-CO 2 kg −1 soil d −1 , and enzyme activities were 2–11-fold higher in treated soils compared to untreated soil. Phytomanagement induced shifts in the bacterial community structure at both, the total community and functional group levels, and generally increased the number of copies of genes involved in the N cycle ( nirK , nirS , nosZ , and amoA ). The influence of the main soil physico-chemical properties and trace element availability were assessed and eventual site-specific effects elucidated. Overall, our results demonstrate that phytomanagement of TECS influences soil biological activity in the long term.

In urban Latin America social housing developments have become a strategy to (re)centre territorial sovereignty with the state, by relocating low-income populations from informal settlements controlled by organized criminal groups. Yet criminal groups wield significant influence in new social housing developments, and states’ monopoly on violence continues to be contested. While studies of urban housing in the region have largely disregarded matters of urban security, research on urban security has ignored houses as material agents. Bridging studies of housing and studies of urban security, I promote a broad understanding of security that conceives the cumulative effect of diverse threats to residents’ livelihoods. By doing so, I further develop a material approach to state sovereignty in which a house operates both as a material referent and as an affective “object of desire” (Berlant, 2011) in urban security politics. By promising a secure home, social housing developments materialize the state’s responsibility to protect its citizens. However, the deficient construction and inadequate design of many new homes expose residents to climatic, health and crime-related threats. I conclude by outlining three interrelated sets of question that arise from conceiving houses as politicized materiality. I base my argument on an ethnographic case study of a social housing development in peripheral Medellin. Resumen: Asegurando el hogar: crimen, soberania estatal y vivienda social en Medellin En la America Latina urbana, las urbanizaciones de vivienda social se han convertido en una estrategia para (re)centrar la soberania territorial en el Estado, reubicando poblaciones de bajos ingresos en asentamientos informales controlados por grupos criminales organizados. Estos grupos criminales ejercen una gran influencia en las nuevas obras de viviendas sociales y se sigue cuestionando el monopolio de violencia de los estados. Mientras los estudios de vivienda urbana en la region han descuidado en gran medida los asuntos de seguridad urbana, las investigaciones sobre seguridad urbana han ignorado la vivienda como agente material. Uniendo los estudios de vivienda y seguridad urbana, promuevo una comprension amplia de la seguridad que concibe el efecto acumulativo de diversas amenazas al medio de vida de los residentes, desarrollando asi un enfoque material de la soberania estatal en el que la vivienda funciona como referente material y “objeto de deseo” afectivo (Berlant, 2011) en la politica de seguridad urbana. Al prometer asegurar el hogar, los proyectos de vivienda social materializan la responsabilidad del Estado de proteger a sus ciudadanos. Sin embargo, construcciones deficientes y el diseno inadecuado de muchas viviendas nuevas exponen a los residentes a amenazas climaticas, de salud y de delincuencia. Concluyo describiendo tres conjuntos interrelacionados de preguntas que surgen de concebir la vivienda como materialidad politizada. Baso mi argumento en un estudio de caso etnografico de una urbanizacion de vivienda social en la periferia de Medellin.

In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7–31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed.

Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4 %) and three in the voriconazole group (6 %). The percentage of patients with adverse events potentially related to clinical drugs were 14 % in the voriconazole group, 12 % in the itraconazole group, and 8 % in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.

Background & Aims Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs. Methods We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14 + HLA-DR −/low monocytes by flow cytometry, quantitative PCR, and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14 + HLA-DR −/low cells by using blocking antibodies or knock-down technology. Results Mature peripheral blood monocytes co-cultured with HSCs downregulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14 + HLA-DR −/low cells. Such CD14 + HLA-DR −/low monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14 + HLA-DR −/low monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. Conclusions Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation, the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.

Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs.

[1] In Titan's upper atmosphere, the density profiles of several constituents (N2, CH4, H2, and 29N2) as measured by the Cassini Ion Neutral Mass Spectrometer show periodical structures which we interpret as internal gravity waves. Compositional effects are frequently seen in the data, in which the wave structures in different constituents show different amplitudes and phase angles. We use a simple linearized wave perturbation theory to explain the observations, emphasizing their role as a useful diagnostic of the basic wave parameters. For the T39 flyby, the data-model comparison constrains typical wavelength to be ~150–500 km, typical wave period from the Brunt-Vaisala period of ~62 min up to ~6 h. Our calculations also illustrate that wave-induced diffusion is important for CH4 and H2.

The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1 patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III–IV aGvHD (HR = 2.45 and 1.82). Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32 % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this subgroup of CML patients.

Background Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for young Hurler patients. Despite halting of neurocognitive decline and improvement of life expectancy, the beneficial effect on the skeletal system is limited. As orthopedic complications are one of the most disabling factors following HSCT, this points to the need for new treatment strategies. The study summarizes musculoskeletal manifestations in 19 transplanted Hurler patients. Methods Data were obtained retrospectively. Patients’ charts for physical examinations of the joint range of motion (JROM) of shoulders, elbows, hips and knees were reviewed. Radiographic evaluations of thorax, spine, pelvis and hands were performed. MRI scans of the craniocervical junction were analyzed to determine odontoid hypoplasia and the prevalence of craniocervical stenosis. Results Nineteen Hurler patients (10 females, 9 males) with an average age of 8.1 years (range 2.5–23.8) at the latest follow-up, who underwent allogenic HSCT between 1991 and 2012, were assessed after an average follow-up period of 6.4 years (range 0.7–22.5). Seventeen patients achieved long-term engraftment, two developed graft failures. The majority of patients showed a steady state or improvements in the mobility of knees (31 %/63 %), hips (47 %/40 %) and elbows (56 %/38 %). However, shoulder abduction was impaired in ¾ of patients and showed the highest rate of progression (31 %). In patients with graft failure, progressive restrictions in JROM were noted. Assessments of the craniocervical junction by MRI showed stable or improved diameters in 67 % of patients. Correction or stabilization of odontoid hypoplasia was found in 64 %. However thoracolumbar kyphosis, scoliosis, hip dysplasia and genua valga were progressive despite HSCT. At the last follow up, 47 % of patients were partially wheelchair dependent, 10 % wheelchair bound and 25 % regularly experienced pain in the spine, hips and lower extremities due to orthopedic problems. Conclusion Joint mobility, odontoid hypoplasia and craniocervical stenosis might stabilize or even improve in Hurler patients following HSCT. However, despite the beneficial effects on some musculoskeletal manifestations, skeletal complications are frequently observed and the overall burden of orthopedic disease is significant. Frequent multi-disciplinary follow-up in a specialized center are essential. Novel therapeutic approaches (e.g. anti-inflammatory drugs) are needed to improve musculoskeletal outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0470-7) contains supplementary material, which is available to authorized users.

Gentle remediation options (GROs) are risk management strategies or technologies involving plant (phyto-), fungi (myco-), and/or bacteria-based methods that result in a net gain (or at least no gross reduction) in soil function as well as effective risk management. GRO strategies can be customised along contaminant linkages, and can generate a range of wider economic, environmental and societal benefits in contaminated land management (and in brownfields management more widely). The application of GROs as practical on-site remedial solutions is still limited however, particularly in Europe and at trace element (typically metal and metalloid) contaminated sites. This paper discusses challenges to the practical adoption of GROs in contaminated land management, and outlines the decision support tools and best practice guidance developed in the European Commission FP7-funded GREENLAND project aimed at overcoming these challenges. The GREENLAND guidance promotes a refocus from phytoremediation to wider GROs- or phyto-management based approaches which place realisation of wider benefits at the core of site design, and where gentle remediation technologies can be applied as part of integrated, mixed, site risk management solutions or as part of “holding strategies” for vacant sites. The combination of GROs with renewables, both in terms of biomass generation but also with green technologies such as wind and solar power, can provide a range of economic and other benefits and can potentially support the return of low-level contaminated sites to productive usage, while combining GROs with urban design and landscape architecture, and integrating GRO strategies with sustainable urban drainage systems and community gardens/parkland (particularly for health and leisure benefits), has large potential for triggering GRO application and in realising wider benefits in urban and suburban systems. Quantifying these wider benefits and value (above standard economic returns) will be important in leveraging funding for GRO application and soft site end-use more widely at vacant or underutilized sites.

When I first met Krzysztof Wilmanski in 1977 he was one of the bright young scientists in the Institute of Fundamental Technological Research of the Polish Academy of Sciences. This was the time of the cold war and it was not altogether easy for us westerners to meet colleagues from beyond the iron curtain. But among all people from the east it was still easiest to meet Polish scientists. Because, indeed, the wise elder scientists at the helm of the Polish Academy—among them Professors Nowacki, Olszak, Fiszdon, and Sawczuk—held some influence in political circles. And they knew that good science requires free and easy communication between scientists. Also they believed in mechanics as an essential part of the natural sciences.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR ??/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.

Visible and near infrared reflectance (VNIR; 350–2500 nm) spectroscopy has greatly been used in soils, especially for studying variability in spectrally active soil components (e.g., organic carbon, clays, and Fe/Al oxides) based on their diagnostic spectral features. In recent years, this technique has also been applied to assess soil metallic ions. In this research, the feasibility of VNIR spectroscopy for determination of soil metals was investigated with two soil data sets: (i) artificially metal-spiked and (ii) in situ metal-contaminated soils. Results showed that reflectance spectra of neither metal-spiked soils with Cd, As, and Pb even at their higher concentrations of 20, 900, and 1200 mg kg−1, respectively, nor in situ metal-contaminated soils (with concentrations of 30 mg Cd, 3019 mg As, and 5725 mg Pb kg−1 soil) showed any recognized absorption peaks that correspond to soil metal concentrations. We observed variations in reflectance intensity for in situ metal-contaminated soils only, showing higher reflectance across the entire spectrum for strongly and lower for less metal-contaminated soils. A significant correlation was found between surface soil metals’ concentrations and continuum removed spectra, while soil metals were also found significantly associated with soil organic matter and total Fe. A partial least square regression with cross-validation approach produced an acceptable prediction of metals (R 2 = 0.58–0.94) for both soil data sets, metal-spiked and in situ metal-contaminated soils. However, high values of root mean square error ruled out practical application of the achieved prediction models.

A complete set of equations for the description of the properties of monatomic ideal gases is formed by the balance equations of all moments of the distribution function which satisfies the Boltzmann equation. In a manner of speaking these balance equations describe a continuum and the elements of its microstructure are the moments. There are infinitely many moments and for rapidly changing processes with steep gradients they are all needed. However, for slow and smooth processes the necessary set of balance equations may be cut off at some point and may then still be useful. The most drastic cut-off provides the Euler equations in which no dissipation occurs, so that its applicability is limited to isentropic flows. A less rigorous cut-off leads to the equations of Navier-Stokes and Fourier which permit the mathematical treatment of viscous flow and heat conduction. Those curtailed sets of balance equations have been studied at great length: Their study is the subject of ordinary thermodynamics. A still less drastic cut-off leads to Grad’s 13- and 14-moment equations. These provide some improvement upon both Euler and Navier-Stokes-Fourier. Thus they forbid rigid rotation of a gas in the presence of heat conduction. Even so, the Grad theory is not suitable for high frequency sound propagation and high frequency light scattering and for the study of shock structures. The study of Grad’s equations and of the balance equations for higher moments is the subject of extended thermodynamics. Mathematically speaking the set of balance equations of moments in the kinetic theory of gases provides a prototype of the hyperbolic balance laws of continuum physics. Indeed, the equations are hyperbolic and the entropy principle makes them symmetric hyperbolic. High frequency light scattering in monatomic gases proves the applicability and usefulness of extended thermodynamics, because it furnishes results that are in full agreementwith experiments at any frequency, while ordinary thermodynamics merely describes the low-frequency limit. In hyperbolic equations there is a competition between non-linearity and dissipation: Non-linearity attempts to steepen a field to a shock while dissipation smoothes it out. And if dissipation is big enough, no shock singularities will appear. In extended thermodynamics singularities can be prevented by adding more equations, hence more dissipative terms. The study of shock structures makes this evident. Hyperbolic equations have as many sound modes as there are equations and all their speeds are different from the ordinary sound speed. Extended thermodynamics proves that the highest sound speed increases monotonically as more equations are added. It is when a shock structure moves more rapidly than the highest sound speed that discontinuities appear in the theory. One may thus say that the flow is truely supersonic only when its speed is quicker than the highest characteristic speed. However, that will generally happen at Mach numbers well beyond Ma equal to 1. It is a clear sign that more equations are needed.

Graft failure is a life-threatening complication after allogeneic haematopoietic stem cell transplantation (HSCT). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias (n = 14) and non-malignant diseases (n = 5) who experienced graft failure after previous HSCT from matched (n = 3) or haploidentical donors (n = 16) between 2003 and 2012. After total nodal irradiation (TNI)-based reconditioning combined with fludarabine, thiotepa and anti-T cell serotherapy, all patients received T cell-depleted peripheral blood stem cell grafts from a second, haploidentical donor. Median time between graft failure and retransplantation was 14 d (range 7-40). Sustained engraftment (median: 10 d, range 9-32) and complete donor chimerism was observed in all evaluable patients. 5 patients additionally received donor lymphocyte infusions. Graft-versus-host disease (GvHD) grade II and III occurred in 1 patient each (22%); no GvHD grade IV was observed. 2 patients had transient chronic GvHD. The regimen was well tolerated with transient interstitial pneumonitis in one patient. Treatment-related mortality after one year was 11%. Event-free survival and overall survival 3 years after retransplantation were 63% and 68%. Thus, a TNI-based reconditioning regimen followed by transplantation of haploidentical stem cells is an option to rescue patients with graft failure within a short time span and with low toxicity. OA hybrid

Using the Saturn Thermosphere Ionosphere Model (STIM), we present a study of the diurnal variation of electron density, with a focus on comparisons with peak electron densities (NMAX) inferred from the low-frequency cutoff of radio emission due to lightning in the lower atmosphere, called Saturn Electrostatic Discharges (SEDs). It is demonstrated that photochemistry in Saturn’s ionosphere cannot reproduce the SED-inferred diurnal variation in NMAX unless additional production and loss sources outside of the current best estimates are considered. Additional explanations of the SED-inferred diurnal variation of NMAX are presented and analyzed, such as the possibility that the low-frequency cutoff seen in SEDs is due to the presence of sharp low-altitude layers of plasma, as frequently seen in radio occultation measurements. Finally, we outline the observational constraints that must be fulfilled by any candidate explanations of the SED-inferred diurnal variation of NMAX.

Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.

Metachromatic leukodystrophy (MLD) is a rare inborn error of metabolism leading to severe neurological symptoms and early death. Hematopoietic SCT (HSCT) is considered a treatment option, but results are inconsistent and comparison with natural history is practically missing. We compare a girl with juvenile MLD 10 years after allogeneic HSCT not only with her untreated sister, but also with a large cohort of untreated patients. The girl received HSCT at the age of 5 years when first motor signs appeared. Over 10 years she was stable with respect to her clinical course and gained cognitive abilities. Magnetic resonance imaging (MRI) showed clear regression of white matter changes and magnetic resonance spectroscopy (MRS) demonstrated a reversal of the initial choline increase and N-acetyl-aspartate (NAA) decrease. Only axonal demyelinating neuropathy showed some progression. Her gross motor function and MRI-scores were clearly better compared with her sister and the cohort of untreated patients. Difference to her sister became apparent only 4 years after HSCT. We conclude that HSCT, early in the course of disease, can lead to stabilization of juvenile MLD with a course clearly different from the natural history. HSCT may prevent disease progression, if performed sufficient time before loss of walking, which typically initiates rapid deterioration.

Cell surface glycosylation has important regulatory functions in the maturation, activation, and homeostasis of lymphocytes. The family of human sialic acid-binding immunoglobulin-like lectins (siglecs) comprises inhibitory as well as activating receptors intimately involved in the regulation of immune responses. Analyses of the interaction between siglecs and glycans are hampered by the low affinity of this interaction. Therefore, we expressed siglec-7 in eukaryotic cells, allowing for glycosylation, and oligomerized the protein in analogy to MHC tetramers. Using this tool, flow cytometric analysis of lymphocytes became possible. Sialic acid-dependent binding of siglec-7 tetramers was confirmed by glycan array analysis and loss of siglec tetramer binding after neuraminidase treatment of lymphocytes. In contrast to most lymphocyte subpopulations, which showed high siglec-7 ligand expression, B-cell subpopulations could be further subdivided according to different siglec-7 ligand expression levels. We also analyzed blasts from acute lymphoblastic leukemias of the B-cell lineage as well as the T-cell lineage, since malignant transformation is often associated with aberrant cell surface glycosylation. While pediatric T-ALL blasts highly expressed siglec-7 ligands, siglec-7 ligands were barely detectable on cALL blasts. Taken together, oligomerization of recombinant soluble siglec-7 enabled flow cytometric identification of physiologic lymphocyte subpopulations and malignant blasts.

Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948.Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.Gentium SpA, European Group for Blood and Marrow Transplantation.

On its highly elliptical 24. h orbit around Venus, the Venus Express (VEX) spacecraft briefly reaches a periapsis altitude of nominally 250. km. Recently, however, dedicated and intense radio tracking campaigns have taken place in August 2008, October 2009, February and April 2010, for which the periapsis altitude was lowered to the 186-176. km altitude range in order to be able to probe the upper atmosphere of Venus above the North Pole for the first time ever in situ. As the spacecraft experiences atmospheric drag, its trajectory is measurably perturbed during the periapsis pass, allowing us to infer total atmospheric mass density at the periapsis altitude. A Precise Orbit Determination (POD) of the VEX motion is performed through an iterative least-squares fitting process to the Doppler tracking data, acquired by the VEX radioscience experiment (VeRa). The drag acceleration is modelled using an initial atmospheric density model (VTS3 model, Hedin, A.E., Niemann, H.B., Kasprzak, W.T., Seiff, A. [1983]. J. Geophys. Res. 88, 73-83). A scale factor of the drag acceleration is estimated for each periapsis pass, which scales Hedin's density model in order to best fit the radio tracking data. Reliable density scale factors have been obtained for 10 passes mainly from the second (October 2009) and third (April 2010) VExADE campaigns, which indicate a lower density by a factor of about 1.8 than Hedin's model predicts. These first ever in situ polar density measurements at solar minimum have allowed us to construct a diffusive equilibrium density model for Venus' thermosphere, constrained in the lower thermosphere primarily by SPICAV-SOIR measurements and above 175. km by the VExADE drag measurements (Muller-Wodarg et al., in preparation). The preliminary results of the VExADE campaigns show that it is possible to obtain with the POD technique reliable estimates of Venus' upper atmosphere densities at an altitude of around 175. km. Future VExADE campaigns will benefit from the planned further lowering of VEX pericenter altitude to below 170. km. © 2011 Elsevier Inc.

A 9-year-old girl was admitted to our hospital with juvenile metachromatic leukodystrophy (arylsulfatase A deficiency). Symptoms of this lysosomal storage disease, such as decreased school performance and compromised motor skills, had started 1 year earlier. She underwent bone marrow transplantation from a matched unrelated donor after receiving conditioning with fludarabine, treosulfan, and thiotepa, together with thymoglobulin, a rabbit antithymocyte globulin. Conditioning was well tolerated, and the posttransplantation period was uneventful except for 1 febrile episode. Graft-vs-host disease (GvHD)4 prophylaxis consisted of 3 methotrexate doses in combination with a starting daily cyclosporin A (CsA) dosage of 3 mg · kg−1 · day−1. Trough CsA concentrations were monitored with the antibody-conjugated magnetic immunoassay (ACMIA) for CsA (RxL Dimension; Siemens). CsA concentrations entered the therapeutic interval after 3 days, and the dosage was adjusted to achieve trough concentrations of 120–150 μg/L (Fig. 1). The patient received CsA for 16 weeks. During this period, the CsA concentration was measured 31 times, with results from 98 μg/L to 219 μg/L (mean, 156 μg/L). Four weeks after transplantation, the patient developed a mild GvHD of the skin, which disappeared immediately after commencement of prednisolone treatment. Because B lymphocytes were absent or low early after transplantation, the patient received immunoglobulins for 5 months (Fig. 1). Endogenous immunoglobulin production started only in the later phase of immune reconstitution. Six weeks after discontinuation of CsA therapy, a concentration of 147 μg/L was still detected in whole blood. Although the patient was not supposed to have received CsA and the parents had denied the administration of CsA or drugs other than those prescribed, CsA concentrations between 116 μg/L and 174 μg/L were obtained over the next 4 months. Fig. 1. Time courses of the whole-blood CsA concentration measured with the ACMIA CsA assay, the administered daily CsA dose, and the B-lymphocyte count. ### QUESTIONS TO CONSIDER 1. Has the CsA therapy really been discontinued? 2. Can delayed drug elimination explain the continued increased CsA concentrations? 3. What …

This brief note revisits an idea originally expressed by Mach according to which the inertial forces are a consequence of the far away masses of the universe. As it is well known this idea lead to Einstein's field equations of gravity. An attempt is made to derive the classical inertial acceleration of a mass from the field equations.