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Hypothesis Supramolecular structures determine properties of optoelectronically active materials and can be tailored via the Langmuir-Blodgett (LB) technique. Interactions between dyes can cause high crystallinities of Langmuir monolayers, thus rendering retaining their integrity during the LB-deposition challenging. However, increasing degrees of freedom exclusively at the polar anchoring moieties of dyes might improve processability without perturbing the dye’s optoelectronic properties nor the function-determining crystallinity of the layer. Experiments (Amphiphilic) thiazole dyes without, with a mono-polar, and with a double-polar anchor were synthesized, whereas the two constituting polar moieties of the latter derivate are separated by a flexible alkyl chain. The supramolecular structures and crystallinities of Langmuir and LB monolayers were characterized by means of LB isotherms, atomic force microscopy and polarization-resolved fluorescence spectroscopy. Findings As compared to the mono-polar reference the introduction of a flexible double-polar head did not deteriorate UV-vis absorption, emission or electrochemical properties of the thiazole but significantly extended the range of constant compressibility modulus, thus indicating improved processability of the Langmuir monolayers. Indeed, AFM studies revealed that the integrity of the monolayers could be retained during LB-deposition. Additionally, also the underlying supramolecular structure of the chromophore moieties is largely identical to those obtained from the mono-polar reference thiazoles.

Rocket is rich in glucosinolates and valued for its hot and spicy taste. Here we report the structure elucidation, bioactivity, and stability of the mainly formed glucosinolate hydrolysis product, namely sativin, which was formerly thought to be 4-mercaptobutyl isothiocyanate. However, by NMR characterization we revealed that sativin is in fact 1,3-thiazepane-2-thione, a tautomer of 4-mercaptobutyl isothiocyanate with 7-membered ring structure and so far unknown. This finding was further substantiated by conformation sampling using molecular modeling and total enthalpy calculation with density functional theory. During aqueous heat treatment sativin in general was quite stable, while the isothiocyanates erucin and sulforaphane were labile, having half-lives of 132 min and 56 min (pH 5, 100 °C), respectively. Moreover, using a WST-1 assay, we found that sativin did not reduce cell viability of HepG2 cells in a range of 0.3–30 µM, and, therefore, exhibited no cytotoxic effects in this cell line.

GLORIA (Gimballed Limb Observer for Radiance Imaging of the Atmosphere) is a new remote sensing instrument essentially combining a Fourier transform infrared spectrometer with a two-dimensional (2-D) detector array in combination with a highly flexible gimbal mount. It will be housed in the belly pod of the German research aircraft HALO (High Altitude and Long Range Research Aircraft). It is unique in its combination of high spatial and state-of-the art spectral resolution. Furthermore, the horizontal view angle with respect to the aircraft flight direction can be varied from 45° to 135°. This allows for tomographic measurements of mesoscale events for a wide variety of atmospheric constituents. In this paper, a tomographic retrieval scheme is presented, which is able to fully exploit the manifold radiance observations of the GLORIA limb sounder. The algorithm is optimized for massive 3-D retrievals of several hundred thousands of measurements and atmospheric constituents on common hardware. The new scheme is used to explore the capabilities of GLORIA to sound the atmosphere in full 3-D with respect to the choice of the flightpath and to different measurement modes of the instrument using ozone as a test species. It is demonstrated that the achievable resolution should approach 200 m vertically and 20 km–30 km horizontally. Finally, a comparison of the 3-D inversion with conventional 1-D inversions using the assumption of a horizontally homogeneous atmosphere is performed.

Analyzing the 1H NMR spectrum of d-glucose, the resonance frequencies of the anomeric protons of five d-glucose anomers could be determined in dependence on temperature. Besides, the relative concentrations of all cyclic d-glucose anomers could be quantified. Based on that, thermodynamic parameters were calculated. In addition, ring opening rate constants of all cyclic d-glucose anomers were measured for the first time using 1H selective blind saturation transfer NMR spectroscopy. The results presented here give rise to the assumption that furanoid anomers highly influence the reactivity of total d-glucose. Finally, the complex anomeric equilibration curves for a freshly prepared solution of crystalline α-d-glucopyranose are presented. Based on that, it is hypothesized that the reactivity of a solution of a reducing sugar in general and d-glucose in particular depends on time until the thermodynamic equilibrium state is reached.

Based on theoretical and mechanistical considerations, an equation is presented that describes the observed rate of a pH sensitive reaction. In contrast to the commonly used catalytic catenary, the new approach enables the calculation of non-biased thermodynamic activation parameters. Applying this model, the general acid/base catalysis of the ring opening of β-d-fructopyranose was analyzed polarimetrically. Thereby, it could be shown that acids (bases) catalyze the ring opening of anionic (cationic) sugar species. Since anomerization rate constants correlate with the rate of sugar degradation, catalysts of anomerization will increase the sugar's reactivity as well. The most effective catalysts of the ring opening of β-d-fructopyranose in the food relevant pH milieu are weak acids and their conjugated bases. Consequently, the enhanced reactivity of reducing sugars in the presence of amino acids is not solely due to classical Maillard reaction but primarily due to carboxylic acid catalysis of degradation reactions.

A CubeSat-sized limb sounder utilizing a Spatial Heterodyne Spectrometer for the detection of the O2 Atmospheric A-Band is presented. The purpose of the instrument is to measure vertical profiles of temperature in the middle atmosphere.

This work is distributed under the Creative Commons Attribution 4.0 License., In this paper we describe the stratospheric and mesospheric ozone (version V5r-O3-m22) distributions retrieved from MIPAS observations in the three middle atmosphere modes (MA, NLC, and UA) taken with an unapodized spectral resolution of 0.0625 cm from 2005 until April 2012. O is retrieved from microwindows in the 14.8 and 10 μm spectral regions and requires non-local thermodynamic equilibrium (non-LTE) modelling of the O and vibrational levels. Ozone is reliably retrieved from 20 km in the MA mode (40 km for UA and NLC) up to ∼105 km during dark conditions and up to ∼95 km during illuminated conditions. Daytime MIPAS O has an average vertical resolution of 3-4 km below 70 km, 6-8 km at 70-80 km, 8-10 km at 80-90, and 5-7 km at the secondary maximum (90-100 km). For nighttime conditions, the vertical resolution is similar below 70 km and better in the upper mesosphere and lower thermosphere: 4-6 km at 70-100 km, 4-5 km at the secondary maximum, and 6-8 km at 100-105 km. The noise error for daytime conditions is typically smaller than 2% below 50 km, 2-10% between 50 and 70 km, 10-20% at 70-90 km, and ∼30% above 95 km. For nighttime, the noise errors are very similar below around 70 km but significantly smaller above, being 10-20% at 75-95 km, 20-30% at 95-100 km, and larger than 30% above 100 km. The additional major O errors are the spectroscopic data uncertainties below 50 km (10-12 %) and the non-LTE and temperature errors above 70 km. The validation performed suggests that the spectroscopic errors below 50 km, mainly caused by the O air-broadened half-widths of the band, are overestimated. The non-LTE error (including the uncertainty of atomic oxygen in nighttime) is relevant only above ∼85 km with values of 15-20 %. The temperature error varies from ∼3% up to 80 km to 15-20% near 100 km. Between 50 and 70 km, the pointing and spectroscopic errors are the dominant uncertainties. The validation performed in comparisons with SABER, GOMOS, MLS, SMILES, and ACE-FTS shows that MIPAS O has an accuracy better than 5% at and below 50 km, with a positive bias of a few percent. In the 50-75 km region, MIPAS O has a positive bias of ∼10 %, which is possibly caused in part by O spectroscopic errors in the 10 μm region. Between 75 and 90 km, MIPAS nighttime O is in agreement with other instruments by 10 %, but for daytime the agreement is slightly larger, ∼10-20 %. Above 90 km, MIPAS daytime O is in agreement with other instruments by 10 %. At night, however, it shows a positive bias increasing from 10% at 90 km to 20% at 95-100 km, the latter of which is attributed to the large atomic oxygen abundance used. We also present MIPAS O distributions as function of altitude, latitude, and time, showing the major O features in the middle and upper mesosphere. In addition to the rapid diurnal variation due to photochemistry, the data also show apparent signatures of the diurnal migrating tide during both day-and nighttime, as well as the effects of the semi-Annual oscillation above ∼70 km in the tropics and mid-latitudes. The tropical. daytime O at 90 km shows a solar signature in phase with the solar cycle. © Author(s) 2018., The IAA team was supported by the Spanish MICINN under the project ESP2014-54362-P and EC FEDER funds. The IAA and IMK teams were partially supported by ESA O3-CCI and MesosphEO projects. Maya Garcia-Comas was financially supported by MINECO through its >Ramon y Cajal> subprogram. Funding for the Atmospheric Chemistry Experiment comes primarily from the Canadian Space Agency. Work at the Jet Propulsion Laboratory was performed under contract with the National Aeronautics and Space Administration.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has emerged as the gold standard technique with the capability for reliable, accurate, and high-throughput quantification of circulating vitamin D metabolites. The complexity of vitamin D metabolism has driven the continuous development of the basic steps involved in LC-MS/MS methodology including sample extraction, derivatization, separation, and mass spectrometry, used to interrogate the role of vitamin D nutrition and metabolism in human health and disease states. From the perspective of both the high-throughput clinical chemistry laboratory and basic research applications, this chapter describes how LC-MS/MS can be optimized to provide sensitive and specific measurements of 25-hydroxyvitamin D, along with other low-abundance metabolites including 24-25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D, simultaneously. Furthermore, we describe the advantages of using LC-MS/MS in studying mouse models of vitamin D metabolism and how this work has contributed to an improved understanding of the pathophysiology of certain vitamin D-related disease states.

Analyzing classical model reaction systems of Amadori rearrangement products (ARP) it became apparent that the formation of 3-deoxy- d -threo-hexo-2-ulose (3-deoxygalactosone, 3-DGal) during the degradation of ARPs is highly dependent on pH and the amino acid residue of the respective ARP. Based on a detailed analysis of the NMR chemical shifts of the sugar moieties of different ARPs, it could be derived that the formation of 3-DGal is sensitive to the stability of a co-operative hydrogen bond network which involves HO-C3, the deprotonated carboxyl functionality and the protonated amino nitrogen of the amino acid substituent. Participating in this bond network, HO-C3 is partially protonated which facilitates the elimination of water at C3. Based on that, a new mechanism of 3-deoxyglycosone formation is proposed.

The supramolecular structure essentially determines the properties of organic thin films. Therefore, it is of utmost importance to understand the influence of molecular structure modifications on supramolecular structure formation. In this article, we demonstrate how to tune molecular orientations of amphiphilic 4-hydroxy thiazole derivatives by means of the Langmuir-Blodgett (LB) technique and how this depends on the length of an alkylic spacer between the thiazole chromophore and the polar anchor group. Therefore, we characterize their corresponding supramolecular structures, thermodynamic, absorption, and fluorescence properties. Particularly, the polarization-dependence of the fluorescence is analyzed to deduce molecular orientations and their possible changes after annealing, i.e., to characterize the thermodynamic stability of the individual solid state phases. Because the investigated thiazoles are amphiphilic, the different solid state phases can be formed and be controlled by means of the Langmuir-Blodgett (LB) technique. This technique also allows to deduce atomistic supramolecular structure motives of the individual solid phases and to characterize their thermodynamic stabilities. Utilizing the LB technique, we demonstrate that subtle molecular changes, like the variation in spacer length, can yield entirely different solid state phases with distinct supramolecular structures and properties.

This paper presents new data sets relating to the abundance of atomic oxygen in the upper mesosphere and lower thermosphere, which were derived from the nighttime green line emission measurements of the SCIAMACHY (Scanning Imaging Absorption Spectrometer for Atmospheric CHartographY) instrument on the European Environmental Satellite (Envisat). These are compared to recently published data sets from the same SCIAMACHY green line measurements through the application of a different photochemical model and to data collected by the Sounding of the Atmosphere using Broadband Emission Radiometry instrument. We find that the retrieved atomic oxygen concentration depends on the choice of the underlying photochemical model. These dependencies explain a large proportion of the differences between recently published data sets. The impact of the 11 year solar cycle on volume emission rates and atomic oxygen abundances was analyzed for various data sets, with the finding that the solar cycle effect varies with the atomic oxygen data set used. The solar cycle impact on the SCIAMACHY data increases with altitude. Above 96 km, it is significantly larger than predicted by Hamburg Model of the Neutral and Ionized Atmosphere. Investigations indicate that these variations are primarily driven by total density compression/expansion variations during the solar cycle, rather than different photolysis rates.

Calcium metabolism changes in pregnancy and lactation to meet fetal needs, with increases in 1,25-dihydroxyvitamin D [1,25-(OH)2D] during pregnancy playing an important role. However, these changes rarely cause maternal hypercalcemia. When maternal hypercalcemia occurs, further investigation is essential, and disorders of 1,25-(OH)2D catabolism should be carefully considered in the differential diagnosis.A patient with a childhood history of recurrent renal stone disease and hypercalciuria presented with recurrent hypercalcemia and elevated 1,25-(OH)2D levels during pregnancy. Laboratory tests in the fourth pregnancy showed suppressed PTH, elevated 1,25-(OH)2D, and high-normal 25-hydroxyvitamin D levels, suggesting disordered vitamin D metabolism. Analysis revealed low 24,25-dihydroxyvitamin D3 and high 25-hydroxyvitamin D3 levels, suggesting loss of function of CYP24A1 (25-hydroxyvitamin-D3-24-hydroxylase). Gene sequencing confirmed that she was a compound heterozygote with the E143del and R396W mutations in CYP24A1.This case broadens presentations of CYP24A1 mutations and hypercalcemia in pregnancy. Furthermore, it illustrates that patients with CYP24A1 mutations can maintain normal calcium levels during the steady state but can develop hypercalcemia when challenged, such as in pregnancy when 1,25-(OH)2D levels are physiologically elevated.

The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.

The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D3 to its hormonal form, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH)2D3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1. We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfill separate functional roles, first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease.

Six laboratories associated with the Vitamin D Standardization Program (VDSP) participated in an interlaboratory comparison of LC with tandem MS (MS/MS) methods for the determination of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in human serum. The laboratories analyzed two different serum-based Standard Reference Materials (SRMs) intended for use in the determination of 25-hydroxyvitamin D and 30 samples from the Vitamin D External Quality Assessment Scheme (DEQAS). All laboratory methods for 24,25(OH)2D3 were based on isotope dilution LC-MS/MS; three of the methods used derivatization of the vitamin D metabolites before LC-MS/MS. Laboratory results were compared to the National Institute of Standards and Technology (NIST) results, which were obtained using their newly developed candidate reference measurement procedure for 24,25(OH)2D3. Laboratory results for the SRM samples varied in comparability to the NIST results, with one laboratory in excellent agreement (-1.6% mean bias), three laboratories at 10-15% mean bias, and the remaining laboratory at 36% mean bias. For the 30 DEQAS samples, the mean bias for the five laboratories ranged from 6 to 15%; however, the SD of the bias ranged from 8 to 29%. As a result of this intercomparison study, one laboratory discovered and corrected a method calculation error and another laboratory modified and improved their LC-MS/MS method.

In this study, we describe the construction of the first genetically modified mutant of a halovirus infecting haloalkaliphilic Archaea . By random choice, we targeted ORF79, a currently uncharacterized viral gene of the haloalkaliphilic virus ϕCh1. We used a polyethylene glycol (PEG)-mediated transformation method to deliver a disruption cassette into a lysogenic strain of the haloalkaliphilic archaeon Natrialba magadii bearing ϕCh1 as a provirus. This approach yielded mutant virus particles carrying a disrupted version of ORF79. Disruption of ORF79 did not influence morphology of the mature virions. The mutant virus was able to infect cured strains of N. magadii , resulting in a lysogenic, ORF79-disrupted strain. Analysis of this strain carrying the mutant virus revealed a repressor function of ORF79. In the absence of gp79, onset of lysis and expression of viral proteins occurred prematurely compared to their timing in the wild-type strain. Constitutive expression of ORF79 in a cured strain of N. magadii reduced the plating efficiency of ϕCh1 by seven orders of magnitude. Overexpression of ORF79 in a lysogenic strain of N. magadii resulted in an inhibition of lysis and total absence of viral proteins as well as viral progeny. In further experiments, gp79 directly regulated the expression of the tail fiber protein ORF34 but did not influence the methyltransferase gene ORF94. Further, we describe the establishment of an inducible promoter for in vivo studies in N. magadii . IMPORTANCE Genetic analyses of haloalkaliphilic Archaea or haloviruses are only rarely reported. Therefore, only little insight into the in vivo roles of proteins and their functions has been gained so far. We used a reverse genetics approach to identify the function of a yet undescribed gene of ϕCh1. We provide evidence that gp79, a currently unknown protein of ϕCh1, acts as a repressor protein of the viral life cycle, affecting the transition from the lysogenic to the lytic state of the virus. Thus, repressor genes in other haloviruses could be identified by sequence homologies to gp79 in the future. Moreover, we describe the use of an inducible promoter of N. magadii . Our work provides valuable tools for the identification of other unknown viral genes by our approach as well as for functional studies of proteins by inducible expression.

Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker. Iohexol plasma clearance and inulin plasma clearance had a very high agreement and minimal bias when using 12‐sample models. However, only iohexol could be accurately simplified to a two‐sample, one‐compartment estimation strategy. Following an IV injection of low‐dose iohexol and two timed blood samples at 30 and 90 min, one can accurately approximate a complex 12‐sample strategy of plasma clearance. This method is simple enough to use in routine, longitudinal analysis of larger cohort animal studies.

Atmospheric gravity waves are a major cause of uncertainty in atmosphere general circulation models. This uncertainty affects regional climate projections and seasonal weather predictions. Improving the representation of gravity waves in general circulation models is therefore of primary interest. In this regard, measurements providing an accurate 3-D characterization of gravity waves are needed. Using the Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA), the first airborne implementation of a novel infrared limb imaging technique, a gravity wave event over Iceland was observed. An air volume disturbed by this gravity wave was investigated from different angles by encircling the volume with a closed flight pattern. Using a tomographic retrieval approach, the measurements of this air mass at different angles allowed for a 3-D reconstruction of the temperature and trace gas structure. The temperature measurements were used to derive gravity wave amplitudes, 3-D wave vectors, and direction-resolved momentum fluxes. These parameters facilitated the backtracing of the waves to their sources on the southern coast of Iceland. Two wave packets are distinguished, one stemming from the main mountain ridge in the south of Iceland and the other from the smaller mountains in the north. The total area-integrated fluxes of these two wave packets are determined. Forward ray tracing reveals that the waves propagate laterally more than 2000 km away from their source region. A comparison of a 3-D ray-tracing version to solely column-based propagation showed that lateral propagation can help the waves to avoid critical layers and propagate to higher altitudes. Thus, the implementation of oblique gravity wave propagation into general circulation models may improve their predictive skills.

Gravity waves (GWs) play an important role in atmospheric dynamics. Especially in the mesosphere and lower thermosphere (MLT) dissipating GWs provide a major contribution to the driving of the global wind system. Therefore global observations of GWs in the MLT region are of particular interest. The small scales of GWs, however, pose a major problem for the observation of GWs from space. We propose a new observation strategy for GWs in the mesopause region by combining limb and sub-limb satellite-borne remote sensing measurements for improving the spatial resolution of temperatures that are retrieved from atmospheric soundings. In our study, we simulate satellite observations of the rotational structure of the O2 A-band nightglow. A key element of the new method is the ability of the instrument or the satellite to operate in so called target mode, i.e. to stare at a particular point in the atmosphere and collect radiances at different viewing angles. These multi-angle measurements of a selected region allow for tomographic reconstruction of a 2-dimensional atmospheric state, in particular of gravity wave structures. As no real data is available, the feasibility of this tomographic retrieval is carried out with simulation data in this work. It shows that one major advantage of this observation strategy is that much smaller scale GWs can be observed. We derive a GW sensitivity function, and it is shown that target mode observations are able to capture GWs with horizontal wavelengths as short as ~ 50 km for a large range of vertical wavelengths. This is far better than the horizontal wavelength limit of 100–200 km obtained for conventional limb sounding.

A highly miniaturized limb sounder for the observation of the O2 A-Band to derive temperatures in the mesosphere and lower thermosphere is presented. The instrument consists of a monolithic spatial heterodyne spectrometer (SHS), which is able to resolve the rotational structure of the R-branch of that band. The relative intensities of the emission lines follow a Boltzmann distribution and the ratio of the lines can be used to derive the kinetic temperature. The SHS operates at a Littrow wavelength of 761.8 nm and heterodynes a wavelength regime between 761.9 nm and 765.3 nm with a resolving power of about 8000 considering apodization effects. The size of the SHS is 38 × 38 × 27 mm3 and its acceptance angle is ±5°. It has an etendue of 0.014 cm2 sr. Complemented by a front optics with a solid angle of 0.65° and a detector optics, the entire optical system fits into a volume of about 1.5 liters. This allows to fly this instrument on a 3 or 6 unit CubeSat. The vertical field of view of the instrument is about 60 km at the Earth's limb if operated in a typical low Earth orbit. Integration times to obtain an entire altitude profile of nighttime temperatures are in the order of one minute for a vertical resolution of 1.5 km and a random noise level of 1.5 K. Daytime integration times are one order of magnitude shorter. This work presents the design parameters of the optics and a radiometric assessment of the instrument. Furthermore it gives an overview of the required characterization and calibration steps. This includes the characterization of image distortions in the different parts of the optics, flat fielding and the spectral power estimation.

ObjectiveThe objective of the present study was to determine if vitamin D intake and status are associated with pre-eclampsia in a country without a vitamin D fortification policy.DesignA case–control study of pregnancies with (case) and without (control) pre-eclampsia was conducted from January to April when UVB is minimal. Maternal and cord blood obtained at delivery were measured for plasma 25-hydroxycholecalciferol (25-OH-D3), 3-epimer of 25-OH-D3(3-epi-25-OH-D3) and 24,25-dihydroxycholecalciferol (24,25-(OH)2D3) by LC–MS/MS and maternal 1,25-dihydroxyvitamin D (1,25-(OH)2D). Differences between groups were tested with ANOVA and Bonferronipost hoctests (PSettingClinical Center of Serbia.SubjectsPregnant women with and without pre-eclampsia (n60) and their infants.ResultsExogenous vitamin D intake (0·95–16·25 µg/d (38–650 IU/d)) was not significantly different between groups. Women with pre-eclampsia delivered infants at an earlier gestational age and had significantly lower mean total plasma 25-hydroxyvitamin D (25-OH-D; case: 11·2 (sd5·1); control: 16·1 (sd5·7) ng/ml;P=0·0006), 25-OH-D3(case: 10·0 (sd4·9); control: 14·2 (sd5·8) ng/ml;P=0·002), 3-epi-25-OH-D3(case: 0·5 (sd0·2); control: 0·7 (sd0·2) ng/ml;P=0·0007) and 1,25-(OH)2D (case: 56·5 (sd26·6); control: 81·0 (sd25·7) pg/ml;P=0·018), while 24,25-(OH)2D3was not different between groups. Infants did not differ in total plasma 25-OH-D, 25-OH-D3, 3-epi-25-OH-D3and 24,25-(OH)2D3, but the mean proportion of 3-epi-25-OH-D3was higher in the infant case group (case: 7·9 (sd1·1); control: 7·0 (sd1·4) % of total 25-OH-D3;P=0·005).ConclusionsA high prevalence of vitamin D deficiency, as defined by plasma 25-OH-D

A new data set of atomic oxygen abundance in the upper mesosphere and lower thermosphere is presented. The data are derived from the nighttime atomic oxygen green line limb emission measurements of the SCIAMACHY (Scanning Imaging Absorption Spectrometer for Atmospheric Chartography) instrument on the European Environmental Satellite. The temporal coverage is October 2002 until April 2012, and the latitudinal extent is 50°S to 80°N at 10 P.M. local time. This data set is compared to other satellite data sets, in particular to recently published data of SABER (Sounding of the Atmosphere using Broadband Emission Radiometry) and the Mass Spectrometer and Incoherent Scatter model. SCIAMACHY atomic oxygen peak abundances are typically 3–6×1011 mol/cm3 at the atomic oxygen maximum region, depending on latitude and season. These values are similar to previous values based on chemiluminescence measurements of the atomic oxygen three-body recombination reaction but at least 30% lower than atomic oxygen abundances obtained from SABER.

Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting. Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients. Median overall survival (OS) after relapse of the whole study group was 19 months. A long (> 12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis. Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation. MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.

Bacterial pathogens require iron for proliferation and pathogenesis. Pseudomonas aeruginosa is a prevalent Gram-negative opportunistic human pathogen that takes advantage of immunocompromised hosts and encodes a number of proteins for uptake and utilization of iron. Here we report the crystal structures of PhuS, previously known as the cytoplasmic heme-trafficking protein from P. aeruginosa, in both the apo- and the holo-forms. In comparison to its homologue ChuS from Escherichia coli O157:H7, the heme orientation is rotated 180° across the α-γ axis, which may account for some of the unique functional properties of PhuS. In contrast to previous findings, heme binding does not result in an overall conformational change of PhuS. We employed spectroscopic analysis and CO measurement by gas chromatography to analyze heme degradation, demonstrating that PhuS is capable of degrading heme using ascorbic acid or cytochrome P450 reductase-NADPH as an electron donor and produces five times more CO than ChuS. Addition of catalase slows down but does not stop PhuS-catalyzed heme degradation. Through spectroscopic and mass spectrometry analysis, we identified the enzymatic product of heme degradation to be verdoheme. These data taken together suggest that PhuS is a potent heme-degrading enzyme, in addition to its proposed heme-trafficking function.

The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field.

Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and >15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; >95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and >15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, >15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and >60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

The Institute for Atmospheric and Environmental Research at the University of Wuppertal and the Institute of Energy and Climate Research Stratosphere at Research Center Juelich developed a CubeSat payload for atmospheric research. The payload consists of a small interferometer for the observation of airglow near 762 nm. The line intensities of the oxygen A-band are used to derive temperatures in the mesosphere and lower thermosphere region. The temperature data will be used to analyze dynamical wave structures in the atmosphere. The interferometer technology chosen to measure the ro-vibrational structure of the O2 atmospheric band near 762 nm is a spatial heterodyne interferometer originally proposed by Connes in 1958. It can be designed to deliver extraordinary spectral resolution to resolve individual emission lines. The utilization of a two-dimensional imaging detector allows for recording interferograms at adjacent locations simultaneously. Integrated in a six-unit CubeSat, the instrument is designed for limb sounding of the atmosphere. The agility of a CubeSat will be used to sweep the line-of-sight through specific regions of interest to derive a three-dimensional image of an atmospheric volume using tomographic reconstruction techniques.

In this paper a method for correcting the radial distortion of interferograms generated by a spatial heterodyne spectrometer system is presented. Instead of utilizing calibration patterns, the distortion model parameters are estimated based on the distorted fringe features generated by projecting the straight interference stripes onto the detector. Comparisons between polynomial models and division models indicate that division models can deliver competitive performance on the reconstructed image with fewer parameters. Simulated interferograms based on ray-tracing are used to demonstrate the correction of errors in the spatial, phase, and spectral domain caused by optical distortion.

Cardiotoxicity of fluoropyrimidines like the orally administered capecitabine and the intravenous 5-fluorouracil (5-FU) is a well-known clinical challenge [1, 2]. The cardiotoxic effects of both agents seem to occur through the same mechanisms [3]. However, capecitabine-induced cardiotoxicity is less common because it obtains its pharmacological active form through a three-step enzymatic conversion, while the last step is catalyzed by the enzyme thymidine phosphorylase, which is more active in neoplastic tissues [4, 5]. But this enzyme is also actively expressed in arteriosclerotic plaques, which is thought to be one potential mechanism leading to coronary side effects, especially in patients with a history of coronary artery disease [3]. Until today, numerous reports have shown cardiac side effects of fluoropyrimidines. However, there is no explicit evidence of capecitabine as a direct trigger for tako tsubo cardiomyopathy (TTC). Amongst other causes, coronary artery spasm is discussed as a potential cause of TTC [6]. Epicardial vasospasm is a widely accepted hypothetical pathomechanism of 5-FU-associated cardiac side effects [7, 8]. Therefore, fluoropyrimidines could be plausible triggers for TTC and the following case will strengthen this possible connection. An 81-year-old female with metastatic breast cancer was admitted to our emergency unit with acute chest pain and severe dyspnoea. The symptoms began at about 4 p.m., shortly after a 1-h workout as part of a diabetes group training. On the same day, in the morning at about 9 a.m., the patient had received the first dose of capecitabine (1,500 mg). The patient did not report any extraordinary emotional stress, but had a history of obstructive coronary artery disease. Five years ago she had undergone percutaneous coronary intervention in the left anterior descending coronary artery (LAD). The patient further suffered from insulin-dependent diabetes mellitus type 2, hypercholesterolemia, hypertension and peripheral vascular disease. On admission the symptoms were relieved by sublingual nitroglycerin, but recurred after a few minutes. The electrocardiogram (ECG) showed sinus rhythm with ST-segment elevations, which had not been detected in a routine ECG 3 weeks ago (Fig. 1a). High sensitive cardiac troponin T concentration was 282 pg/ml (n \ 14 pg/ml). The patient was treated with acetylsalicylic acid (500 mg intravenous), clopidogrel (600 mg orally) and heparin (5,000 units intravenous) because of the suspicion of acute ST-elevation myocardial infarction. No abnormalities were discovered by physical examination. Blood pressure was 140/63 mm/Hg. Cardiac catheterization was performed immediately. Ventriculography showed apical dyskinesia Electronic supplementary material The online version of this article (doi:10.1007/s00392-013-0636-4) contains supplementary material, which is available to authorized users.

The neuroprotective action of dehydroepiandrosterone (DHEA) in the absence of a known specific receptor has been attributed to its metabolism by different cell types in the brain to various steroids, with a preference to its 7-hydroxylated products. The E(t)C cerebellar granule cell line converts DHEA almost exclusively to 7α-hydroxy-DHEA (7α-OH-DHEA). It has been postulated that DHEA's 7-OH and 7-oxo metabolites can decrease glucocorticoid levels by an interactive mechanism involving 11β-hydroxysteroid dehydrogenase (11β-HSD). In order to study the relationship of 7-hydroxylation of DHEA and glucocorticoid metabolism in intact brain cells, we examined whether E(t)C cerebellar neurons, which are avid producers of 7α-OH-DHEA, could also metabolize glucocorticoids. We report that E(t)C neuronal cells exhibit 11β-HSD1 reductase activity, and are able to convert 11-dehydrocorticosterone into corticosterone, whereas they do not demonstrate 11β-HSD2 dehydrogenase activity. Consequently, E(t)C cells incubated with DHEA did not yield 7-oxo- or 7β-OH-DHEA. Our findings are supported by the reductive environment of E(t)C cells through expression of hexose-6-phosphate dehydrogenase (H6PDH), which fosters 11β-HSD1 reductase activity. To further explore the role of 7α-OH-DHEA in E(t)C neuronal cells, we examined the effect of preventing its formation using the CYP450 inhibitor ketoconazole. Treatment of the cells with this drug decreased the yield of 7α-OH-DHEA by about 75% without the formation of alternate DHEA metabolites, and had minimal effects on glucocorticoid conversion. Likewise, elevated levels of corticosterone, the product of 11β-HSD1, had no effect on the metabolic profile of DHEA. This study shows that in a single population of whole-cells, with a highly reductive environment, 7α-OH-DHEA is unable to block the reducing activity of 11β-HSD1, and that 7-hydroxylation of DHEA does not interfere with the activation of glucocorticoids. Our investigation on the metabolism of DHEA in E(t)C neuronal cells suggest that other alternate mechanisms must be at play to explain the in vivo anti-glucocorticoid properties of DHEA and its 7-OH-metabolites.

In this demo, we present a prototype of a main memory database system which provides a wide range of temporal operators featuring predictable and interactive response times. Much of real-life data is temporal in nature, and there is an increasing application demand for temporal models and operations in databases. Nevertheless, SQL:2011 has only recently overcome a decade-long standstill on standardizing temporal features. As a result, few database systems provide any temporal support, and even those only have limited expressiveness and poor performance. Our prototype combines an in-memory column store and a novel, generic temporal index structure named Timeline Index. As we will show on a workload based on real customer use cases, it achieves predictable and interactive query performance for a wide range of temporal query types and data sizes.

Managing and accessing temporal data is of increasing importance in industry. So far, most companies model the time dimension on the application layer rather than pushing down the operators to the database, which leads to a significant performance overhead. The goal of this PhD thesis is to develop a native support of temporal features for SAP HANA, which is a commercial in-memory column store database system. We investigate different alternatives to store temporal data physically and analyze the trade-offs arising from different memory layouts which cluster the data either by time or by space dimension. Taking into account the underlying physical representation, different temporal operators such as temporal aggregation, time travel and temporal join have to be executed efficiently. We present a novel data structure called Timeline Index and algorithms based on this index, which have a very competitive performance for all temporal operators beating existing best-of-breed approaches by factors, sometimes even by orders of magnitude. The results of this thesis are currently being integrated into HANA, with the goal of being shipped to the customers as a productive release within the next few months.

[1] Amplitudes of quasi two-day waves (QTDWs) are derived from temperature observations of the High Resolution Dynamics Limb Sounder and Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) satellite instruments. In particular, a global climatology of QTDW amplitudes is derived from 10 years of SABER data, covering the mesosphere and lower thermosphere. This climatology is compared with geostrophic winds and climatologies of gravity wave (GW) momentum flux and GW drag absolute values derived from the same data set. We find that QTDWs are forced shortly after the maximum of the mesospheric summertime zonal wind jet in regions of jet instability where the meridional gradient of quasi-geostrophic zonal mean potential vorticity is strongly negative. The jet instability regions are closely linked to enhanced GW drag that likely seeds those instabilities by decelerating the jet and causing the jet curvature responsible for the negative potential vorticity gradient. The vertical phase structure and the Eliassen-Palm flux of the QTDWs are derived from SABER data and investigated. It is shown that QTDWs propagate upward starting from the jet instability regions. They exert eastward drag in the jet core, and strong westward drag at higher altitudes. Strikingly, the QTDWs are forced in regions where the global distribution of GWs exhibits a characteristic longitudinal structure caused by the GW source patterns in the summer hemisphere. This longitudinal structure might play an important role in the forcing of QTDWs; however, no clear link has been found to the observed QTDW zonal wavenumbers.

While vitamin D deficiency is common in patients with end stage renal disease on dialysis and treatment with Vitamin D680 samples from three controlled trials of Vitamin DThe subjects given Vitamin DWe conclude that the enzymatic activity of CYP24A1 is abnormal in end stage renal patients on dialysis. These trials were registered on clinicaltrials.govNCT00511225 on 8/1/2007; NCT01325610 on 1/17/2011; and NCT01675557 on 8/28/2012.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D

Global change refers to changes in the atmosphere, oceans, biosphere, pedosphere and lithosphere over the past century. It is a long process with large dimensions. Nowadays, satellite provides a regular platform to take measurements of all sensitivity factors of Earth. However, measurements taken from satellite platform is only available in a limited region on Earth with a short observing time. This is a new challenge for the purpose to observe large scale, long period Earth phenomena. In recent years, there has been a renewed interest in the development of robotic and manned exploration missions to the Moon. Here we propose the possibility of observing large-scale Earth phenomena from a lunar base. Atmospheric gravity waves, which is of interest to atmospheric research and important to the global change, are discussed as a sensitivity factor for lunar-based observation.

This paper presents ParTime, a parallel algorithm for temporal aggregation. Temporal aggregation is one of the most important, yet most complex temporal query operators. It has been extensively studied in the past, but so far there has only been one attempt to parallelize this operator. ParTime supports data parallelism and has a number of additional advantages: It supports the full bitemporal data model, it requires no a-priori indexing, it supports shared computation, and it runs well on modern hardware (i.e., NUMA machines with large main memories). We implemented ParTime in a parallel database system and carried out comprehensive performance experiments with a real workload from the airline industry and a synthetic benchmark, the TPC-BiH benchmark. The results show that ParTime significantly outperforms any other available temporal database system. Furthermore, the results show that ParTime is competitive as compared to the Timeline Index, the best known technique to process temporal queries from the research literature and which is based on pre-computation and indexing.

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n = 127]; 9/10, 22.3% [n = 142]; 8/10, 38.2% [n = 60]; MICA-129 mismatched 10/10, 3.9% [n = 54]; 9/10, 10.2% [n = 65]; 8/10, 17.2% [n = 27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.

Sudden stratospheric warmings (SSWs) are circulation anomalies in the polar region during winter. They mostly occur in the Northern Hemisphere and affect also surface weather and climate. Both planetary waves and gravity waves contribute to the onset and evolution of SSWs. While the role of planetary waves for SSW evolution has been recognized, the effect of gravity waves is still not fully understood, and has not been comprehensively analyzed based on global observations. In particular, information on the gravity wave driving of the background winds during SSWs is still missing. We investigate the boreal winters 2001/2002 until 2013/2014. Absolute gravity wave momentum fluxes and gravity wave dissipation (potential drag) are estimated from temperature observations of the satellite instruments HIRDLS and SABER. In agreement with previous work, we find that sometimes gravity wave activity is enhanced before the central date of major SSWs, particularly during vortex-split events. Often, SSWs are associated with polar-night jet oscillation (PJO) events. For these events, we find that gravity wave activity is strongly suppressed when winds reverse from eastward to westward (usually after the central date of a major SSW). In addition, gravity wave potential drag at the bottom of the newly forming eastward directed jet is remarkably weak, while considerable potential drag at the top of the jet likely contributes to the downward propagation of both the jet and the new elevated stratopause. During PJO events, we also find some indication for poleward propagation of gravity waves. Another striking finding is that obviously localized gravity wave sources, likely mountain waves and jet-generated gravity waves, play an important role during the evolution of SSWs and potentially contribute to the triggering of SSWs by preconditioning the shape of the polar vortex. The distribution of these hot spots is highly variable and strongly depends on the zonal and meridional shape of the background wind field, indicating that a pure zonal average view sometimes is a too strong simplification for the strongly perturbed conditions during the evolution of SSWs.

A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ⩾4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

Item does not contain fulltext Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.