Iron Status and Analysis of Efficacy and Safety of Ferric Carboxymaltose Treatment in Patients with Inflammatory Bowel Disease

Background and Aims:We analyzed iron deficiency and the therapeutic response following intravenous ferric carboxymaltose in a large single-center inflammatory bowel disease (IBD) cohort. Methods: 250 IBD patients were retrospectively analyzed for iron deficiency and iron deficiency anemia. A subgroup was analyzed regarding efficacy and side effects of iron supplementation with ferric carboxymaltose. Results: In the cohort (n = 250), 54.4% of the patients had serum iron levels 60 mu g/dl, 61.6% had ferritin >100 ng/ml, and 90.7% reached Hb >12/13 g/dl at follow-up (p < 0.0001 for all parameters vs. pretreatment values). The most frequent adverse event was a transient increase of liver enzymes with male gender as risk factor (p = 0.008, OR 8.62, 95% CI 1.74-41.66). Conclusions: Iron deficiency and anemia are frequent in IBD patients. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients. Copyright (C) 2011 S. Karger AG, Base

Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6. We show that both the G660R and R510stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases

Mutations that affect the surface expression of TRPV6 are associated with the upregulation of serine proteases in the placenta of an infant

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R(510)stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G(660)R) that, surprisingly, does not affect the Ca(2+) permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G(660)R and R(510)stop mutants and combinations with wild type TRPV6. We show that both the G(660)R and R(510)stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases

Emergence and rapid global dissemination of CTX-M-15-associated Klebsiella pneumoniae strain ST307

Objectives: Recent reports indicate the emergence of a new carbapenemase-producing Klebsiella pneumoniae clone, ST307. We sought to better understand the global epidemiology and evolution of this clone and evaluate its association with antimicrobial resistance (AMR) genes. Methods: We collated information from the literature and public databases and performed a comparative analysis of 95 ST307 genomes (including 37 that were newly sequenced). Results: We show that ST307 emerged in the mid-1990s (nearly 20 years prior to its first report), is already globally distributed and is intimately associated with a conserved plasmid harbouring the blaCTX-M-15 ESBL gene and several other AMR determinants. Conclusions: Our findings support the need for enhanced surveillance of this widespread ESBL clone in which carbapenem resistance has occasionally emerged.publishedVersio

MicroRNAs miR-221 and miR-181c regulation of liver tumor growth and metastasis in mouse progeny from Dibenzo[def,p]chrysene dosed mothers fed a sulforaphane diet

Dibenzo[def,p]chrysene (DBC) is a polycyclic aromatic hydrocarbon (PAH) and an IARC classified 2A probable human carcinogen. Mouse progeny transplacentally exposed to DBC have been shown to develop lung and liver tumors, with liver tumors developing predominantly in males later in life. Sulforaphane (SFN) is an isothiocyanate that plays a crucial role in cellular protection from carcinogens and can be found in cruciferous vegetables. MicroRNAs (miRNAs) are a class of small, <200bp, non-coding RNAs that regulate gene expression post-transcriptionally. Emerging evidence has shown that miRNAs play critical roles in the development and progression of hepatocellular carcinoma (HCC). Pregnant mice were given one dose of DBC (15mg/kg) on gestation day (GD) 17 while fed a control or SFN diet (400ppm) starting on GD 9 and continued through weaning. Weaned offspring were maintained for 10 months and tissues analyzed for tumors. In this experiment, it was found that miR-181c was significantly up-regulated in both treatment groups. miR-221 was found to be significantly upregulated in the DBC/SFN treatment group. Proteins that are targeted by miR-181c have been shown to inactivate mechanisms which oncogenes use to metastasize in tissues. [Chen, Wang, Xu, Guo, Jiang, 2015] The upregulation of miR-181c and miR-221 suggests these miRNAs may be involved in hepatic cancer development in this model. Future research will explore candidate targets for mRNA level and protein expression thought to be regulated by these miRNAs

Detection of the 205 um [NII] Line from the Carina Nebula

We report the first detection of the 205 um 3P1 - 3P0 [NII] line from a ground-based observatory using a direct detection spectrometer. The line was detected from the Carina star formation region using the South Pole Imaging Fabry-Perot Interferometer (SPIFI) on the Antarctic Submillimeter Telescope and Remote Observatory (AST/RO) at South Pole. The [NII] 205 um line strength indicates a low-density (n ~ 32 cm^-3 ionized medium, similar to the low-density ionized halo reported previously in its [OIII] 52 and 88 um line emission. When compared with the ISO [CII] observations of this region, we find that ~27% of the [CII] line emission arises from this low-density ionized gas, but the large majority ~ 73% of the observed [CII] line emission arises from the neutral interstellar medium. This result supports and underpins prior conclusions that most of the observed [CII] 158 um line emission from Galactic and extragalactic sources arises from the warm, dense photodissociated surfaces of molecular clouds. The detection of the [NII] line demonstrates the utility of Antarctic sites for THz spectroscopy.Comment: 8 pages, 2 figures. To appear in the Astrophysical Journal Letter

Palaeo-environmental evolution of Central Asia during the Cenozoic: new insights from the continental sedimentary archive of the Valley of Lakes (Mongolia)

The Valley of Lakes basin (Mongolia) contains a unique continental sedimentary archive, suitable for constraining the influence of tectonics and climate change on the aridification of Central Asia in the Cenozoic. We identify the sedimentary provenance, the (post)depositional environment and the palaeo-climate based on sedimentological, petrographical, mineralogical, and (isotope) geochemical signatures recorded in authigenic and detrital silicates as well as soil carbonates in a sedimentary succession spanning from ~34 to 21 Ma. The depositional setting was characterized by an ephemeral braided river system draining prograding alluvial fans, with episodes of lake, playa or open-steppe sedimentation. Metamorphics from the northern adjacent Neoarchean to late Proterozoic hinterlands provided a continuous influx of silicate detritus to the basin, as indicated by K-Ar ages of detrital muscovite (~798-728 Ma) and discrimination function analysis. The authigenic clay fraction is dominated by illite-smectite and “hairy” illite (K-Ar ages of ~34-25 Ma), which formed during coupled petrogenesis and precipitation from hydrothermal fluids originating from major basalt flow events (~32-29 and ~29-25 Ma). Changes in hydroclimate are recorded in [delta]18O and [delta]13C profiles of soil carbonates and in silicate mineral weathering patterns, indicating that comparatively humid to semi-arid conditions prevailed in the late(st) Eocene, changing into arid conditions in the Oligocene and back to humid to semi-arid conditions in the early Miocene. Aridification steps are indicated at ~34-33, ~31, ~28 and ~23 Ma and coincide with some episodes of high-latitude ice-sheet expansion inferred from marine deep-sea sedimentary records. This suggests that long-term variations in the ocean-atmosphere circulation patterns due to pCO2 fall, reconfiguration of ocean gateways and ice-sheet expansion in Antarctica could have impacted the hydroclimate and weathering regime in the basin. We conclude that the aridification in Central Asia was triggered by reduced moisture influx by westerly winds driven by Cenozoic climate forcing and the exhumation of the Tian Shan and Altai Mountains and modulated by global climate events

The Role of Regulated mRNA Stability in Establishing Bicoid Morphogen Gradient in Drosophila Embryonic Development

The Bicoid morphogen is amongst the earliest triggers of differential spatial pattern of gene expression and subsequent cell fate determination in the embryonic development of Drosophila. This maternally deposited morphogen is thought to diffuse in the embryo, establishing a concentration gradient which is sensed by downstream genes. In most model based analyses of this process, the translation of the bicoid mRNA is thought to take place at a fixed rate from the anterior pole of the embryo and a supply of the resulting protein at a constant rate is assumed. Is this process of morphogen generation a passive one as assumed in the modelling literature so far, or would available data support an alternate hypothesis that the stability of the mRNA is regulated by active processes? We introduce a model in which the stability of the maternal mRNA is regulated by being held constant for a length of time, followed by rapid degradation. With this more realistic model of the source, we have analysed three computational models of spatial morphogen propagation along the anterior-posterior axis: (a) passive diffusion modelled as a deterministic differential equation, (b) diffusion enhanced by a cytoplasmic flow term; and (c) diffusion modelled by stochastic simulation of the corresponding chemical reactions. Parameter estimation on these models by matching to publicly available data on spatio-temporal Bicoid profiles suggests strong support for regulated stability over either a constant supply rate or one where the maternal mRNA is permitted to degrade in a passive manner

Swift: primary data analysis for the Illumina Solexa sequencing platform

Motivation: Primary data analysis methods are of critical importance in second generation DNA sequencing. Improved methods have the potential to increase yield and reduce the error rates. Openly documented analysis tools enable the user to understand the primary data, this is important for the optimization and validity of their scientific work

Limits on the effective quark radius from inclusive epep scattering at HERA

The high-precision HERA data allows searches up to TeV scales for Beyond the Standard Model contributions to electron-quark scattering. Combined measurements of the inclusive deep inelastic cross sections in neutral and charged current $ep$ scattering corresponding to a luminosity of around 1 fb$^{-1}$ have been used in this analysis. A new approach to the beyond the Standard Model analysis of the inclusive $ep$ data is presented; simultaneous fits of parton distribution functions together with contributions of "new physics" processes were performed. Results are presented considering a finite radius of quarks within the quark form-factor model. The resulting 95% C.L. upper limit on the effective quark radius is $0.43\cdot 10^{-16}$ cm.Comment: 10 pages, 4 figures, accepted by Phys. Lett.