Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease.

BACKGROUND/AIMS: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. METHODS: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. RESULTS: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. CONCLUSION: Treatment with VKA predisposes to the development of calciphylaxis.TFH is funded by the Cambridge BRC and NIHR.This is the accepted manuscript for a paper published in Nephron Clinical Practice, Vol. 129, No. 3, 2015, DOI:10.1159/00037144

Proximity, maps and conflict: New measures, New maps and New findings

This article introduces two new datasets. The first is a new interstate distance dataset. It is recognized that different theories regarding distance and conflict will call for different understandings of “distance” and accordingly, ten different types of distance measurement are presented. Moreover, it is argued that in order for a distance dataset to contain accurate distances, it is necessary for it to be based on maps reflecting state border changes over time. As such, a new map dataset is presented, including annualized maps for all states, stored in KML format. It will be shown that the frequent border changes experienced by states can have large impacts on distance calculations. The significance of the relationship between distance and conflict will be tested for the ten different types of distance measurement, not with the aim of finding a “best measure” but in order to demonstrate that distance remains an important variable and that each different form of distance measure can be significant

Plasticity of fimbrial genotype and serotype within populations of <em>Bordetella pertussis</em>:analysis by paired flow cytometry and genome sequencing

The fimbriae of Bordetella pertussis are required for colonization of the human respiratory tract. Two serologically distinct fimbrial subunits, Fim2 and Fim3, considered important vaccine components for many years, are included in the Sanofi Pasteur 5-component acellular pertussis vaccine, and the World Health Organization recommends the inclusion of strains expressing both fimbrial serotypes in whole-cell pertussis vaccines. Each of the fimbrial major subunit genes, fim2, fim3, and fimX, has a promoter poly(C) tract upstream of its −10 box. Such monotonic DNA elements are susceptible to changes in length via slipped-strand mispairing in vitro and in vivo, which potentially causes on/off switching of genes at every cell division. Here, we have described intra-culture variability in poly(C) tract lengths and the resulting fimbrial phenotypes in 22 recent UK B. pertussis isolates. Owing to the highly plastic nature of fimbrial promoters, we used the same cultures for both genome sequencing and flow cytometry. Individual cultures of B. pertussis contained multiple fimbrial serotypes and multiple different fimbrial promoter poly(C) tract lengths, which supports earlier serological evidence that B. pertussis expresses both serotypes during infection.</jats:p

Structure-guided design of purine-based probes for selective Nek2 inhibition

Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: measuring structure growth using passive galaxies

We explore the benefits of using a passively evolving population of galaxies to measure the evolution of the rate of structure growth between z=0.25 and z=0.65 by combining data from the SDSS-I/II and SDSS-III surveys. The large-scale linear bias of a population of dynamically passive galaxies, which we select from both surveys, is easily modeled. Knowing the bias evolution breaks degeneracies inherent to other methodologies, and decreases the uncertainty in measurements of the rate of structure growth and the normalization of the galaxy power-spectrum by up to a factor of two. If we translate our measurements into a constraint on sigma_8(z=0) assuming a concordance cosmological model and General Relativity (GR), we find that using a bias model improves our uncertainty by a factor of nearly 1.5. Our results are consistent with a flat Lambda Cold Dark Matter model and with GR.Comment: Accepted for publication in MNRAS (clarifications added, results and conclusions unchanged

Manipulating ultracold atoms with a reconfigurable nanomagnetic system of domain walls

The divide between the realms of atomic-scale quantum particles and lithographically-defined nanostructures is rapidly being bridged. Hybrid quantum systems comprising ultracold gas-phase atoms and substrate-bound devices already offer exciting prospects for quantum sensors, quantum information and quantum control. Ideally, such devices should be scalable, versatile and support quantum interactions with long coherence times. Fulfilling these criteria is extremely challenging as it demands a stable and tractable interface between two disparate regimes. Here we demonstrate an architecture for atomic control based on domain walls (DWs) in planar magnetic nanowires that provides a tunable atomic interaction, manifested experimentally as the reflection of ultracold atoms from a nanowire array. We exploit the magnetic reconfigurability of the nanowires to quickly and remotely tune the interaction with high reliability. This proof-of-principle study shows the practicability of more elaborate atom chips based on magnetic nanowires being used to perform atom optics on the nanometre scale.Comment: 4 pages, 4 figure

The clustering of massive galaxies at z~0.5 from the first semester of BOSS data

We calculate the real- and redshift-space clustering of massive galaxies at z~0.5 using the first semester of data by the Baryon Oscillation Spectroscopic Survey (BOSS). We study the correlation functions of a sample of 44,000 massive galaxies in the redshift range 0.4<z<0.7. We present a halo-occupation distribution modeling of the clustering results and discuss the implications for the manner in which massive galaxies at z~0.5 occupy dark matter halos. The majority of our galaxies are central galaxies living in halos of mass 10^{13}Msun/h, but 10% are satellites living in halos 10 times more massive. These results are broadly in agreement with earlier investigations of massive galaxies at z~0.5. The inferred large-scale bias (b~2) and relatively high number density (nbar=3e-4 h^3 Mpc^{-3}) imply that BOSS galaxies are excellent tracers of large-scale structure, suggesting BOSS will enable a wide range of investigations on the distance scale, the growth of large-scale structure, massive galaxy evolution and other topics.Comment: 11 pages, 12 figures, matches version accepted by Ap

Urinary trace metals, maternal circulating angiogenic biomarkers, and preeclampsia: a single-contaminant and mixture-based approach

Abstract Background Exposures to toxic metals and deficiencies in essential metals disrupt placentation and may contribute to preeclampsia. However, effects of exposure to combinations of metals remain unknown. Objective We investigated the relationship between urinary trace metals, circulating angiogenic biomarkers, and preeclampsia using the LIFECODES birth cohort. Methods Urine samples collected during pregnancy were analyzed for 17 trace metals and plasma samples were analyzed for soluble fms-like tyrosine-1 (sFlt-1) and placental growth factor (PlGF). Cox proportional hazard models were used to estimate the hazard ratios (HR) of preeclampsia associated with urinary trace metals. Linear regression models were used to estimate the relationship between urinary trace metals and angiogenic biomarkers. Principal components analysis (PCA) was used to identify groups of metals and interactions between principal components (PCs) loaded by toxic and essential metals were examined. Results In single-contaminant models, several toxic and essential metals were associated with lower PlGF and higher sFlt-1/PlGF ratio. Detection of urinary chromium was associated with preeclampsia: HR (95% Confidence Interval [CI]) = 3.48 (1.02, 11.8) and an IQR-increase in urinary selenium was associated with reduced risk of preeclampsia (HR: 0.28, 95% CI: 0.08, 0.94). Using PCA, 3 PCs were identified, characterized by essential metals (PC1), toxic metals (PC2), and seafood-associated metals (PC3). PC1 and PC2 were associated with lower PlGF levels, but not preeclampsia risk in the overall cohort. Conclusions Trace urinary metals may be associated with adverse profiles of angiogenic biomarkers and preeclampsia.https://deepblue.lib.umich.edu/bitstream/2027.42/152235/1/12940_2019_Article_503.pd

Chronic Hepatitis B Finite Treatment: similar and different concerns with new drug classes

Chronic hepatitis B, a major cause of liver disease and cancer, affects over 250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative HBV therapies are underway, consisting of combinations of multiple novel agents +/- nucleos(t)ide reverse transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, and subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives and regulatory agencies. This Viewpoint outlines areas of consensus within our multi-stakeholder group for stopping finite therapies in chronic Hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, pre-defined stopping criteria, pre-defined retreatment criteria, duration of investigational therapies, and follow up after stopping therapy. Future research of unmet needs are discussed

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314