Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control

Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation

In the mammary gland Bcl-x is the most abundant cell survival factor from the Bcl-2 family. Since Bcl-x null mice die around day 12 of embryogenesis, the relevance of this protein in organ development and function is poorly understood. In erythroid cells bcl-x gene expression is controlled by cytokines and the transcription factor Stat5 (signal transducer and activator of transcription). However, we identified that bcl-x RNA levels in mammary tissue from prolactin receptor- and Stat5-null mice were indistinguishable from wild type mice. We have proposed that Bcl-x might control the survival of mammary epithelial cells throughout pregnancy, lactation, and the early stages of involution, and we have now tested this hypothesis through the conditional deletion of the bcl-x gene from mouse mammary epithelium. Conditional (floxed) bcl-x alleles were excised from alveolar cells during pregnancy using a Cre transgene under the control of the whey acidic protein gene promoter. Deletion of the bcl-x gene from the entire epithelial compartment (ducts and alveoli) was achieved by expressing Cre-recombinase under control of the mouse mammary tumor virus long terminal repeat. The absence of Bcl-x did not compromise proliferation and differentiation of mammary ductal and alveolar epithelial cells in virgin mice and during pregnancy and lactation. However, epithelial cell death and tissue remodeling were accelerated in the bcl-x conditional knockout mice during the first stage of involution. Concomitant deletion of the bax gene did not significantly modify the Bcl-x phenotype. Our results suggest that Bcl-x is not essential during mammopoiesis, but is critical for controlled apoptosis during the first phase of involution. Published by Elsevier Science Ireland Ltd

Optimized survey design for electrical resistivity tomography: combined optimization of measurement configuration and electrode placement

Within geoelectrical imaging, the choice of measurement configurations and electrode locations is known to control the image resolution. Previous work has shown that optimized survey designs can provide a model resolution that is superior to standard survey designs. This paper demonstrates a methodology to optimize resolution within a target area, while limiting the number of required electrodes, thereby selecting optimal electrode locations. This is achieved by extending previous work on the ‘Compare-R’ algorithm, which by calculating updates to the resolution matrix optimizes the model resolution in a target area. Here, an additional weighting factor is introduced that allows to preferentially adding measurement configurations that can be acquired on a given set of electrodes. The performance of the optimization is tested on two synthetic examples and verified with a laboratory study. The effect of the weighting factor is investigated using an acquisition layout comprising a single line of electrodes. The results show that an increasing weight decreases the area of improved resolution, but leads to a smaller number of electrode positions. Imaging results superior to a standard survey design were achieved using 56 per cent fewer electrodes. The performance was also tested on a 3-D acquisition grid, where superior resolution within a target at the base of an embankment was achieved using 22 per cent fewer electrodes than a comparable standard survey. The effect of the underlying resistivity distribution on the performance of the optimization was investigated and it was shown that even strong resistivity contrasts only have minor impact. The synthetic results were verified in a laboratory tank experiment, where notable image improvements were achieved. This work shows that optimized surveys can be designed that have a resolution superior to standard survey designs, while requiring significantly fewer electrodes. This methodology thereby provides a means for improving the efficiency of geoelectrical imaging

Detection of intrinsic source structure at ~3 Schwarzschild radii with Millimeter-VLBI observations of SAGITTARIUS A*

We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional {\it uv} coverage in the N-S direction, and leads to a spatial resolution of $\sim$30 $\mu$as ($\sim$3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of $\sim$4-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of $\sim$3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk- and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow a more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary.Comment: 11 pages, 5 figures, accepted to Ap

Expression of Distal-less, dachshund, and optomotor blind in Neanthes arenaceodentata (Annelida, Nereididae) does not support homology of appendage-forming mechanisms across the Bilateria

The similarity in the genetic regulation of arthropod and vertebrate appendage formation has been interpreted as the product of a plesiomorphic gene network that was primitively involved in bilaterian appendage development and co-opted to build appendages (in modern phyla) that are not historically related as structures. Data from lophotrochozoans are needed to clarify the pervasiveness of plesiomorphic appendage forming mechanisms. We assayed the expression of three arthropod and vertebrate limb gene orthologs, Distal-less (Dll), dachshund (dac), and optomotor blind (omb), in direct-developing juveniles of the polychaete Neanthes arenaceodentata. Parapodial Dll expression marks premorphogenetic notopodia and neuropodia, becoming restricted to the bases of notopodial cirri and to ventral portions of neuropodia. In outgrowing cephalic appendages, Dll activity is primarily restricted to proximal domains. Dll expression is also prominent in the brain. dac expression occurs in the brain, nerve cord ganglia, a pair of pharyngeal ganglia, presumed interneurons linking a pair of segmental nerves, and in newly differentiating mesoderm. Domains of omb expression include the brain, nerve cord ganglia, one pair of anterior cirri, presumed precursors of dorsal musculature, and the same pharyngeal ganglia and presumed interneurons that express dac. Contrary to their roles in outgrowing arthropod and vertebrate appendages, Dll, dac, and omb lack comparable expression in Neanthes appendages, implying independent evolution of annelid appendage development. We infer that parapodia and arthropodia are not structurally or mechanistically homologous (but their primordia might be), that Dll’s ancestral bilaterian function was in sensory and central nervous system differentiation, and that locomotory appendages possibly evolved from sensory outgrowths

Leisure craft sacrificial anodes as a source of zinc and cadmium to saline waters

12 months embarg

The flower garden banks Siderastrea siderea coral as a candidate global boundary stratotype section and point for the Anthropocene series

The proposed Anthropocene Global Boundary Stratotype Section and Point (GSSP) candidate site of West Flower Garden Bank (27.8762°N, 93.8147°W) is an open ocean location in the Gulf of Mexico with a submerged coral reef and few direct human impacts. Corals contain highly accurate and precise (<±1 year) internal chronologies, similar to tree rings, and their exoskeletons are formed of aragonite and can be preserved in the rock record. Here we present results from a large Siderastrea siderea coral (core 05WFGB3; 1755–2005 CE) sampled with annual and monthly resolutions that show clear markers of global and regional human impacts. Atmospheric nuclear bomb testing by-products (14C, 239+240Pu) have clear increases in this coral starting in 1957 for 14C and the first increase in 1956 for 239+240Pu (potential bases for the Anthropocene GSSP). Coral δ13C declined especially after 1956 consistent with the Suess Effect resulting from the burning of fossil fuels. Coral skeletal δ15N starts to increase in 1963 corresponding with the increase in agricultural fertilizers. Coral Hg concentrations (1933–1980) loosely track fluctuations in industrial pollution and coral Ba/Ca increases from 1965–1983 when offshore oil operations expand after 1947. Coral temperature proxies contain the 20th-century global warming trend whereas coral growth declines during this interval