Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen

Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy. The drug is given intrathecally at 12 mg, beginning with 3 loading doses at 2-week intervals, a fourth loading dose 30 days thereafter, and maintenance doses at 4-month intervals. This population pharmacokinetic model was developed to clarify how to maintain targeted nusinersen exposure after an unforeseen one-time delay or missed dose. Simulations demonstrated that the impact of a one-time delay in dosing or a missed dose on median cerebrospinal fluid exposures depended on duration of interruption and the regimen phase in which it occurred. Delays in loading doses delayed reaching the peak trough concentration by approximately the duration of the interruption. Resumption of the regimen as soon as possible resulted in achieving steady state trough concentration upon completion of the loading phase. A short delay (30-90 days) during the maintenance phase led to prolonged lower median cerebrospinal fluid concentration if all subsequent doses were shifted by the same 4-month interval. However, administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored trough concentration. If a dose must be delayed, patients should return to the original dosing schedule as soon as possible

Speed Partitioning for Indexing Moving Objects

Indexing moving objects has been extensively studied in the past decades. Moving objects, such as vehicles and mobile device users, usually exhibit some patterns on their velocities, which can be utilized for velocity-based partitioning to improve performance of the indexes. Existing velocity-based partitioning techniques rely on some kinds of heuristics rather than analytically calculate the optimal solution. In this paper, we propose a novel speed partitioning technique based on a formal analysis over speed values of the moving objects. We first show that speed partitioning will significantly reduce the search space expansion which has direct impacts on query performance of the indexes. Next we formulate the optimal speed partitioning problem based on search space expansion analysis and then compute the optimal solution using dynamic programming. We then build the partitioned indexing system where queries are duplicated and processed in each index partition. Extensive experiments demonstrate that our method dramatically improves the performance of indexes for moving objects and outperforms other state-of-the-art velocity-based partitioning approaches

The conserved C-terminus of the PcrA/UvrD helicase interacts directly with RNA polymerase

Copyright: © 2013 Gwynn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a Wellcome Trust project grant to MD (Reference: 077368), an ERC starting grant to MD (Acronym: SM-DNA-REPAIR) and a BBSRC project grant to PM, NS and MD (Reference: BB/I003142/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

Meconium pseudocyst secondary to ileum volvulus perforation without peritoneal calcification: a case report

<p>Abstract</p> <p>Introduction</p> <p>A case of giant meconium pseudocyst secondary to ileum volvulus perforation is presented. Conventional radiographic features of meconium peritonitis with secondary meconium pseudocyst formation are well described. Our case is unusual in comparison to other cases reported in the literature and needs to be reported because the meconium pseudocyst presented without the typical ultrasound features (calcifications, polyhydramnios and ascites) and was initially identified as an abdominal mass.</p> <p>Case presentation</p> <p>We describe the case of a 29-year-old Caucasian woman in her third trimester of pregnancy, in which an abdominal mass was detected in the fetus. The newborn was diagnosed in the early neonatal period with meconium pseudocyst secondary to ileum volvulus perforation.</p> <p>Conclusions</p> <p>The prenatal appearance of a meconium pseudocyst can be complemented by other signs of bowel obstruction (if present) such as polyhydramnios and fetal bowel dilatation. This is an original case report of interest to all clinicians in the perinatology and fetal ultrasound field. We consider that the utility of this case is the recognition that a meconium pseudocyst might appear without the typical ultrasound features and should be considered as a differential diagnosis when an echogenic intra-abdominal cyst is seen.</p

Representations of sl(2,?) in category O and master symmetries

We show that the indecomposable sl(2,?)-modules in the Bernstein-Gelfand-Gelfand category O naturally arise for homogeneous integrable nonlinear evolution systems. We then develop a new approach called the O scheme to construct master symmetries for such integrable systems. This method naturally allows computing the hierarchy of time-dependent symmetries. We finally illustrate the method using both classical and new examples. We compare our approach to the known existing methods used to construct master symmetries. For new integrable equations such as a Benjamin-Ono-type equation, a new integrable Davey-Stewartson-type equation, and two different versions of (2+1)-dimensional generalized Volterra chains, we generate their conserved densities using their master symmetries

NOX2, p22phox and p47phox are targeted to the nuclear pore complex in ischemic cardiomyocytes colocalizing with local reactive oxygen species.

BACKGROUND: NADPH oxidases play an essential role in reactive oxygen species (ROS)-based signaling in the heart. Previously, we have demonstrated that (peri)nuclear expression of the catalytic NADPH oxidase subunit NOX2 in stressed cardiomyocytes, e.g. under ischemia or high concentrations of homocysteine, is an important step in the induction of apoptosis in these cells. Here this ischemia-induced nuclear targeting and activation of NOX2 was specified in cardiomyocytes. METHODS: The effect of ischemia, mimicked by metabolic inhibition, on nuclear localization of NOX2 and the NADPH oxidase subunits p22(phox) and p47(phox), was analyzed in rat neonatal cardiomyoblasts (H9c2 cells) using Western blot, immuno-electron microscopy and digital-imaging microscopy. RESULTS: NOX2 expression significantly increased in nuclear fractions of ischemic H9c2 cells. In addition, in these cells NOX2 was found to colocalize in the nuclear envelope with nuclear pore complexes, p22(phox), p47(phox) and nitrotyrosine residues, a marker for the generation of ROS. Inhibition of NADPH oxidase activity, with apocynin and DPI, significantly reduced (peri)nuclear expression of nitrotyrosine. CONCLUSION: We for the first time show that NOX2, p22(phox) and p47(phox) are targeted to and produce ROS at the nuclear pore complex in ischemic cardiomyocytes

A scalable machine-learning approach to recognize chemical names within large text databases

MOTIVATION: The use or study of chemical compounds permeates almost every scientific field and in each of them, the amount of textual information is growing rapidly. There is a need to accurately identify chemical names within text for a number of informatics efforts such as database curation, report summarization, tagging of named entities and keywords, or the development/curation of reference databases. RESULTS: A first-order Markov Model (MM) was evaluated for its ability to distinguish chemical names from words, yielding ~93% recall in recognizing chemical terms and ~99% precision in rejecting non-chemical terms on smaller test sets. However, because total false-positive events increase with the number of words analyzed, the scalability of name recognition was measured by processing 13.1 million MEDLINE records. The method yielded precision ranges from 54.7% to 100%, depending upon the cutoff score used, averaging 82.7% for approximately 1.05 million putative chemical terms extracted. Extracted chemical terms were analyzed to estimate the number of spelling variants per term, which correlated with the total number of times the chemical name appeared in MEDLINE. This variability in term construction was found to affect both information retrieval and term mapping when using PubMed and Ovid

Distributions of phytoplankton carbohydrate, protein and lipid in the world oceans from satellite ocean colour

Energy value of phytoplankton regulates the growth of higher trophic species, affecting the tropic balance and sustainability of marine food webs. Therefore, developing our capability to estimate and monitor, on a global scale, the concentrations of macromolecules that determine phytoplankton energy value, would be invaluable. Reported here are the first estimates of carbohydrate, protein, lipid, and overall energy value of phytoplankton in the world oceans, using ocean-colour data from satellites. The estimates are based on a novel bio-optical method that utilises satellite-derived bio-optical fingerprints of living phytoplankton combined with allometric relationships between phytoplankton cells and cellular macromolecular contents. The annually-averaged phytoplankton energy value, per cubic meter of sub-surface ocean, varied from less than 0.1 kJ in subtropical gyres, to 0.5–1.0 kJ in parts of the equatorial, northern and southern latitudes, and rising to more than 10 kJ in certain coastal and optically complex waters. The annually-averaged global stocks of carbohydrate, protein and lipid were 0.044, 0.17 and 0.108 gigatonnes, respectively, with monthly stocks highest in September and lowest in June, over 1997-2013. The fractional contributions of phytoplankton size classes e.g., picoplankton, nanoplankton and microplankton to surface concentrations and global stocks of macromolecules varied considerably across marine biomes classified as Longhurst provinces. Among these provinces, the highest annually-averaged surface concentrations of carbohydrate, protein, and lipid were in North-East Atlantic Coastal Shelves, whereas, the lowest concentration of carbohydrate or lipid were in North Atlantic Tropical Gyral, and that of protein was in North Pacific Subtropical Gyre West. The regional accuracy of the estimates and their sensitivity to satellite inputs are quantified from the bio-optical model, which show promise for possible operational monitoring of phytoplankton energy value from satellite ocean colour. Adequate in situ measurements of macromolecules and improved retrievals of inherent optical properties from high-resolution satellite images, would be required to validate these estimates at local sites, and to further improve their accuracy in the world oceans