Arterial hypertension in aortic valve stenosis: A critical update

Aortic stenosis (AS) is a very common valve disease and is associated with high mortality once it becomes symptomatic. Arterial hypertension (HT) has a high prevalence among patients with AS leading to worse left ventricle remodeling and faster degeneration of the valve. HT also interferes with the assessment of the severity of AS, leading to an underestimation of the real degree of stenosis. Treatment of HT in AS has not historically been pursued due to the fear of excess reduction in afterload without a possibility of increasing stroke volume due to the fixed aortic valve, but most recent evidence shows that several drugs are safe and effective in reducing BP in patients with HT and AS. RAAS inhibitors and beta‐blockers provide benefit in selected populations based on their profile of pharmacokinetics and pharmacodynamics. Different drugs, on the other hand, have proved to be unsafe, such as calcium channel blockers, or simply not easy enough to handle to be recommended in clinical practice, such as PDE5i, MRA or sodium nitroprusside. The present review highlights all available studies on HT and AS to guide antihypertensive treatment

What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommende

U.S. GLOBEC Georges Bank long-term moored program : part 1 - mooring configuration

As part of the U.S. GLOBEC Northwest Atlantic/Georges Bank program, moorings were deployed on Georges Bank as part of the broad-scale survey component to help measure the temporal variability of both physical and biological characteristics on the Bank. The array consisted of a primary mooring site on the Southern Flank which was maintained for the full 5-year duration of the field program, plus secondary moorings, with fewer sensors and of shorter duration, in the well-mixed water on the Crest and in the cod/haddock spawning region on the Northeast Peak. Temperature and conductivity (salinity) were measured at 5-m intervals, ADCP velocity profiles were obtained with 1-m vertical resolution, and bio-optical packages (measuring fluorescence, optical transmission and photosynthetically active radiation) were deployed at 10-m and 40-m depths. Bottom pressure was measured at the Southern Flank site. The buoy design, sensors and mooring configuration is presented and discussed below, and the data obtained is presented and discussed in an accompanying reports “U.S. GLOBEC Georges Bank Long-Term Moored Program: Part 2 – Yearly Data Summary and Report,” and “U.S. GLOBEC Georges Bank Long-Term Moored Program: Part 3 – Data Summary.”Funding was provided by the National Science Foundation under grant numbers OCE-93-13670, OCE-96-32348, OCE98-06379, OCE-98-06445 and OCE-02-27679

An autonomous, in situ light-dark bottle device for determining community respiration and net community production

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Limnology and Oceanography-Methods 16 (2018): 323-338, doi:10.1002/lom3.10247.We describe a new, autonomous, incubation-based instrument that is deployed in situ to determine rates of gross community respiration and net community production in marine and aquatic ecosystems. During deployments at a coastal pier and in the open ocean, the PHORCYS (PHOtosynthesis and Respiration Comparison-Yielding System) captured dissolved oxygen fluxes over hourly timescales that were missed by traditional methods. The instrument uses fluorescence-quenching optodes fitted into separate light and dark chambers; these are opened and closed with piston-like actuators, allowing the instrument to make multiple, independent rate estimates in the course of each deployment. Consistent with other studies in which methods purporting to measure the same metabolic processes have yielded divergent results, respiration rate estimates from the PHORCYS were systematically higher than those calculated for the same waters using a traditional two-point Winkler titration technique. However, PHORCYS estimates of gross respiration agreed generally with separate incubations in bottles fitted with optode sensor spots. An Appendix describes a new method for estimating uncertainties in metabolic rates calculated from continuous dissolved oxygen data. Multiple successful, unattended deployments of the PHORCYS represent a small step toward fully autonomous observations of community metabolism. Yet the persistence of unexplained disagreements among aquatic metabolic rate estimates — such as those we observed between rates calculated with the PHORCYS and two existing, widely-accepted bottle-based methods — suggests that a new community intercalibration effort is warranted to address lingering sources of error in these critical measurements.This research was supported by the U.S. National Science Foundation (awards OCE-1155438 to B.A.S.V.M., J.R.V., and R.G.K., and OCE- 1059884 to B.A.S.V.M.), the Woods Hole Oceanographic Institution through a Cecil and Ida Green Foundation Innovative Technology Award and an Interdisciplinary Science Award, and a U.S. Environmental Protection Agency (EPA) STAR Graduate Fellowship to J.R.C. under Fellowship Assistance Agreement no. FP-91744301-0

Properties of healthcare teaming networks as a function of network construction algorithms

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: The Center for Medicare Services Outpatient Claims DE-SynPUF (DE-SynPUF)\cite{RN120} test set is publicly available from the CMS web site. The full 2013 Medicare Part B Limited Data Set for Medicare claims can be obtained from the Center for Medicare Services. This data is bound by a privacy and limited distribution agreement, as well as HIPAA regulations, and thus cannot be made public with this manuscript. However, the files can be requested from the Center for Medicare Services by individual investigators and used to reproduce our findings. Release of the derived networks is also limited by Medicare requirements to remove nodes and edges where the total number of shared patients 11 shared patients, and these are available on figshare.com as referenced in the Supplemental Data section of the manuscript.Network models of healthcare systems can be used to examine how providers collaborate, communicate, refer patients to each other, and to map how patients traverse the network of providers. Most healthcare service network models have been constructed from patient claims data, using billing claims to link a patient with a specific provider in time. The data sets can be quite large (106±108 individual claims per year), making standard methods for network construction computationally challenging and thus requiring the use of alternate construction algorithms. While these alternate methods have seen increasing use in generating healthcare networks, there is little to no literature comparing the differences in the structural properties of the generated networks, which as we demonstrate, can be dramatically different. To address this issue, we compared the properties of healthcare networks constructed using different algorithms from 2013 Medicare Part B outpatient claims data. Three different algorithms were compared: Binning, sliding frame, and trace-route. Unipartite networks linking either providers or healthcare organizations by shared patients were built using each method. We find that each algorithm produced networks with substantially different topological properties, as reflected by numbers of edges, network density, assortativity, clustering coefficients and other structural measures. Provider networks adhered to a power law, while organization networks were best fit by a power law with exponential cutoff. Censoring networks to exclude edges with less than 11 shared patients, a common de-identification practice for healthcare network data, markedly reduced edge numbers and network density, and greatly altered measures of vertex prominence such as the betweenness centrality. Data analysis identified patterns in the distance patients travel between network providers, and a striking set of teaming relationships between providers in the Northeast United States and Florida, likely due to seasonal residence patterns of Medicare beneficiaries. We conclude that the choice of network construction algorithm is critical for healthcare network analysis, and discuss the implications of our findings for selecting the algorithm best suited to the type of analysis to be performed.National Institute of HealthPhilip Templeton FoundationUniversity of Rochester Center for Health Informatic

Chronic neural interfacing with cerebral cortex using single-walled carbon nanotube-polymer grids

Objective. The development of electrode arrays able to reliably record brain electrical activity is a critical issue in brain machine interface (BMI) technology. In the present study we undertook a comprehensive physico-chemical, physiological, histological and immunohistochemical characterization of new single-walled carbon nanotubes (SWCNT)-based electrode arrays grafted onto medium-density polyethylene (MD-PE) films. Approach. The long-term electrical stability, flexibility, and biocompatibility of the SWCNT arrays were investigated in vivo in laboratory rats by two-months recording and analysis of subdural electrocorticogram (ECoG). Ex-vivo characterization of a thin flexible and single probe SWCNT/polymer electrode is also provided. Main results. The SWCNT arrays were able to capture high quality and very stable ECoG signals across 8 weeks. The histological and immunohistochemical analyses demonstrated that SWCNT arrays show promising biocompatibility properties and may be used in chronic conditions. The SWCNT-based arrays are flexible and stretchable, providing low electrode-tissue impedance, and, therefore, high compliance with the irregular topography of the cortical surface. Finally, reliable evoked synaptic local field potentials in rat brain slices were recorded using a special SWCNT-polymer-based flexible electrode. Significance. The results demonstrate that the SWCNT arrays grafted in MD-PE are suitable for manufacturing flexible devices for subdural ECoG recording and might represent promising candidates for long-term neural implants for epilepsy monitoring or neuroprosthetic BMI

A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody

Influenza's propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1. KPF1 has broad and potent neutralizing activity against H1 influenza viruses, and recognized 83% of all H1 isolates tested, including the pandemic 1918 H1. Prophylactically, KPF1 treatment resulted in 100% survival of mice from lethal challenge with multiple H1 influenza strains and when given as late as 72 h after challenge with A/California/04/2009 H1N1, resulted in 80% survival. KPF1 recognizes a novel epitope in the HA globular head, which includes a highly conserved amino acid, between the Ca and Cb antigenic sites. Although recent HA stalk-specific mAbs have broader reactivity, their potency is substantially limited, suggesting that cocktails of broadly reactive and highly potent HA globular head-specific mAbs, like KPF1, may have greater clinical feasibility for the treatment of influenza infections.Peer reviewe

The Phyre2 web portal for protein modeling, prediction and analysis

Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30 min and 2 h after submission

1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma

BACKGROUND: Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway. METHODS: We established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used 1H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG5kDa-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice. RESULTS: We found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted 1H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with \u3b1-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition. CONCLUSIONS: Our results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor