A review of ADM1 extensions, applications, and analysis: 2002-2005.

PubMed

Batstone, D J; Keller, J; Steyer, J P

2006-01-01

Since publication of the Scientific and Technical Report (STR) describing the ADM1, the model has been extensively used, and analysed in both academic and practical applications. Adoption of the ADM1 in popular systems analysis tools such as the new wastewater benchmark (BSM2), and its use as a virtual industrial system can stimulate modelling of anaerobic processes by researchers and practitioners outside the core expertise of anaerobic processes. It has been used as a default structural element that allows researchers to concentrate on new extensions such as sulfate reduction, and new applications such as distributed parameter modelling of biofilms. The key limitations for anaerobic modelling originally identified in the STR were: (i) regulation of products from glucose fermentation, (ii) parameter values, and variability, and (iii) specific extensions. Parameter analysis has been widespread, and some detailed extensions have been developed (e.g., sulfate reduction). A verified extension that describes regulation of products from glucose fermentation is still limited, though there are promising fundamental approaches. This is a critical issue, given the current interest in renewable hydrogen production from carbohydrate-type waste. Critical analysis of the model has mainly focused on model structure reduction, hydrogen inhibition functions, and the default parameter set recommended in the STR. This default parameter set has largely been verified as a reasonable compromise, especially for wastewater sludge digestion. One criticism of note is that the ADM1 stoichiometry focuses on catabolism rather than anabolism. This means that inorganic carbon can be used unrealistically as a carbon source during some anabolic reactions. Advances and novel applications have also been made in the present issue, which focuses on the ADM1. These papers also explore a number of novel areas not originally envisaged in this review.

An Empirical Function for Bidirectional Reflectance Characterization for Smoke Aerosols Using Multi-angular Airborne Measurements

NASA Astrophysics Data System (ADS)

Poudyal, R.; Singh, M. K.; Gatebe, C. K.; Gautam, R.; Varnai, T.

2015-12-01

Using airborne Cloud Absorption Radiometer (CAR) reflectance measurements of smoke, an empirical relationship between reflectances measured at different sun-satellite geometry is established, in this study. It is observed that reflectance of smoke aerosol at any viewing zenith angle can be computed using a linear combination of reflectance at two viewing zenith angles. One of them should be less than 30° and other must be greater than 60°. We found that the parameters of the linear combination computation follow a third order polynomial function of the viewing geometry. Similar relationships were also established for different relative azimuth angles. Reflectance at any azimuth angle can be written as a linear combination of measurements at two different azimuth angles. One must be in the forward scattering direction and the other in backward scattering, with both close to the principal plane. These relationships allowed us to create an Angular Distribution Model (ADM) for smoke, which can estimate reflectances in any direction based on measurements taken in four view directions. The model was tested by calculating the ADM parameters using CAR data from the SCAR-B campaign, and applying these parameters to different smoke cases at three spectral channels (340nm, 380nm and 470nm). We also tested our modelled smoke ADM formulas with Absorbing Aerosol Index (AAI) directly computed from the CAR data, based on 340nm and 380nm, which is probably the first study to analyze the complete multi-angular distribution of AAI for smoke aerosols. The RMSE (and mean error) of predicted reflectance for SCAR-B and ARCTAS smoke ADMs were found to be 0.002 (1.5%) and 0.047 (6%), respectively. The accuracy of the ADM formulation is also tested through radiative transfer simulations for a wide variety of situations (varying smoke loading, underlying surface types, etc.).

Preparation and characterization of the Adriamycin-loaded amphiphilic chitosan nanoparticles and their application in the treatment of liver cancer

PubMed Central

Kou, Chang-Hua; Han, Jin; Han, Xi-Lin; Zhuang, Hui-Jie; Zhao, Zi-Ming

2017-01-01

In the present study, two nanoparticles including lactose myristoyl carboxymethyl chitosan (LMCC) and algal polysaccharide myristoyl carboxymethyl chitosan (AMCC), were obtained for hepatic-targeted Adriamycin (ADM) drug delivery systems. ADM was successfully loaded into the LMCC or AMCC nanoparticle by dialysis. The release function and liver targeting of the nanoparticles was explored, and it was revealed that ADM release from the nanoparticles was greatest at acidic pH 5.5. ADM-conjugated nanoparticles were readily taken up by HU7 human hepatocellular carcinoma cells, relative to HT22 mouse hippocampal neuron cells in vitro. In vivo, ADM-loaded nanoparticles had significant antitumor efficacy with a 62.7% inhibition rate, followed by ADM and ADM-AMCC (51.2 and 42.5%, respectively). The tissue distribution study confirmed that ADM-LMCC had an improved liver delivery efficacy, by comparison with ADM. Furthermore, a series of safety studies, including hemolysis, acute toxicity and organ toxicity, revealed that the ADM-loaded LMCC and AMCC nanoparticles had advantages over the commercially available injectable preparation of Adriamycin hydrochloride, in terms of low toxicity levels and increased tolerated dose. These results indicated that LMCC is a promising carrier for injectable ADM nanoparticle and ADM-conjugated nanoparticles may improve the efficacy of ADM by hepatic targeting. PMID:29344229

Pharmacokinetic properties and in silico ADME modeling in drug discovery.

PubMed

Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

2013-03-01

The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

High throughput ADME screening: practical considerations, impact on the portfolio and enabler of in silico ADME models.

PubMed

Hop, Cornelis E C A; Cole, Mark J; Davidson, Ralph E; Duignan, David B; Federico, James; Janiszewski, John S; Jenkins, Kelly; Krueger, Suzanne; Lebowitz, Rebecca; Liston, Theodore E; Mitchell, Walter; Snyder, Mark; Steyn, Stefan J; Soglia, John R; Taylor, Christine; Troutman, Matt D; Umland, John; West, Michael; Whalen, Kevin M; Zelesky, Veronica; Zhao, Sabrina X

2008-11-01

Evaluation and optimization of drug metabolism and pharmacokinetic data plays an important role in drug discovery and development and several reliable in vitro ADME models are available. Recently higher throughput in vitro ADME screening facilities have been established in order to be able to evaluate an appreciable fraction of synthesized compounds. The ADME screening process can be dissected in five distinct steps: (1) plate management of compounds in need of in vitro ADME data, (2) optimization of the MS/MS method for the compounds, (3) in vitro ADME experiments and sample clean up, (4) collection and reduction of the raw LC-MS/MS data and (5) archival of the processed ADME data. All steps will be described in detail and the value of the data on drug discovery projects will be discussed as well. Finally, in vitro ADME screening can generate large quantities of data obtained under identical conditions to allow building of reliable in silico models.

Exploring different strategies for imbalanced ADME data problem: case study on Caco-2 permeability modeling.

PubMed

Pham-The, Hai; Casañola-Martin, Gerardo; Garrigues, Teresa; Bermejo, Marival; González-Álvarez, Isabel; Nguyen-Hai, Nam; Cabrera-Pérez, Miguel Ángel; Le-Thi-Thu, Huong

2016-02-01

In many absorption, distribution, metabolism, and excretion (ADME) modeling problems, imbalanced data could negatively affect classification performance of machine learning algorithms. Solutions for handling imbalanced dataset have been proposed, but their application for ADME modeling tasks is underexplored. In this paper, various strategies including cost-sensitive learning and resampling methods were studied to tackle the moderate imbalance problem of a large Caco-2 cell permeability database. Simple physicochemical molecular descriptors were utilized for data modeling. Support vector machine classifiers were constructed and compared using multiple comparison tests. Results showed that the models developed on the basis of resampling strategies displayed better performance than the cost-sensitive classification models, especially in the case of oversampling data where misclassification rates for minority class have values of 0.11 and 0.14 for training and test set, respectively. A consensus model with enhanced applicability domain was subsequently constructed and showed improved performance. This model was used to predict a set of randomly selected high-permeability reference drugs according to the biopharmaceutics classification system. Overall, this study provides a comparison of numerous rebalancing strategies and displays the effectiveness of oversampling methods to deal with imbalanced permeability data problems.

An “ADME Module” in the Adverse Outcome Pathway ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway (AOP) framework has generated intense interest for its utility to organize knowledge on the toxicity mechanisms, starting from a molecular initiating event (MIE) to an adverse outcome across various levels of biological organization. While the AOP framework is designed to be chemical agnostic, it is widely recognized that considering chemicals’ absorption, distribution, metabolism, and excretion (ADME) behaviors is critical in applying the AOP framework in chemical-specific risk assessment. Currently, information being generated as part of the Organisation for Economic Co-operation and Development (OECD) AOP Development Programme is being consolidated into an AOP Knowledgebase (http://aopwiki.org). To enhance the use of this Knowledgebase in risk assessment, an ADME Module has been developed to contain the ADME information needed to connect MIEs and other key events in an AOP for specific chemicals. The conceptual structure of this module characterizes the potential of a chemical to reach the target MIE based on either its structure-based features or relative rates of ADME. The key features of this module include (1) a framework for connecting biology-based AOP to biochemical-based ADME and chemical/human activity-based exposure pathways; (2) links to qualitative tools (e.g., structure-based cheminformatic model) that screen for chemicals that could potentially reach the target MIE; (3) links to quantitative tools (e.g., dose-r

Use of qualitative environmental and phenotypic variables in the context of allele distribution models: detecting signatures of selection in the genome of Lake Victoria cichlids.

PubMed

Joost, Stéphane; Kalbermatten, Michael; Bezault, Etienne; Seehausen, Ole

2012-01-01

When searching for loci possibly under selection in the genome, an alternative to population genetics theoretical models is to establish allele distribution models (ADM) for each locus to directly correlate allelic frequencies and environmental variables such as precipitation, temperature, or sun radiation. Such an approach implementing multiple logistic regression models in parallel was implemented within a computing program named MATSAM: . Recently, this application was improved in order to support qualitative environmental predictors as well as to permit the identification of associations between genomic variation and individual phenotypes, allowing the detection of loci involved in the genetic architecture of polymorphic characters. Here, we present the corresponding methodological developments and compare the results produced by software implementing population genetics theoretical models (DFDIST: and BAYESCAN: ) and ADM (MATSAM: ) in an empirical context to detect signatures of genomic divergence associated with speciation in Lake Victoria cichlid fishes.

Reduced Current Spread by Concentric Electrodes in Transcranial Electrical Stimulation (tES).

PubMed

Bortoletto, M; Rodella, C; Salvador, R; Miranda, P C; Miniussi, C

2016-01-01

We propose the use of a new montage for transcranial direct current stimulation (tDCS), called concentric electrodes tDCS (CE-tDCS), involving two concentric round electrodes that may improve stimulation focality. To test efficacy and focality of CE-tDCS, we modelled the current distribution and tested physiological effects on cortical excitability. Motor evoked potentials (MEPs) from first dorsal interosseous (FDI) and abductor digiti minimi (ADM) were recorded before and after the delivery of anodal, cathodal and sham stimulation on the FDI hotspot for 10 minutes. MEP amplitude of FDI increased after anodal-tDCS and decreased after cathodal-tDCS, supporting the efficacy of CE-tDCS in modulating cortical excitability. Moreover, modelled current distribution and no significant effects of stimulation on MEP amplitude of ADM suggest high focality of CE-tDCS. CE-tDCS may allow a better control of current distribution and may represent a novel tool for applying tDCS and other transcranial current stimulation approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

Renewable Electricity-to-Grid Integration | Energy Systems Integration

Science.gov Websites

distribution management system (ADMS) use cases at the ESIF's national, vendor-neutral ADMS test bed. Example use cases include: Integration of transmission-to-building operations for demand response

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

EPA Science Inventory

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we ...

Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model.

PubMed

Kono, Toru; Kaneko, Atsushi; Hira, Yoshiki; Suzuki, Tatsuya; Chisato, Naoyuki; Ohtake, Nobuhiro; Miura, Naoko; Watanabe, Tsuyoshi

2010-06-01

Adrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model. Colitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR. DKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract. DKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD. Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

ADME-Space: a new tool for medicinal chemists to explore ADME properties.

PubMed

Bocci, Giovanni; Carosati, Emanuele; Vayer, Philippe; Arrault, Alban; Lozano, Sylvain; Cruciani, Gabriele

2017-07-25

We introduce a new chemical space for drugs and drug-like molecules, exclusively based on their in silico ADME behaviour. This ADME-Space is based on self-organizing map (SOM) applied to 26,000 molecules. Twenty accurate QSPR models, describing important ADME properties, were developed and, successively, used as new molecular descriptors not related to molecular structure. Applications include permeability, active transport, metabolism and bioavailability studies, but the method can be even used to discuss drug-drug interactions (DDIs) or it can be extended to additional ADME properties. Thus, the ADME-Space opens a new framework for the multi-parametric data analysis in drug discovery where all ADME behaviours of molecules are condensed in one map: it allows medicinal chemists to simultaneously monitor several ADME properties, to rapidly select optimal ADME profiles, retrieve warning on potential ADME problems and DDIs or select proper in vitro experiments.

Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates.

PubMed

Mandagere, Arun K; Thompson, Thomas N; Hwang, Kin-Kai

2002-01-17

This paper describes a graphical model for simplifying in vitro absorption, metabolism, distribution, and elimination (ADME) data analysis through the estimation of oral bioavailability (%F) of drugs in humans and other species. This model integrates existing in vitro ADME data, such as Caco-2 permeability (P(app)) and metabolic stability (percent remaining - %R) in liver S9 or microsomes, to estimate %F into groups of low, medium, or high regions. To test the predictive accuracy of our model, we examined 21 drugs and drug candidates with a wide range of oral bioavailability values, which represent approximately 10 different therapeutic areas in humans, rats, dogs, and guinea pigs. In vitro data from model compounds were used to define the boundaries of the low, medium, and high regions of the %F estimation plot. On the basis of the in vitro data, warfarin (93%), indomethacin (98%), timolol (50%), and carbamazepine (70%) were assigned to the high %F region; propranolol (26%) and metoprolol (38%) to medium %F region; and verapamil (22%) and mannitol (18%) to the low %F region. Similarly, the %F of 11 drug candidates from Elastase Inhibitor, NK1/NK2 antagonist, and anti-viral projects in rats, guinea pigs, and dogs were correctly estimated. This model estimates the oral bioavailability ranges of neutral, polar, esters, acidic, and basic drugs in all species. For a large number of drug candidates, this graphical model provides a tool to estimate human oral bioavailability from in vitro ADME data. When combined with the high throughput in vitro ADME screening process, it has the potential to significantly accelerate the processes of lead identification and optimization.

ADME-Tox profiles of some food additives and pesticides

NASA Astrophysics Data System (ADS)

Craciun, Dana; Modra, Dorina; Isvoran, Adriana

2015-12-01

Within this study we compute the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profiles of several commonly used food additives and some pesticides. As expected, all the food additives considered in this study provided to be safe, their ADME-Tox profiles indicating that they have a good oral bioavailability and they do not produce phosphoslipidosis. The ADME-Tox profiles of the pesticides indicate that, with a few exceptions, they are highly toxic (some of them being not approved in the EU, but still used in other countries) and may cause many diseases. Our results are in good agreement with published data concerning the considered food additives and pesticides revealing that the ADME-Tox profiling method may be successfully used to test other chemicals than drug candidates.

SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

PubMed Central

Daina, Antoine; Michielin, Olivier; Zoete, Vincent

2017-01-01

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours. PMID:28256516

A multi-approach monitoring of particulate matter, metals and PAHs in an urban street canyon.

PubMed

De Nicola, Flavia; Murena, Fabio; Costagliola, M Antonietta; Alfani, Anna; Baldantoni, Daniela; Prati, M Vittoria; Sessa, Ludovica; Spagnuolo, Valeria; Giordano, Simonetta

2013-07-01

For the first time until now, the results from a prediction model (Atmospheric Dispersion Modelling System (ADMS)-Road) of pollutant dispersion in a street canyon were compared to the results obtained from biomonitors. In particular, the instrumental monitoring of particulate matter (PM10) and the biomonitoring of 14 polycyclic aromatic hydrocarbons (PAHs) and 11 metals by Quercus ilex leaves and Hypnum cupressiforme moss bags, acting as long- and short-term accumulators, respectively, were carried out. For both PAHs and metals, similar bioaccumulation trends were observed, with higher concentrations in biomonitors exposed at the leeward canyon side, affected by primary air vortex. The major pollutant accumulation at the leeward side was also predicted by the ADMS-Road model, on the basis of the prevailing wind direction that determines different exposure of the street canyon sides to pollutants emitted by vehicular traffic. A clear vertical (3, 6 and 9 m) distribution gradient of pollutants was not observed, so that both the model and biomonitoring results suggested that local air turbulences in the street canyon could contribute to uniform pollutant distribution at different heights.

It takes a team: reflections on insecticide discoveries, toxicological problems and enjoying the unexpected.

PubMed

Wing, Keith D

2017-04-01

Absorption/distribution/metabolism/excretion (ADME)-related studies are mandatory in agrochemical development/registration, but can also play a valuable role in the discovery process. In combination with target-site potency, bioavailability/ADME characteristics determine agrochemical bioactivity and selectivity, and these concerns can dictate the fate of a discovery lead area. Bioavailability/ADME research was critical to the eventual commercialization of three different insecticide chemistries examined in this paper. In one situation, improved systemicity in anthranilic diamides was required to expand pest spectrum. In another, ADME tools were needed to improve the selective toxicity and non-target safety of sodium channel blocker insecticides. Finally, differential ADME characteristics of two classes of hormone agonists dictated differential insecticidal activity, and were useful in optimizing the dibenzoylhydrazine ecdysone agonists. ADME discovery research will help companies to advance novel, efficacious and selective agrochemicals, but organizational patience and a desire to understand lead areas in depth are required. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

National Renewable Energy Laboratory (NREL) Topic 2 Final Report: End-to-End Communication and Control System to Support Clean Energy Technologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudgins, Andrew P.; Carrillo, Ismael M.; Jin, Xin

This document is the final report of a two-year development, test, and demonstration project, 'Cohesive Application of Standards- Based Connected Devices to Enable Clean Energy Technologies.' The project was part of the National Renewable Energy Laboratory's (NREL's) Integrated Network Testbed for Energy Grid Research and Technology (INTEGRATE) initiative hosted at Energy Systems Integration Facility (ESIF). This project demonstrated techniques to control distribution grid events using the coordination of traditional distribution grid devices and high-penetration renewable resources and demand response. Using standard communication protocols and semantic standards, the project examined the use cases of high/low distribution voltage, requests for volt-ampere-reactive (VAR)more » power support, and transactive energy strategies using Volttron. Open source software, written by EPRI to control distributed energy resources (DER) and demand response (DR), was used by an advanced distribution management system (ADMS) to abstract the resources reporting to a collection of capabilities rather than needing to know specific resource types. This architecture allows for scaling both horizontally and vertically. Several new technologies were developed and tested. Messages from the ADMS based on the common information model (CIM) were developed to control the DER and DR management systems. The OpenADR standard was used to help manage grid events by turning loads off and on. Volttron technology was used to simulate a homeowner choosing the price at which to enter the demand response market. Finally, the ADMS used newly developed algorithms to coordinate these resources with a capacitor bank and voltage regulator to respond to grid events.« less

Implementing ADM1 for plant-wide benchmark simulations in Matlab/Simulink.

PubMed

Rosen, C; Vrecko, D; Gernaey, K V; Pons, M N; Jeppsson, U

2006-01-01

The IWA Anaerobic Digestion Model No.1 (ADM1) was presented in 2002 and is expected to represent the state-of-the-art model within this field in the future. Due to its complexity the implementation of the model is not a simple task and several computational aspects need to be considered, in particular if the ADM1 is to be included in dynamic simulations of plant-wide or even integrated systems. In this paper, the experiences gained from a Matlab/Simulink implementation of ADM1 into the extended COST/IWA Benchmark Simulation Model (BSM2) are presented. Aspects related to system stiffness, model interfacing with the ASM family, mass balances, acid-base equilibrium and algebraic solvers for pH and other troublesome state variables, numerical solvers and simulation time are discussed. The main conclusion is that if implemented properly, the ADM1 will also produce high-quality results in dynamic plant-wide simulations including noise, discrete sub-systems, etc. without imposing any major restrictions due to extensive computational efforts.

Effects of adrenomedullin on cyclic AMP formation and on relaxation in iris sphincter smooth muscle.

PubMed

Yousufzai, S Y; Ali, N; Abdel-Latif, A A

1999-12-01

To determine whether iris sphincter and other tissues of the iris-ciliary body secrete adrenomedullin (ADM), a novel hypotensive peptide that is classified into the calcitonin gene-related peptide (CGRP) family and to determine the binding sites for ADM and compare the effects of ADM and CGRP in the absence and presence of their receptor antagonists on cAMP formation and relaxation in the iris sphincter. Sphincter muscle was incubated in Krebs-Ringer bicarbonate buffer in the absence and presence of ADM for 10 minutes. Accumulation of cAMP in the tissue extract was determined by radioimmunoassay (RIA). The binding of [125I]ADM to iris sphincter membranes was carried out by rapid filtration. Distribution of ADM in the ocular tissues was determined by RIA. Changes in muscle tension were recorded isometrically. Immunoreactive ADM was present in all tissues of the cat iris-ciliary body. In the isolated cat iris sphincter, ADM increased cAMP accumulation in a time- (t1/2 = 2.2 minutes) and concentration- (EC50 = 13 nM) dependent manner, and this effect was sixfold more efficacious than CGRP. ADM, CGRP, vasoactive intestinal peptide, prostaglandin E2, isoproterenol, and forskolin increased cAMP formation in cat sphincter by 12.5-, 2-, 2.2-, 1-, 2.6-, and 2.4-fold, respectively. The rank of the effects of ADM on cAMP formation in iris sphincter isolated from different animal species was in the following order: cat > dog > bovine > human > rabbit. In the cat iris sphincter, the CGRP antagonist, CGRP(8 to 37), was more effective than the ADM antagonist, ADM (26 to 52), in inhibiting both ADM- and CGRP-induced cAMP formation. ADM and CGRP inhibited carbachol-induced contraction in a concentration-dependent manner with IC50 values of 10 and 90 nM, respectively. Both ADM and CGRP displaced the binding of [125I]ADM to sphincter membranes effectively, with IC50 values of 0.81 and 1.15 nM, respectively. In iris sphincter isolated from cat and other mammalian species including human, ADM is a much more efficacious activator of adenylate cyclase and a much more effective relaxant than CGRP. Its biological effects may be due to direct involvement of ADM receptors, but also to activation of CGRP receptors. Activation of ADM receptors by the peptide leads to concentration-dependent increases in cAMP accumulation and subsequent inhibition (relaxation) of smooth muscle contraction. These findings suggest a role for ADM as a local modulator of smooth muscle tone. A possible function for this potent hypotensive peptide in the regulation of intraocular pressure remains to be investigated.

Influences of the current density on the performances of the chrome-plated layer in deterministic electroplating repair

NASA Astrophysics Data System (ADS)

Xia, H.; Shen, X. M.; Yang, X. C.; Xiong, Y.; Jiang, G. L.

2018-01-01

Deterministic electroplating repair is a novel method for rapidly repairing the attrited parts. By the qualitative contrast and quantitative comparison, influences of the current density on performances of the chrome-plated layer were concluded in this study. The chrome-plated layers were fabricated under different current densities when the other parameters were kept constant. Hardnesses, thicknesses and components, surface morphologies and roughnesses, and wearability of the chrome-plated layers were detected by the Vickers hardness tester, scanning electron microscope / energy dispersive X-ray detector, digital microscope in the 3D imaging mode, and the ball-milling instrument with profilograph, respectively. In order to scientifically evaluate each factor, the experimental data was normalized. A comprehensive evaluation model was founded to quantitative analyse influence of the current density based on analytic hierarchy process method and the weighted evaluation method. The calculated comprehensive evaluation indexes corresponding to current density of 40A/dm2, 45A/dm2, 50A/dm2, 55A/dm2, 60A/dm2, and 65A/dm2 were 0.2246, 0.4850, 0.4799, 0.4922, 0.8672, and 0.1381, respectively. Experimental results indicate that final optimal option was 60A/dm2, and the priority orders were 60A/dm2, 55A/dm2, 45A/dm2, 50A/dm2, 40A/dm2, and 65A/dm2.

Development of an Excel-based laboratory information management system for improving workflow efficiencies in early ADME screening.

PubMed

Lu, Xinyan

2016-01-01

There is a clear requirement for enhancing laboratory information management during early absorption, distribution, metabolism and excretion (ADME) screening. The application of a commercial laboratory information management system (LIMS) is limited by complexity, insufficient flexibility, high costs and extended timelines. An improved custom in-house LIMS for ADME screening was developed using Excel. All Excel templates were generated through macros and formulae, and information flow was streamlined as much as possible. This system has been successfully applied in task generation, process control and data management, with a reduction in both labor time and human error rates. An Excel-based LIMS can provide a simple, flexible and cost/time-saving solution for improving workflow efficiencies in early ADME screening.

Rotator cuff bridging repair using acellular dermal matrix in large to massive rotator cuff tears: histologic and clinical analysis.

PubMed

Kim, Jong Ok; Lee, Jong-Ho; Kim, Kwang-Sup; Ji, Jong-Hun; Koh, Sung-Jun; Lee, Jae-Ho

2017-11-01

This study investigated the efficacy of the bridging repair using an acellular dermal matrix (ADM) and an ADM with stem cells in rabbits. Also investigated were clinical outcomes of ADM bridging repair for large to massive rotator cuff tears. ADM, with and without stem cells, was used to cover a 5- × 5-mm-sized cuff defect in 17 rabbits, and biomechanical, histologic, and immunohistochemical analyses were conducted. Also evaluated were 24 patients with large to massive rotator cuff tears after ADM bridging repair. In the biomechanical test, the normal rotator cuff, cuff with ADM plus stem cells, and cuff with ADM in the rabbit model showed a maximum load (N) of 287.3, 217.5, and 170.3 and ultimate tensile strength (N/mm 2 ) of 11.1, 8.0, and 5.2, respectively. Histologically, the cuff tendons with the ADM or ADM plus stem cells showed characteristically mature tendons as time passed. In the clinical study, the mean American Shoulder and Elbow Surgeons score improved from preoperative 50 to postoperative 83, the University of California Los Angeles Shoulder Rating Scale from 17 to 30, and the Simple Shoulder Test from 4 to 8, respectively. No further fatty deteriorations or muscle atrophy were observed on follow-up magnetic resonance imaging. A retear was found in 5 of 24 patients (21%). Bridging repair with ADM or stem cells in the rabbit model showed cellular infiltration into the graft and some evidence of neotendon formation. Clinically, ADM repair was a safe alternative that did not show any further fatty deterioration nor muscle atrophy in large to massive rotator cuff tears. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Modelling wastewater treatment in a submerged anaerobic membrane bioreactor.

PubMed

Spagni, Alessandro; Ferraris, Marco; Casu, Stefania

2015-01-01

Mathematical modelling has been widely applied to membrane bioreactor (MBRs) processes. However, to date, very few studies have reported on the application of the anaerobic digestion model N.1 (ADM1) to anaerobic membrane processes. The aim of this study was to evaluate the applicability of the ADM1 to a submerged anaerobic MBR (SAMBR) treating simulated industrial wastewater composed of cheese whey and sucrose. This study demonstrated that the biological processes involved in SAMBRs can be modelled by using the ADM1. Moreover, the results showed that very few modifications of the parameters describing the ADM1 were required to reasonably fit the experimental data. In particular, adaptation to the specific conditions of the coefficients describing the wastewater characterisation and the reduction of the hydrolysis rate of particulate carbohydrate (khyd,ch) from 0.25 d(-1) (as suggested by the ADM1 for high-rate mesophilic reactors) to 0.13 d(-1) were required to fit the experimental data.

Modified ADM1 for modeling free ammonia inhibition in anaerobic acidogenic fermentation with high-solid sludge.

PubMed

Bai, Jie; Liu, He; Yin, Bo; Ma, Huijun; Chen, Xinchun

2017-02-01

Anaerobic acidogenic fermentation with high-solid sludge is a promising method for volatile fatty acid (VFA) production to realize resource recovery. In this study, to model inhibition by free ammonia in high-solid sludge fermentation, the anaerobic digestion model No. 1 (ADM1) was modified to simulate the VFA generation in batch, semi-continuous and full scale sludge. The ADM1 was operated on the platform AQUASIM 2.0. Three kinds of inhibition forms, e.g., simple inhibition, Monod and non-inhibition forms, were integrated into the ADM1 and tested with the real experimental data for batch and semi-continuous fermentation, respectively. The improved particle swarm optimization technique was used for kinetic parameter estimation using the software MATLAB 7.0. In the modified ADM1, the K s of acetate is 0.025, the k m,ac is 12.51, and the K I_NH3 is 0.02, respectively. The results showed that the simple inhibition model could simulate the VFA generation accurately while the Monod model was the better inhibition kinetics form in semi-continuous fermentation at pH10.0. Finally, the modified ADM1 could successfully describe the VFA generation and ammonia accumulation in a 30m 3 full-scale sludge fermentation reactor, indicating that the developed model can be applicable in high-solid sludge anaerobic fermentation. Copyright © 2016. Published by Elsevier B.V.

Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice

PubMed Central

Portal-Nuñez, Sergio; Shankavaram, Uma; Rao, Mahadev; Datrice, Nicole; Scott, Atay; Aparicio, Marta; Camphausen, Kevin A.; Fernández-Salguero, Pedro M.; Chang, Han; Lin, Pinpin; Schrump, David S.; Garantziotis, Stavros; Cuttitta, Frank; Zudaire, Enrique

2015-01-01

Cigarette smoke (CS) is a leading cause of death worldwide. The aryl hydrocarbon receptor (AHR) is partially responsible for tobacco-induced carcinogenesis although the underlying mechanisms involving early effector genes have yet to be determined. Here, we report that adrenomedullin (ADM) significantly contributes to the carcinogenicity of tobacco activated AHR. CS and AHR activating ligands induced ADM in vitro and in vivo but not in AHR-deficient fibroblasts and mice. Ectopic transfection of AHR rescued ADM expression in AHR−/− fibroblasts while AHR blockage with siRNA in wild type cells significantly decreased ADM expression. AHR regulates ADM expression through two intronic xenobiotic response elements located close to the start codon in the ADM gene. Using tissue microarrays we showed that ADM and AHR were coupregulated in lung tumor biopsies from smoker patients. Microarray metaanalysis of 304 independent microarray experiments showed that ADM is elevated in smokers and smokers with cancer. Additionally, ADM coassociated with a subset of AHR responsive genes and efficiently differentiated patients with lung cancer from non-smokers. In a novel preclinical model of CS-induced tumor progression, host exposure to CS extracts significantly elevated tumor ADM while systemic treatment with the ADM antagonist NSC16311 efficiently blocked tobacco-induced tumor growth. In conclusion, ADM significantly contributes the carcinogenic effect of AHR and tobacco combustion products. We suggest that therapeutics targeting the AHR/ADM axis may be of clinical relevance in the treatment of tobacco-induced pulmonary malignancies. PMID:22993405

In silico platform for xenobiotics ADME-T pharmacological properties modeling and prediction. Part II: The body in a Hilbertian space.

PubMed

Jacob, Alexandre; Pratuangdejkul, Jaturong; Buffet, Sébastien; Launay, Jean-Marie; Manivet, Philippe

2009-04-01

We have broken old surviving dogmas and concepts used in computational chemistry and created an efficient in silico ADME-T pharmacological properties modeling and prediction toolbox for any xenobiotic. With the help of an innovative and pragmatic approach combining various in silico techniques, like molecular modeling, quantum chemistry and in-house developed algorithms, the interactions between drugs and those enzymes, transporters and receptors involved in their biotransformation can be studied. ADME-T pharmacological parameters can then be predicted after in vitro and in vivo validations of in silico models.

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process

PubMed Central

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-01-01

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery. PMID:27122192

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process.

PubMed

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-04-28

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage

PubMed Central

LaCerte, C; Peyret, T; Gosselin, NH; Marier, JF; Hofmann, AF; Shapiro, D

2016-01-01

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4‐, 8‐, and 13‐fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1‐, 1.5‐, and 1.7‐fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2‐fold). PMID:27743502

Pharmacometrics in pregnancy: An unmet need.

PubMed

Ke, Alice Ban; Rostami-Hodjegan, Amin; Zhao, Ping; Unadkat, Jashvant D

2014-01-01

Pregnant women and their fetuses are orphan populations with respect to the safety and efficacy of drugs. Physiological and absorption, distribution, metabolism, and excretion (ADME) changes during pregnancy can significantly affect drug pharmacokinetics (PK) and may necessitate dose adjustment. Here, the specific aspects related to the design, execution, and analysis of clinical studies in pregnant women are discussed, underlining the unmet need for top-down pharmacometrics analyses and bottom-up modeling approaches. The modeling tools that support data analysis for the pregnancy population are reviewed, with a focus on physiologically based pharmacokinetics (PBPK) and population pharmacokinetics (POP-PK). By integrating physiological data, preclinical data, and clinical data (e.g., via POP-PK) to quantify anticipated changes in the PK of drugs during pregnancy, the PBPK approach allows extrapolation beyond the previously studied model drugs to other drugs with well-characterized ADME characteristics. Such a systems pharmacology approach can identify drugs whose PK may be altered during pregnancy, guide rational PK study design, and support dose adjustment for pregnant women.

Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates.

PubMed

Ma, Anlun; Jiang, Li; Song, Lijun; Hu, Yanxin; Dun, Hao; Daloze, Pierre; Yu, Yonglin; Jiang, Jianyuan; Zafarullah, Muhammad; Chen, Huifang

2013-07-01

Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage. This study explored utilization of a new three-dimensional, selected chondrogenic clonal MSC-loaded monkey acellular dermal matrix (MSC-ADM) scaffold to repair damaged cartilage in an experimental model of knee joint cartilage defect in Cynomolgus monkeys. MSCs were characterized for cell size, cell yield, phenotypes, proliferation and chondrogenic differentiation capacity. Chondrogenic differentiation assays were performed at different MSC passages by sulfated glycosaminoglycans (sGAG), collagen, and fluorescence activated cell sorter (FACS) analysis. Selected chondrogenic clonal MSCs were seeded onto ADM scaffold with the sandwich model and MSC-loaded ADM grafts were analyzed by confocal microscopy and scanning electron microscopy. Cartilage defects were treated with normal saline, clonal MSCs and clonal MSC-ADM grafts, respectively. The clinical parameters, and histological and immunohistochemical examinations were evaluated at weeks 8, 16, 24 post-treatment, respectively. Polyclonal and clonal MSCs could differentiate into the chondrogenic lineage after stimulation with suitable chondrogenic factors. They expressed mesenchymal markers and were negative for hematopoietic markers. Articular cartilage defects were considerably improved and repaired by selected chondrogenic clonal MSC-based treatment, particularly, in MSC-ADM-treated group. The histological scores in MSC-ADM-treated group were consistently higher than those of other groups. Our results suggest that selected chondrogenic clonal MSC-loaded ADM grafts could improve the cartilage lesions in Cynomolgus monkey model, which may be applicable for repairing similar human cartilage defects. Copyright © 2013 Elsevier B.V. All rights reserved.

Application of ADM1 for modeling of biogas production from anaerobic digestion of Hydrilla verticillata.

PubMed

Chen, Xiaojuan; Chen, Zhihua; Wang, Xun; Huo, Chan; Hu, Zhiquan; Xiao, Bo; Hu, Mian

2016-07-01

The present study focused on the application of anaerobic digestion model no. 1 (ADM1) to simulate biogas production from Hydrilla verticillata. Model simulation was carried out by implementing ADM1 in AQUASIM 2.0 software. Sensitivity analysis was used to select the most sensitive parameters for estimation using the absolute-relative sensitivity function. Among all the kinetic parameters, disintegration constant (kdis), hydrolysis constant of protein (khyd_pr), Monod maximum specific substrate uptake rate (km_aa, km_ac, km_h2) and half-saturation constants (Ks_aa, Ks_ac) affect biogas production significantly, which were optimized by fitting of the model equations to the data obtained from batch experiments. The ADM1 model after parameter estimation was able to well predict the experimental results of daily biogas production and biogas composition. The simulation results of evolution of organic acids, bacteria concentrations and inhibition effects also helped to get insight into the reaction mechanisms. Copyright © 2016. Published by Elsevier Ltd.

Conference report: a hitchhiker's guide to outsourcing ADME studies: the inside of outsourcing.

PubMed

Pritchard, J Fred; Anderson, Shelby R; Breuckner, Claudia; Premkumar, Noel D; Polli, Joseph W

2013-02-01

This report gives a summary of the key points raised during a roundtable discussion convened at the American Association of Pharmaceutical Scientists 2012 Annual Meeting and Exposition held in Chicago on 17 October 2012. The science of ADME continues to grow, as does the impact of these studies on drug development. Understanding ADME requires efforts from several scientific specialties. With reductions in pharmaceutical company R&D staff there has been a corresponding growth in CROs with the capabilities and expertise to perform ADME work. This roundtable explored the challenges inherent in understanding ADME and the issues that arise when ADME studies shift from in-house study directors to external scientists working within the business model of a CRO. Pharmaceutical industry scientists and procurement specialists can satisfy their expectations by awareness of the growing expertise within CROs and the need for open communication among all partners involved in outsourced work.

Application of Anaerobic Digestion Model No. 1 for simulating anaerobic mesophilic sludge digestion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mendes, Carlos, E-mail: carllosmendez@gmail.com; Esquerre, Karla, E-mail: karlaesquerre@ufba.br; Matos Queiroz, Luciano, E-mail: lmqueiroz@ufba.br

2015-01-15

Highlights: • The behavior of a anaerobic reactor was evaluated through modeling. • Parametric sensitivity analysis was used to select most sensitive of the ADM1. • The results indicate that the ADM1 was able to predict the experimental results. • Organic load rate above of 35 kg/m{sup 3} day affects the performance of the process. - Abstract: Improving anaerobic digestion of sewage sludge by monitoring common indicators such as volatile fatty acids (VFAs), gas composition and pH is a suitable solution for better sludge management. Modeling is an important tool to assess and to predict process performance. The present studymore » focuses on the application of the Anaerobic Digestion Model No. 1 (ADM1) to simulate the dynamic behavior of a reactor fed with sewage sludge under mesophilic conditions. Parametric sensitivity analysis is used to select the most sensitive ADM1 parameters for estimation using a numerical procedure while other parameters are applied without any modification to the original values presented in the ADM1 report. The results indicate that the ADM1 model after parameter estimation was able to predict the experimental results of effluent acetate, propionate, composites and biogas flows and pH with reasonable accuracy. The simulation of the effect of organic shock loading clearly showed that an organic shock loading rate above of 35 kg/m{sup 3} day affects the performance of the reactor. The results demonstrate that simulations can be helpful to support decisions on predicting the anaerobic digestion process of sewage sludge.« less

New role of biomarkers: mid-regional pro-adrenomedullin, the biomarker of organ failure

PubMed Central

Valenzuela-Méndez, Blanca; Rodríguez-Gutiérrez, Juan Francisco; Estella-García, Ángel; González-García, María Ángela

2016-01-01

Mid-regional pro-adrenomedullin (MR-proADM) has a good biomarker profile: its half-life is several hours, and its plasma concentrations can be determined in clinical practice, it is essentially irrelevant, but proportionally represents the levels and activity of adrenomedullin (ADM). ADM synthesis is widely distributed in tissues, including bone, adrenal cortex, kidney, lung, blood vessels and heart. Its fundamental biological effects include vasodilator, positive inotropic, diuretic, natriuretic and bronchodilator. It has been described high levels in septic patients, interacting directly with the relaxation of vascular tone, triggering hypotension of these patients. It is also found high levels in other diseases such as hypertension, heart failure, respiratory failure, renal failure, cirrhosis and cancer. MR-proADM has been identified as a prognostic marker, stratifying the mortality risk in patients with sepsis in emergency department (ED) and ICU. Evolutionary MR-proADM levels and clearance marker to the 2nd–5th days of admission help to determine the poor performance and the risk of mortality in patients with severe sepsis admitted to the ICU. The MR-proADM levels are more effective than procalcitonin (PCT) and C-reactive protein (CRP) levels to determine an unfavorable outcome and the risk of mortality in patients with sepsis admitted to the ICU. It has also proved useful in patients diagnosed with organ dysfunction of infectious etiology. MR-proADM levels are independent of the germ conversely it is related to the magnitude of organ failure and therefore severity. We consider advisable incorporating the MR-proADM the panel of biomarkers necessary for the diagnosis and treatment of critically ill patients admitted to the ICU with severe sepsis. The combined PCT and MR-proADM levels could represent a valid tool in the clinical practice to timely identify patients with bacterial infections and guide the diagnosis and treatment of sepsis and septic shock. PMID:27713887

A novel fluoride anion modified gelatin nanogel system for ultrasound-triggered drug release.

PubMed

Wu, Daocheng; Wan, Mingxi

2008-01-01

Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. The ADM-GNMF was stable in solution with an average diameter of 46+/-12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 +/- 12 nm to 1212 +/- 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

Combat Identification Systems COMO Integrated Air Defense Model Evaluation (CISE) Study

DTIC Science & Technology

1989-02-01

use K or IR , whichever one applies) E-6 CAA-SR-89- 3 Subroutine PDECLR 1/21/88 Before label 1000 Insert: IF (IR.GT.10) IR a 10 These changes were made...Internal Distribution: Unclassified Library 2 F-2 CAA-SR-89- 3 GLOSSARY 1. ABBREVIATIONS, ACRONYMS, AND SHORT TERMS ADM2 Air Defense Models Modification...STUDY REPORT ’ , CAA-Sn-89- 3 i , .- CD o COMBAT IDENTIFICATION SYSTEMS N COMO INTEGRATED AIR DEFENSE MODEL EVALUATION (CISE) STUDY FEBRUARY 1989

Further development of the attitude difference method for estimating deflections of the vertical in real time

NASA Astrophysics Data System (ADS)

Zhu, Jing; Zhou, Zebo; Li, Yong; Rizos, Chris; Wang, Xingshu

2016-07-01

An improvement of the attitude difference method (ADM) to estimate deflections of the vertical (DOV) in real time is described in this paper. The ADM without offline processing estimates the DOV with a limited accuracy due to the response delay. The proposed model selection-based self-adaptive delay feedback (SDF) method takes the results of the ADM as the a priori information, then uses fitting and extrapolation to estimate the DOV at the current epoch. The active region selection factor F th is used to take full advantage of the Earth model EGM2008 and the SDF with different DOV exhibitions. The factors which affect the DOV estimation accuracy are analyzed and modeled. An external observation which is specified by the velocity difference between the global navigation satellite system (GNSS) and the inertial navigation system (INS) with DOV compensated is used to select the optimal model. The response delay induced by the weak observability of an integrated INS/GNSS to the violent DOV disturbances in the ADM is compensated. The DOV estimation accuracy of the SDF method is improved by approximately 40% and 50% respectively compared to that of the EGM2008 and the ADM. With an increase in GNSS accuracy, the DOV estimation accuracy could improve further.

Improvements, testing and development of the ADM-τ sub-grid surface tension model for two-phase LES

NASA Astrophysics Data System (ADS)

Aniszewski, Wojciech

2016-12-01

In this paper, a specific subgrid term occurring in Large Eddy Simulation (LES) of two-phase flows is investigated. This and other subgrid terms are presented, we subsequently elaborate on the existing models for those and re-formulate the ADM-τ model for sub-grid surface tension previously published by these authors. This paper presents a substantial, conceptual simplification over the original model version, accompanied by a decrease in its computational cost. At the same time, it addresses the issues the original model version faced, e.g. introduces non-isotropic applicability criteria based on resolved interface's principal curvature radii. Additionally, this paper introduces more throughout testing of the ADM-τ, in both simple and complex flows.

Plasma mid-regional pro-adrenomedullin levels are inversely associated with anxiety but unrelated to depression: Results from the observational DIAST-CHF study in patients with cardiovascular risk factors.

PubMed

Meyer, Thomas; Herrmann-Lingen, Christoph; Chavanon, Mira-Lynn; Pieske, Burkert; Wachter, Rolf; Edelmann, Frank

2015-12-01

It has been postulated that patients with heart failure have a high risk of ventricular arrhythmias and sudden cardiac death resulting from anxiety-induced autonomic arousal. In the prospective and multicenter DIAST-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, we therefore, tested the hypothesis that adrenomedullin (ADM), a well-established predictor for cardiovascular outcome, is associated with self-rated anxiety symptoms in patients at risk of suffering from or actually with overt heart failure. Study participants with risk factors for diastolic dysfunction were requested to complete the Hospital Anxiety and Depression Scale (HADS), and plasma mid-regional pro-adrenomedullin (MR-proADM) concentrations were measured. In bivariate analysis, we found significantly lower plasma MR-proADM levels in patients with elevated HADS-anxiety scores above the clinically relevant cut-off level of ≥11 (n=118, 536pmol/l, interquartile range [IQR] 449-626) as compared to non-anxious study participants (n=1,292, 573pmol/l, IQR 486-702, p=0.001). A set of multivariate models adjusted for potential confounders confirmed the negative association between self-rated anxiety symptoms and plasma MR-proADM. In similar models, no significant association was detected between HADS-depression scores and MR-proADM. The inverse relationship between plasma MR-proADM and anxiety observed in patients with cardiovascular risk factors supports a previous experimental study using a mutant mouse line with a brain-specific loss of ADM expression which displayed hyperactive and over-anxious behavior. Further experimental and clinical studies are warranted to test the hypothesis that also in humans ADM acts as a neuromodulator with anxiolytic properties. Copyright © 2015. Published by Elsevier Ltd.

Long-Term Outcomes after Abdominal Wall Reconstruction with Acellular Dermal Matrix.

PubMed

Garvey, Patrick B; Giordano, Salvatore A; Baumann, Donald P; Liu, Jun; Butler, Charles E

2017-03-01

Long-term outcomes data for hernia recurrence rates after abdominal wall reconstruction (AWR) with acellular dermal matrix (ADM) are lacking. The aim of this study was to assess the long-term durability of AWR using ADM. We studied patients who underwent AWR with ADM at a single center in 2005 to 2015 with a minimum follow-up of 36 months. Hernia recurrence was the primary end point and surgical site occurrence (SSO) was a secondary end point. The recurrence-free survival curves were estimated by Kaplan-Meier product limit method. Univariate and multivariable Cox proportional hazards regression models and logistic regression models were used to evaluate the associations of risk factors at surgery with subsequent risks for hernia recurrence and SSO, respectively. A total of 512 patients underwent AWR with ADM. After excluding those with follow-up less than 36 months, 191 patients were included, with a median follow-up of 52.9 months (range 36 to 104 months). Twenty-six of 191 patients had a hernia recurrence documented in the study. The cumulative recurrence rates were 11.5% at 3 years and 14.6% by 5 years. Factors significantly predictive of hernia recurrence developing included bridged repair, wound skin dehiscence, use of human cadaveric ADM, and coronary disease; component separation was protective. In a subset analysis excluding bridged repairs and human cadaveric ADM patients, cumulative hernia recurrence rates were 6.4% by 3 years and 8.3% by 5 years. The crude rate of SSO was 25.1% (48 of 191). Factors significantly predictive of the incidence of SSO included at least 1 comorbidity, BMI ≥30 kg/m 2 , and defect width >15 cm. Use of ADM for AWR was associated with 11.5% and 14.6% hernia recurrence rates at 3- and 5-years follow-up, respectively. Avoiding bridged repairs and human cadaveric ADM can improve long-term AWR outcomes using ADM. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Aorta-derived mesoangioblasts differentiate into the oligodendrocytes by inhibition of the Rho kinase signaling pathway.

PubMed

Wang, Lei; Kamath, Anant; Frye, Janie; Iwamoto, Gary A; Chun, Ju Lan; Berry, Suzanne E

2012-05-01

Mesoangioblasts are vessel-derived stem cells that differentiate into mesodermal derivatives. We have isolated postnatal aorta-derived mesoangioblasts (ADMs) that differentiate into smooth, skeletal, and cardiac muscle, and adipocytes, and regenerate damaged skeletal muscle in a murine model for Duchenne muscular dystrophy. We report that the marker profile of ADM is similar to that of mesoangioblasts isolated from embryonic dorsal aorta, postnatal bone marrow, and heart, but distinct from mesoangioblasts derived from skeletal muscle. We also demonstrate that ADM differentiate into myelinating glial cells. ADM localize to peripheral nerve bundles in regenerating muscles and exhibit morphology and marker expression of mature Schwann cells, and myelinate axons. In vitro, ADM spontaneously express markers of oligodendrocyte progenitors, including the chondroitin sulphate proteoglycan NG2, nestin, platelet-derived growth factor (PDGF) receptor α, the A2B5 antigen, thyroid hormone nuclear receptor α, and O4. Pharmacological inhibition of Rho kinase (ROCK) initiated process extension by ADM, and when combined with insulin-like growth factor 1, PDGF, and thyroid hormone, enhanced ADM expression of oligodendrocyte precursor markers and maturation into the oligodendrocyte lineage. ADM injected into the right lateral ventricle of the brain migrate to the corpus callosum, and cerebellar white matter, where they express components of myelin. Because ADM differentiate or mature into cell types of both mesodermal and ectodermal origin, they may be useful for treatment of a variety of degenerative diseases, or repair and regeneration of multiple cell types in severely damaged tissue.

Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics.

PubMed

Xu, Xin; Vugmeyster, Yulia

2012-12-01

With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.

Involvement of DNA polymerase beta in repairing oxidative damages induced by antitumor drug adriamycin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Shukun; Wu Mei; Zhang Zunzhen, E-mail: zhangzunzhen@163.co

2010-08-01

Adriamycin (ADM) is a widely used antineoplastic drug. However, the increasing cellular resistance has become a serious limitation to ADM clinical application. The most important mechanism related to ADM-induced cell death is oxidative DNA damage mediated by reactive oxygen species (ROS). Base excision repair (BER) is a major pathway in the repair of DNA single strand break (SSB) and oxidized base. In this study, we firstly applied the murine embryo fibroblasts wild-type (pol {beta} +/+) and homozygous pol {beta} null cell (pol {beta} -/-) as a model to investigate ADM DNA-damaging effects and the molecular basis underlying these effects. Here,more » cellular sensitivity to ADM was examined using colorimetric assay and colony forming assay. ADM-induced cellular ROS level and the alteration of superoxide dismutase (SOD) activity were measured by commercial kits. Further, DNA strand break, chromosomal damage and gene mutation were assessed by comet assay, micronucleus test and hprt gene mutation assay, respectively. The results showed that pol {beta} -/- cells were more sensitive to ADM compared with pol {beta} +/+ cells and more severe SSB and chromosomal damage as well as higher hprt gene mutation frequency were observed in pol {beta} -/- cells. ROS level in pol {beta} -/- cells increased along with decreased activity of SOD. These results demonstrated that pol {beta} deficiency could enable ROS accumulation with SOD activity decrease, further elevate oxidative DNA damage, and subsequently result in SSB, chromosome cleavage as well as gene mutation, which may be partly responsible for the cytotoxicity of ADM and the hypersensitivity of pol {beta} -/- cells to ADM. These findings suggested that pol {beta} is vital for repairing oxidative damage induced by ADM.« less

Investigation of holdup and axial dispersion of liquid phase in a catalytic exchange column using radiotracer technique.

PubMed

Kumar, Rajesh; Pant, H J; Goswami, Sunil; Sharma, V K; Dash, A; Mishra, S; Bhanja, K; Mohan, Sadhana; Mahajani, S M

2017-03-01

Holdup and axial dispersion of liquid phase in a catalytic exchange column were investigated by measuring residence time distributions (RTD) using a radiotracer technique. RTD experiments were independently carried out with two different types of packings i.e. hydrophobic water-repellent supported platinum catalyst and a mixture (50% (v/v)) of hydrophobic catalyst and a hydrophillic wettable packing were used in the column. Mean residence times and hold-ups of the liquid phase were estimated at different operating conditions. Axial dispersion model (ADM) and axial dispersion with exchange model (ADEM) were used to simulate the measured RTD data. Both the models were found equally suitable to describe the measured data. The degree of axial mixing was estimated in terms of Peclet number (Pe) and Bodenstein number (Bo). Based on the obtained parameters of the ADM, correlations for total liquid hold-up (H T ) and axial mixing in terms of Bo were proposed for design and scale up of the full-scale catalytic exchange column. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identifiability of large-scale non-linear dynamic network models applied to the ADM1-case study.

PubMed

Nimmegeers, Philippe; Lauwers, Joost; Telen, Dries; Logist, Filip; Impe, Jan Van

2017-06-01

In this work, both the structural and practical identifiability of the Anaerobic Digestion Model no. 1 (ADM1) is investigated, which serves as a relevant case study of large non-linear dynamic network models. The structural identifiability is investigated using the probabilistic algorithm, adapted to deal with the specifics of the case study (i.e., a large-scale non-linear dynamic system of differential and algebraic equations). The practical identifiability is analyzed using a Monte Carlo parameter estimation procedure for a 'non-informative' and 'informative' experiment, which are heuristically designed. The model structure of ADM1 has been modified by replacing parameters by parameter combinations, to provide a generally locally structurally identifiable version of ADM1. This means that in an idealized theoretical situation, the parameters can be estimated accurately. Furthermore, the generally positive structural identifiability results can be explained from the large number of interconnections between the states in the network structure. This interconnectivity, however, is also observed in the parameter estimates, making uncorrelated parameter estimations in practice difficult. Copyright © 2017. Published by Elsevier Inc.

Improved ADM1 model for anaerobic digestion process considering physico-chemical reactions.

PubMed

Zhang, Yang; Piccard, Sarah; Zhou, Wen

2015-11-01

The "Anaerobic Digestion Model No. 1" (ADM1) was modified in the study by improving the bio-chemical framework and integrating a more detailed physico-chemical framework. Inorganic carbon and nitrogen balance terms were introduced to resolve the discrepancies in the original bio-chemical framework between the carbon and nitrogen contents in the degraders and substrates. More inorganic components and solids precipitation processes were included in the physico-chemical framework of ADM1. The modified ADM1 was validated with the experimental data and used to investigate the effects of calcium ions, magnesium ions, inorganic phosphorus and inorganic nitrogen on anaerobic digestion in batch reactor. It was found that the entire anaerobic digestion process might exist an optimal initial concentration of inorganic nitrogen for methane gas production in the presence of calcium ions, magnesium ions and inorganic phosphorus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Drug-like properties and the causes of poor solubility and poor permeability.

PubMed

Lipinski, C A

2000-01-01

There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.

Modeling microbial diversity in anaerobic digestion through an extended ADM1 model.

PubMed

Ramirez, Ivan; Volcke, Eveline I P; Rajinikanth, Rajagopal; Steyer, Jean-Philippe

2009-06-01

The anaerobic digestion process comprises a whole network of sequential and parallel reactions, of both biochemical and physicochemical nature. Mathematical models, aiming at understanding and optimization of the anaerobic digestion process, describe these reactions in a structured way, the IWA Anaerobic Digestion Model No. 1 (ADM1) being the most well established example. While these models distinguish between different microorganisms involved in different reactions, to our knowledge they all neglect species diversity between organisms with the same function, i.e. performing the same reaction. Nevertheless, available experimental evidence suggests that the structure and properties of a microbial community may be influenced by process operation and on their turn also determine the reactor functioning. In order to adequately describe these phenomena, mathematical models need to consider the underlying microbial diversity. This is demonstrated in this contribution by extending the ADM1 to describe microbial diversity between organisms of the same functional group. The resulting model has been compared with the traditional ADM1 in describing experimental data of a pilot-scale hybrid Upflow Anaerobic Sludge Filter Bed (UASFB) reactor, as well as in a more detailed simulation study. The presented model is further shown useful in assessing the relationship between reactor performance and microbial community structure in mesophilic CSTRs seeded with slaughterhouse wastewater when facing increasing levels of ammonia.

ERBE Geographic Scene and Monthly Snow Data

NASA Technical Reports Server (NTRS)

Coleman, Lisa H.; Flug, Beth T.; Gupta, Shalini; Kizer, Edward A.; Robbins, John L.

1997-01-01

The Earth Radiation Budget Experiment (ERBE) is a multisatellite system designed to measure the Earth's radiation budget. The ERBE data processing system consists of several software packages or sub-systems, each designed to perform a particular task. The primary task of the Inversion Subsystem is to reduce satellite altitude radiances to fluxes at the top of the Earth's atmosphere. To accomplish this, angular distribution models (ADM's) are required. These ADM's are a function of viewing and solar geometry and of the scene type as determined by the ERBE scene identification algorithm which is a part of the Inversion Subsystem. The Inversion Subsystem utilizes 12 scene types which are determined by the ERBE scene identification algorithm. The scene type is found by combining the most probable cloud cover, which is determined statistically by the scene identification algorithm, with the underlying geographic scene type. This Contractor Report describes how the geographic scene type is determined on a monthly basis.

A tiered approach for integrating exposure and dosimetry with ...

EPA Pesticide Factsheets

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The chemical-agnostic Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which pathway-based data can be arranged to aid in the understanding of in vitro toxicity testing results. In addition, risk estimation also requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with concentrations that trigger a molecular initiating event (MIE) at the relevant biological target in vivo. Such target site exposures (TSEs) can be estimated using computational models to integrate exposure information with a chemical’s absorption, distribution, metabolism, and elimination (ADME) processes. In this presentation, the utility of a tiered approach for integrating exposure, ADME, and hazard into risk-based decision making will be demonstrated using several case studies, along with the investigation of how uncertainties in exposure and ADME might impact risk estimates. These case studies involve 1) identifying and prioritizing chemicals capable of altering biological pathways based on their potential to reach an in vivo target; 2) evaluating the infl

Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients.

PubMed

Adlbrecht, Christopher; Hülsmann, Martin; Strunk, Guido; Berger, Rudolf; Mörtl, Deddo; Struck, Joachim; Morgenthaler, Nils G; Bergmann, Andreas; Jakowitsch, Johannes; Maurer, Gerald; Lang, Irene M; Pacher, Richard

2009-04-01

The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF. We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF. Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

Comparison of histological structure and biocompatibility between human acellular dermal matrix (ADM) and porcine ADM.

PubMed

Ge, Liangpeng; Zheng, Shuquan; Wei, Hong

2009-02-01

The present study was to compare the difference of histological structure and biocompatibility between human ADM and porcine ADM. The scaffold structure, collagen arrangement and collagen structure of human ADM and those of porcine ADM were very similar except for a slight difference in their black and white bands assessed by both light microscopy and electron microscopy. The positive immunohistochemical staining results of porcine ADM using human antibodies of collagen I, collagen III, collagen IV, fibronectin, laminin and vimentin and the result of SDS-PAGE implied a strong homology between the main proteins of human ADM and porcine ADM. In addition, statistical analysis indicated that there was no significant difference (P<0.05) between the biocompatibility of the two ADMs. Based on these results, we conclude that porcine ADM bears a strong similarity to human ADM, and might be a substitute for human ADM in the future.

Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.

PubMed

Ding, Li; Liou, Geou-Yarh; Schmitt, Daniel M; Storz, Peter; Zhang, Jin-San; Billadeau, Daniel D

2017-09-01

Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras G12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Outcomes of Acellular Dermal Matrix for Immediate Tissue Expander Reconstruction with Radiotherapy: A Retrospective Cohort Study.

PubMed

Craig, Elizabeth S; Clemens, Mark W; Koshy, John C; Wren, James; Hong, Zhang; Butler, Charles; Garvey, Patrick; Selber, Jesse; Kronowitz, Steven

2018-05-24

Despite increasing literature support for the use of acellular dermal matrix (ADM) in expander-based breast reconstruction, the effect of ADM on clinical outcomes in the presence of post-mastectomy radiation therapy (PMRT) has not been well described. To analyze the impact ADM plays on clinical outcomes on immediate tissue expander (ITE) reconstruction undergoing PMRT. We retrospectively reviewed patients who underwent ITE breast reconstruction from 2004 to 2014 at MD Anderson Cancer Center. Patients were categorized into four cohorts: ADM, ADM with PMRT, non-ADM, and non-ADM with PMRT. Outcomes and complications were compared between cohorts. Over ten years, 957 patients underwent ITE reconstruction (683 non-ADM, 113 non-ADM with PMRT, 486 ADM, and 88 ADM with PMRT) with 1,370 reconstructions. Overall complication rates for the ADM and non-ADM cohorts were 39.0 and 16.7%, respectively (p <0.001). Within both cohorts, mastectomy skin flap necrosis (MSFN) was the most common complication, followed by infection. ADM use was associated with a significantly higher rate of infections and seromas in both radiated and non-radiated groups; however, when comparing radiated cohorts, the incidence of explantation was significantly lower with the use of ADM. The decision to use ADM for expander-based breast reconstruction should be performed with caution, given higher overall rates of complications, including infections and seromas. There may, however, be a role for ADM in cases requiring PMRT, as the overall incidence of implant failure is lower than non-ADM cases.

ADM Analysis of gravity models within the framework of bimetric variational formalism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Golovnev, Alexey; Karčiauskas, Mindaugas; Nyrhinen, Hannu J., E-mail: agolovnev@yandex.ru, E-mail: mindaugas.karciauskas@helsinki.fi, E-mail: hannu.nyrhinen@helsinki.fi

2015-05-01

Bimetric variational formalism was recently employed to construct novel bimetric gravity models. In these models an affine connection is generated by an additional tensor field which is independent of the physical metric. In this work we demonstrate how the ADM decomposition can be applied to study such models and provide some technical intermediate details. Using ADM decomposition we are able to prove that a linear model is unstable as has previously been indicated by perturbative analysis. Moreover, we show that it is also very difficult if not impossible to construct a non-linear model which is ghost-free within the framework ofmore » bimetric variational formalism. However, we demonstrate that viable models are possible along similar lines of thought. To this end, we consider a set up in which the affine connection is a variation of the Levi-Civita one. As a proof of principle we construct a gravity model with a massless scalar field obtained this way.« less

Approximate deconvolution model for the simulation of turbulent gas-solid flows: An a priori analysis

NASA Astrophysics Data System (ADS)

Schneiderbauer, Simon; Saeedipour, Mahdi

2018-02-01

Highly resolved two-fluid model (TFM) simulations of gas-solid flows in vertical periodic channels have been performed to study closures for the filtered drag force and the Reynolds-stress-like contribution stemming from the convective terms. An approximate deconvolution model (ADM) for the large-eddy simulation of turbulent gas-solid suspensions is detailed and subsequently used to reconstruct those unresolved contributions in an a priori manner. With such an approach, an approximation of the unfiltered solution is obtained by repeated filtering allowing the determination of the unclosed terms of the filtered equations directly. A priori filtering shows that predictions of the ADM model yield fairly good agreement with the fine grid TFM simulations for various filter sizes and different particle sizes. In particular, strong positive correlation (ρ > 0.98) is observed at intermediate filter sizes for all sub-grid terms. Additionally, our study reveals that the ADM results moderately depend on the choice of the filters, such as box and Gaussian filter, as well as the deconvolution order. The a priori test finally reveals that ADM is superior compared to isotropic functional closures proposed recently [S. Schneiderbauer, "A spatially-averaged two-fluid model for dense large-scale gas-solid flows," AIChE J. 63, 3544-3562 (2017)].

An ASM/ADM model interface for dynamic plant-wide simulation.

PubMed

Nopens, Ingmar; Batstone, Damien J; Copp, John B; Jeppsson, Ulf; Volcke, Eveline; Alex, Jens; Vanrolleghem, Peter A

2009-04-01

Mathematical modelling has proven to be very useful in process design, operation and optimisation. A recent trend in WWTP modelling is to include the different subunits in so-called plant-wide models rather than focusing on parts of the entire process. One example of a typical plant-wide model is the coupling of an upstream activated sludge plant (including primary settler, and secondary clarifier) to an anaerobic digester for sludge digestion. One of the key challenges when coupling these processes has been the definition of an interface between the well accepted activated sludge model (ASM1) and anaerobic digestion model (ADM1). Current characterisation and interface models have key limitations, the most critical of which is the over-use of X(c) (or lumped complex) variable as a main input to the ADM1. Over-use of X(c) does not allow for variation of degradability, carbon oxidation state or nitrogen content. In addition, achieving a target influent pH through the proper definition of the ionic system can be difficult. In this paper, we define an interface and characterisation model that maps degradable components directly to carbohydrates, proteins and lipids (and their soluble analogues), as well as organic acids, rather than using X(c). While this interface has been designed for use with the Benchmark Simulation Model No. 2 (BSM2), it is widely applicable to ADM1 input characterisation in general. We have demonstrated the model both hypothetically (BSM2), and practically on a full-scale anaerobic digester treating sewage sludge.

Prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with community-acquired pneumonia: a systematic review and meta-analysis.

PubMed

Liu, Dan; Xie, Lixin; Zhao, Haiyan; Liu, Xueyao; Cao, Jie

2016-05-26

The early identification of patients at risk of dying from community-acquired pneumonia (CAP) is critical for their treatment and for defining hospital resource consumption. Mid-regional pro-adrenomedullin (MR-proADM) has been extensively investigated for its prognostic value in CAP. However, the results are conflicting. The purpose of the present meta-analysis was to explore the diagnostic accuracy of MR-proADM for predicting mortality in patients suffering from CAP, particularly emergency department (ED) patients. We systematically searched the PubMed, Embase, Web of Knowledge and Cochrane databases. Studies were included if a 2 × 2 contingency table could be constructed based on both the MR-proADM level and the complications or mortality of patients diagnosed with CAP. The prognostic accuracy of MR-proADM in CAP was assessed using the bivariate meta-analysis model. We used the Q-test and I (2) index to evaluate heterogeneity. MR-proADM displayed moderate diagnostic accuracy for predicting complications in CAP, with an overall area under the SROC curve (AUC) of 0.74 (95 % CI: 0.70-0.78). Eight studies with a total of 4119 patients in the emergency department (ED) were included. An elevated MR-proADM level was associated with increased risk of death from CAP (RR 6.16, 95 % CI 4.71-8.06); the I (2) value was 0.0 %, and a fixed-effects model was used to pool RR. The pooled sensitivity and specificity were 0.74 (95 % CI: 0.67-0.79) and 0.73 (95 % CI: 0.70-0.77), respectively. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.8 (95 % CI, 2.3-3.3) and 0.36 (95 % CI, 0.29-0.45), respectively. In addition, the diagnostic odds ratio (DOR) was 8 (95 % CI, 5-11), and the overall area under the SROC curve was 0.76 (95 % CI, 0.72-0.80). Our study has demonstrated that MR-proADM is predictive of increased complications and higher mortality rates in patients suffering from CAP. Future studies are warranted to determine the prognostic accuracy of MR-proADM in conjunction with severity scores or other biomarkers and to determine an optimal cut-off level.

Temporal Large-Eddy Simulation

NASA Technical Reports Server (NTRS)

Pruett, C. D.; Thomas, B. C.

2004-01-01

In 1999, Stolz and Adams unveiled a subgrid-scale model for LES based upon approximately inverting (defiltering) the spatial grid-filter operator and termed .the approximate deconvolution model (ADM). Subsequently, the utility and accuracy of the ADM were demonstrated in a posteriori analyses of flows as diverse as incompressible plane-channel flow and supersonic compression-ramp flow. In a prelude to the current paper, a parameterized temporal ADM (TADM) was developed and demonstrated in both a priori and a posteriori analyses for forced, viscous Burger's flow. The development of a time-filtered variant of the ADM was motivated-primarily by the desire for a unifying theoretical and computational context to encompass direct numerical simulation (DNS), large-eddy simulation (LES), and Reynolds averaged Navier-Stokes simulation (RANS). The resultant methodology was termed temporal LES (TLES). To permit exploration of the parameter space, however, previous analyses of the TADM were restricted to Burger's flow, and it has remained to demonstrate the TADM and TLES methodology for three-dimensional flow. For several reasons, plane-channel flow presents an ideal test case for the TADM. Among these reasons, channel flow is anisotropic, yet it lends itself to highly efficient and accurate spectral numerical methods. Moreover, channel-flow has been investigated extensively by DNS, and a highly accurate data base of Moser et.al. exists. In the present paper, we develop a fully anisotropic TADM model and demonstrate its utility in simulating incompressible plane-channel flow at nominal values of Re(sub tau) = 180 and Re(sub tau) = 590 by the TLES method. The TADM model is shown to perform nearly as well as the ADM at equivalent resolution, thereby establishing TLES as a viable alternative to LES. Moreover, as the current model is suboptimal is some respects, there is considerable room to improve TLES.

Comprehensive asymmetric dark matter model

NASA Astrophysics Data System (ADS)

Lonsdale, Stephen J.; Volkas, Raymond R.

2018-05-01

Asymmetric dark matter (ADM) is motivated by the similar cosmological mass densities measured for ordinary and dark matter. We present a comprehensive theory for ADM that addresses the mass density similarity, going beyond the usual ADM explanations of similar number densities. It features an explicit matter-antimatter asymmetry generation mechanism, has one fully worked out thermal history and suggestions for other possibilities, and meets all phenomenological, cosmological and astrophysical constraints. Importantly, it incorporates a deep reason for why the dark matter mass scale is related to the proton mass, a key consideration in ADM models. Our starting point is the idea of mirror matter, which offers an explanation for dark matter by duplicating the standard model with a dark sector related by a Z2 parity symmetry. However, the dark sector need not manifest as a symmetric copy of the standard model in the present day. By utilizing the mechanism of "asymmetric symmetry breaking" with two Higgs doublets in each sector, we develop a model of ADM where the mirror symmetry is spontaneously broken, leading to an electroweak scale in the dark sector that is significantly larger than that of the visible sector. The weak sensitivity of the ordinary and dark QCD confinement scales to their respective electroweak scales leads to the necessary connection between the dark matter and proton masses. The dark matter is composed of either dark neutrons or a mixture of dark neutrons and metastable dark hydrogen atoms. Lepton asymmetries are generated by the C P -violating decays of heavy Majorana neutrinos in both sectors. These are then converted by sphaleron processes to produce the observed ratio of visible to dark matter in the universe. The dynamics responsible for the kinetic decoupling of the two sectors emerges as an important issue that we only partially solve.

Continuous Flavor Symmetries and the Stability of Asymmetric Dark Matter

DOE PAGES

Bishara, Fady; Zupan, Jure

2015-01-19

Generically, the asymmetric interactions in asymmetric dark matter (ADM) models could lead to decaying DM. We show that, for ADM that carries nonzero baryon number, continuous flavor symmetries that generate the flavor structure in the quark sector also imply a looser lower bound on the mass scale of the asymmetric mediators between the dark and visible sectors. Furthermore, the mediators for B = 2 ADM that can produce a signal in the future indirect dark matter searches can thus also be searched for at the LHC. For two examples of the mediator models, with either the MFV or Froggatt-Nielsen flavormore » breaking pattern, we derive the FCNC constraints and discuss the search strategies at the LHC.« less

Continuous Flavor Symmetries and the Stability of Asymmetric Dark Matter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bishara, Fady; Zupan, Jure

Generically, the asymmetric interactions in asymmetric dark matter (ADM) models could lead to decaying DM. We show that, for ADM that carries nonzero baryon number, continuous flavor symmetries that generate the flavor structure in the quark sector also imply a looser lower bound on the mass scale of the asymmetric mediators between the dark and visible sectors. Furthermore, the mediators for B = 2 ADM that can produce a signal in the future indirect dark matter searches can thus also be searched for at the LHC. For two examples of the mediator models, with either the MFV or Froggatt-Nielsen flavormore » breaking pattern, we derive the FCNC constraints and discuss the search strategies at the LHC.« less

Asymmetric dark matter in extended exo-Higgs scenarios

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davoudiasl, Hooman; Giardino, Pier Paolo; Zhang, Cen

Here, the exo-Higgs model can accommodate a successful baryogenesis mechanism that closely mirrors electroweak baryogenesis in the Standard Model, but avoids its shortcomings. We extend the exo- Higgs model by the addition of a singlet complex scalar. In our model, Χ can be a viable asymmetric dark matter (ADM) candidate. We predict the mass of the ADM particle to be m x ≈ 1.3 GeV. The leptophilic couplings of can provide for efficient annihilation of the ADM pairs. We also discuss the LHC signals of our scenario, and in particular the production and decays of exo-leptons which would lead tomore » "lepton pair plus missing energy" final states. Our model typically predicts potentially detectable gravitational waves originating from the assumed strong first order phase transition at a temperature of ~TeV. If the model is further extended to include new heavy vector-like fermions, e.g. from an ultraviolet extension, Χ couplings could explain the ~3.5 muon g – 2 anomaly.« less

Asymmetric dark matter in extended exo-Higgs scenarios

DOE PAGES

Davoudiasl, Hooman; Giardino, Pier Paolo; Zhang, Cen

2017-07-17

Here, the exo-Higgs model can accommodate a successful baryogenesis mechanism that closely mirrors electroweak baryogenesis in the Standard Model, but avoids its shortcomings. We extend the exo- Higgs model by the addition of a singlet complex scalar. In our model, Χ can be a viable asymmetric dark matter (ADM) candidate. We predict the mass of the ADM particle to be m x ≈ 1.3 GeV. The leptophilic couplings of can provide for efficient annihilation of the ADM pairs. We also discuss the LHC signals of our scenario, and in particular the production and decays of exo-leptons which would lead tomore » "lepton pair plus missing energy" final states. Our model typically predicts potentially detectable gravitational waves originating from the assumed strong first order phase transition at a temperature of ~TeV. If the model is further extended to include new heavy vector-like fermions, e.g. from an ultraviolet extension, Χ couplings could explain the ~3.5 muon g – 2 anomaly.« less

Overexpression of adrenomedullin protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the Akt/GSK3β and Bcl-2 signaling pathways

PubMed Central

Song, Yuqing; Li, Lili

2018-01-01

The poor survival rate of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Adrenomedullin (ADM) has been identified as a potent apoptotic inhibitor. The present study aimed to investigate the protective effects of ADM on MSCs against hypoxia and serum deprivation (H/SD)-induced apoptosis, and to determine the potential underlying mechanisms. In the present study, a recombinant adenovirus expressing the ADM gene was established and was infected into MSCs. The infection rate was determined via microscopic detection of green fluorescence and flow cytometric analysis. The mRNA expression levels of ADM were detected by reverse transcription-polymerase chain reaction. In addition, a model of H/SD was generated. The MSCs were randomly separated into six groups: Control, enhanced green fluorescent protein (EGFP)-Adv, EGFP-ADM, H/SD, EGFP-Adv + H/SD and EGFP-ADM + H/SD. Cell viability and proliferation were determined using the Cell Counting kit-8 assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated-dUTP nick-end labeling assay and flow cytometric analysis using Annexin V-phycoerythrin/7-aminoactinomycin D staining. The protein expression levels of total protein kinase B (Akt), phosphorylated (p)-Akt, total glycogen synthase kinase (GSK)3β, p-GSK3β, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and cleaved caspase-3 were detected by western blot analysis. The results indicated that ADM overexpression could improve MSC proliferation and viability, and protect MSCs against H/SD-induced apoptosis. In addition, ADM overexpression increased Akt and GSK3β phosphorylation, and Bcl-2/Bax ratio, and decreased the activation of caspase-3. These results suggested that ADM protects MSCs against H/SD-induced apoptosis, which may be mediated via the Akt/GSK3β and Bcl-2 signaling pathways. PMID:29512737

Usefulness of Midregional Proadrenomedullin to Predict Poor Outcome in Patients with Community Acquired Pneumonia

PubMed Central

Gordo-Remartínez, Susana; Sevillano-Fernández, José A.; Álvarez-Sala, Luis A.; Andueza-Lillo, Juan A.; de Miguel-Yanes, José M.

2015-01-01

Background midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP). We sought to confirm whether MR-proADM added to Pneumonia Severity Index (PSI) improves the potential prognostic value of PSI alone, and tested to what extent this combination could be useful in predicting poor outcome of patients with CAP in an Emergency Department (ED). Methods Consecutive patients diagnosed with CAP were enrolled in this prospective, single-centre, observational study. We analyzed the ability of MR-proADM added to PSI to predict poor outcome using receiver operating characteristic (ROC) curves, logistic regression and risk reclassification and comparing it with the ability of PSI alone. The primary outcome was “poor outcome”, defined as the incidence of an adverse event (ICU admission, hospital readmission, or mortality at 30 days after CAP diagnosis). Results 226 patients were included; 33 patients (14.6%) reached primary outcome. To predict primary outcome the highest area under curve (AUC) was found for PSI (0.74 [0.64-0.85]), which was not significantly higher than for MR-proADM (AUC 0.72 [0.63-0.81, p > 0.05]). The combination of PSI and MR-proADM failed to improve the predictive potential of PSI alone (AUC 0.75 [0.65-0.85, p=0.56]). Ten patients were appropriately reclassified when the combined PSI and MR-proADM model was used as compared with the model of PSI alone. Net reclassification improvement (NRI) index was statistically significant (7.69%, p = 0.03) with an improvement percentage of 3.03% (p = 0.32) for adverse event, and 4.66% (P = 0.02) for no adverse event. Conclusion MR-proADM in combination with PSI may be helpful in individual risk stratification for short-term poor outcome of CAP patients, allowing a better reclassification of patients compared with PSI alone. PMID:26030588

High-End CMOS Active Pixel Sensors For Space-Borne Imaging Instruments

DTIC Science & Technology

2005-07-13

DISTRIBUTION/AVAILABILITY STATEMENT Approved for public release, distribution unlimited 13. SUPPLEMENTARY NOTES See also ADM001791, Potentially Disruptive ... Technologies and Their Impact in Space Programs Held in Marseille, France on 4-6 July 2005. , The original document contains color images. 14

Modified version of ADM1 model for agro-waste application.

PubMed

Galí, A; Benabdallah, T; Astals, S; Mata-Alvarez, J

2009-06-01

Agro-residues account for a large proportion of the wastes generated around the world. There is thus a need for a model to simulate the anaerobic digestion processes used in their treatment. We have developed model based on ADM1, to be applied to agro-wastes. We examined and tested the biodegradability of apple, pear, orange, rape, sunflower, pig manure and glycerol wastes to be used as the basis for feeding the model. Moreover, the fractions of particulate COD (X(c)) were calculated, and the disintegration constant was obtained from biodegradability profiles, considering disintegration to be the limiting process. The other kinetic and stoichiometric parameters were taken from the ADM1 model. The model operating under mono-substrate and co-substrate conditions was then validated with batch tests. At the same time the model was validated on a continuous anaerobic reactor operating with pig manure at lab scale. In both cases the correlation between the model and the experimental results was satisfactory. We conclude that the anaerobic digestion model is a reliable tool for the design and operation of plants in which agro-wastes are treated.

Improving TOGAF ADM 9.1 Migration Planning Phase by ITIL V3 Service Transition

NASA Astrophysics Data System (ADS)

Hanum Harani, Nisa; Akhmad Arman, Arry; Maulana Awangga, Rolly

2018-04-01

Modification planning of business transformation involving technological utilization required a system of transition and migration planning process. Planning of system migration activity is the most important. The migration process is including complex elements such as business re-engineering, transition scheme mapping, data transformation, application development, individual involvement by computer and trial interaction. TOGAF ADM is the framework and method of enterprise architecture implementation. TOGAF ADM provides a manual refer to the architecture and migration planning. The planning includes an implementation solution, in this case, IT solution, but when the solution becomes an IT operational planning, TOGAF could not handle it. This paper presents a new model framework detail transitions process of integration between TOGAF and ITIL. We evaluated our models in field study inside a private university.

THE ACQUISITION AND APPLICATION OF ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS

EPA Science Inventory

A multi-sector international group of government, academic, and industry scientists has developed a proposal for an improved testing scheme for assessing the safety of crop protection chemicals. Incorporation of pharmacokinetic studies describing the absorption, distribution, me...

Deletion of admB gene encoding a fungal ADAM affects cell wall construction in Aspergillus oryzae.

PubMed

Kobayashi, Takuji; Maeda, Hiroshi; Takeuchi, Michio; Yamagata, Youhei

2017-05-01

Mammals possess a unique signaling system based on the proteolytic mechanism of a disintegrin and metalloproteinases (ADAMs) on the cell surface. We found two genes encoding ADAMs in Aspergillus oryzae and named them admA and admB. We produced admA and admB deletion strains to elucidate their biological function and clarify whether fungal ADAMs play a similar role as in mammals. The ∆admA∆admB and ∆admB strains were sensitive to cell wall-perturbing agents, congo red, and calcofluor white. Moreover, the two strains showed significantly increased weights of total alkali-soluble fractions from the mycelial cell wall compared to the control strain. Furthermore, ∆admB showed MpkA phosphorylation at lower concentration of congo red stimulation than the control strain. However, the MpkA phosphorylation level was not different between ∆admB and the control strain without the stimulation. The results indicated that A. oryzae AdmB involved in the cell wall integrity without going through the MpkA pathway.

Model based on GRID-derived descriptors for estimating CYP3A4 enzyme stability of potential drug candidates

NASA Astrophysics Data System (ADS)

Crivori, Patrizia; Zamora, Ismael; Speed, Bill; Orrenius, Christian; Poggesi, Italo

2004-03-01

A number of computational approaches are being proposed for an early optimization of ADME (absorption, distribution, metabolism and excretion) properties to increase the success rate in drug discovery. The present study describes the development of an in silico model able to estimate, from the three-dimensional structure of a molecule, the stability of a compound with respect to the human cytochrome P450 (CYP) 3A4 enzyme activity. Stability data were obtained by measuring the amount of unchanged compound remaining after a standardized incubation with human cDNA-expressed CYP3A4. The computational method transforms the three-dimensional molecular interaction fields (MIFs) generated from the molecular structure into descriptors (VolSurf and Almond procedures). The descriptors were correlated to the experimental metabolic stability classes by a partial least squares discriminant procedure. The model was trained using a set of 1800 compounds from the Pharmacia collection and was validated using two test sets: the first one including 825 compounds from the Pharmacia collection and the second one consisting of 20 known drugs. This model correctly predicted 75% of the first and 85% of the second test set and showed a precision above 86% to correctly select metabolically stable compounds. The model appears a valuable tool in the design of virtual libraries to bias the selection toward more stable compounds. Abbreviations: ADME - absorption, distribution, metabolism and excretion; CYP - cytochrome P450; MIFs - molecular interaction fields; HTS - high throughput screening; DDI - drug-drug interactions; 3D - three-dimensional; PCA - principal components analysis; CPCA - consensus principal components analysis; PLS - partial least squares; PLSD - partial least squares discriminant; GRIND - grid independent descriptors; GRID - software originally created and developed by Professor Peter Goodford.

Gatekeeping versus Promiscuity in the Early Stages of the Andrimid Biosynthetic Assembly Line

PubMed Central

Magarvey, Nathan A.; Fortin, Pascal D.; Thomas, Paul M.; Kelleher, Neil L.; Walsh, Christopher T.

2009-01-01

The antibiotic andrimid, a nanomolar inhibitor of bacterial acetyl coenzyme A carboxylase, is generated on an unusual polyketide/nonribosomal pep-tide enzyme assembly line in that all thiolation (T) domains/small-molecule building stations are on separate proteins. In addition, a transglutaminase homologue is used to condense andrimid building blocks together on the andrimid assembly line. The first two modules of the andrimid assembly line yields an octatrienoyl-β-Phe-thioester tethered to the AdmI T domain, with amide bond formation carried out by a free-standing transglutaminase homologue AdmF. Analysis of the aminomutase AdmH reveals its specific conversion from l-Phe to (S)-β-Phe, which in turn is activated by AdmJ and ATP to form (S)-β-Phe-aminoacyl-AMP. AdmJ then transfers the (S)-β-Phe moiety to one of the free-standing T domains, AdmI, but not AdmA, which instead gets loaded with an octatrienoyl group by other enzymes. AdmF, the amide synthase, will accept a variety of acyl groups in place of the octatrienoyl donor if presented on either AdmA or AdmI. AdmF will also use either stereoisomer of phenylalanine or β-Phe when presented on AdmA and AdmI, but not when placed on noncognate T domains. Further, we show the polyketide synthase proteins responsible for the polyunsaturated acyl cap can be bypassed in vitro with N-acetylcysteamine as a low-molecular-weight acyl donor to AdmF and also in vivo in an Escherichia coli strain bearing the andrimid biosynthetic gene cluster with a knockout in admA. PMID:18652473

Clinical and histological evaluation of an acellular dermal matrix allograft in combination with the coronally advanced flap in the treatment of Miller class I recession defects: an experimental study in the mini-pig.

PubMed

Núñez, Javier; Caffesse, Raul; Vignoletti, Fabio; Guerra, Fernando; San Roman, Fidel; Sanz, Mariano

2009-06-01

To study the wound healing of acellular dermal matrix (ADM) allografts when used together with coronally advanced flaps (CAF) in the treatment of localized gingival recessions in the mini-pig experimental model. Dehiscence defects 4 x 5 mm were surgically created in one buccal root surface in each quadrant of PI, II, or III in three mini-pigs. They were then treated with CAF and the interposition of either a connective tissue graft (CTG) or ADM. As the primary outcome, the histological interface between the ADM and the root surface was studied and was compared with CTG. As secondary outcomes, we assessed the amount and quality of the keratinized tissue and clinical outcomes in terms of root coverage and recession reduction. At 3 months, the CTG group attained a mean 76% root coverage, versus 62% in the ADM group. The histological interface with the root surface was similar in both groups. The apical migration of the epithelium was 1.79+/-0.46 mm for the CTG and 1.21+/-0.35 mm for ADM. Newly formed cementum was observed with both treatments. New bone and a newly formed periodontal ligament were shown in five specimens in the ADM group and in three in the CTG group. Both materials showed similar clinical and histological outcomes.

A Small Aircraft Transportation System (SATS) Demand Model

NASA Technical Reports Server (NTRS)

Long, Dou; Lee, David; Johnson, Jesse; Kostiuk, Peter; Yackovetsky, Robert (Technical Monitor)

2001-01-01

The Small Aircraft Transportation System (SATS) demand modeling is a tool that will be useful for decision-makers to analyze SATS demands in both airport and airspace. We constructed a series of models following the general top-down, modular principles in systems engineering. There are three principal models, SATS Airport Demand Model (SATS-ADM), SATS Flight Demand Model (SATS-FDM), and LMINET-SATS. SATS-ADM models SATS operations, by aircraft type, from the forecasts in fleet, configuration and performance, utilization, and traffic mixture. Given the SATS airport operations such as the ones generated by SATS-ADM, SATS-FDM constructs the SATS origin and destination (O&D) traffic flow based on the solution of the gravity model, from which it then generates SATS flights using the Monte Carlo simulation based on the departure time-of-day profile. LMINET-SATS, an extension of LMINET, models SATS demands at airspace and airport by all aircraft operations in US The models use parameters to provide the user with flexibility and ease of use to generate SATS demand for different scenarios. Several case studies are included to illustrate the use of the models, which are useful to identify the need for a new air traffic management system to cope with SATS.

Abnormal patterns of displacement activities: a review and reinterpretation.

PubMed

Anselme, Patrick

2008-09-01

A series of important theoretical contributions flourished in the years 1950-1970 about displacement activities -- those 'out-of-context' actions expressed by organisms in stressful situations. Nothing really new has appeared thereafter. Although the models address different issues, such as causal factors of displacement, it appears obvious that they do not provide a unified (coherent) approach; they often explain the same phenomena using very different means and turn out to be contradictory on several points. In addition, some problems currently remain unsolved, especially concerning the fact that displacement activities exhibit 'abnormalities' of expression in comparison with the same activities performed in usual context. Each model is here described and criticized in order to evaluate its explanatory power and allow the identification of specific limits. A new, integrative model -- the Anticipatory Dynamics Model (or ADM) -- then attempts to overcome the failures of previous models. The ADM suggests that abnormal patterns of displacement activities result from attentional interference caused by a thwarting experience or conflicting motivations. At least one theoretical prediction of the ADM can be differentiated from that of any other model.

Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: trial design and protocol of the MOMENT study

PubMed Central

2012-01-01

Background Depression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM). Recently, it has been shown that Mindfulness-Based Cognitive Therapy (MBCT) is at least as effective as mADM in reducing the relapse/recurrence risk. However, it is not yet known whether combination treatment of MBCT and mADM is more effective than either of these treatments alone. Given the fact that most patients have a preference for either mADM or for MBCT, the aim of the present study is to answer the following questions. First, what is the effectiveness of MBCT in addition to mADM? Second, how large is the risk of relapse/recurrence in patients withdrawing from mADM after participating in MBCT, compared to those who continue to use mADM after MBCT? Methods/design Two parallel-group, multi-center randomized controlled trials are conducted. Adult patients with a history of depression (3 or more episodes), currently either in full or partial remission and currently treated with mADM (6 months or longer) are recruited. In the first trial, we compare mADM on its own with mADM plus MBCT. In the second trial, we compare MBCT on its own, including tapering of mADM, with mADM plus MBCT. Follow-up assessments are administered at 3-month intervals for 15 months. Primary outcome is relapse/recurrence. Secondary outcomes are time to, duration and severity of relapse/recurrence, quality of life, personality, several process variables, and incremental cost-effectiveness ratio. Discussion Taking into account patient preferences, this study will provide information about a) the clinical and cost-effectiveness of mADM only compared with mADM plus MBCT, in patients with a preference for mADM, and b) the clinical and cost-effectiveness of withdrawing from mADM after MBCT, compared with mADM plus MBCT, in patients with a preference for MBCT. Trial registration ClinicalTrials.gov: NCT00928980 PMID:22925198

Association of antidepressant medication therapy with inpatient rehabilitation outcomes for stroke, traumatic brain injury, or traumatic spinal cord injury.

PubMed

Weeks, Douglas L; Greer, Christopher L; Bray, Brenda S; Schwartz, Catrina R; White, John R

2011-05-01

To study whether outcomes in patients who have undergone inpatient rehabilitation for stroke, traumatic brain injury (TBI), or traumatic spinal cord injury (TSCI) differ based on antidepressant medication (ADM) use. Retrospective cohort study of 867 electronic medical records of patients receiving inpatient rehabilitation for stroke, TBI, or TSCI. Four cohorts were formed within each rehabilitation condition: patients with no history of ADM use and no indication of history of depression; patients with no history of ADM use but with a secondary diagnostic code for a depressive illness; patients with a history of ADM use prior to and during inpatient rehabilitation; and patients who began ADM therapy in inpatient rehabilitation. Freestanding inpatient rehabilitation facility (IRF). Patients diagnosed with stroke (n=625), TBI (n=175), and TSCI (n=67). Not applicable. FIM, rehabilitation length of stay (LOS), deviation between actual LOS and expected LOS, and functional gain per day. In each impairment condition, patients initiating ADM therapy in inpatient rehabilitation had longer LOS than patients in the same impairment condition on ADM at IRF admission, and had significantly longer LOS than patients with no history of ADM use and no diagnosis of depression (P<.05). LOS for patients initiating ADM therapy as inpatients even exceeded LOS for patients without ADM history, but who had a diagnosis for a depressive disorder. Deviation in LOS was significantly larger in the stroke and TBI groups initiating ADM in IRF than their counterparts with no history of ADM use, illustrating that the group initiating ADM therapy in rehabilitation significantly exceeded expected LOS. Increased LOS did not translate into functional gains, and in fact, functional gain per day was lower in the group initiating ADM therapy in IRF. Explanations for unexpectedly long LOS in patients initiating ADM in inpatient rehabilitation focus on the potential for ADM to inhibit therapy-driven remodeling of the nervous system when initiated close in time to nervous system injury, or the possibility that untreated sequelae (eg, depressive symptoms or fatigue) were limiting progress in therapy, which triggered ADM treatment. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

A Workflow to Investigate Exposure and Pharmacokinetic ...

EPA Pesticide Factsheets

Background: Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals.Objectives: We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition.Methods: Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood–brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites.Results: Application of the workflow screened 10 “low-priority” chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation.Conclusions: The incorporation of exposure and ADME properties into the conceptual workflow e

EPRI and Schneider Electric Demonstrate Distributed Resource Communications

Science.gov Websites

Electric Power Research Institute (EPRI) is designing, building, and testing a flexible, open-source Schneider Electric ADMS, open software platforms, an open-platform home energy management system

Doxorubicin plus tumor necrosis factor alpha combination treatments in EL4-lymphoma-bearing C57BL/6 mice.

PubMed

Ehrke, M J; Verstovsek, S; Ujházy, P; Meer, J M; Eppolito, C; Maccubbin, D L; Mihich, E

1998-02-01

The therapeutic efficacy of a total of 42 single-agent or combination protocols involving doxorubicin (Adriamycin, ADM) and tumor necrosis factor alpha (TNFalpha) were evaluated in the syngeneic murine lymphoma model, C57BL/6-EL4. Combination treatments were the most effective and the therapeutic effects were schedule-dependent; e.g. it was generally advantageous for ADM to precede TNFalpha administration. Two protocols selected for further study were 4 mg/kg ADM i.v. on days 1 and 8 plus TNFalpha, i.v., at either 16000 U (7 microg)/injection, on days 1 and 8 or 4000 U (1.7 microg)/injection, on days 11-15. Survival of mice bearing one of four EL4 sublines having different in vitro drug sensitivities was assessed. These sublines were E10 (ADM-sensitive/TNFalpha-resistant), E16 (sensitive/sensitive), ER2 (ADM-resistant/TNFalpha-sensitive) and ER13 (resistant/resistant). Between 80% and 100% long-term survivors (i.e. tumor free on day 60) were obtained with the two treatments in mice bearing ADM-sensitive sublines, even though one of these sublines, E10, was resistant to TNFalpha in vitro. Induction of long-term survival appeared, therefore, to correlate with in vitro defined sensitivity/resistance to ADM, but not to TNFalpha Treatment-induced modulations of tumoricidal immune effector functions were also examined. Taken together, the results indicated that induction of long-term survival involved complex interactions of: (1) ADM-induced tumor modifications, including, but not limited to, tumor debulking, (2) combination-treatment-induced modifications of splenic cytolytic T cell and macrophage activities, and (3) the restoration of thymus cellularity. Finally, when long-term survivors resulting from treatment of E10- or E16-bearing mice were implanted with ER2 on day 120, the majority survived, indicating that long-term immune memory, capable of recognizing drug resistant variants, had been established.

[Adherence to the Mediterranean diet of future teachers].

PubMed

Egeda Manzanera, José Manuel; Rodrigo Vega, Maximiliano

2014-08-01

The Spanish university population is vulnerable in their eating habits for various reasons. This would in many cases the abandonment of a traditional Mediterranean diet. To determine the adherence to the Mediterranean diet (adm) of a university population of future Teachers and analyze various factos that may condition its nutritional quality. Distribution Kidmed test to a sample of 212 university aged between 21 and 24. The Kidmed index (0-12) indicate whether the ADM was low (0 to 3), medium (4-7) or high (8 to 12). Each respondent was recorded age, weight, height and body mass index, and weekly physical activity. For comparison of the data was used Chi square test, the Mann Whitney test and ANOVA factor using SPSS 15. 15.1% had a low Kidmed index, 60.4% intermediate and 24.5% higher. The difference between the different levels of ADM is due to the consumption of fruits and vegetables (p < 0.05) mainly. Among the degrees of ADM and nutritional status (BMI) were not significantly different. The differences between those students who perform physical activity (66%) and no (34%) over the Kidmed index (< 0.05), were due primarily to breakfast consumed more cereals and cereal and pastries least). 75.5% of future Teachers needed improved ADM. In general, enhance a quality breakfast and minimum daily physical activity would be two core aspects in improving habits. It would be appropriate to provide nutritional education campaigns for this population and especially considering their future social role as educators. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Impact of Acellular Dermal Matrix (ADM) Use Under Mastectomy Flap Necrosis on Perioperative Outcomes of Prosthetic Breast Reconstruction.

PubMed

Kim, So Young; Bang, Sa Ik

2017-04-01

There is conflicting data on the potential necrotic complications of acellular dermal matrix (ADM) use in breast reconstruction, and most studies focus on mastectomy flap necrosis as an outcome measure associated with ADM use. The aim of this study was to examine cases with necrotic complications with and without the use of ADM and to investigate whether ADM affected perioperative outcomes in cases with necrotic complications. Patients who experienced mastectomy flap necrosis following mastectomy with tissue expander placement between January 2009 and March 2015 were retrospectively reviewed. The primary outcome was explantation of the expander, and other associated outcomes such as seroma or infection were also recorded. A total of 57 breasts with mastectomy flap necrosis were identified: 32 of which were in the non-ADM group and 25 in the ADM group. The rate of explantation was 28% (7/25) in the ADM group versus 6.3% (2/32) in the non-ADM group, which was significantly different (P = 0.034). The ADM group had a significantly higher rate of "major" infection requiring surgical debridement than the non-ADM group (P = 0.016). Multivariate analysis showed that the use of ADM was trending toward an increasing expander rate with borderline significance (P = 0.05). This study demonstrated that ADM use under mastectomy flap necrosis was a potential risk for explantation of the expander and major infection. Surgeons should be cautious with the use of ADM with devascularized mastectomy skin flaps prone to necrosis. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Methods in Clinical Pharmacology Series

PubMed Central

Beaumont, Claire; Young, Graeme C; Cavalier, Tom; Young, Malcolm A

2014-01-01

Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules. PMID:25041729

Alcohol ADME in primates studied with positron emission tomography.

PubMed

Li, Zizhong; Xu, Youwen; Warner, Don; Volkow, Nora D

2012-01-01

The sensitivity to the intoxicating effects of alcohol as well as its adverse medical consequences differ markedly among individuals, which reflects in part differences in alcohol's absorption, distribution, metabolism, and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol's brain bioavailability, however, is not well understood. The ADME of C-11 labeled alcohol, CH(3) (11)CH(2)OH, 1 and C-11 and deuterium dual labeled alcohol, CH(3) (11)CD(2)OH, 2 in baboons was compared based on the principle that C-D bond is stronger than C-H bond, thus the reaction is slower if C-D bond breaking occurs in a rate-determining metabolic step. The following ADME parameters in peripheral organs and brain were derived from time activity curve (TAC) of positron emission tomography (PET) scans: peak uptake (C(max)); peak uptake time (T(max)), half-life of peak uptake (T(1/2)), the area under the curve (AUC(60 min)), and the residue uptake (C(60 min)). For 1 the highest uptake occurred in the kidney whereas for 2 it occurred in the liver. A deuterium isotope effect was observed in the kidneys in both animals studied and in the liver of one animal but not the other. The highest uptake for 1 and 2 in the brain was in striatum and cerebellum but 2 had higher uptake than 1 in all brain regions most evidently in thalamus and cingulate. Alcohol's brain uptake was significantly higher when given intravenously than when given orally and also when the animal was pretreated with a pharmacological dose of alcohol. The study shows that alcohol metabolism in peripheral organs had a large effect on alcohol's brain bioavailability. This study sets the stage for clinical investigation on how genetics, gender and alcohol abuse affect alcohol's ADME and its relationship to intoxication and medical consequences.

Ammonia emissions from an anaerobic digestion plant estimated using atmospheric measurements and dispersion modelling.

PubMed

Bell, Michael W; Tang, Y Sim; Dragosits, Ulrike; Flechard, Chris R; Ward, Paul; Braban, Christine F

2016-10-01

Anaerobic digestion (AD) is becoming increasingly implemented within organic waste treatment operations. The storage and processing of large volumes of organic wastes through AD has been identified as a significant source of ammonia (NH3) emissions, however the totality of ammonia emissions from an AD plant have not been previously quantified. The emissions from an AD plant processing food waste were estimated through integrating ambient NH3 concentration measurements, atmospheric dispersion modelling, and comparison with published emission factors (EFs). Two dispersion models (ADMS and a backwards Lagrangian stochastic (bLS) model) were applied to calculate emission estimates. The bLS model (WindTrax) was used to back-calculate a total (top-down) emission rate for the AD plant from a point of continuous NH3 measurement downwind from the plant. The back-calculated emission rates were then input to the ADMS forward dispersion model to make predictions of air NH3 concentrations around the site, and evaluated against weekly passive sampler NH3 measurements. As an alternative approach emission rates from individual sources within the plant were initially estimated by applying literature EFs to the available site parameters concerning the chemical composition of waste materials, room air concentrations, ventilation rates, etc. The individual emission rates were input to ADMS and later tuned by fitting the simulated ambient concentrations to the observed (passive sampler) concentration field, which gave an excellent match to measurements after an iterative process. The total emission from the AD plant thus estimated by a bottom-up approach was 16.8±1.8mgs(-1), which was significantly higher than the back-calculated top-down estimate (7.4±0.78mgs(-1)). The bottom-up approach offered a more realistic treatment of the source distribution within the plant area, while the complexity of the site was not ideally suited to the bLS method, thus the bottom-up method is believed to give a better estimate of emissions. The storage of solid digestate and the aerobic treatment of liquid effluents at the site were the greatest sources of NH3 emissions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of Sidestream Darkfield Microscopy for Real-Time Imaging Acellular Dermal Matrix Revascularization.

PubMed

DeGeorge, Brent R; Olenczak, J Bryce; Cottler, Patrick S; Drake, David B; Lin, Kant Y; Morgan, Raymond F; Campbell, Christopher A

2016-06-01

Acellular dermal matrices (ADMs) serve as a regenerative framework for host cell integration and collagen deposition to augment the soft tissue envelope in ADM-assisted breast reconstruction-a process dependent on vascular ingrowth. To date noninvasive intra-operative imaging techniques have been inadequate to evaluate the revascularization of ADM. We investigated the safety, feasibility, and efficacy of sidestream darkfield (SDF) microscopy to assess the status of ADM microvascular architecture in 8 patients at the time of tissue expander to permanent implant exchange during 2-stage ADM-assisted breast reconstruction. The SDF microscopy is a handheld device, which can be used intraoperatively for the real-time assessment of ADM blood flow, vessel density, vessel size, and branching pattern. The SDF microscopy was used to assess the microvascular architecture in the center and border zone of the ADM and to compare the native, non-ADM-associated capsule in each patient as a within-subject control. No incidences of periprosthetic infection, explantation, or adverse events were reported after SDF image acquisition. Native capsules demonstrate a complex, layered architecture with an average vessel area density of 14.9 mm/mm and total vessel length density of 12.3 mm/mm. In contrast to native periprosthetic capsules, ADM-associated capsules are not uniformly vascularized structures and demonstrate 2 zones of microvascular architecture. The ADM and native capsule border zone demonstrates palisading peripheral vascular arcades with continuous antegrade flow. The central zone of the ADM demonstrates punctate perforating vascular plexi with intermittent, sluggish flow, and intervening 2- to 3-cm watershed zones. Sidestream darkfield microscopy allows for real-time intraoperative assessment of ADM revascularization and serves as a potential methodology to compare revascularization parameters among commercially available ADMs. Thr SDF microscopy demonstrates that the periprosthetic capsule in ADM-assisted implant-based breast reconstruction is not a uniformly vascularized structure.

Activation of particulate guanylate cyclase by adrenomedullin in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells.

PubMed

Ali, N; Yousufzai, S Y; Abdel-Latif, A A

2000-07-01

We investigated the effects of adrenomedullin (ADM) on cGMP production in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. ADM increased cGMP accumulation in a time- and concentration- dependent manner. The peptide increased cGMP formation in the transformed cells by 405-fold as compared to 1. 6-fold in primary cultured CISM cells. The basal cGMP concentrations in both cell types were comparable. In addition, ADM increased cAMP accumulation in SV-CISM-2 cells and in primary cultured cells by 18. 9- and 5.8-fold, respectively. The ADM receptor antagonist, ADM(26-52), but not the atrial natriuretic peptide (ANP) receptor antagonist, anantin, inhibited ADM-induced cGMP formation. The phorbol ester, phorbol 12, 13-dibutyrate (PDBu), which inhibits particulate guanylate cyclases in smooth muscle, blocked ADM-stimulated cGMP accumulation. In contrast, inhibitors of the soluble guanylate cyclases, such as LY83583 and ODQ, and inhibitors of the nitric oxide cascade had little effect on ADM-stimulated cGMP production. The stimulatory effect of ADM on cGMP formation is due to activation of the guanylate cyclase system and not to a much reduced phosphodiesterase activity. ADM stimulated guanylate cyclase activity in membrane fractions isolated from SV-CISM-2 cells in a concentration-dependent manner with EC(50) value of 72 nM. Pertussis toxin, an activator of the G-protein, Gi, inhibited ADM-stimulated cGMP accumulation, whereas cholera toxin, a stimulator of the Gs G-protein and subsequently cAMP accumulation, had little effect. Pretreatment of the plasma membrane fraction with Gialpha antibody attenuated ADM-stimulated guanylate cyclase activity by 75%. We conclude that ADM increases intracellular cGMP levels in SV-CISM-2 cells through activation of the ADM receptor and subsequent stimulation of a Gi-mediated membrane-bound guanylate cyclase.

The Effect of Sterile Acellular Dermal Matrix Use on Complication Rates in Implant-Based Immediate Breast Reconstructions

PubMed Central

Park, Youngsoo; Choi, Kyoung Wook; Chung, Kyu-Jin; Kim, Tae Gon; Kim, Yong-Ha

2016-01-01

Background The use of acellular dermal matrix (ADM) in implant-based immediate breast reconstruction has been increasing. The current ADMs available for breast reconstruction are offered as aseptic or sterile. No published studies have compared aseptic and sterile ADM in implant-based immediate breast reconstruction. The authors performed a retrospective study to evaluate the outcomes of aseptic versus sterile ADM in implant-based immediate breast reconstruction. Methods Implant-based immediate breast reconstructions with ADM conducted between April 2013 and January 2016 were included. The patients were divided into 2 groups: the aseptic ADM (AlloDerm) group and the sterile ADM (MegaDerm) group. Archived records were reviewed for demographic data and postoperative complication types and frequencies. The complications included were infection, flap necrosis, capsular contracture, seroma, hematoma, and explantation for any cause. Results Twenty patients were reconstructed with aseptic ADM, and 68 patients with sterile ADM. Rates of infection (15.0% vs. 10.3%), flap necrosis (5.0% vs. 7.4%), capsular contracture (20.0% vs. 14.7%), seroma (10.0% vs. 14.7%), hematoma (0% vs. 1.5%), and explantation (10.0% vs. 8.8%) were not significantly different in the 2 groups. Conclusions Sterile ADM did not provide better results regarding infectious complications than aseptic ADM in implant-based immediate breast reconstruction. PMID:27896182

A novel animal model for skin flap prelamination with biomaterials

NASA Astrophysics Data System (ADS)

Zhou, Xianyu; Luo, Xusong; Liu, Fei; Gu, Chuan; Wang, Xi; Yang, Qun; Qian, Yunliang; Yang, Jun

2016-09-01

Several animal models of skin flap construction were reported using biomaterials in a way similar to prefabrication. However, there are few animal model using biomaterials similar to prelamination, another main way of clinical skin flap construction that has been proved to be reliable. Can biomaterials be added in skin flap prelamination to reduce the use of autogenous tissues? Beside individual clinical attempts, animal model is needed for randomized controlled trial to objectively evaluate the feasibility and further investigation. Combining human Acellular Dermal Matrix (hADM) and autologous skin graft, we prelaminated flaps based on inguinal fascia. One, two, three and four weeks later, hADM exhibited a sound revascularization and host cell infiltration. Prelaminated skin flaps were then raised and microsurgically transplanted back to groin region. Except for flaps after one week of prelamination, flaps from other subgroups successfully reconstructed defects. After six to sixteen weeks of transplantation, hADM was proved to being able to maintain its original structure, having a wealth of host tissue cells and achieving full revascularization.To our knowledge, this is the first animal model of prelaminating skin flap with biomaterials. Success of this animal model indicates that novel flap prelamination with biomaterials is feasible.

U.S. Navy Capstone Strategies and Concepts: Introduction, Background and Analyses

DTIC Science & Technology

2011-12-01

Zumwalt  Jun 1974 ADM James Holloway  Jul 1978 ADM Thomas Hayward  Jun 1982 ADM James Watkins  Jul 1986 ADM Carlisle Trost  Jun 1990 ADM Frank...RDML Bill Center USN (Ret) • Dr. Eugene Cobble (CNA) • CAPT Bud Cole USN (Ret) • Mr. Tim Colton • Dr. Greg Cox (CNA) • Hon. Seth Cropsey • RDML

Novel biomarkers in acute heart failure: MR-pro-adrenomedullin.

PubMed

Peacock, W Frank

2014-10-01

First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR-proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP.

Simplified contaminant source depletion models as analogs of multiphase simulators

NASA Astrophysics Data System (ADS)

Basu, Nandita B.; Fure, Adrian D.; Jawitz, James W.

2008-04-01

Four simplified dense non-aqueous phase liquid (DNAPL) source depletion models recently introduced in the literature are evaluated for the prediction of long-term effects of source depletion under natural gradient flow. These models are simple in form (a power function equation is an example) but are shown here to serve as mathematical analogs to complex multiphase flow and transport simulators. The spill and subsequent dissolution of DNAPLs was simulated in domains having different hydrologic characteristics (variance of the log conductivity field = 0.2, 1 and 3) using the multiphase flow and transport simulator UTCHEM. The dissolution profiles were fitted using four analytical models: the equilibrium streamtube model (ESM), the advection dispersion model (ADM), the power law model (PLM) and the Damkohler number model (DaM). All four models, though very different in their conceptualization, include two basic parameters that describe the mean DNAPL mass and the joint variability in the velocity and DNAPL distributions. The variability parameter was observed to be strongly correlated with the variance of the log conductivity field in the ESM and ADM but weakly correlated in the PLM and DaM. The DaM also includes a third parameter that describes the effect of rate-limited dissolution, but here this parameter was held constant as the numerical simulations were found to be insensitive to local-scale mass transfer. All four models were able to emulate the characteristics of the dissolution profiles generated from the complex numerical simulator, but the one-parameter PLM fits were the poorest, especially for the low heterogeneity case.

Simplified contaminant source depletion models as analogs of multiphase simulators.

PubMed

Basu, Nandita B; Fure, Adrian D; Jawitz, James W

2008-04-28

Four simplified dense non-aqueous phase liquid (DNAPL) source depletion models recently introduced in the literature are evaluated for the prediction of long-term effects of source depletion under natural gradient flow. These models are simple in form (a power function equation is an example) but are shown here to serve as mathematical analogs to complex multiphase flow and transport simulators. The spill and subsequent dissolution of DNAPLs was simulated in domains having different hydrologic characteristics (variance of the log conductivity field=0.2, 1 and 3) using the multiphase flow and transport simulator UTCHEM. The dissolution profiles were fitted using four analytical models: the equilibrium streamtube model (ESM), the advection dispersion model (ADM), the power law model (PLM) and the Damkohler number model (DaM). All four models, though very different in their conceptualization, include two basic parameters that describe the mean DNAPL mass and the joint variability in the velocity and DNAPL distributions. The variability parameter was observed to be strongly correlated with the variance of the log conductivity field in the ESM and ADM but weakly correlated in the PLM and DaM. The DaM also includes a third parameter that describes the effect of rate-limited dissolution, but here this parameter was held constant as the numerical simulations were found to be insensitive to local-scale mass transfer. All four models were able to emulate the characteristics of the dissolution profiles generated from the complex numerical simulator, but the one-parameter PLM fits were the poorest, especially for the low heterogeneity case.

Adrenomedullin increases the short-circuit current in the mouse seminal vesicle: actions on chloride secretion.

PubMed

Liao, S B; Cheung, K H; O, W S; Tang, Fai

2014-08-01

Adrenomedullin (ADM) may regulate seminal vesicle fluid secretion, and this may affect sperm quality. In this study, we investigated the effect of ADM on chloride secretion in the mouse seminal vesicle. The presence of ADM in mouse seminal vesicle was confirmed using immunostaining, and the molecular species was determined using gel filtration chromatography coupled with enzyme-linked assay for ADM. The effects of ADM on chloride secretion were studied by short-circuit current technique in a whole-mount preparation of mouse seminal vesicle in an Ussing chamber. The effects of specific ADM and calcitonin gene-related peptide (CGRP) receptor antagonists were investigated. Whether the ADM effect depended on the cAMP- and/or calcium-activated chloride channel was also studied using specific chloride channel blockers. The results showed that ADM was present in seminal vesicle epithelial cells. The major molecular species was precursor in the mouse seminal vesicle. ADM increased short-circuit current through the calcium-activated chloride channel in mouse seminal vesicle, and CGRP receptor was involved. We conclude that ADM may regulate chloride and fluid secretion from the seminal vesicle, which may affect the composition of the seminal plasma bathing the sperm and, hence, fertility. © 2014 by the Society for the Study of Reproduction, Inc.

Computerized Algorithms: Evaluation of Capability to Predict Graduation from Air Force Training.

DTIC Science & Technology

1980-09-01

Distribution of the ASVAB Administrative Aptitude Test Scores for the 1976 AFSC 64530 Population ..................................... 73 ASO Distribution...2.34 2.15 PDA 4.11 3.12 I83 ... Table .. (on LAioi; M.iix of the Ind ’pedttit Variab Independent us .l Variable Merh Adm Gel Elec AF)T Ed Aig Bi Math

Predicting Subnational Ebola Virus Disease Epidemic Dynamics from Sociodemographic Indicators

PubMed Central

Valeri, Linda; Patterson-Lomba, Oscar; Gurmu, Yared; Ablorh, Akweley; Bobb, Jennifer; Townes, F. William; Harling, Guy

2016-01-01

Background The recent Ebola virus disease (EVD) outbreak in West Africa has spread wider than any previous human EVD epidemic. While individual-level risk factors that contribute to the spread of EVD have been studied, the population-level attributes of subnational regions associated with outbreak severity have not yet been considered. Methods To investigate the area-level predictors of EVD dynamics, we integrated time series data on cumulative reported cases of EVD from the World Health Organization and covariate data from the Demographic and Health Surveys. We first estimated the early growth rates of epidemics in each second-level administrative district (ADM2) in Guinea, Sierra Leone and Liberia using exponential, logistic and polynomial growth models. We then evaluated how these growth rates, as well as epidemic size within ADM2s, were ecologically associated with several demographic and socio-economic characteristics of the ADM2, using bivariate correlations and multivariable regression models. Results The polynomial growth model appeared to best fit the ADM2 epidemic curves, displaying the lowest residual standard error. Each outcome was associated with various regional characteristics in bivariate models, however in stepwise multivariable models only mean education levels were consistently associated with a worse local epidemic. Discussion By combining two common methods—estimation of epidemic parameters using mathematical models, and estimation of associations using ecological regression models—we identified some factors predicting rapid and severe EVD epidemics in West African subnational regions. While care should be taken interpreting such results as anything more than correlational, we suggest that our approach of using data sources that were publicly available in advance of the epidemic or in real-time provides an analytic framework that may assist countries in understanding the dynamics of future outbreaks as they occur. PMID:27732614

Network Enabled Capabilities - Grassroots Perspectives

DTIC Science & Technology

2006-10-01

public release, distribution unlimited 13. SUPPLEMENTARY NOTES See also ADM202422., The original document contains color images. 14. ABSTRACT 15...RTO-MP-IST-062 UNCLASSIFIED/UNLIMITED UNCLASSIFIED/UNLIMITED ActiveX component. The other parts of the page depend on the application requirements

The TRIAGE-ProADM Score for an Early Risk Stratification of Medical Patients in the Emergency Department - Development Based on a Multi-National, Prospective, Observational Study

PubMed Central

Hausfater, Pierre; Amin, Devendra; Amin, Adina; Canavaggio, Pauline; Sauvin, Gabrielle; Bernard, Maguy; Conca, Antoinette; Haubitz, Sebastian; Struja, Tristan; Huber, Andreas; Mueller, Beat; Schuetz, Philipp

2016-01-01

Introduction The inflammatory biomarker pro-adrenomedullin (ProADM) provides additional prognostic information for the risk stratification of general medical emergency department (ED) patients. The aim of this analysis was to develop a triage algorithm for improved prognostication and later use in an interventional trial. Methods We used data from the multi-national, prospective, observational TRIAGE trial including consecutive medical ED patients from Switzerland, France and the United States. We investigated triage effects when adding ProADM at two established cut-offs to a five-level ED triage score with respect to adverse clinical outcome. Results Mortality in the 6586 ED patients showed a step-wise, 25-fold increase from 0.6% to 4.5% and 15.4%, respectively, at the two ProADM cut-offs (≤0.75nmol/L, >0.75–1.5nmol/L, >1.5nmol/L, p ANOVA <0.0001). Risk stratification by combining ProADM within cut-off groups and the triage score resulted in the identification of 1662 patients (25.2% of the population) at a very low risk of mortality (0.3%, n = 5) and 425 patients (6.5% of the population) at very high risk of mortality (19.3%, n = 82). Risk estimation by using ProADM and the triage score from a logistic regression model allowed for a more accurate risk estimation in the whole population with a classification of 3255 patients (49.4% of the population) in the low risk group (0.3% mortality, n = 9) and 1673 (25.4% of the population) in the high-risk group (15.1% mortality, n = 252). Conclusions Within this large international multicenter study, a combined triage score based on ProADM and established triage scores allowed a more accurate mortality risk discrimination. The TRIAGE-ProADM score improved identification of both patients at the highest risk of mortality who may benefit from early therapeutic interventions (rule in), and low risk patients where deferred treatment without negatively affecting outcome may be possible (rule out). PMID:28005916

Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels.

PubMed

Riera, J; Senna, A; Cubero, M; Roman, A; Rello, J

2016-02-01

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty-two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47-38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53-0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65-0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits.

PubMed

Gong, Yuping; Wang, Zhigang; Dong, Guifang; Sun, Yang; Wang, Xi; Rong, Yue; Li, Maoping; Wang, Dong; Ran, Haitao

2016-09-01

To explore the antitumor effects of low-intensity focused ultrasound (LIFU) mediated localized drug delivery of adriamycin-microbubble-PLGA nanoparticle complexes on rabbits VX2 liver tumor. ADM-NMCs were prepared by covalent linking of ADM-PLGA nanoparticles (ADM-NPs) to the shell of the microbubbles. A fixed water bag filled with microbubbles was subjected to LIFU and non-focused ultrasound respectively, and the ultrasound images of which were recorded before and after ultrasonication. A total of 54 VX2 liver tumor-burdened rabbits were divided into six groups randomly, including control, ADM-NPs combined with LIFU, microbubbles combined with LIFU, ADM-NPs and microbubbles combined with LIFU, ADM-NMCs combined with LIFU and ADM-NMCs combined with Non-FUS. The tumor volume and volume inhibition rate (VIR) of tumor progression were calculated and compared. Apoptotic cells were labeled by terminal deoxyuridine nick end. Proliferating cell nuclear antigen was detected by immunohistochemistry. The median survival time of the animals were recorded and compared. ADM-NMCs were successfully prepared with an average diameter of 1721 nm. The highest VIR and apoptotic index (AI) were found in the group of ADM-NMCs combined with LIFU while the lowest proliferating index (PI) was simultaneously observed in this group. The median survival time of the rabbits in the ADM-NMCs combined with LIFU group was the longest (71days) among all groups. ADM-NMCs combined with LIFU could inhibit the rabbits VX2 liver tumor progress by delaying the tumor proliferation and accelerating apoptosis, which presents a novel process for liver tumor targeting chemotherapy.

Differing antidepressant maintenance methodologies.

PubMed

Safer, Daniel J

2017-10-01

The principle evidence that antidepressant medication (ADM) is an effective maintenance treatment for adults with major depressive disorder (MDD) is from placebo substitution trials. These trials enter responders from ADM efficacy trials into randomized, double-blind placebo-controlled (RDBPC) effectiveness trials to measure the rate of MDD relapse over time. However, other randomized maintenance trial methodologies merit consideration and comparison. A systematic review of ADM randomized maintenance trials included research reports from multiple databases. Relapse rate was the main effectiveness outcome assessed. Five ADM randomized maintenance methodologies for MDD responders are described and compared for outcome. These effectiveness trials include: placebo-substitution, ADM/placebo extension, ADM extension, ADM vs. psychotherapy, and treatment as usual. The placebo-substitution trials for those abruptly switched to placebo resulted in unusually high (46%) rates of relapse over 6-12months, twice the continuing ADM rate. These trials were characterized by selective screening, high attrition, an anxious anticipation of a switch to placebo, and a risk of drug withdrawal symptoms. Selectively screened ADM efficacy responders who entered into 4-12month extension trials experienced relapse rates averaging ~10% with a low attrition rate. Non-industry sponsored randomized trials of adults with multiple prior MDD episodes who were treated with ADM maintenance for 1-2years experienced relapse rates averaging 40%. Placebo substitution trial methodology represents only one approach to assess ADM maintenance. Antidepressant maintenance research for adults with MDD should be evaluated for industry sponsorship, attrition, the impact of the switch to placebo, and major relapse differences in MDD subpopulations. Copyright © 2017. Published by Elsevier Inc.

Direct Hospital Cost of Outcome Pathways in Implant-Based Reconstruction with Acellular Dermal Matrices.

PubMed

Qureshi, Ali A; Broderick, Kristen; Funk, Susan; Reaven, Nancy; Tenenbaum, Marissa M; Myckatyn, Terence M

2016-08-01

Current cost data on tissue expansion followed by exchange for permanent implant (TE/I) reconstruction lack a necessary assessment of the experience of a heterogenous breast cancer patient population and their multiple outcome pathways. We extend our previous analysis to that of direct hospital cost as bundling of payments is likely to follow the changing centralization of cancer care at the hospital level. We performed a retrospective analysis (2003-2009) of TE/I reconstructions with or without an acellular dermal matrix (ADM), namely Alloderm RTM. Postreconstructive events were analyzed and organized into outcome pathways as previously described. Aggregated and normalized inpatient and outpatient hospital direct costs and physician reimbursement were generated for each outcome pathway with or without ADM. Three hundred sixty-seven patients were analyzed. The average 2-year hospital direct cost per TE/I breast reconstruction patient was $11,862 in the +ADM and $12,319 in the -ADM groups (P > 0.05). Initial reconstructions were costlier in the +ADM ($6,868) than in the -ADM ($5,615) group, but the average cost of subsequent postreconstructive events within 2 years was significantly lower in +ADM ($5,176) than -ADM ($6,704) patients (P < 0.05). When a complication occurred, but reconstruction was still completed within 2 years, greater costs were incurred in the -ADM than in the +ADM group for most scenarios, leading to a net equalization of cost between study groups. Although direct hospital cost is an important factor for resource and fund allocation, it should not remain the sole factor when deciding to use ADM in TE/I reconstruction.

Tissue Reinforcement in Implant-based Breast Reconstruction

PubMed Central

Scheflan, Michael

2014-01-01

Background: Tissue reinforcement with allogeneic or xenogeneic acellular dermal matrices (ADMs) is increasingly used in single-stage (direct-to-implant) and 2-stage implant-based breast reconstruction following mastectomy. ADMs allow surgeons to control implant position and obviate the need for submuscular implant placement. Here, we review the benefits and risks of using ADMs in implant-based breast reconstruction based on available data. Methods: A comprehensive analysis of the literature with focus on recent publications was performed. Additional information regarding the proper use of ADMs was based on our institutional experience. Results: ADM use may improve definition of the lateral confines of the breast and lower pole projection. It may facilitate direct-to-implant procedures and improve aesthetic outcomes. The effect of ADMs on complication rates remains controversial. Known patient risk factors such as obesity, smoking, and radiotherapy should be considered during patient selection. For patients with healthy, well-vascularized skin envelopes, ADM-assisted direct-to- implant reconstruction is a safe and cost-effective alternative to 2-stage implant reconstruction, with low complication rates. ADMs may be used to treat capsular contracture, and limited available data further suggest the possibility that ADMs may reduce the risk of capsular contracture. Novel synthetic or biosynthetic tissue reinforcement devices with different physical and ease-of-use properties than ADMs are emerging options for reconstructive surgeons and patients who seek to avoid tissue products from human or mammalian cadavers. Conclusions: ADM-assisted implant-based breast reconstruction may improve aesthetic outcomes. However, appropriate patient selection, surgical technique, and postoperative management are critical for its success, including minimizing the risk of complications. PMID:25426375

Chernobyl and Fukushima nuclear accidents: what has changed in the use of atmospheric dispersion modeling?

PubMed

Benamrane, Y; Wybo, J-L; Armand, P

2013-12-01

The threat of a major accidental or deliberate event that would lead to hazardous materials emission in the atmosphere is a great cause of concern to societies. This is due to the potential large scale of casualties and damages that could result from the release of explosive, flammable or toxic gases from industrial plants or transport accidents, radioactive material from nuclear power plants (NPPs), and chemical, biological, radiological or nuclear (CBRN) terrorist attacks. In order to respond efficiently to such events, emergency services and authorities resort to appropriate planning and organizational patterns. This paper focuses on the use of atmospheric dispersion modeling (ADM) as a support tool for emergency planning and response, to assess the propagation of the hazardous cloud and thereby, take adequate counter measures. This paper intends to illustrate the noticeable evolution in the operational use of ADM tools over 25 y and especially in emergency situations. This study is based on data available in scientific publications and exemplified using the two most severe nuclear accidents: Chernobyl (1986) and Fukushima (2011). It appears that during the Chernobyl accident, ADM were used few days after the beginning of the accident mainly in a diagnosis approach trying to reconstruct what happened, whereas 25 y later, ADM was also used during the first days and weeks of the Fukushima accident to anticipate the potentially threatened areas. We argue that the recent developments in ADM tools play an increasing role in emergencies and crises management, by supporting stakeholders in anticipating, monitoring and assessing post-event damages. However, despite technological evolutions, its prognostic and diagnostic use in emergency situations still arise many issues. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pharmacokinetic properties and drug interactions of apigenin, a natural flavone.

PubMed

Tang, Ding; Chen, Keli; Huang, Luqi; Li, Juan

2017-03-01

Apigenin, a natural flavone, is widely distributed in plants such as celery, parsley and chamomile. It is present principally as glycosylated in nature. Higher intake of apigenin could reduce the risk of chronic diseases. It has gained particular interest in recent years as a beneficial, health-promoting agent with low intrinsic toxicity. Areas covered: This review summarizes and the absorption, distribution, metabolism and excretion (ADME) properties of apigenin, and drug-drug interaction of apigenin. Expert opinion: Since apigenin is a bioactive plant flavone and is widely distributed in common food, its consumption through the diet is recommended. Apigenin-enriched drugs are better for some chronic diseases, but may affect animal and human health if present in the daily diet. Dietary or therapeutic apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract. Due to apigenin's limitations on absorption and bioavailability, novel carriers would need to be developed to enhance the oral bioavailability of apigenin. Further research about its ADME properties and drug-drug interactions are needed before apigenin can be brought to clinical trials.

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

PubMed

Blom, Jan J; Giove, Thomas J; Favazza, Tara L; Akula, James D; Eldred, William D

2011-06-01

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

Diagnostic value of the plasmatic ADM level for early ectopic pregnancy.

PubMed

Yan, Qi; Lu, Qi; Tao, Yu; Wang, Yu-Dong; Zhao, Wen-Xia

2015-01-01

To analyze the plasmatic ADM level in early pregnancy and to investigate the diagnostic value of ADM in early ectopic pregnancy (EP). 70 patients with EP who had menopause for 5~8 weeks were included as study group, while 155 women with normal intrauterine pregnancy were also included as control group. The correlation between ADM level and menopause weeks was statistically analyzed and ROC curve was used to identify the diagnostic value of ADM. (1) In 155 cases of normal intrauterine pregnancy, the plasmatic ADM level was increased with menopause weeks in linear relationship, and the correlation coefficient (R) was 0.991 (P<0.05). In 70 patients with EP, no significant increase was found with menopause weeks and no linear relationship can be found between ADM level and menopause weeks in EP group. The correlation coefficient (R) was 0.744 (P>0.05). (2) The multiple of median of plasmatic ADM level in EP group of menopause for 8 weeks was obviously lower than the intrauterine control group (P<0.01). (3) ROC curve was used to analyze the cut-off value of ADM level in the diagnosis of EP, and the area under the ROC curve was 0.523 (P>0.05) regardless of menopause weeks, however, the area under the ROC curve was 0.702 (P<0.05) at 8 weeks after menopause with sensitivity of 53.50% and specificity of 85.00%. Different from normal intrauterine pregnancy, plasmatic ADM level in early EP was relatively lower and no significant increase was found with menopause weeks; further studies are still needed for plasmatic ADM level as an indicator in the early diagnosis of EP.

Effects of adrenomedullin on tumour necrosis factor alpha, interleukins, endothelin-1, leptin, and adiponectin in the epididymal fat and soleus muscle of the rat.

PubMed

Liao, S B; Wong, P F; Cheung, B M Y; Tang, F

2013-01-01

Adrenomedullin (ADM) is a peptide hormone, which participates in the development of metabolic syndrome. In this study, we have investigated the interaction of ADM and cytokines, endothelin-1 (EDN-1) and adipokines in the epididymal fat and the soleus muscle. Epididymal fat and soleus muscles from adult male Sprague-Dawley rat were incubated with ADM at concentration of 100 nM for the study of the gene expression and secretion of tumour necrosis factor (TNF-α), EDN-1, leptin, adiponectin, interleukin 1β (IL-1β), and IL-6. The effects of TNF-α and EDN-1 on ADM gene expression and secretion were also investigated. The results showed that ADM decreased the gene expression and protein secretion of TNF-α in both the epididymal fat and the soleus muscle and decreased IL-1β gene expression and secretion in the soleus muscle. It also decreased endothelin gene expression and adiponectin gene expression and release and increased IL-6 and leptin gene expression and secretion in the epididymal fat. These effects were effectively blocked by the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP8-37, but not by the ADM receptor antagonist, hADM22-52. The reduction of inflammatory cytokines and EDN-1 may help to decrease insulin resistance and increase glucose uptake. As TNF-α also increases ADM levels in the epididymal fat and the soleus muscle and EDN-1 also increases ADM levels in the epididymal fat, they may form a feedback loop with ADM in these tissues. The increase in leptin and the decrease in adiponectin by ADM in the epididymal fat may have opposite effects on metabolism. © Georg Thieme Verlag KG Stuttgart · New York.

Implementation of an ADME enabling selection and visualization tool for drug discovery.

PubMed

Stoner, Chad L; Gifford, Eric; Stankovic, Charles; Lepsy, Christopher S; Brodfuehrer, Joanne; Prasad, J V N Vara; Surendran, Narayanan

2004-05-01

The pharmaceutical industry has large investments in compound library enrichment, high throughput biological screening, and biopharmaceutical (ADME) screening. As the number of compounds submitted for in vitro ADME screens increases, data analysis, interpretation, and reporting will become rate limiting in providing ADME-structure-activity relationship information to guide the synthetic strategy for chemical series. To meet these challenges, a software tool was developed and implemented that enables scientists to explore in vitro and in silico ADME and chemistry data in a multidimensional framework. The present work integrates physicochemical and ADME data, encompassing results for Caco-2 permeability, human liver microsomal half-life, rat liver microsomal half-life, kinetic solubility, measured log P, rule of 5 descriptors (molecular weight, hydrogen bond acceptors, hydrogen bond donors, calculated log P), polar surface area, chemical stability, and CYP450 3A4 inhibition. To facilitate interpretation of this data, a semicustomized software solution using Spotfire was designed that allows for multidimensional data analysis and visualization. The solution also enables simultaneous viewing and export of chemical structures with the corresponding ADME properties, enabling a more facile analysis of ADME-structure-activity relationship. In vitro and in silico ADME data were generated for 358 compounds from a series of human immunodeficiency virus protease inhibitors, resulting in a data set of 5370 experimental values which were subsequently analyzed and visualized using the customized Spotfire application. Implementation of this analysis and visualization tool has accelerated the selection of molecules for further development based on optimum ADME characteristics, and provided medicinal chemistry with specific, data driven structural recommendations for improvements in the ADME profile. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1131-1141, 2004

Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP)

PubMed Central

Wilkinson, Ian B; McEniery, Carmel M; Bongaerts, Katherine H; MacCallum, Helen; Webb, David J; Cockcroft, John R

2001-01-01

Aims To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. Methods On two separate occasions, ADM (1–30 pmol min−1) and PAMP (100–3000 pmol min−1) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol min−1) or the control vasoconstrictor noradrenaline (120 pmol min−1), on separate occasions. Both studies were conducted in a double-blind, randomized manner. Results ADM and PAMP produced a dose-dependent increase in FBF (P ≤ 0.002). Based on the dose producing a 50% increase in FBF, ADM was ∼60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 ± 4% (mean ± s.e. mean) and 22 ± 6%, respectively (P = 0.4). However, the area under the dose–response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 ± 1.0 vs 1.2 ± 0.2; P = 0.030). Conclusions ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is ∼60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM. PMID:11488772

Midregional Proadrenomedullin as a Prognostic Tool in Community-Acquired Pneumonia

PubMed Central

Huang, David T.; Angus, Derek C.; Kellum, John A.; Pugh, Nathan A.; Weissfeld, Lisa A.; Struck, Joachim; Delude, Russell L.; Rosengart, Matthew R.; Yealy, Donald M.

2009-01-01

Background: Midregional proadrenomedullin (MR-proADM) is a potential prognostic biomarker in patients with community-acquired pneumonia (CAP). Previous work has been hampered by sample size and illness spectrum limits. We sought to describe the pattern of MR-proADM in a broad CAP cohort, confirm its prognostic role, and compare its performance to procalcitonin, a novel biomarker of infection. Methods: We conducted a multicenter prospective cohort study in 28 community and teaching EDs. Patients with a clinical and radiographic diagnosis of CAP were enrolled. We stratified MR-proADM levels a priori into quartiles and quantified severity of illness using the pneumonia severity index (PSI); and confusion (abbreviated mental test score of ≤ 8), urea ≥ 7 mmol/L, respiratory rate ≥ 30 breaths/min, BP < 90 mm Hg systolic or < 60 mm Hg diastolic, age ≥ 65 years (CURB-65). The primary outcome was 30-day mortality. Results: A total of 1,653 patients formed the study cohort. MR-proADM levels consistently rose with PSI class and 30-day mortality (p < 0.001). MR-proADM had a higher area under the curve for 30-day mortality than procalcitonin (0.76 vs 0.65, respectively; p < 0.001), but adding MR-proADM to the PSI in all subjects minimally improved performance. Among low-risk subjects (PSI classes I to III), mortality was low and did not differ by MR-proADM quartile. However, among high-risk subjects (PSI class IV/V; n = 546), subjects in the highest MR-proADM quartile (n = 232; 42%) had higher 30-day mortality than those in MR-proADM quartiles 1 to 3 (23% vs 9%, respectively; p < 0.0001). Similar results were seen with CURB-65. MR-proADM and procalcitonin levels were generally concordant; only 6% of PSI class IV/V subjects in the highest MR-proADM quartile had very low procalcitonin levels (< 0.1 ng/mL). Conclusions: In our multicenter CAP cohort, MR-proADM levels correlate with increasing severity of illness and death. High MR-proADM levels offer additional risk stratification in high-risk CAP patients, but otherwise MR-proADM levels do not alter PSI-based risk assessment in most CAP patients. PMID:19363212

Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.

PubMed

Wauters, Elke; Sanchez-Arévalo Lobo, Victor J; Pinho, Andreia V; Mawson, Amanda; Herranz, Daniel; Wu, Jianmin; Cowley, Mark J; Colvin, Emily K; Njicop, Erna Ngwayi; Sutherland, Rob L; Liu, Tao; Serrano, Manuel; Bouwens, Luc; Real, Francisco X; Biankin, Andrew V; Rooman, Ilse

2013-04-01

The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. ©2012 AACR.

Absorption, Distribution, Metabolism, and Excretion of the Androgen Receptor Inhibitor Enzalutamide in Rats and Dogs.

PubMed

Ohtsu, Yoshiaki; Gibbons, Jacqueline A; Suzuki, Katsuhiro; Fitzsimmons, Michael E; Nozawa, Kohei; Arai, Hiroshi

2017-08-01

Enzalutamide is an androgen receptor inhibitor that has been approved in several countries. Absorption, distribution, metabolism, and excretion (ADME) data in animals would facilitate understanding of the efficacy and safety profiles of enzalutamide, but little information has been reported in public. The purpose of this study was to clarify the missing ADME profile in animals. ADME of 14 C-enzalutamide after oral administration as Labrasol solution were investigated in non-fasted male Sprague-Dawley rats and beagle dogs. Plasma concentrations of 14 C-enzalutamide peaked in rats and dogs at 6-8 h after a single oral administration. In most tissues, radioactivity concentration peaked at 4 h after administration. Excluding the gastrointestinal tract, tissues with the highest concentration of radioactivity were liver, fat, and adrenal glands. The tissue concentrations of radioactivity declined below the limit of quantitation or <0.89 % of maximum concentration by 168 h post-dose. Two known metabolites (M1 and M2) and at least 15 novel possible metabolites were detected in this study. M1 was the most abundant metabolite in both rats and dogs. Unchanged drug was a minor component in excreta. In intact rats, the mean urinary and fecal excretion of radioactivity accounted for 44.20 and 49.80 % of administered radioactivity, respectively. In intact dogs, mean urinary and fecal excretion was 62.00 and 22.30 % of the administered radioactivity, respectively. Rapid oral absorption was observed in rats and dogs when 14 C-enzalutamide was administered as Labrasol solution. Tissue distribution in rats was clarified. The elimination of enzalutamide is mediated primarily by metabolism. Species differences were observed in excretion route.

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

PubMed Central

Dola, Vasantha Rao; Soni, Awakash; Agarwal, Pooja; Ahmad, Hafsa; Raju, Kanumuri Siva Rama; Rashid, Mamunur; Wahajuddin, Muhammad; Srivastava, Kumkum; Haq, W.; Dwivedi, A. K.; Puri, S. K.

2016-01-01

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile. PMID:27956423

The association of antidepressant and statin use with death and incident cardiovascular disease varies by depression severity.

PubMed

May, Heidi T; Bair, Tami L; Reiss-Brennan, Brenda; Knight, Stacey; Anderson, Jeffrey L; Horne, Benjamin D; Brunisholz, Kimberly D; Muhlestein, Joseph B

2017-09-01

Depression has been reported to be associated with a greater risk of death and cardiovascular disease (CVD); however, the impact of antidepressants (ADM) on CVD risk remains controversial. Statin use is known to decrease CVD risk. Whether the use of these medications together affects CVD risk has not been studied. Patients (N = 26,828) completing the patient health questionnaire (PHQ-9), ≥40 years of age, without prior CVD, and no prior ADM use were studied. Depressive severity was categorized as none-mild (PHQ-9 score ≤14, n = 21,517) and moderate-severe (PHQ-9 score ≥15, n = 5311). Cox hazard regression was used to evaluate the association of no ADM/no statin use (n = 23,104 [86.1%]), ADM/no statin use (n = 877 [3.3%]), no ADM/statin use (n = 2627 [9.8%]), and ADM/statin use (n = 220 [.8%]) with major adverse cardiovascular events (MACE: death, CAD, stroke). Patients averaged 56 ± 12 years; 61% female. There were 1182 (4.4%) 3 year MACE events. The association of ADM and statin use with MACE varied by depressive symptom severity, with statin therapy associated with a decreased risk in the none-mild group (HR = .78, p = .007) and ADM in the moderate-high group (HR = 0.58, p = 0.02). Concomitant use of ADMs and statins did not appear to provide additive benefit.

In Vitro Investigation of Crosstalk between Fatty Acid and Polyketide Synthases in the Andrimid Biosynthetic Assembly Line.

PubMed

Ishikawa, Fumihiro; Sugimoto, Hiroyasu; Kakeya, Hideaki

2016-11-17

Andrimid (Adm) synthase, which belongs to the type II system of enzymes, produces Adm in Pantoea agglomerans. The adm biosynthetic gene cluster lacks canonical acyltransferases (ATs) to load the malonyl group to acyl carrier proteins (ACPs), thus suggesting that a malonyl-CoA ACP transacylase (MCAT) from the fatty acid synthase (FAS) complex provides the essential AT activity in Adm biosynthesis. Here we report that an MCAT is essential for catalysis of the transacylation of malonate from malonyl-CoA to AdmA polyketide synthase (PKS) ACP in vitro. Catalytic self-malonylation of AdmA (PKS ACP) was not observed in reactions without MCAT, although many type II PKS ACPs are capable of catalyzing self-acylation. This lack of self-malonylation was explained by amino acid sequence analysis of the AdmA PKS ACP and the type II PKS ACPs. The results show that MCAT from the organism's FAS complex can provide the missing AT activity in trans, thus suggesting a protein-protein interaction between the fatty acid and polyketide synthases in the Adm assembly line. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Scientific motivation for ADM/Aeolus mission

NASA Astrophysics Data System (ADS)

Källén, Erland

2018-04-01

The ADM/Aeolus wind lidar mission will provide a global coverage of atmospheric wind profiles. Atmospheric wind observations are required for initiating weather forecast models and for predicting and monitoring long term climate change. Improved knowledge of the global wind field is widely recognised as fundamental to advancing the understanding and prediction of weather and climate. In particular over tropical areas there is a need for better wind data leading to improved medium range (3-10 days) weather forecasts over the whole globe.

Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

PubMed

Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

2018-08-14

The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

DefenseLink Feature: Chairman Visits Japan and Republic of Korea, Nov. 5-8,

Science.gov Websites

Staff Navy Adm. Michael G. Mullen answers questions at a press availability with local media following Staff Navy Adm. Michael G. Mullen visits greets marines and staff assigned to the U.S. Embassy, Tokyo the Joint Chiefs of Staff U.S. Navy Adm. Michael G. Mullen, right, and Japanese Chief of Defense Adm

[Adrenomedullin--the link between the sympathetic nervous system activation and peripheral vasodilatation in some patients with vasovagal syncope].

PubMed

Gajek, Jacek; Zyśko, Dorota; Halawa, Bogumił

2004-09-01

Adrenomedullin (ADM) is a potent vasodilator playing role in regulation of central hemodynamic. The concentration of plasma ADM in healthy people increases under the influence of orthostatic stress. In patients with vasovagal syncope (VS) the changes in ADM concentration could be responsible either for syncope provocation or prevention. The aim of the study was to assess the influence of phase of the head-up tilt test (HUTT) in which the syncope occurred on the plasma concentration of ADM. The study was performed in 25 patients (pts) (18 women and 7 men), mean age 45.0+/-16.1 years with cardiodepressive reactions during HUTT according to the Italian protocol with nitroglycerine (NTG) provocation if necessary: Syncope was caused in 23 pts due to vasovagal reaction: in 17 pts syncope occurred after NTG provocation (group 1), and in 6 pts occurred in the passive phase of tilt (group 2a), in 2 pts due to dysautonomic reactions (group 2b). The head-up tilt test was performed according to ESC guidelines. The blood for ADM concentration was drawn after 30 min supine rest (ADM 1) and immediately after syncope (ADM 2). ADM level was measured using radioimmunological method. The results. In group 1 plasma level of ADM significantly decreased after the HUTT (3.2+/-3.4 vs 1.7+/-1,4 pg/0.1 ml; p<0.05) and in group 2a increased significantly (1.3+/-0.8 vs 2.7+/-1.3 pg/0.1 ml; p<0.05) comparing to baseline values. The ADM concentration did not differ between the groups in baseline conditions and was significantly higher after the syncope in group 2a (p<0.05). Conclusions. The excessive increase of ADM concentration during the passive phase of HUTT could play the causative role in pathogenesis of VS occurring early during the HUTT. In patients with VS after NTG provocation the decrease of ADM concentration can be the result of hemodynamic changes in the presence of vasodilating drug and may be the mechanism that could prevent the syncope.

Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis.

PubMed

Caironi, Pietro; Latini, Roberto; Struck, Joachim; Hartmann, Oliver; Bergmann, Andreas; Maggio, Giuseppe; Cavana, Marco; Tognoni, Gianni; Pesenti, Antonio; Gattinoni, Luciano; Masson, Serge

2017-08-01

The biological role of adrenomedullin (ADM), a hormone involved in hemodynamic homeostasis, is controversial in sepsis because administration of either the peptide or an antibody against it may be beneficial. Plasma biologically active ADM (bio-ADM) was assessed on days 1, 2, and 7 after randomization of 956 patients with sepsis or septic shock to albumin or crystalloids for fluid resuscitation in the multicenter Albumin Italian Outcome Sepsis trial. We tested the association of bio-ADM and its time-dependent variation with fluid therapy, vasopressor administration, organ failures, and mortality. Plasma bio-ADM on day 1 (median [Q1-Q3], 110 [59-198] pg/mL) was higher in patients with septic shock, associated with 90-day mortality, multiple organ failures and the average extent of hemodynamic support therapy (fluids and vasopressors), and serum lactate time course over the first week. Moreover, it predicted incident cardiovascular dysfunction in patients without shock at enrollment (OR [95% CI], 1.9 [1.4-2.5]; P < .0001, for an increase of 1 interquartile range of bio-ADM concentration). bio-ADM trajectory during the first week of treatment clearly predicted 90-day mortality after adjustment for clinically relevant covariates (hazard ratio [95% CI], 1.3 [1.2-1.4]; P < .0001), and its reduction below 110 pg/mL at day 7 was associated with a marked reduction in 90-day mortality. Changes over the first 7 days of bio-ADM concentrations were not dependent on albumin treatment. In patients with sepsis, the circulating, biologically active form of ADM may help individualizing hemodynamic support therapy, while avoiding harmful effects. Its possible pathophysiologic role makes bio-ADM a potential candidate for future targeted therapies. ClinicalTrials.gov; No.: NCT00707122. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation.

PubMed

Decker, Sebastian O; Sigl, Annette; Grumaz, Christian; Stevens, Philip; Vainshtein, Yevhen; Zimmermann, Stefan; Weigand, Markus A; Hofer, Stefan; Sohn, Kai; Brenner, Thorsten

2017-08-18

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% ( n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp.

Contextual influences on animal decision-making: Significance for behavior-based wildlife conservation and management.

PubMed

Owen, Megan A; Swaisgood, Ronald R; Blumstein, Daniel T

2017-01-01

Survival and successful reproduction require animals to make critical decisions amidst a naturally dynamic environmental and social background (i.e. "context"). However, human activities have pervasively, and rapidly, extended contextual variation into evolutionarily novel territory, potentially rendering evolved animal decision-making mechanisms and strategies maladaptive. We suggest that explicitly focusing on animal decision-making (ADM), by integrating and applying findings from studies of sensory ecology, cognitive psychology, behavioral economics and eco-evolutionary strategies, may enhance our understanding of, and our ability to predict how, human-driven changes in the environment and population demography will influence animal populations. Fundamentally, the decisions animals make involve evolved mechanisms, and behaviors emerge from the combined action of sensory integration, cognitive mechanisms and strategic rules of thumb, and any of these processes may have a disproportionate influence on behavior. Although there is extensive literature exploring ADM, it generally reflects a canalized, discipline-specific approach that lacks a unified conceptual framework. As a result, there has been limited application of ADM theory and research findings into predictive models that can enhance management outcomes, even though it is likely that the relative resilience of species to rapid environmental change is fundamentally a result of how ADM is linked to contextual variation. Here, we focus on how context influences ADM, and highlight ideas and results that may be most applicable to conservation biology. © 2016 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

Efficient traffic grooming in SONET/WDM BLSR Networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Awwal, A S; Billah, A B; Wang, B

2004-04-02

In this paper, we study traffic grooming in SONET/WDM BLSR networks under the uniform all-to-all traffic model with an objective to reduce total network costs (wavelength and electronic multiplexing costs), in particular, to minimize the number of ADMs while using the optimal number of wavelengths. We derive a new tighter lower bound for the number of wavelengths when the number of nodes is a multiple of 4. We show that this lower bound is achievable. All previous ADM lower bounds except perhaps that in were derived under the assumption that the magnitude of the traffic streams (r) is one unitmore » (r = 1) with respect to the wavelength capacity granularity g. We then derive new, more general and tighter lower bounds for the number of ADMs subject to that the optimal number of wavelengths is used, and propose heuristic algorithms (circle construction algorithm and circle grooming algorithm) that try to minimize the number of ADMs while using the optimal number of wavelengths in BLSR networks. Both the bounds and algorithms are applicable to any value of r and for different wavelength granularity g. Performance evaluation shows that wherever applicable, our lower bounds are at least as good as existing bounds and are much tighter than existing ones in many cases. Our proposed heuristic grooming algorithms perform very well with traffic streams of larger magnitude. The resulting number of ADMs required is very close to the corresponding lower bounds derived in this paper.« less

Increased genetic diversity of ADME genes in African Americans compared with their putative ancestral source populations and implications for Pharmacogenomics

PubMed Central

2014-01-01

Background African Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies. However, the contribution of European ancestry is expected to result in considerable differences in the genetic architecture of African American individuals compared with an African genome. In particular, the genetic admixture influences the genomic diversity of drug metabolism-related genes, and may cause high heterogeneity of drug responses in admixed populations such as African Americans. Results The genomic ancestry information of African-American (ASW) samples was obtained from data of the 1000 Genomes Project, and local ancestral components were also extracted for 32 core genes and 252 extended genes, which are associated with drug absorption, distribution, metabolism, and excretion (ADME) genes. As expected, the global genetic diversity pattern in ASW was determined by the contributions of its putative ancestral source populations, and the whole profiles of ADME genes in ASW are much closer to those in YRI than in CEU. However, we observed much higher diversity in some functionally important ADME genes in ASW than either CEU or YRI, which could be a result of either genetic drift or natural selection, and we identified some signatures of the latter. We analyzed the clinically relevant polymorphic alleles and haplotypes, and found that 28 functional mutations (including 3 missense, 3 splice, and 22 regulator sites) exhibited significantly higher differentiation between the three populations. Conclusions Analysis of the genetic diversity of ADME genes showed differentiation between admixed population and its ancestral source populations. In particular, the different genetic diversity between ASW and YRI indicated that the ethnic differences in pharmacogenomic studies are broadly existed despite that African ancestry is dominant in Africans Americans. This study should advance our understanding of the genetic basis of the drug response heterogeneity between populations, especially in the case of population admixture, and have significant implications for evaluating potential inter-population heterogeneity in drug treatment effects. PMID:24884825

Advanced Development Model (ADM) Program for the Shipboard Meteorological and Oceanographic Observing System (SMOOS).

DTIC Science & Technology

1986-05-20

SOURCE DOCUMENTS 1. N62269-84- R -0309 SHOOS Request for Proposal (RFP) 2. N62269-84-C-0309, SOOS Advanced Development Model (ADM) Contract 3. SA-TS-7833...b.n . II ii t .. ~ r 5* t **v *...to, $me$ d.v.... 0", tc htlo I . .. vtod. - BT 9S.td Fig. 3.5- Susse Funtina AlloatinMtri ittnits 0~~~~~~4. vii...LSyes T ttiL e Request To r Transmit 9 Upper Air II aaDspDatalay *S Ocear Sea Depth I71 dg I Dept Data3ttu tts Data Display Data Display Controller

ADM1-based methodology for the characterisation of the influent sludge in anaerobic reactors.

PubMed

Huete, E; de Gracia, M; Ayesa, E; Garcia-Heras, J L

2006-01-01

This paper presents a systematic methodology to characterise the influent sludge in terms of the ADM1 components from the experimental measurements traditionally used in wastewater engineering. For this purpose, a complete characterisation of the model components in their elemental mass fractions and charge has been used, making a rigorous mass balance for all the process transformations and enabling the future connection with other unit-process models. It also makes possible the application of mathematical algorithms for the optimal characterisation of several components poorly defined in the ADM1 report. Additionally, decay and disintegration have been necessarily uncoupled so that the decay proceeds directly to hydrolysis instead of producing intermediate composites. The proposed methodology has been applied to the particular experimental work of a pilot-scale CSTR treating real sewage sludge, a mixture of primary and secondary sludge. The results obtained have shown a good characterisation of the influent reflected in good model predictions. However, its limitations for an appropriate prediction of alkalinity and carbon percentages in biogas suggest the convenience of including the elemental characterisation of the process in terms of carbon in the analytical program.

Antidepressant medication use and glycaemic control in co-morbid type 2 diabetes and depression.

PubMed

Brieler, Jay A; Lustman, Patrick J; Scherrer, Jeffrey F; Salas, Joanne; Schneider, F David

2016-02-01

Depression is prevalent in diabetes and is associated with increased risks of hyperglycaemia, morbidity and mortality. The effect of antidepressant medication (ADM) on glycaemic control is uncertain owing to a paucity of relevant data. We sought to determine whether the use of ADM is associated with glycaemic control in depressed patients with type 2 diabetes. A retrospective cohort study (n = 1399) was conducted using electronic medical record registry data of ambulatory primary care visits from 2008 to 2013. Depression and type 2 diabetes were identified from ICD-9-CM codes; ADM use was determined from prescription orders; and glycaemic control was determined from measures of glycated haemoglobin (A1c). Good glycaemic control was defined as A1c < 7.0% (53 mmol/mol). Generalized estimating equations were used to determine the effect of depression and ADM use on glycaemic control. Good glycaemic control was achieved by 50.9% of depressed subjects receiving ADM versus 34.6% of depressed subjects without ADM. After adjusting for covariates, depressed patients receiving ADM were twice as likely as those not receiving ADM to achieve good glycaemic control (odds ratio = 1.95; 95% confidence interval: 1.02-3.71). In this retrospective cohort study of a large sample of primary care patients with type 2 diabetes, ADM use was associated with improved glycaemic control. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Low Dose PET Image Reconstruction with Total Variation Using Alternating Direction Method.

PubMed

Yu, Xingjian; Wang, Chenye; Hu, Hongjie; Liu, Huafeng

2016-01-01

In this paper, a total variation (TV) minimization strategy is proposed to overcome the problem of sparse spatial resolution and large amounts of noise in low dose positron emission tomography (PET) imaging reconstruction. Two types of objective function were established based on two statistical models of measured PET data, least-square (LS) TV for the Gaussian distribution and Poisson-TV for the Poisson distribution. To efficiently obtain high quality reconstructed images, the alternating direction method (ADM) is used to solve these objective functions. As compared with the iterative shrinkage/thresholding (IST) based algorithms, the proposed ADM can make full use of the TV constraint and its convergence rate is faster. The performance of the proposed approach is validated through comparisons with the expectation-maximization (EM) method using synthetic and experimental biological data. In the comparisons, the results of both LS-TV and Poisson-TV are taken into consideration to find which models are more suitable for PET imaging, in particular low-dose PET. To evaluate the results quantitatively, we computed bias, variance, and the contrast recovery coefficient (CRC) and drew profiles of the reconstructed images produced by the different methods. The results show that both Poisson-TV and LS-TV can provide a high visual quality at a low dose level. The bias and variance of the proposed LS-TV and Poisson-TV methods are 20% to 74% less at all counting levels than those of the EM method. Poisson-TV gives the best performance in terms of high-accuracy reconstruction with the lowest bias and variance as compared to the ground truth (14.3% less bias and 21.9% less variance). In contrast, LS-TV gives the best performance in terms of the high contrast of the reconstruction with the highest CRC.

Low Dose PET Image Reconstruction with Total Variation Using Alternating Direction Method

PubMed Central

Yu, Xingjian; Wang, Chenye; Hu, Hongjie; Liu, Huafeng

2016-01-01

In this paper, a total variation (TV) minimization strategy is proposed to overcome the problem of sparse spatial resolution and large amounts of noise in low dose positron emission tomography (PET) imaging reconstruction. Two types of objective function were established based on two statistical models of measured PET data, least-square (LS) TV for the Gaussian distribution and Poisson-TV for the Poisson distribution. To efficiently obtain high quality reconstructed images, the alternating direction method (ADM) is used to solve these objective functions. As compared with the iterative shrinkage/thresholding (IST) based algorithms, the proposed ADM can make full use of the TV constraint and its convergence rate is faster. The performance of the proposed approach is validated through comparisons with the expectation-maximization (EM) method using synthetic and experimental biological data. In the comparisons, the results of both LS-TV and Poisson-TV are taken into consideration to find which models are more suitable for PET imaging, in particular low-dose PET. To evaluate the results quantitatively, we computed bias, variance, and the contrast recovery coefficient (CRC) and drew profiles of the reconstructed images produced by the different methods. The results show that both Poisson-TV and LS-TV can provide a high visual quality at a low dose level. The bias and variance of the proposed LS-TV and Poisson-TV methods are 20% to 74% less at all counting levels than those of the EM method. Poisson-TV gives the best performance in terms of high-accuracy reconstruction with the lowest bias and variance as compared to the ground truth (14.3% less bias and 21.9% less variance). In contrast, LS-TV gives the best performance in terms of the high contrast of the reconstruction with the highest CRC. PMID:28005929

ATAMM enhancement and multiprocessor performance evaluation

NASA Technical Reports Server (NTRS)

Stoughton, John W.; Mielke, Roland R.; Som, Sukhamoy; Obando, Rodrigo; Malekpour, Mahyar R.; Jones, Robert L., III; Mandala, Brij Mohan V.

1991-01-01

ATAMM (Algorithm To Architecture Mapping Model) enhancement and multiprocessor performance evaluation is discussed. The following topics are included: the ATAMM model; ATAMM enhancement; ADM (Advanced Development Model) implementation of ATAMM; and ATAMM support tools.

Estimation of rate constants of PCB dechlorination reactions using an anaerobic dehalogenation model.

PubMed

Karakas, Filiz; Imamoglu, Ipek

2017-02-15

This study aims to estimate anaerobic dechlorination rate constants (k m ) of reactions of individual PCB congeners using data from four laboratory microcosms set up using sediment from Baltimore Harbor. Pathway k m values are estimated by modifying a previously developed model as Anaerobic Dehalogenation Model (ADM) which can be applied to any halogenated hydrophobic organic (HOC). Improvements such as handling multiple dechlorination activities (DAs) and co-elution of congeners, incorporating constraints, using new goodness of fit evaluation led to an increase in accuracy, speed and flexibility of ADM. DAs published in the literature in terms of chlorine substitutions as well as specific microorganisms and their combinations are used for identification of pathways. The best fit explaining the congener pattern changes was found for pathways of Phylotype DEH10, which has the ability to remove doubly flanked chlorines in meta and para positions, para flanked chlorines in meta position. The range of estimated k m values is between 0.0001-0.133d -1 , the median of which is found to be comparable to the few available published biologically confirmed rate constants. Compound specific modelling studies such as that performed by ADM can enable monitoring and prediction of concentration changes as well as toxicity during bioremediation. Copyright © 2016 Elsevier B.V. All rights reserved.

Insecticide ADME for support of early-phase discovery: combining classical and modern techniques.

PubMed

David, Michael D

2017-04-01

The two factors that determine an insecticide's potency are its binding to a target site (intrinsic activity) and the ability of its active form to reach the target site (bioavailability). Bioavailability is dictated by the compound's stability and transport kinetics, which are determined by both physical and biochemical characteristics. At BASF Global Insecticide Research, we characterize bioavailability in early research with an ADME (Absorption, Distribution, Metabolism and Excretion) approach, combining classical and modern techniques. For biochemical assessment of metabolism, we purify native insect enzymes using classical techniques, and recombinantly express individual insect enzymes that are known to be relevant in insecticide metabolism and resistance. For analytical characterization of an experimental insecticide and its metabolites, we conduct classical radiotracer translocation studies when a radiolabel is available. In discovery, where typically no radiolabel has been synthesized, we utilize modern high-resolution mass spectrometry to probe complex systems for the test compounds and its metabolites. By using these combined approaches, we can rapidly compare the ADME properties of sets of new experimental insecticides and aid in the design of structures with an improved potential to advance in the research pipeline. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Comparison of Laboratory Measured BCFs, BMFs, and BSAFs to Field Measured BAFs, BMFs, and BSAFs

EPA Science Inventory

A series of workshops on bioaccumulation science and issues have been held since 2005, and the foci of these past workshops were1) Bioaccumulation Data Sources, 2) In Vitro/ADME (absorption, distribution, metabolism, and excretion) in Bioaccumulation Assessments, and 3) Bioaccumu...

Prioritization of pharmaceuticals for potential environmental hazard through leveraging a large-scale mammalian pharmacological dataset.

PubMed

Berninger, Jason P; LaLone, Carlie A; Villeneuve, Daniel L; Ankley, Gerald T

2016-04-01

The potential for pharmaceuticals in the environment to cause adverse ecological effects is of increasing concern. Given the thousands of active pharmaceutical ingredients (APIs) that can enter the aquatic environment through human and/or animal (e.g., livestock) waste, a current challenge in aquatic toxicology is identifying those that pose the greatest risk. Because empirical toxicity information for aquatic species is generally lacking for pharmaceuticals, an important data source for prioritization is that generated during the mammalian drug development process. Applying concepts of species read-across, mammalian pharmacokinetic data were used to systematically prioritize APIs by estimating their potential to cause adverse biological consequences to aquatic organisms, using fish as an example. Mammalian absorption, distribution, metabolism, and excretion (ADME) data (e.g., peak plasma concentration, apparent volume of distribution, clearance rate, and half-life) were collected and curated, creating the Mammalian Pharmacokinetic Prioritization For Aquatic Species Targeting (MaPPFAST) database representing 1070 APIs. From these data, a probabilistic model and scoring system were developed and evaluated. Individual APIs and therapeutic classes were ranked based on clearly defined read-across assumptions for translating mammalian-derived ADME parameters to estimate potential hazard in fish (i.e., greatest predicted hazard associated with lowest mammalian peak plasma concentrations, total clearance and highest volume of distribution, half-life). It is anticipated that the MaPPFAST database and the associated API prioritization approach will help guide research and/or inform ecological risk assessment. Published 2015 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.

The influence of patients' preference/attitude towards psychotherapy and antidepressant medication on the treatment of major depressive disorder.

PubMed

Moradveisi, Latif; Huibers, Marcus; Renner, Fritz; Arntz, Arnoud

2014-03-01

Preferences and attitudes patients hold towards treatment are important, as these can influence treatment outcome. In depression research, the influence of patients' preference/attitudes on outcome and dropout has mainly been studied for antidepressant medication, and less for psychological treatments. We investigated the effects of patients' preference and attitudes towards psychological treatment and antidepressant medication on treatment outcome and dropout, and tested specificity of effects. Data are based on a randomized trial testing the effectiveness of behavioural activation (BA) vs antidepressant medication (ADM) for major depression (MDD) in Iran. Patients with MDD (N = 100) were randomized to BA (N = 50) or ADM (N = 50). Patients' preference/attitudes towards psychotherapy and ADM were assessed at baseline and associated with dropout and treatment outcome using logistic regression and multilevel analysis. High scores on psychotherapy preference/attitude and low scores on ADM preference/attitude predicted dropout from ADM, while no association between dropout and preference/attitude was found in BA. Psychotherapy preference/attitude moderated the differential effect of BA and ADM on one outcome measure, but the association disappeared after one year. Because in Iran most patients have only access to ADM, offering a psychological treatment for depression could attract especially those patients that prefer this newly available treatment. Patients' preferences and attitudes towards depression treatments influence dropout from ADM, and moderate the short-term difference in effectiveness between BA and ADM. The fact that dropout from BA was not affected by preference/attitude speaks for its acceptability among patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

Acellular dermal matrix for mucogingival surgery: a meta-analysis.

PubMed

Gapski, Ricardo; Parks, Christopher Allen; Wang, Hom-Lay

2005-11-01

Many clinical studies revealed the effectiveness of acellular dermal matrix (ADM) in the treatment of mucogingival defects. The purpose of this meta-analysis was to compare the efficacy of ADM-based root coverage (RC) and ADM-based increase in keratinized tissues to other commonly used mucogingival surgeries. Meta-analysis was limited to randomized clinical trials (RCT). Articles from January 1, 1990 to October 2004 related to ADM were searched utilizing the MEDLINE database from the National Library of Medicine, the Cochrane Oral Health Group Specialized Trials Registry, and through hand searches of reviews and recent journals. Relevant studies were identified, ranked independently, and mean data from each were weighted accordingly. Selected outcomes were analyzed using a meta-analysis software program. The significant estimates of the treatment effects from different trials were assessed by means of Cochrane's test of heterogeneity. 1) Few RCT studies were found to compile the data. In summary, selection identified eight RCT that met the inclusion criteria. There were four studies comparing ADM versus a connective tissue graft for root coverage procedures, two studies comparing ADM versus coronally advanced flap (CAF) for root coverage procedures, and two studies comparing ADM to free gingival graft in augmentation of keratinized tissue. 2) There were no statistically significant differences between groups for any of the outcomes measured (recession coverage, keratinized tissue formation, probing depths, and clinical attachment levels). 3) The majority of the analyses demonstrated moderate to high levels of heterogeneity. 4) Considering the heterogeneity values found among the studies, certain trends could be found: a) three out of four studies favored the ADM-RC group for recession coverage; b) a connective tissue graft tended to increase keratinized tissue compared to ADM (0.52-mm difference; P = 0.11); c) there were trends of increased clinical attachment gains comparing ADM to CAF procedures (0.56-mm difference; P = 0.16). Differences in study design and lack of data precluded an adequate and complete pooling of data for a more comprehensive analysis. Therefore, considering the trends presented in this study, there is a need for further randomized clinical studies of ADM procedures in comparison to common mucogingival surgical procedures to confirm our findings. It is difficult to draw anything other than tentative conclusions from this meta-analysis of ADM for mucogingival surgery, primarily because of the weakness in the design and reporting of existing trials.

ADMET in silico modelling: towards prediction paradise?

PubMed

van de Waterbeemd, Han; Gifford, Eric

2003-03-01

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

Biosynthesis of the acetyl‐CoA carboxylase‐inhibiting antibiotic, andrimid in Serratia is regulated by Hfq and the LysR‐type transcriptional regulator, AdmX

PubMed Central

Nogellova, Veronika; Morel, Bertrand; Krell, Tino

2016-01-01

Summary Infections due to multidrug‐resistant bacteria represent a major global health challenge. To combat this problem, new antibiotics are urgently needed and some plant‐associated bacteria are a promising source. The rhizobacterium Serratia plymuthica A153 produces several bioactive secondary metabolites, including the anti‐oomycete and antifungal haterumalide, oocydin A and the broad spectrum polyamine antibiotic, zeamine. In this study, we show that A153 produces a second broad spectrum antibiotic, andrimid. Using genome sequencing, comparative genomics and mutagenesis, we defined new genes involved in andrimid (adm) biosynthesis. Both the expression of the adm gene cluster and regulation of andrimid synthesis were investigated. The biosynthetic cluster is operonic and its expression is modulated by various environmental cues, including temperature and carbon source. Analysis of the genome context of the adm operon revealed a gene encoding a predicted LysR‐type regulator, AdmX, apparently unique to Serratia strains. Mutagenesis and gene expression assays demonstrated that AdmX is a transcriptional activator of the adm gene cluster. At the post‐transcriptional level, the expression of the adm cluster is positively regulated by the RNA chaperone, Hfq, in an RpoS‐independent manner. Our results highlight the complexity of andrimid biosynthesis – an antibiotic with potential clinical and agricultural utility. PMID:26914969

The effects of health sector market factors and vulnerable group membership on access to alcohol, drug, and mental health care.

PubMed

Stockdale, Susan E; Tang, Lingqi; Zhang, Lily; Belin, Thomas R; Wells, Kenneth B

2007-06-01

This study adapts Andersen's Behavioral Model to determine if health sector market conditions affect vulnerable subgroups' use of alcohol, drug, and mental health services (ADM) differently than the general population, focusing specifically on community-level predisposing and enabling characteristics. Wave 2 data (2000-2001) from the Health Care for Communities study, supplemented with cases from wave 1 (1997-1998), were merged with area characteristics taken from Census, Area Resource File (ARF), and other data sources. The study used four-level hierarchical logistic regression to examine access to ADM care from any provider and specialty ADM access. Interactions between community-level predisposing and enabling vulnerability characteristics with individual race/ethnicity, age, income category, and insurance type were explored. Nonwhites, the poor, uninsured, and elderly had lower likelihoods of service use, but interactions between race/ethnicity, income, age and insurance status with community-level vulnerability factors were not statistically significant for any service use. For ADM specialty care, those with Medicare, Medicaid, private fully managed, and private partially managed insurance, the likelihood of utilization was higher in areas with higher HMO penetration. However, for those with other insurance or no insurance plan, the likelihood of utilization was lower in areas with higher HMO penetration. Community-level enabling factors explain part of the effect of disadvantaged status but, with the exception of the effect of HMO penetration on the relationship between insurance and specialty care use, do not modify any of the residual individual-level effects of disadvantage. Interventions targeting both structural and individual levels may be necessary to address the problem of health disparities. More research with longitudinal data is necessary to sort out the causal direction of social context and ADM access outcomes, and whether policy interventions to change health sector market conditions can shift ADM treatment utilization.

Magnetic shielding and vacuum test for passive hydrogen masers

NASA Technical Reports Server (NTRS)

Gubser, D. U.; Wolf, S. A.; Jacoby, A. B.; Jones, L. D.

1982-01-01

Vibration tests on high permeability magnetic shields used in the SAO-NRL Advanced Development Model (ADM) hydrogen maser were made. Magnetic shielding factors were measured before and after vibration. Preliminary results indicate considerable (25%) degradation. Test results on the NRL designed vacuum pumping station for the ADM hydrogen maser are also discussed. This system employs sintered zirconium carbon getter pumps to pump hydrogen plus small ion pumps to pump the inert gases. In situ activation tests and pumping characteristics indicate that the system can meet design specifications.

Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock—Results of a Combined Clinical and Experimental Investigation

PubMed Central

Decker, Sebastian O.; Sigl, Annette; Grumaz, Christian; Stevens, Philip; Vainshtein, Yevhen; Zimmermann, Stefan; Weigand, Markus A.; Hofer, Stefan; Sohn, Kai; Brenner, Thorsten

2017-01-01

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% (n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp. PMID:28820494

A modeling approach to describe ZVI-based anaerobic system.

PubMed

Xiao, Xiao; Sheng, Guo-Ping; Mu, Yang; Yu, Han-Qing

2013-10-15

Zero-valent iron (ZVI) is increasingly being added into anaerobic reactors to enhance the biological conversion of various less biodegradable pollutants (LBPs). Our study aimed to establish a new structure model based on the Anaerobic Digestion Model No. 1 (ADM1) to simulate such a ZVI-based anaerobic reactor. Three new processes, i.e., electron release from ZVI corrosion, H2 formation from ZVI corrosion, and transformation of LBPs, were integrated into ADM1. The established model was calibrated and tested using the experimental data from one published study, and validated using the data from another work. A good relationship between the predicted and measured results indicates that the proposed model was appropriate to describe the performance of the ZVI-based anaerobic system. Our model could provide more precise strategies for the design, development, and application of anaerobic systems especially for treating various LBPs-containing wastewaters. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pilot-in-the-Loop CFD Method Development

DTIC Science & Technology

2015-02-01

expensive alternatives [1]. ALM represents the blades as a set of segments along with each blade axis and the ADM represents the entire rotor as...fine grid, Δx = 1.00 m Figure 4 – Time-averaged vertical velocity distributions on downwash and rotor disk plane for hybrid and loose coupling...cases with fine and coarse grid refinement levels. Figure 4 shows the time-averaged distributions of vertical velocities on both downwash and rotor disk

The statistical evaluation and comparison of ADMS-Urban model for the prediction of nitrogen dioxide with air quality monitoring network.

PubMed

Dėdelė, Audrius; Miškinytė, Auksė

2015-09-01

In many countries, road traffic is one of the main sources of air pollution associated with adverse effects on human health and environment. Nitrogen dioxide (NO2) is considered to be a measure of traffic-related air pollution, with concentrations tending to be higher near highways, along busy roads, and in the city centers, and the exceedances are mainly observed at measurement stations located close to traffic. In order to assess the air quality in the city and the air pollution impact on public health, air quality models are used. However, firstly, before the model can be used for these purposes, it is important to evaluate the accuracy of the dispersion modelling as one of the most widely used method. The monitoring and dispersion modelling are two components of air quality monitoring system (AQMS), in which statistical comparison was made in this research. The evaluation of the Atmospheric Dispersion Modelling System (ADMS-Urban) was made by comparing monthly modelled NO2 concentrations with the data of continuous air quality monitoring stations in Kaunas city. The statistical measures of model performance were calculated for annual and monthly concentrations of NO2 for each monitoring station site. The spatial analysis was made using geographic information systems (GIS). The calculation of statistical parameters indicated a good ADMS-Urban model performance for the prediction of NO2. The results of this study showed that the agreement of modelled values and observations was better for traffic monitoring stations compared to the background and residential stations.

Repair of Primary Cleft Palate and Oronasal Fistula With Acellular Dermal Matrix: A Systematic Review and Surgeon Survey.

PubMed

Simpson, Andrew; Samargandi, Osama A; Wong, Alison; Graham, M Elise; Bezuhly, Michael

2018-01-01

The current review and survey aim to assess the effectiveness of acellular dermal matrix (ADM) in the repair of cleft palate and oronasal fistula and to evaluate the current trends of ADM use in palate surgery. A systematic review of English articles was conducted using MEDLINE (1960 to July 1, 2016), the Cochrane Controlled Trials Register (1960 to July 1, 2016), and EMBASE (1991 to July 1, 2016). Additional studies were identified through a review of references cited in initially identified articles. Search terms included "cleft palate," "palatal," "oronasal fistula," "acellular dermal matrix," and "Alloderm®." An online survey was disseminated to members of the American Cleft Palate-Craniofacial Association to assess current trends in ADM use in palate surgery. All studies evaluating the outcome of primary palate repair or repair of oronasal fistula with the use of aceullar dermal matrix products were included in the review. Twelve studies met inclusion criteria for review. Studies were generally of low quality, as indicated by methodological index for non-randomized studies (MINORS) scores ranging from 7 to 14. The pooled estimate for fistula formation after primary palatoplasty following ADM use was 7.1%. The pooled estimate for recurrence of fistula after attempted repair using ADM was 11%. Thirty-six cleft surgeons responded to the online survey study. Of these, 45% used ADM in primary cleft palate repair, while 67% used ADM for repair of oronasal fistulae. Use of ADM products is commonplace in palate surgery. Despite this, there is a paucity of high-quality data demonstrating benefit. Further randomized controlled trials examining ADM in palate surgery are required to help develop structured guidelines and improve care.

Depressive symptoms, antidepressant medication use, and new onset of diabetes in participants of the diabetes prevention program and the diabetes prevention program outcomes study.

PubMed

Marrero, David G; Ma, Yong; de Groot, Mary; Horton, Edward S; Price, David W; Barrett-Connor, Elizabeth; Carnethon, Mercedes R; Knowler, William C

2015-04-01

To assess in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study whether diagnosis of diabetes predicted elevated depressive symptoms (DS) or use of antidepressant medicine (ADM) following diagnosis; whether diabetes status or duration had significant effect on DS or ADM use; and to determine the associations between A1C, fasting plasma glucose (FPG), normalization of FPG, and DS or ADM use after diagnosis. Diabetes Prevention Program participants in three treatment arms (intensive life style, metformin, placebo) were assessed for diabetes, glucose control, ADM use, and DS, measured using the Beck Depression Inventory (BDI). Among 3234 participants, 1285 developed diabetes. Depression levels were measured before and after diabetes diagnosis. Neither DS nor use of ADM increased after diagnosis; higher FPG was associated with greater ADM use in the intensive life style arm; a 10-mg/dl rise in FPG is associated with greater odds of ADM use. Higher FPG and A1C were associated with higher BDI scores in all three arms; A 10-mg/dl rise in FPG had a 0.07 increase in BDI. A 1% higher A1c was associated with a 0.21-point increase in BDI. Normalization of FPG was associated with lower BDI. When FPG had normalized, there was a decrease of 0.30 points in the BDI score compared when FPG had not normalized. Contrary to clinical attributions, diabetes diagnosis did not show an immediate impact on BDI scores or ADM use. Higher glucose levels after diagnosis were associated with a small but significantly higher BDI score and more ADM use. DPPOS: NCT00038727; DPP: NCT00004992.

The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review.

PubMed

Schuetz, Philipp; Marlowe, Robert J; Mueller, Beat

2015-03-01

Plasma proadrenomedullin (ProADM) is a blood biomarker that may aid in multidimensional risk assessment of patients with chronic obstructive pulmonary disease (COPD). Co-secreted 1:1 with adrenomedullin (ADM), ProADM is a less biologically active, more chemically stable surrogate for this pluripotent regulatory peptide, which due to biological and ex vivo physical characteristics is difficult to reliably directly quantify. Upregulated by hypoxia, inflammatory cytokines, bacterial products, and shear stress and expressed widely in pulmonary cells and ubiquitously throughout the body, ADM exerts or mediates vasodilatory, natriuretic, diuretic, antioxidative, anti-inflammatory, antimicrobial, and metabolic effects. Observational data from four separate studies totaling 1366 patients suggest that as a single factor, ProADM is a significant independent, and accurate, long-term all-cause mortality predictor in COPD. This body of work also suggests that combined with different groups of demographic/clinical variables, ProADM provides significant incremental long-term mortality prediction power relative to the groups of variables alone. Additionally, the literature contains indications that ProADM may be a global cardiopulmonary stress marker, potentially supplying prognostic information when cardiopulmonary exercise testing results such as 6-min walk distance are unavailable due to time or other resource constraints or to a patient's advanced disease. Prospective, randomized, controlled interventional studies are needed to demonstrate whether ProADM use in risk-based guidance of site-of-care, monitoring, and treatment decisions improves clinical, quality-of-life, or pharmacoeconomic outcomes in patients with COPD.

Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline

USDA-ARS?s Scientific Manuscript database

Mitragyna speciosa (Kratom) is a popular herb in Southeast Asia which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine and mitraphylline are reported to be the central nervous system (CNS) active alkaloids which bind to the opiat...

Multifunctional Information Distribution System (MIDS)

DTIC Science & Technology

2015-12-01

UNCLASSIFIED 2 Table of Contents Common Acronyms and Abbreviations for MDAP Programs 3 Program Information 5 Responsible Office 5...Contracts 77 Deliveries and Expenditures 84 Operating and Support Cost 85 Common Acronyms and Abbreviations for MDAP Programs Acq O&M...Acquisition-Related Operations and Maintenance ACAT - Acquisition Category ADM - Acquisition Decision Memorandum APB - Acquisition Program Baseline

Identification of Absorption, Distribution, Metabolism, and Excretion (ADME) Genes Relevant to Steatosis Using a Systems Biology Approach

EPA Science Inventory

Ensuring chemical safety and sustainability form a main priority of the U.S. Environmental Protection Agency. This entails efforts on multiple fronts to characterize the potential hazard posed by chemicals currently in use and those to be commercialized in the future. The use of ...

Sensitivity of predicted bioaerosol exposure from open windrow composting facilities to ADMS dispersion model parameters.

PubMed

Douglas, P; Tyrrel, S F; Kinnersley, R P; Whelan, M; Longhurst, P J; Walsh, K; Pollard, S J T; Drew, G H

2016-12-15

Bioaerosols are released in elevated quantities from composting facilities and are associated with negative health effects, although dose-response relationships are not well understood, and require improved exposure classification. Dispersion modelling has great potential to improve exposure classification, but has not yet been extensively used or validated in this context. We present a sensitivity analysis of the ADMS dispersion model specific to input parameter ranges relevant to bioaerosol emissions from open windrow composting. This analysis provides an aid for model calibration by prioritising parameter adjustment and targeting independent parameter estimation. Results showed that predicted exposure was most sensitive to the wet and dry deposition modules and the majority of parameters relating to emission source characteristics, including pollutant emission velocity, source geometry and source height. This research improves understanding of the accuracy of model input data required to provide more reliable exposure predictions. Copyright © 2016. Published by Elsevier Ltd.

Integrated control strategy for autonomous decentralized conveyance systems based on distributed MEMS arrays

NASA Astrophysics Data System (ADS)

Zhou, Lingfei; Chapuis, Yves-Andre; Blonde, Jean-Philippe; Bervillier, Herve; Fukuta, Yamato; Fujita, Hiroyuki

2004-07-01

In this paper, the authors proposed to study a model and a control strategy of a two-dimensional conveyance system based on the principles of the Autonomous Decentralized Microsystems (ADM). The microconveyance system is based on distributed cooperative MEMS actuators which can produce a force field onto the surface of the device to grip and move a micro-object. The modeling approach proposed here is based on a simple model of a microconveyance system which is represented by a 5 x 5 matrix of cells. Each cell is consisted of a microactuator, a microsensor, and a microprocessor to provide actuation, autonomy and decentralized intelligence to the cell. Thus, each cell is able to identify a micro-object crossing on it and to decide by oneself the appropriate control strategy to convey the micro-object to its destination target. The control strategy could be established through five simple decision rules that the cell itself has to respect at each calculate cycle time. Simulation and FPGA implementation results are given in the end of the paper in order to validate model and control approach of the microconveyance system.

Iron-catalysed tritiation of pharmaceuticals

NASA Astrophysics Data System (ADS)

Pony Yu, Renyuan; Hesk, David; Rivera, Nelo; Pelczer, István; Chirik, Paul J.

2016-01-01

A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process—ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials—to elucidate a drug molecule’s metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct 3H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.

Alloplastic adjuncts in breast reconstruction

PubMed Central

Cabalag, Miguel S.; Rostek, Marie; Miller, George S.; Chae, Michael P.; Quinn, Tam; Rozen, Warren M.

2016-01-01

Background There has been an increasing role of acellular dermal matrices (ADMs) and synthetic meshes in both single- and two-stage implant/expander breast reconstruction. Numerous alloplastic adjuncts exist, and these vary in material type, processing, storage, surgical preparation, level of sterility, available sizes and cost. However, there is little published data on most, posing a significant challenge to the reconstructive surgeon trying to compare and select the most suitable product. The aims of this systematic review were to identify, summarize and evaluate the outcomes of studies describing the use of alloplastic adjuncts for post-mastectomy breast reconstruction. The secondary aims were to determine their cost-effectiveness and analyze outcomes in patients who also underwent radiotherapy. Methods Using the PRSIMA 2009 statement, a systematic review was conducted to find articles reporting on the outcomes on the use of alloplastic adjuncts in post-mastectomy breast reconstruction. Multiple databases were searched independently by three authors (Cabalag MS, Miller GS and Chae MP), including: Ovid MEDLINE (1950 to present), Embase (1980 to 2015), PubMed and Cochrane Database of Systematic Reviews. Results Current published literature on available alloplastic adjuncts are predominantly centered on ADMs, both allogeneic and xenogeneic, with few outcome studies available for synthetic meshes. Outcomes on the 89 articles, which met the inclusion criteria, were summarized and analyzed. The reported outcomes on alloplastic adjunct-assisted breast reconstruction were varied, with most data available on the use of ADMs, particularly AlloDerm® (LifeCell, Branchburg, New Jersey, USA). The use of ADMs in single-stage direct-to-implant breast reconstruction resulted in lower complication rates (infection, seroma, implant loss and late revision), and was more cost effective when compared to non-ADM, two-stage reconstruction. The majority of studies demonstrated inferior outcomes in ADM assisted, two-stage expander-to-implant reconstruction compared to non-ADM use. Multiple studies suggest that the use of ADMs results in a reduction of capsular contracture rates. Additionally, the reported beneficial effects of ADM use in irradiated tissue were varied. Conclusions ADM assisted two-stage breast reconstruction was associated with inferior outcomes when compared to non-ADM use. However, alloplastic adjuncts may have a role in single stage, direct-to-implant breast reconstruction. Published evidence comparing the long-term outcomes between the different types of adjuncts is lacking, and further level one studies are required to identify the ideal product. PMID:27047784

Prediction of anaerobic biodegradability and bioaccessibility of municipal sludge by coupling sequential extractions with fluorescence spectroscopy: towards ADM1 variables characterization.

PubMed

Jimenez, Julie; Gonidec, Estelle; Cacho Rivero, Jesús Andrés; Latrille, Eric; Vedrenne, Fabien; Steyer, Jean-Philippe

2014-03-01

Advanced dynamic anaerobic digestion models, such as ADM1, require both detailed organic matter characterisation and intimate knowledge of the involved metabolic pathways. In the current study, a methodology for municipal sludge characterization is investigated to describe two key parameters: biodegradability and bioaccessibility of organic matter. The methodology is based on coupling sequential chemical extractions with 3D fluorescence spectroscopy. The use of increasingly strong solvents reveals different levels of organic matter accessibility and the spectroscopy measurement leads to a detailed characterisation of the organic matter. The results obtained from testing 52 municipal sludge samples (primary, secondary, digested and thermally treated) showed a successful correlation with sludge biodegradability and bioaccessibility. The two parameters, traditionally obtained through the biochemical methane potential (BMP) lab tests, are now obtain in only 5 days compared to the 30-60 days usually required. Experimental data, obtained from two different laboratory scale reactors, were used to validate the ADM1 model. The proposed approach showed a strong application potential for reactor design and advanced control of anaerobic digestion processes. Copyright © 2013 Elsevier Ltd. All rights reserved.

A workflow to investigate exposure and pharmacokinetic ...

EPA Pesticide Factsheets

Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption, distribution, metabolism, excretion (ADME) properties of chemicals. We developed a conceptual workflow to consider exposure and ADME properties in relationship to an MIE and demonstrated the utility of this workflow using a previously established AOP, acetylcholinesterase (AChE) inhibition. Thirty active chemicals found to inhibit AChE in the ToxCastTM assay were examined with respect to their exposure and absorption potentials, and their ability to cross the blood-brain barrier. Structural similarities of active compounds were compared against structures of inactive compounds to detect possible non-active parents that might have active metabolites. Fifty-two of the 1,029 inactive compounds exhibited a similarity threshold above 75% with their nearest active neighbors. Excluding compounds that may not be absorbed, 22 could be potentially toxic following metabolism. The incorporation of exposure and ADME properties into the conceptual workflow resulted in prioritization of 20 out of 30 active compounds identified in an AChE inhibition assay for further analysis, along with identification of several inactive parent compounds of active metabolites. This qualitative approach can minimize co

Large eddy simulation of orientation and rotation of ellipsoidal particles in isotropic turbulent flows

NASA Astrophysics Data System (ADS)

Chen, Jincai; Jin, Guodong; Zhang, Jian

2016-03-01

The rotational motion and orientational distribution of ellipsoidal particles in turbulent flows are of significance in environmental and engineering applications. Whereas the translational motion of an ellipsoidal particle is controlled by the turbulent motions at large scales, its rotational motion is determined by the fluid velocity gradient tensor at small scales, which raises a challenge when predicting the rotational dispersion of ellipsoidal particles using large eddy simulation (LES) method due to the lack of subgrid scale (SGS) fluid motions. We report the effects of the SGS fluid motions on the orientational and rotational statistics, such as the alignment between the long axis of ellipsoidal particles and the vorticity, the mean rotational energy at various aspect ratios against those obtained with direct numerical simulation (DNS) and filtered DNS. The performances of a stochastic differential equation (SDE) model for the SGS velocity gradient seen by the particles and the approximate deconvolution method (ADM) for LES are investigated. It is found that the missing SGS fluid motions in LES flow fields have significant effects on the rotational statistics of ellipsoidal particles. Alignment between the particles and the vorticity is weakened; and the rotational energy of the particles is reduced in LES. The SGS-SDE model leads to a large error in predicting the alignment between the particles and the vorticity and over-predicts the rotational energy of rod-like particles. The ADM significantly improves the rotational energy prediction of particles in LES.

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639

PubMed Central

2015-01-01

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat. PMID:26101566

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

PubMed

Zhang, Qingwei; Xia, Zhiren; Joshi, Shailen; Scott, Victoria E; Jarvis, Michael F

2015-06-11

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat.

Modelling anaerobic digestion acclimatisation to a biodegradable toxicant: application to cyanide.

PubMed

Zaher, U; Moussa, M S; Widyatmika, I N; van Der Steen, P; Gijzen, H J; Vanrolleghem, P A

2006-01-01

The observed acclimatisation to biodegradable toxicants in anaerobic cassava wastewater treatment is explained by modelling anaerobic cyanide degradation. A complete degradation pathway is proposed for cyanide. Cyanide degradation is modelled as enzymatic hydrolysis to formate and ammonia. Ammonia is added to the inorganic nitrogen content of the digester while formate is degraded by the hydrogenotrophic methanogens. Cyanide irreversible enzyme inhibition is modelled as an inhibition factor to acetate uptake processes. Cyanide irreversible toxicity is modelled as a decay factor to the acetate degraders. Cyanide as well as added phosphorus buffer solution were considered in the chemical equilibrium calculations of pH. The observed reversible effect after acclimatisation of sludge is modelled by a population shift between two aceticlastic methanogens that have different tolerance to cyanide toxicity. The proposed pathway is added to the IWA Anaerobic Digestion Model no.1 (ADM1). The ADM1 model with the designed extension is validated by an experiment using three lab-scale upflow anaerobic sludge bed reactors which were exposed to different cyanide loadings.

Adrenomedullin increased the short-circuit current in the pig oviduct through chloride channels via the CGRP receptor: mediation by cAMP and calcium ions but not by nitric oxide.

PubMed

Liao, S B; Cheung, K H; Cheung, M P L; To, Y T; O, W S; Tang, F

2013-10-01

The oviduct serves as a site for the fertilization of the ovum and the transport of the conceptus down to the uterus for implantation. In this study, we investigated the presence of adrenomedullin (ADM) and its receptor component proteins in the pig oviduct. The effect of ADM on oviductal secretion, the specific receptor, and the mechanisms involved were also investigated. The presence of ADM and its receptor component proteins in the pig oviduct were confirmed using immunostaining. Short-circuit current (I(sc)) technique was employed to study chloride ion secretion in the oviductal epithelium. ADM increased I(sc) through cAMP- and calcium-activated chloride channels, and this effect could be inhibited by the CGRP receptor antagonist, hCGRP8-37. In contrast, the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME), could not block the effect of ADM on I(sc). In summary, ADM may increase oviductal fluid secretion via chloride secretion independent of the nitric oxide pathway for the transport of sperm and the conceptus.

Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

NASA Astrophysics Data System (ADS)

Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C.; Crawford, Howard C.; Fields, Alan P.; Murray, Nicole R.; Wang, Q. Jane; Leitges, Michael; Storz, Peter

2015-02-01

The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

Comparison of minipig, dog, monkey and human drug metabolism and disposition.

PubMed

Dalgaard, Lars

2015-01-01

This article gives an overview of the drug metabolism and disposition (ADME) characteristics of the most common non-rodent species used in toxicity testing of drugs (minipigs, dogs, and monkeys) and compares these to human characteristics with regard to enzymes mediating the metabolism of drugs and the transport proteins which contribute to the absorption, distribution and excretion of drugs. Literature on ADME and regulatory guidelines of relevance in drug development of small molecules has been gathered. Non-human primates (monkeys) are the species that is closest to humans in terms of genetic homology. Dogs have an advantage due to the ready availability of comprehensive background data for toxicological safety assessment and dogs are easy to handle. Pigs have been used less than dogs and monkeys as a model in safety assessment of drug candidates. However, when a drug candidate is metabolised by aldehyde oxidase (AOX1), N-acetyltransferases (NAT1 and NAT2) or cytochrome (CYP2C9-like) enzymes which are not expressed in dogs, but are present in pigs, this species may be a better choice than dogs, provided that adequate exposure can be obtained in pigs. Conversely, pigs might not be the right choice if sulfation, involving 3-phospho-adenosyl-5-phosphosulphate sulphotransferase (PAPS) is an important pathway in the human metabolism of a drug candidate. In general, the species selection should be based on comparison between in vitro studies with human cell-based systems and animal-cell-based systems. Results from pharmacokinetic studies are also important for decision-making by establishing the obtainable exposure level in the species. Access to genetically humanized mouse models and highly sensitive analytical methods (accelerator mass spectrometry) makes it possible to improve the chance of finding all metabolites relevant for humans before clinical trials have been initiated and, if necessary, to include another animal species before long term toxicity studies are initiated. In conclusion, safety testing can be optimized by applying knowledge about species ADME differences and utilising advanced analytical techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

Anaerobic Digestion Model No. 1 Simulation of High Solids Anaerobic Digestion with Feasibility Study for El Gabal El Asfar Water Resource Recovery Facility.

PubMed

Aboulfotoh, Ahmed M

2018-03-01

  Performance of continuous mesophilic high solids anaerobic digestion (HSAD) was simulated using Anaerobic Digestion Model No. 1 (ADM1), under different conditions (solids concentrations, sludge retention time (SRT), organic loading rate (OLR), and type of sludge). Implementation of ADM1, using the proposed biochemical parameters, proved to be a useful tool for the prediction and control of HSAD as the model predicted the behavior of the tested sets of data with considerable accuracy, especially for SRT more than 13 days. The model was then used to investigate the possibility of changing the existing conventional anaerobic digestion (CAD) units in Gabal El Asfar water resource recovery facility into HSAD, instead of establishing new CAD units, and results show that the system will be feasible. HSAD will produce the same bioenergy combined with a decrease in capital, operational, and maintenance costs.

Depressive symptoms, antidepressant medication use and new onset of diabetes in participants of the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study

PubMed Central

Marrero, David G.; Ma, Yong; de Groot, Mary; Horton, Edward S.; Price, David W.; Barrett-Connor, Elizabeth; Carnethon, Mercedes R.; Knowler, William C.

2015-01-01

Objective To assess in participants in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study (DPP/DPPOS) whether diagnosis of diabetes predicted: elevated depressive symptoms (DS) or antidepressant medicine (ADM) use after diagnosis; diabetes status or duration had significant effect on DS or ADM use; and associations between A1C, fasting plasma glucose (FPG), normalization of FPG and DS or ADM use post diagnosis. Methods DPP participants in 3 treatment arms [intensive lifestyle (ILS), metformin (MET), placebo (PLC)] were assessed semiannually or annually for diabetes, glucose control, ADM use, and DS. DS was measured using Beck Depression Inventory (BDI) questionnaire. Among the total 3234 enrolled participants, 1285 developed diabetes whose levels of depression were measured before and after their diabetes diagnosis. Results Neither DS nor ADM use increased significantly following diabetes diagnosis. After diabetes diagnosis, higher FPG was associated with greater ADM use in the ILS arm independent of potential confounders; a 10 mg/dl higher in FPG is associated with 8.8% more odds of ADM use. Higher FPG, and higher A1C were associated with higher BDI scores in all three arms. On average, a participant with 10 mg/dl higher rise in FPG had a 0.07 increase in BDI score. Similarly, 1% higher A1c was associated with a 0.21 point increase in BDI score. On contrary, normalization of FPG was associated with lower BDI scores. In participants with FPG that had normalized, there was a decrease of 0.30 points in the BDI score compared to those whose FPG had not normalized. Conclusions Contrary to clinical attributions, the diagnosis of diabetes did not show an immediate impact on BDI scores or ADM use. However, higher glucose levels after diagnosis were associated with small but significant higher BDI score and more ADM use. PMID:25775165

[Prevention of adriamycin-induced alopecia by scalp hypothermia with a deep-frozen Duncool-Cap].

PubMed

Konishi, Y; Kuroki, T

1988-11-01

In order to prevent Adriamycin (ADM)-induced alopecia, scalp hypothermia with a Duncool-Cap frozen in a freezer at -70 degrees C was carried out. Of the 18 patients studied, one patient given total ADM doses of 240 mg developed alopecia of moderate degree, and another patient treated with ADM at a dose level of 50 mg developed mild alopecia. Alopecia could be almost completely prevented in 10 of the 11 patients given total ADM doses of 100 mg or less, and in 6 of the 7 patients given total doses of 200 mg or more.

Wavelets and Multifractal Analysis

DTIC Science & Technology

2004-07-01

distribution unlimited 13. SUPPLEMENTARY NOTES See also ADM001750, Wavelets and Multifractal Analysis (WAMA) Workshop held on 19-31 July 2004., The original...f)] . . . 16 2.5.4 Detrended Fluctuation Analysis [DFA(m)] . . . . . . . . . . . . . . . 17 2.6 Scale-Independent Measures...18 2.6.1 Detrended -Fluctuation- Analysis Power-Law Exponent (αD) . . . . . . 18 2.6.2 Wavelet-Transform Power-Law Exponent

Reducing the Anaerobic Digestion Model No. 1 for its application to an industrial wastewater treatment plant treating winery effluent wastewater.

PubMed

García-Diéguez, Carlos; Bernard, Olivier; Roca, Enrique

2013-03-01

The Anaerobic Digestion Model No. 1 (ADM1) is a complex model which is widely accepted as a common platform for anaerobic process modeling and simulation. However, it has a large number of parameters and states that hinder its calibration and use in control applications. A principal component analysis (PCA) technique was extended and applied to simplify the ADM1 using data of an industrial wastewater treatment plant processing winery effluent. The method shows that the main model features could be obtained with a minimum of two reactions. A reduced stoichiometric matrix was identified and the kinetic parameters were estimated on the basis of representative known biochemical kinetics (Monod and Haldane). The obtained reduced model takes into account the measured states in the anaerobic wastewater treatment (AWT) plant and reproduces the dynamics of the process fairly accurately. The reduced model can support on-line control, optimization and supervision strategies for AWT plants. Copyright © 2013 Elsevier Ltd. All rights reserved.

Modified ADM1 disintegration/hydrolysis structures for modeling batch thermophilic anaerobic digestion of thermally pretreated waste activated sludge.

PubMed

Ramirez, Ivan; Mottet, Alexis; Carrère, Hélène; Déléris, Stéphane; Vedrenne, Fabien; Steyer, Jean-Philippe

2009-08-01

Anaerobic digestion disintegration and hydrolysis have been traditionally modeled according to first-order kinetics assuming that their rates do not depend on disintegration/hydrolytic biomass concentrations. However, the typical sigmoid-shape increase in time of the disintegration/hydrolysis rates cannot be described with first-order models. For complex substrates, first-order kinetics should thus be modified to account for slowly degradable material. In this study, a slightly modified IWA ADM1 model is presented to simulate thermophilic anaerobic digestion of thermally pretreated waste activated sludge. Contois model is first included for disintegration and hydrolysis steps instead of first-order kinetics and Hill function is then used to model ammonia inhibition of aceticlastic methanogens instead of a non-competitive function. One batch experimental data set of anaerobic degradation of a raw waste activated sludge is used to calibrate the proposed model and three additional data sets from similar sludge thermally pretreated at three different temperatures are used to validate the parameters values.

Mindfulness-Based Cognitive Therapy to Prevent Relapse in Recurrent Depression

ERIC Educational Resources Information Center

Kuyken, Willem; Byford, Sarah; Taylor, Rod S.; Watkins, Ed; Holden, Emily; White, Kat; Barrett, Barbara; Byng, Richard; Evans, Alison; Mullan, Eugene; Teasdale, John D.

2008-01-01

For people at risk of depressive relapse, mindfulness-based cognitive therapy (MBCT) has an additive benefit to usual care (H. F. Coelho, P. H. Canter, & E. Ernst, 2007). This study asked if, among patients with recurrent depression who are treated with antidepressant medication (ADM), MBCT is comparable to treatment with maintenance ADM (m-ADM)…

Effect of Cognitive Therapy With Antidepressant Medications vs Antidepressants Alone on the Rate of Recovery in Major Depressive Disorder

PubMed Central

Hollon, Steven D.; DeRubeis, Robert J.; Fawcett, Jan; Amsterdam, Jay D.; Shelton, Richard C.; Zajecka, John; Young, Paula R.; Gallop, Robert

2015-01-01

IMPORTANCE Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone. OBJECTIVE To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved. INTERVENTIONS Antidepressant medication with or without CT. MAIN OUTCOMES AND MEASURES Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation. RESULTS Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6% vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95% CI, 1.06–1.68; number needed to treat [NNT], 10; 95% CI, 5–72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3% vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95% CI, 1.54–3.57; NNT, 3; 95% CI, 2–5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9% vs 26.8%; t451 = −2.04; P = .04; HR, 0.66; 95% CI, 0.45–0.98). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode. CONCLUSIONS AND RELEVANCE Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00057577 PMID:25142196

Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial.

PubMed

Hollon, Steven D; DeRubeis, Robert J; Fawcett, Jan; Amsterdam, Jay D; Shelton, Richard C; Zajecka, John; Young, Paula R; Gallop, Robert

2014-10-01

Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone. To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD). A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved. Antidepressant medication with or without CT. Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation. Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6% vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95% CI, 1.06-1.68; number needed to treat [NNT], 10; 95% CI, 5-72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3% vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95% CI, 1.54-3.57; NNT, 3; 95% CI, 2-5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9% vs 26.8%; t451 = -2.04; P = .04; HR, 0.66; 95% CI, 0.45-0.98). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode. Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression. clinicaltrials.gov Identifier: NCT00057577.

Acellular dermal matrix allograft versus free gingival graft: a histological evaluation and split-mouth randomized clinical trial.

PubMed

de Resende, Daniel Romeu Benchimol; Greghi, Sebastião Luiz Aguiar; Siqueira, Aline Franco; Benfatti, César Augusto Magalhães; Damante, Carla Andreotti; Ragghianti Zangrando, Mariana Schutzer

2018-04-30

This split-mouth controlled randomized clinical trial evaluated clinical and histological results of acellular dermal matrix allograft (ADM) compared to autogenous free gingival graft (FGG) for keratinized tissue augmentation. Twenty-five patients with the absence or deficiency of keratinized tissue (50 sites) were treated with FGG (control group) and ADM (test group). Clinical parameters included keratinized tissue width (KTW) (primary outcome), soft tissue thickness (TT), recession depth (RD), probing depth (PD), and clinical attachment level (CAL). Esthetic perception was evaluated by patients and by a calibrated periodontist using visual analog scale (VAS). Histological analysis included biopsies of five different patients from both test and control sites for each evaluation period (n = 25). The analysis included percentage of connective tissue components, epithelial luminal to basal surface ratio, tissue maturation, and presence of elastic fibers. Data were evaluated by ANOVA complemented by Tukey's tests (p < 0.05). After 6 months, PD and CAL demonstrated no differences between groups. ADM presented higher RD compared to FGG in all periods. Mean tissue shrinkage for control and test groups was 12.41 versus 55.7%. TT was inferior for ADM group compared to FGG. Esthetics perception by professional evaluation showed superior results for ADM. Histomorphometric analysis demonstrated higher percentage of cellularity, blood vessels, and epithelial luminal to basal surface ratio for FGG group. ADM group presented higher percentage of collagen fibers and inflammatory infiltrate. Both treatments resulted in improvement of clinical parameters, except for RD. ADM group presented more tissue shrinkage and delayed healing, confirmed histologically, but superior professional esthetic perception. This study added important clinical and histological data to contribute in the decision-making process between indication of FGG or ADM.

The clinical effect of acellular dermal matrix on gingival thickness and root coverage compared to coronally positioned flap alone.

PubMed

Woodyard, James G; Greenwell, Henry; Hill, Margaret; Drisko, Connie; Iasella, John M; Scheetz, James

2004-01-01

The primary aim of this randomized, controlled, blinded, clinical investigation was to compare the coronally positioned flap (CPF) plus an acellular dermal matrix (ADM) allograft to CPF alone to determine their effect on gingival thickness and percent root coverage. Twenty-four subjects with one Miller Class I or II buccal recession defect of > or = 3 mm were treated with a CPF plus ADM or a CPF alone. Multiple additional recession sites were treated with the same flap procedure, and all sites were studied for 6 months. Tissue thickness was measured at the sulcus base and at the mucogingival junction of all teeth, with an SDM ultrasonic gingival thickness meter. For the ADM sites, mean initial recession of 3.46 mm was reduced to 0.04 mm for defect coverage of 3.42 mm or 99% (P < 0.05). For the CPF group, mean initial recession of 3.27 mm was reduced to 1.08 mm for defect coverage of 2.19 mm or 67% (P < 0.05). The difference between ADM and CPF groups was statistically significant (P < 0.05). Marginal soft-tissue thickness was increased by 0.40 mm (P < 0.05) for the ADM group, whereas the CPF group remained essentially unchanged. Keratinized tissue was increased for the ADM group by 0.81 mm (P < 0.05), whereas the CPF group increased by 0.33 mm (P > 0.05). No additional root coverage was gained due to creeping attachment between 2 and 6 months for either group. Treatment with a CPF plus an ADM allograft significantly increased gingival thickness when compared with a CPF alone. Recession defect coverage was significantly improved with the use of ADM.

Long-term Prognosis in COPD Exacerbation: Role of Biomarkers, Clinical Variables and Exacerbation Type.

PubMed

Grolimund, Eva; Kutz, Alexander; Marlowe, Robert J; Vögeli, Alaadin; Alan, Murat; Christ-Crain, Mirjam; Thomann, Robert; Falconnier, Claudine; Hoess, Claus; Henzen, Christoph; Zimmerli, Werner; Mueller, Beat; Schuetz, Philipp

2015-06-01

Long-term outcome prediction in COPD is challenging. We conducted a prospective 5-7-year follow-up study in patients with COPD to determine the association of exacerbation type, discharge levels of inflammatory biomarkers including procalctionin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and plasma proadrenomedullin (ProADM), alone or combined with demographic/clinical characteristics, with long-term all-cause mortality in the COPD setting. The analyzed cohort comprised 469 patients with index hospitalization for pneumonic (n = 252) or non-pneumonic (n = 217) COPD exacerbation. Five-to-seven-year vital status was ascertained via structured phone interviews with patients or their household members/primary care physicians. We investigated predictive accuracy using univariate and multivariate Cox regression models and area under the receiver operating characteristic curve (AUC). After a median [25th-75th percentile] 6.1 [5.6-6.5] years, mortality was 55% (95%CI 50%-59%). Discharge ProADM concentration was strongly associated with 5-7-year non-survival: adjusted hazard ratio (HR)/10-fold increase (95%CI) 10.4 (6.2-17.7). Weaker associations were found for PCT and no significant associations were found for CRP or WBC. Combining ProADM with demographic/clinical variables including age, smoking status, BMI, New York Heart Association dyspnea class, exacerbation type, and comorbidities significantly improved long-term predictive accuracy over that of the demographic/clinical model alone: AUC (95%CI) 0.745 (0.701-0.789) versus 0.727 (0.681-0.772), (p) = .043. In patients hospitalized for COPD exacerbation, discharge ProADM levels appeared to accurately predict 5-7-year all-cause mortality and to improve long-term prognostic accuracy of multidimensional demographic/clinical mortality risk assessment.

Activities of mixtures of soil-applied herbicides with different molecular targets.

PubMed

Kaushik, Shalini; Streibig, Jens Carl; Cedergreen, Nina

2006-11-01

The joint action of soil-applied herbicide mixtures with similar or different modes of action has been assessed by using the additive dose model (ADM). The herbicides chlorsulfuron, metsulfuron-methyl, pendimethalin and pretilachlor, applied either singly or in binary mixtures, were used on rice (Oryza sativa L.). The growth (shoot) response curves were described by a logistic dose-response model. The ED50 values and their corresponding standard errors obtained from the response curves were used to test statistically if the shape of the isoboles differed from the reference model (ADM). Results showed that mixtures of herbicides with similar molecular targets, i.e. chlorsulfuron and metsulfuron (acetolactate synthase (ALS) inhibitors), and with different molecular targets, i.e. pendimethalin (microtubule assembly inhibitor) and pretilachlor (very long chain fatty acids (VLCFAs) inhibitor), followed the ADM. Mixing herbicides with different molecular targets gave different results depending on whether pretilachlor or pendimethalin was involved. In general, mixtures of pretilachlor and sulfonylureas showed synergistic interactions, whereas mixtures of pendimethalin and sulfonylureas exhibited either antagonistic or additive activities. Hence, there is a large potential for both increasing the specificity of herbicides by using mixtures and lowering the total dose for weed control, while at the same time delaying the development of herbicide resistance by using mixtures with different molecular targets. Copyright (c) 2006 Society of Chemical Industry.

In silico prediction of cytochrome P450-mediated drug metabolism.

PubMed

Zhang, Tao; Chen, Qi; Li, Li; Liu, Limin Angela; Wei, Dong-Qing

2011-06-01

The application of combinatorial chemistry and high-throughput screening technique enables the large number of chemicals to be generated and tested simultaneously, which will facilitate the drug development and discovery. At the same time, it brings about a challenge of how to efficiently identify the potential drug candidates from thousands of compounds. A way used to deal with the challenge is to consider the drug pharmacokinetic properties, such as absorption, distribution, metabolism and excretion (ADME), in the early stage of drug development. Among ADME properties, metabolism is of importance due to the strong association with efficacy and safety of drug. The review will focus on in silico approaches for prediction of Cytochrome P450-mediated drug metabolism. We will describe these predictive methods from two aspects, structure-based and data-based. Moreover, the applications and limitations of various methods will be discussed. Finally, we provide further direction toward improving the predictive accuracy of these in silico methods.

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

PubMed Central

2010-01-01

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic. PMID:22778836

ADM For Solving Linear Second-Order Fredholm Integro-Differential Equations

NASA Astrophysics Data System (ADS)

Karim, Mohd F.; Mohamad, Mahathir; Saifullah Rusiman, Mohd; Che-Him, Norziha; Roslan, Rozaini; Khalid, Kamil

2018-04-01

In this paper, we apply Adomian Decomposition Method (ADM) as numerically analyse linear second-order Fredholm Integro-differential Equations. The approximate solutions of the problems are calculated by Maple package. Some numerical examples have been considered to illustrate the ADM for solving this equation. The results are compared with the existing exact solution. Thus, the Adomian decomposition method can be the best alternative method for solving linear second-order Fredholm Integro-Differential equation. It converges to the exact solution quickly and in the same time reduces computational work for solving the equation. The result obtained by ADM shows the ability and efficiency for solving these equations.

Axial dispersion, holdup and slip velocity of dispersed phase in a pulsed sieve plate extraction column by radiotracer residence time distribution analysis.

PubMed

Din, Ghiyas Ud; Chughtai, Imran Rafiq; Inayat, Mansoor Hameed; Khan, Iqbal Hussain

2008-12-01

Axial dispersion, holdup and slip velocity of dispersed phase have been investigated for a range of dispersed and continuous phase superficial velocities in a pulsed sieve plate extraction column using radiotracer residence time distribution (RTD) analysis. Axial dispersion model (ADM) was used to simulate the hydrodynamics of the system. It has been observed that increase in dispersed phase superficial velocity results in a decrease in its axial dispersion and increase in its slip velocity while its holdup increases till a maximum asymptotic value is achieved. An increase in superficial velocity of continuous phase increases the axial dispersion and holdup of dispersed phase until a maximum value is obtained, while slip velocity of dispersed phase is found to decrease in the beginning and then it increases with increase in superficial velocity of continuous phase.

Current Status of Human Resource Training Program for Fostering RIBiomics Professionals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Dong-Eun; Jang, Beom-Su; Choi, Dae Seong

RI-Biomics is a state-of-the-art radiation fusion technology for evaluating in-vivo dynamics such as absorption, distribution, metabolism and excretion (ADME) of new drug candidates and biomaterials using radioisotope (RI), and quantitative evaluation of their efficacy via molecular imaging techniques and animal models. The RI-Biomics center is the sole comprehensive research and experiment complex in Korea that can simultaneously perform the radio-synthesis of drug candidate with radioisotope, analysis, and molecular imaging evaluation with animal model. Molecular imaging techniques, including nuclear imaging (SPECT and PET), near-infrared fluorescent (NIRF) imaging, and magnetic resonance imaging (MRI), are the cutting-edge technologies for evaluating drug candidates. Sincemore » they allow in vivo real-time imaging of the diseased site, monitoring the biodistribution of drug and determining the optimal therapeutic efficacy following treatments, we have integrated RI-ADME and molecular imaging to provide useful information for drug evaluation and to accelerate the development of new drugs and biomaterials. The RI-Biomics center was established with total investment of 18 million $ during four years from 2009 to 2012 in order to develop a comprehensive analyzing system using RI for new drug development as an axis for national growth in the next generation. The RI-Biomics center has labeling synthesis facility for the radiosynthesis of drug candidate with radioisotope such as Tc-99m, I-125, I-131, F-18, H-3 and C-14 using hot cell. It also includes RI-general analysis facilities, such as Radio-HPLC, LC/MS, GC/MS, gamma counter that can analyzing the radio-synthesized materials, and animal image analysis facilities that developed small animal imaging equipment such as SPECT/PET/CT, 7 T MRI, in-vivo optical imaging system and others. In order to achieve the system to verify safety and effectiveness of the new drugs using RI, it is necessary to establish a human resource training program for fostering RI-Biomics professionals in the following key fields; (1) Radio-pharmaceuticals synthesis and labeled compound development, (2) Development of RI-ADME in the living object and image assessment technology. Personnel training program that carries out theoretical education and practical training in the field related to RI-Biomics in parallel is being conducted. Internship training for university students has been administered twice already while educational program for the existing professionals in the RI-Biomics field will be carried out during the summer of 2014. The human resource training program for combination of RIADME and different molecular imaging techniques can offer synergistic advantages to facilitate understanding RIADME and fostering RI-ADME professionals. (authors)« less

Histologic evaluation of autogenous connective tissue and acellular dermal matrix grafts in humans.

PubMed

Cummings, Lewis C; Kaldahl, Wayne B; Allen, Edward P

2005-02-01

The clinical success of root coverage with autogenous connective tissue (CT) or acellular dermal matrix (ADM) has been well documented. However, limited histological results of CT grafts have been reported, and a case report of a human block section has been published documenting an ADM graft. The purpose of this study is to document the histological results of CT grafts, ADM grafts, and coronally advanced flaps to cover denuded roots in humans. This study included four patients previously treatment planned for extractions of three or more anterior teeth. Three teeth in each patient were selected and randomly designated to receive either a CT or ADM graft beneath a coronally advanced flap (tests) or coronally advanced flap alone (control). Six months postoperatively block section extractions were performed and the teeth processed for histologic evaluation with hematoxylin-eosin and Verhoeff's stains. Histologically, both the CT and ADM were well incorporated within the recipient tissues. New fibroblasts, vascular elements, and collagen were present throughout the ADM, while retention of the transplanted elastic fibers was apparent. No effect on the keratinization or connective tissue organization of the overlying alveolar mucosa was evident with either graft. For both materials, areas of cemental deposition were present within the root notches, the alveolar bone was essentially unaffected, and the attachments to the root surfaces were similar. Although CT and ADM have a slightly different histological appearance, both can successfully be used to cover denuded roots with similar attachments and no adverse healing.

Cost analysis of postmastectomy reconstruction: A comparison of two staged implant reconstruction using tissue expander and acellular dermal matrix with abdominal-based perforator free flaps.

PubMed

Tran, Bao Ngoc N; Fadayomi, Ayotunde; Lin, Samuel J; Singhal, Dhruv; Lee, Bernard T

2017-09-01

Two staged tissue expander-implant with acellular dermal matrix (TE/I + ADM) and deep inferior epigastric perforator (DIEP) flap are the most common implant and autologous methods of reconstruction in the U.S. Implant-based techniques are disproportionally more popular, partially due to its presumed cost effectiveness. We performed a comprehensive cost analysis to compare TE/I + ADM and DIEP flap. A comparative cost analysis of TE/I + ADM and DIEP flap was performed. Medicare reimbursement costs for each procedure and their associated complications were calculated. Pooled probabilities of complications including cellulitis, seroma, skin necrosis, implant removal, flap loss, partial flap loss, and fat necrosis, were calculated using published studies from 2010 to 2016. Average actual cost for successful TE/I + ADM and DIEP flap were $13 304.55 and $10 237.13, respectively. Incorporating pooled complication data from published literature resulted in an increase in cost to $13 963.46 for TE/I + ADM and $12 624.29 for DIEP flap. The expected costs for successful TE/I + ADM and DIEP flap were $9700.35 and $8644.23, which are lower than the actual costs. DIEP flap breast reconstruction incurs lower costs compared to TE/I + ADM. These costs are lower at baseline and when additional costs from pooled complications are incorporated. © 2017 Wiley Periodicals, Inc.

A patient-centered clinical evaluation of acellular dermal matrix graft in the treatment of gingival recession defects.

PubMed

Mahajan, Ajay; Dixit, Jaya; Verma, Umesh Pratap

2007-12-01

The present randomized controlled trial was conducted to evaluate acellular dermal matrix (ADM) graft in terms of patient satisfaction and its effectiveness and efficiency in the treatment of gingival recession. Fourteen patients (seven males and seven females) with Miller Class I and II recessions > or =3 mm participated in this 6-month clinical study. They were assigned randomly to the ADM group (ADM graft and coronally positioned flap [CPF]) or the CPF group (CPF alone). Results were evaluated based on parameters measuring patient satisfaction and clinical outcomes associated with the two treatment procedures. Significance was set at P <0.05. The mean recession was 4.0 +/- 1.0 mm and 3.7 +/- 0.7 mm for the ADM and CPF groups, respectively. For the ADM group, the defect coverage was 3.85 +/- 0.89 mm or 97.14% compared to the CPF group, in which the defect coverage was 2.85 +/- 0.89 mm or 77.42%. The difference between the two groups was statistically significant (P <0.05). There were no statistically significant differences between the two groups in the remaining clinical parameters and overall patient satisfaction except in criteria related to patient comfort and cost effectiveness, in which CPF alone produced significantly better results (P <0.03). ADM graft is significantly superior with regard to effectiveness and efficiency in the treatment of gingival recession than CPF alone. CPF emerges as a better option than ADM graft in terms of cost effectiveness and patient comfort.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaplan, David E.; Krnjaic, Gordan Z.; Rehermann, Keith R.

We present a simple UV completion of Atomic Dark Matter (aDM) in which heavy right-handed neutrinos decay to induce both dark and lepton number densities. This model addresses several outstanding cosmological problems: the matter/anti-matter asymmetry, the dark matter abundance, the number of light degrees of freedom in the early universe, and the smoothing of small-scale structure. Additionally, this realization of aDM may reconcile the CoGeNT excess with recently published null results and predicts a signal in the CRESST Oxygen band. We also find that, due to unscreened long-range interactions, the residual un recombined dark ions settle into a diffuse isothermalmore » halo.« less

Variability Analysis of MOS Differential Amplifier

NASA Astrophysics Data System (ADS)

Aoki, Masakazu; Seto, Kenji; Yamawaki, Taizo; Tanaka, Satoshi

Variation characteristics in MOS differential amplifier are evaluated by using the concise statistical model parameters for SPICE simulation. We find that the variation in the differential-mode gain, Adm, induced by the current factor variation, Δβ0, in the Id-variation of the differential MOS transistors is more than one order of magnitude larger than that induced by the threshold voltage variation, ΔVth, which has been regarded as a major factor for circuit variations in SoC's (2). The results obtained by the Monte Carlo simulations are verified by the theoretical analysis combined with the sensitivity analysis which clarifies the specific device parameter dependences of the variation in Adm.

Nuclear structure of bound states of asymmetric dark matter

NASA Astrophysics Data System (ADS)

Gresham, Moira I.; Lou, Hou Keong; Zurek, Kathryn M.

2017-11-01

Models of asymmetric dark matter (ADM) with a sufficiently attractive and long-range force give rise to stable bound objects, analogous to nuclei in the Standard Model, called nuggets. We study the properties of these nuggets and compute their profiles and binding energies. Our approach, applicable to both elementary and composite fermionic ADM, utilizes relativistic mean field theory, and allows a more systematic computation of nugget properties, over a wider range of sizes and force mediator masses, compared to previous literature. We identify three separate regimes of nugget property behavior corresponding to (1) nonrelativistic and (2) relativistic constituents in a Coulomb-like limit, and (3) saturation in an anti-Coulomb limit when the nuggets are large compared to the force range. We provide analytical descriptions for nuggets in each regime. Through numerical calculations, we are able to confirm our analytic descriptions and also obtain smooth transitions for the nugget profiles between all three regimes. We also find that over a wide range of parameter space, the binding energy in the saturation limit is an O (1 ) fraction of the constituent's mass, significantly larger than expectations in the nonrelativistic case. In a companion paper, we apply our results to the synthesis of ADM nuggets in the early Universe.

CA 2025: The Strategic Design of Civil Affairs

DTIC Science & Technology

2015-06-01

NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA CAPSTONE PROJECT Approved for public release; distribution is unlimited CA 2025...Paperwork Reduction Project (0704-0188) Washington DC 20503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE June 2015 3. REPORT TYPE AND...Airborne) 96th CA BN(A) 96th Civil Affairs Battalion (Airborne) AAA American Anthropological Association AC active component ADM Army Design

Use of latissimus dorsi muscle onlay patch alternative to acellular dermal matrix in implant-based breast reconstruction

PubMed Central

Lee, Jeeyeon

2015-01-01

Background An acellular dermal matrix (ADM) is applied to release the surrounding muscles and prevent dislocation or rippling of the implant. We compared implant-based breast reconstruction using the latissimus dorsi (LD) muscle, referred to as an “LD muscle onlay patch,” with using an ADM. Method A total of 56 patients (60 breasts) underwent nipple sparing mastectomy with implant-based breast reconstruction using an ADM or LD muscle onlay patch. Cosmetic outcomes were assessed 4 weeks after chemotherapy or radiotherapy, and statistical analyses were performed. Results Mean surgical time and hospital stay were significantly longer in the LD muscle onlay patch group than the ADM group. However, there were no statistically significant differences between groups in postoperative complications. Cosmetic outcomes for breast symmetry and shape were higher in the LD muscle onlay patch group. Conclusions Implant-based breast reconstruction with an LD muscle onlay patch would be a feasible alternative to using an ADM. PMID:26161312

Adrenomedullin increases the short-circuit current in the rat prostate: Receptors, chloride channels, the effects of cAMP and calcium ions and implications on fluid secretion.

PubMed

Liao, S B; Cheung, K H; Cheung, M P L; Wong, P F; O, W S; Tang, F

2014-05-01

In this study, we have investigated the effects of adrenomedullin on chloride and fluid secretion in the rat prostate. The presence of adrenomedullin (ADM) in rat prostate was confirmed using immunostaining, and the molecular species was determined using gel filtration chromatography coupled with an enzyme-linked assay for ADM. The effects of ADM on fluid secretion were studied by short-circuit current technique in a whole mount preparation of the prostate in an Ussing chamber. The results indicated that the ADM level was higher in the ventral than the dorso-lateral prostate and the major molecular species was the active peptide. ADM increased the short-circuit current through both the cAMP- and calcium-activated chloride channels in the ventral lobe, but only through the calcium-activated channels in the dorso-lateral lobe. These stimulatory effects were blocked by the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP8-37. We conclude that ADM may regulate prostatic fluid secretion through the chloride channels, which may affect the composition of the seminal plasma bathing the spermatozoa and hence fertility. © 2014 American Society of Andrology and European Academy of Andrology.

[Comparison of composite grafting of autoskin with acellular dermal matrix from different sources].

PubMed

Chen, Jin-Hui; Qi, Shun-Zhen; Sun, Hui-Chen; He, Zhan-Guo; Li, Hui; Zhu, Yu-Feng; Chen, Xing

2003-10-01

To compare the composite grafts of acellular dermal matrix (ADM) from different sources with autoskin. Six local white mini pigs were employed for the experiment. The pigs were randomly divided into four groups according to different skin grafts, i.e. A (human ADM with razor thin autoskin), B (porcine ADM with razor thin autoskin), C (razor thin autoskin only), and D (split thickness autoskin) as control. The survival rate, the contraction degree of the grafts, and the histological changes in grafting area were observed at 2, 4, 8, 12 and 24 hours after the operation. The grafted area in both A and B groups appeared smooth and elastic with satisfactory graft survival. The in growth of the host reparative cells such as fibroblast and vascular endothelium could be induced by composite grafts of different ADMs with skin grafting. The contraction areas in A and B groups seemed bigger than those in C and D groups. The tissue structure of grafting areas was similar to that of split thickness skin grafting area at 24 post-operation weeks. Combination of the homogenous and heterogeneous ADMs with autografts exhibited similar biological function during the observation period (24 weeks after operation). Xenogenous ADMs might have broader clinical applications.

Melancholic and atypical depression as predictor and moderator of outcome in cognitive behavior therapy and pharmacotherapy for adult depression.

PubMed

Cuijpers, Pim; Weitz, Erica; Lamers, Femke; Penninx, Brenda W; Twisk, Jos; DeRubeis, Robert J; Dimidjian, Sona; Dunlop, Boadie W; Jarrett, Robin B; Segal, Zindel V; Hollon, Steven D

2017-03-01

Melancholic and atypical depression are widely thought to moderate or predict outcome of pharmacological and psychological treatments of adult depression, but that has not yet been established. This study uses the data from four earlier trials comparing cognitive behavior therapy (CBT) versus antidepressant medications (ADMs; and pill placebo when available) to examine the extent to which melancholic and atypical depression moderate or predict outcome in an "individual patient data" meta-analysis. We conducted a systematic search for studies directly comparing CBT versus ADM, contacted the researchers, integrated the resulting datasets from these studies into one big dataset, and selected the studies that included melancholic or atypical depressive subtyping according to DSM-IV criteria at baseline (n = 4, with 805 patients). After multiple imputation of missing data at posttest, mixed models were used to conduct the main analyses. In none of the analyses was melancholic or atypical depression found to significantly moderate outcome (indicating a better or worse outcome of these patients in CBT compared to ADM; i.e., an interaction), predict outcome independent of treatment group (i.e., a main effect), or predict outcome within a given modality. The outcome differences between patients with melancholia or atypical depression versus those without were consistently very small (all effect sizes g < 0.10). We found no indication that melancholic or atypical depressions are significant or relevant moderators or predictors of outcome of CBT and ADM. © 2016 Wiley Periodicals, Inc.

Effect of microneedles on transdermal permeation enhancement of amlodipine.

PubMed

Nalluri, Buchi N; Uppuluri, Chandrateja; Devineni, Jyothirmayee; Nayak, Atul; Nair, Karthik J; Whiteside, Benjamin R; Das, Diganta B

2017-06-01

The present study aimed to investigate the effect of microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of amlodipine (AMLO). Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77-cm 2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses were done using dimensionless parameters like concentration of AMLO (C t /C s ), thickness (h/L) and surface area of the skin (Sa/L 2 ). Microinjection moulding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 6.84- and 6.11-fold increase in the cumulative amount (48 h) of AMLO permeated was observed with 1.5 mm ADM and PM-3 treatments respectively, when compared to passive permeation amounts. Good correlations (R 2  > 0.89) were observed between different dimensionless parameters with scaling analyses. The enhancement in AMLO permeation was found to be in the order of 1.5 mm ADM ≥ PM-3 > 1.2 mm ADM > 0.6 mm ADM ≥PM-1 > passive. The study suggests that MN application enhances the AMLO transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway.

PubMed

Yan, Wenxia; Liu, Hanping; Deng, Xiaoyuan; Jin, Ying; Wang, Ning; Chu, Jing

2018-03-01

The regional injection of connective tissue growth factor (CTGF) for diabetic wound healing requires multiple components and results in a substantial loss of its biological activity. Acellular dermal matrix (ADM) scaffolds are optimal candidates for delivering these factors to local ischaemic environments. In this study, we explored whether CTGF loaded on ADM scaffolds can enhance fibronectin (FN) expression to accelerate diabetic wound healing via the protein kinase C (PKC) signalling pathway. The performance of CTGF and CTGF + PKC inhibitor, which were loaded on ADM scaffolds to treat dorsal skin wounds in streptozotocin-induced diabetic mice, was evaluated with naked ADM as a control. Wound closure showed that ADM scaffolds loaded with CTGF induced greater diabetic wound healing in the early stage of the wound in diabetic mice. Moreover, ADM scaffolds loaded with CTGF obviously increased the expression of FN both at the mRNA and protein levels, whereas the expression of FN was significantly reduced in the inhibitor group. Furthermore, the ADM + CTGF group, which produce FN, obviously promoted alpha-smooth muscle actin and transforming growth factor-beta expression and enhanced neovasculature and collagen synthesis at the wound sites. ADM scaffolds loaded with CTGF + PKC inhibitor delayed diabetic wound healing, indicating that FN expression was mediated by the PKC signalling pathway. Our findings offer new perspectives for the treatment of diabetic wound healing and suggest a rationale for the clinical evaluation of CTGF use in diabetic wound healing. Copyright © 2017 John Wiley & Sons, Ltd.

Permafrost investigation in the Mont Blanc massif steep rock walls: a combined measurement, modelling and geophysical approach

NASA Astrophysics Data System (ADS)

Magnin, Florence; Deline, Philip; Ravanel, Ludovic; Gruber, Stephan; Krautblatter, Michael

2014-05-01

The steep rockwalls of the Mont Blanc massif have been affected by an increase in rockfall activity in the last decades. Permafrost degradation is suggested as the most likely triggering factor. To better understand geomorphic processes we investigate permafrost distribution and address questions on its pattern in steep alpine bedrock. We use GIS-modeling to simulate Mean Annual Rock Surface Temperature (MARST) distribution. Rock temperature measurements including three 10-m-deep borehole monitoring at the Aiguille du Midi (AdM, 3842 m a.s.l) serve to estimate the temperature offset (i.e. temperature difference between rock surface and depth of negligible inter-annual temperature varibility). The estimation of the lower extent of permafrost distribution is derived from a combination of both approaches and hypotheses on permafrost occurrence are evaluated with Electrical Resistivity Tomography (ERT) measurements. The MARST model indicates that the 0°C isotherm extends down to 2600 m a.s.l in the most shaded faces and rises up to 3800 m in the most sun-exposed areas. According to recent literature and the AdM borehole thermal profiles, we postulate that permafrost could extends down below MARST reaching up to 3°C due to temperature offset processes. ERT measurements performed along 160-m-long profiles at six different sites which the top are located from 3360 m a.s.l to 2760 m a.s.l and the MARST range from <-1°C to > 3°C are the first of this kind. Five of sites are located in the granite area making them directly comparable. They all show high resistivity values at depth (>200 kΩ) interpreted as permafrost bodies. Lower resistivity values (< 90 kΩ) are found either above the high resistivity bodies and interpreted as thawed active layer, or below MARST warmer than 2-3°C and interpreted as non-perenially frozen rock. Two sites were measured in autumn 2012 and autumn 2013 allowing for time-lapse investigation which demonstrates the change in resistivity in repeated measurements. These preliminary results could confirm that steep alpine bedrock permafrost exists below surface temperature reaching up to 3°C. A temperature-resistivity calibration will be performed in a freezing laboratory at the Technical University of Munich to better assess ERT results and their interpretation in terms of permafrost occurrence and interannual changes.

Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin.

PubMed

Wang, Rui-lan; Kang, Fu-xin

2010-06-01

Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of pro-atrial natriuretic peptide (pro-ANP) and pro-adrenomedullin (pro-ADM) levels in a cohort of medical intensive care patients and to compare it with that of other known biomarkers and physiological scores. Blood samples of 51 consecutive critically ill patients admitted to the intensive care unit and 53 age-matched healthy control people were evaluated in this prospective study. The prognostic value of pro-ANP and pro-ADM levels was compared with that of acute physiology and chronic health evaluation (APACHE) II scores and various biomarkers such as C-reactive protein, interleukin-6 and procalcitonin. Pro-ANP and pro-ADM were detected by a new sandwich immunoassay. On admission, 25 patients had systemic inflammatory response syndrome (SIRS), 12 sepsis, 9 severe sepsis and 5 septic shock. At that time, the median levels (ng/ml) of pro-ANP and pro-ADM were 87.22 and 0.34 respectively in patients with SIRS, 1533.30 and 2.23 in those with sepsis, 1098.73 and 4.57 in those with severe sepsis, and 1933.94 and 8.21 in those with septic shock. With the increasing severity of disease, the levels of pro-ANP and pro-ADM were gradually increased. On admission, the circulating levels of pro-ANP and pro-ADM in patients with sepsis, severe sepsis, or septic shock were significantly higher in non-survivors than in survivors (P less than 0.05). In a receiver operating characteristic curve analysis for the survival of patients with sepsis, the areas under the curve (AUCs) for pro-ANP and pro-ADM were 0.89 and 0.87 respectively, which was similar to the AUCs for procalcitonin and APACHE II scores. Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

Mid-regional proadrenomedullin: An early marker of response in critically ill patients with severe community-acquired pneumonia?

PubMed

Pereira, J M; Azevedo, A; Basílio, C; Sousa-Dias, C; Mergulhão, P; Paiva, J A

Mid-regional proadrenomedullin (MR-proADM) is a novel biomarker with potential prognostic utility in patients with community-acquired pneumonia (CAP). To evaluate the value of MR-proADM levels at ICU admission for further severity stratification and outcome prediction, and its kinetics as an early predictor of response in severe CAP (SCAP). Prospective, single-center, cohort study of 19 SCAP patients admitted to the ICU within 12h after the first antibiotic dose. At ICU admission median MR-proADM was 3.58nmol/l (IQR: 2.83-10.00). No significant association was found between its serum levels at admission and severity assessed by SAPS II (Spearman's correlation=0.24, p=0.31) or SOFA score (SOFA<10: <3.45nmol/l vs. SOFA≥10: 3.90nmol/l, p=0.74). Hospital and one-year mortality were 26% and 32%, respectively. No significant difference in median MR-proADM serum levels was found between survivors and non-survivors and its accuracy to predict hospital mortality was bad (aROC 0.53). After 48h of antibiotic therapy, MR-proADM decreased in all but 5 patients (median -20%; IQR -56% to +0.1%). Its kinetics measured by the percent change from baseline was a good predictor of clinical response (aROC 0.80). The best discrimination was achieved by classifying patients according to whether MR-proADM decreased or not within 48h. No decrease in MR-proADM serum levels significantly increased the chances of dying independently of general severity (SAPS II-adjusted OR 174; 95% CI 2-15,422; p=0.024). In SCAP patients, a decrease in MR-proADM serum levels in the first 48h after ICU admission was a good predictor of clinical response and better outcome. Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

Modelling mono-digestion of grass silage in a 2-stage CSTR anaerobic digester using ADM1.

PubMed

Thamsiriroj, T; Murphy, J D

2011-01-01

This paper examines 174 days of experimental data and modelling of mono-digestion of grass silage in a two stage wet process with recirculation of liquor; the two vessels have an effective volume of 312 L each. The organic loading rate is initiated at 0.5 kg VS m(-3) d(-1) (first 74 days) and subsequently increased to 1 kg VS m(-3) d(-1). The experimental data was used to generate a mathematical model (ADM1) which was calibrated over the first 74 days of operation. Good accuracy with experimental data was found for the subsequent 100 days. Results of the model would suggest starting the process without recirculation and thus building up the solids content of the liquor. As the level of VFA increases, recirculation should be employed to control VFA. Recirculation also controls solids content and pH. Methane production was estimated at 88% of maximum theoretical production. Copyright © 2010 Elsevier Ltd. All rights reserved.

Scalar hairy black holes and scalarons in the isolated horizons formalism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Corichi, Alejandro; Instituto de Matematicas, Universidad Nacional Autonoma de Mexico, A. Postal 61-3, Morelia, Michoacan, 58090; Nucamendi, Ulises

The Isolated Horizons (IH) formalism, together with a simple phenomenological model for colored black holes has been used to predict nontrivial formulas that relate the ADM mass of the solitons and hairy Black Holes of Gravity-Matter system on the one hand, and several horizon properties of the black holes in the other. In this article, the IH formalism is tested numerically for spherically symmetric solutions to an Einstein-Higgs system where hairy black holes were recently found to exist. It is shown that the mass formulas still hold and that, by appropriately extending the current model, one can account for themore » behavior of the horizon properties of these new solutions. An empirical formula that approximates the ADM mass of hairy solutions is put forward, and some of its properties are analyzed.« less

The effect of Employee Assistance Programs use on healthcare utilization.

PubMed

Zarkin, G A; Bray, J W; Qi, J

2000-04-01

To estimate the effect of Employee Assistance Program (EAP) use on healthcare utilization as measured by health claims. A unique data set that combines individual-level information on EAP utilization, demographic information, and health insurance claims from 1991 to 1995 for all employees of a large midwestern employer. Using "fixed-effect" econometric models that control for unobserved differences between individuals' propensities to use healthcare resources and the EAP, we perform our analyses in two steps. First, for those employees who visited the EAP, we test whether post-EAP claims differ from pre-EAP claims. Second, we combine claims data of individuals who went to an EAP with those of individuals who did not use an EAP to test whether differences in utilization exist between EAP users and nonusers. From the EAP we obtained the date of first EAP contact for all employees who used the service, and from the company's human resources department we obtained limited demographic data on all employees. We obtained healthcare utilization claims data on all employees and their dependents from the company's two healthcare plans: a fee-for-service (FFS) plan and a health maintenance organization (HMO) plan. We found that going to an EAP substantially increases both the probability of an alcohol, drug abuse, or mental health (ADM) claim and the number of ADM claims in the same quarter as EAP contact. The increased probability of an ADM claim persists for approximately 11 quarters after the initial contact, while the increased ADM charges persist for approximately six quarters after the initial EAP contact. Our results strongly suggest that the EAP is able to identify behavioral and other health problems that may affect workplace performance and prompt EAP users to access ADM and other healthcare. Consistent with the stated goals of many EAPs, including the one examined in this study, this process should improve individuals' health, family functioning, and workplace performance.

The effect of Employee Assistance Programs use on healthcare utilization.

PubMed Central

Zarkin, G A; Bray, J W; Qi, J

2000-01-01

OBJECTIVE: To estimate the effect of Employee Assistance Program (EAP) use on healthcare utilization as measured by health claims. DATA SOURCES: A unique data set that combines individual-level information on EAP utilization, demographic information, and health insurance claims from 1991 to 1995 for all employees of a large midwestern employer. STUDY DESIGN: Using "fixed-effect" econometric models that control for unobserved differences between individuals' propensities to use healthcare resources and the EAP, we perform our analyses in two steps. First, for those employees who visited the EAP, we test whether post-EAP claims differ from pre-EAP claims. Second, we combine claims data of individuals who went to an EAP with those of individuals who did not use an EAP to test whether differences in utilization exist between EAP users and nonusers. DATA COLLECTION METHODS: From the EAP we obtained the date of first EAP contact for all employees who used the service, and from the company's human resources department we obtained limited demographic data on all employees. We obtained healthcare utilization claims data on all employees and their dependents from the company's two healthcare plans: a fee-for-service (FFS) plan and a health maintenance organization (HMO) plan. PRINCIPAL FINDINGS: We found that going to an EAP substantially increases both the probability of an alcohol, drug abuse, or mental health (ADM) claim and the number of ADM claims in the same quarter as EAP contact. The increased probability of an ADM claim persists for approximately 11 quarters after the initial contact, while the increased ADM charges persist for approximately six quarters after the initial EAP contact. CONCLUSIONS: Our results strongly suggest that the EAP is able to identify behavioral and other health problems that may affect workplace performance and prompt EAP users to access ADM and other healthcare. Consistent with the stated goals of many EAPs, including the one examined in this study, this process should improve individuals' health, family functioning, and workplace performance. PMID:10778825

A waste characterisation procedure for ADM1 implementation based on degradation kinetics.

PubMed

Girault, R; Bridoux, G; Nauleau, F; Poullain, C; Buffet, J; Steyer, J-P; Sadowski, A G; Béline, F

2012-09-01

In this study, a procedure accounting for degradation kinetics was developed to split the total COD of a substrate into each input state variable required for Anaerobic Digestion Model n°1. The procedure is based on the combination of batch experimental degradation tests ("anaerobic respirometry") and numerical interpretation of the results obtained (optimisation of the ADM1 input state variable set). The effects of the main operating parameters, such as the substrate to inoculum ratio in batch experiments and the origin of the inoculum, were investigated. Combined with biochemical fractionation of the total COD of substrates, this method enabled determination of an ADM1-consistent input state variable set for each substrate with affordable identifiability. The substrate to inoculum ratio in the batch experiments and the origin of the inoculum influenced input state variables. However, based on results modelled for a CSTR fed with the substrate concerned, these effects were not significant. Indeed, if the optimal ranges of these operational parameters are respected, uncertainty in COD fractionation is mainly limited to temporal variability of the properties of the substrates. As the method is based on kinetics and is easy to implement for a wide range of substrates, it is a very promising way to numerically predict the effect of design parameters on the efficiency of an anaerobic CSTR. This method thus promotes the use of modelling for the design and optimisation of anaerobic processes. Copyright © 2012 Elsevier Ltd. All rights reserved.

Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.

PubMed

Ishida, Saeko; Sakamoto, Yu; Nishio, Takeshi; Baulac, Stéphanie; Kuwamura, Mitsuru; Ohno, Yukihiro; Takizawa, Akiko; Kaneko, Shuji; Serikawa, Tadao; Mashimo, Tomoji

2012-01-30

Mutations in the KCNA1 gene, which encodes for the α subunit of the voltage-gated potassium channel Kv1.1, cause episodic ataxia type 1 (EA1). EA1 is a dominant human neurological disorder characterized by variable phenotypes of brief episodes of ataxia, myokymia, neuromyotonia, and associated epilepsy. Animal models for EA1 include Kcna1-deficient mice, which recessively display severe seizures and die prematurely, and V408A-knock-in mice, which dominantly exhibit stress-induced loss of motor coordination. In the present study, we have identified an N-ethyl-N-nitrosourea-mutagenized rat, named autosomal dominant myokymia and seizures (ADMS), with a missense mutation (S309T) in the voltage-sensor domain, S4, of the Kcna1 gene. ADMS rats dominantly exhibited myokymia, neuromyotonia and generalized tonic-clonic seizures. They also showed cold stress-induced tremor, neuromyotonia, and motor incoordination. Expression studies of homomeric and heteromeric Kv1.1 channels in HEK cells and Xenopus oocytes, showed that, although S309T channels are transferred to the cell membrane surface, they remained non-functional in terms of their biophysical properties, suggesting a dominant-negative effect of the S309T mutation on potassium channel function. ADMS rats provide a new model, distinct from previously reported mouse models, for studying the diverse functions of Kv1.1 in vivo, as well as for understanding the pathology of EA1. Copyright © 2011 Elsevier B.V. All rights reserved.

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer.

PubMed

Chen, Ke; Qian, Weikun; Jiang, Zhengdong; Cheng, Liang; Li, Jie; Sun, Liankang; Zhou, Cancan; Gao, Luping; Lei, Meng; Yan, Bin; Cao, Junyu; Duan, Wanxing; Ma, Qingyong

2017-07-24

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer. LSL-Kras G12D/+ ; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-Kras G12D/+ ; Trp53 fl/+ ; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein. Following metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson's trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival. Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

Experience with the delegation of anaesthesia for disbudding and castration to trained and certified livestock owners.

PubMed

Alsaaod, Maher; Doherr, Marcus G; Greber, Deborah; Steiner, Adrian

2014-02-04

Anaesthesia is mandatory for disbudding and castrating calves and lambs of any age, in Switzerland. According to the "anaesthesia delegation model" (ADM), anaesthesia for disbudding calves <3 weeks of age and castrating calves and lambs <2 weeks of age may be administered by certified farmers. Experience with this unique model is not available. The aim was to evaluate the experience of the veterinary practitioners with the ADM. The response rate was 42%. The survey consisted of one questionnaire for each procedure. Procedure I was the delegation of anaesthesia for disbudding calves and procedures II and III were anaesthesia for castrating calves and lambs. Procedure I was performed with local anaesthesia in all farms of 51.8% of the veterinary practices, while this was only 39.3% and 7.6% for procedures II and III (p < 0.001). Anaesthesia for procedure I was administered technically correctly by farmers in at least 66% of the farms of 58.3% of the practitioners, while this was 45.4% and only 23.6% for procedures II and III (p < 0.001). The ADM was assessed as a moderate to very good model to reinforce the legal obligations for procedures I, II, or III by 74.8%, 76.5% and 62.0% of the veterinary practitioners (p < 0.005). The delegation of anaesthesia to certified farmers may be a promising model to reinforce the obligation to provide local anaesthesia for disbudding and castrating calves, but to a lesser extent for castrating lambs.

Introduction to Design and Analysis of High Speed Pumps

DTIC Science & Technology

2006-11-01

for public release, distribution unlimited 13 . SUPPLEMENTARY NOTES See also ADM002051., The original document contains color images. 14. ABSTRACT 15...fluctuations in the pump and the installation, vibration and noise). Figure ( 13 ) presents schematically, for a meridional section in a radial flow pump...impeller. Figure (14) illustrates what can be observed in different types of pumps when recirculation is present. Figure 13 : Schematic Illustration

Evaluation of In Silico Anti-parkinson potential of β-asarone.

PubMed

Gupta, Meenakshi; Kant, Kamal; Sharma, Ruchika; Kumar, Anoop

2018-04-16

Parkinson's disease is affecting millions of people worldwide. The prevalence of Parkinson's disease is 0.3% globally, rising to 1% in more than 60 years of age and 4% in more than 80 years of age and the figures are thought to be doubled by 2030. Thus, there is a great need to identify novel therapeutic strategies or candidate drug molecule which can rescue neuronal degeneration. β-asarone has potential to act as a neuroprotective agent but regarding its role in Parkinson disease, very few reports are available. Thus, this study was undertaken to unlock the potential of β-asarone against Parkinson's disease. The Absorption, Distribution, Metabolism, and Excretion (ADME) analysis has been done by using Swiss ADME Predictor. The interactions of β-asarone towards dopaminergic receptors were investigated by Glide Program 5.0. The crystal structures of dopamine receptors were retrieved from Research Collaboratory for Structural Bioinformatics- Protein Data Bank (RCSB-PDB). The structure of β-asarone was drawn in Chem Draw Ultra 7.0.1. Finally, the toxicity of β-asarone has been predicted by using online web-servers like Lazar and Protox. The ADME data of current investigation has shown good oral bioavailability of β-asarone. It also showed a good binding affinity towards dopaminergic receptors. Further, it was found to be interacting through hydrogen bond with different amino acid residues of D2 and D3 receptors. However, β-asarone was predicted to be toxic in various species of rodents, as per the results of toxicity online web servers. Based on the current finding from ADME and docking studies, these preliminary results may act as effective precursor tool for development of β-asarone as a promising anti-Parkinson agent. However, furthermore experimental validation using in-vitro & in-vivo studies is needed to explore their therapeutic & toxic effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Asymmetric dark matter, baryon asymmetry and lepton number violation

NASA Astrophysics Data System (ADS)

Frandsen, Mads T.; Hagedorn, Claudia; Huang, Wei-Chih; Molinaro, Emiliano; Päs, Heinrich

2018-07-01

We study the effect of lepton number violation (LNV) on baryon asymmetry, generated in the early Universe, in the presence of a dark sector with a global symmetry U(1)X, featuring asymmetric dark matter (ADM). We show that in general LNV, observable at the LHC or in neutrinoless double beta decay experiments, cannot wash out a baryon asymmetry generated at higher scales, unlike in scenarios without such dark sector. An observation of LNV at the TeV scale may thus support ADM scenarios. Considering several models with different types of dark matter (DM), we find that the DM mass is of the order of a few GeV or below in our scenario.

Reducing postoperative infections and red breast syndrome in patients with acellular dermal matrix-based breast reconstruction: the relative roles of product sterility and lower body mass index.

PubMed

Lewis, Priya; Jewell, James; Mattison, Gennaya; Gupta, Subhas; Kim, Hahns

2015-05-01

The use of human acellular dermal matrices (ADM) has become routinely used in implant-based breast surgery. Notwithstanding the many benefits for tissue support, the morbidity associated with its use includes seroma and infection, among other potential complications. Some patients experience a specific complication called red breast syndrome (RBS), which has been linked to ADM use, but its exact etiology remains elusive. In our institution, AlloDerm aseptic regenerative tissue matrix was recently replaced with a ready-to-use sterile version that undergoes terminal sterilization, eliminating the need for rehydration. We want to determine if this change in processing affected complications, including RBS. We conducted a retrospective chart review analyzing patients from January 1, 2011, to June 1, 2013, who underwent breast surgery with human ADM. Patients with aseptic AlloDerm were compared to patients with sterile AlloDerm. Data were analyzed using the Fisher exact test. A total of 167 reconstructed breasts from 105 patients met inclusion criteria: 56% (n=93) with aseptic ADM, 44% (n=74) with sterile ADM. When comparing the two, patients had a decrease in overall necrosis, infection, seroma, and RBS with sterile ADM. However, the rates did not reach statistical significance. For example, the incidence of RBS decreased from 7.5% to 2.7% (P=0.301) and seroma decreased from 8.6% to 2.7% (P=0.188). The infection rate proved to be equivocal at 11.8% with aseptic ADM to 10.8% with sterile ADM (P=1.000). The only statistically significant change was a decrease in the total complication rate from 41.9% to 27.0% (P=0.046). The absolute risk reduction for total complications was 14.9% with a number-needed-to-treat of 7. According to our study, sterile AlloDerm has a clinically decreased incidence of complications compared to aseptic AlloDerm. Whereas RBS decreased, it was interesting to see that it was not eliminated altogether. This suggests that the etiology may be unrelated to ADM processing and warrants further investigation. Overall, the most notable difference was the statistically significant decrease in the total complication rate. Therefore, the change to sterile AlloDerm seems to be beneficial. Further benefit arises from ease of preparation in the operating room.

Reconciling Time, Space and Function: A New Dorsal-Ventral Stream Model of Sentence Comprehension

ERIC Educational Resources Information Center

Bornkessel-Schlesewsky, Ina; Schlesewsky, Matthias

2013-01-01

We present a new dorsal-ventral stream framework for language comprehension which unifies basic neurobiological assumptions (Rauschecker & Scott, 2009) with a cross-linguistic neurocognitive sentence comprehension model (eADM; Bornkessel & Schlesewsky, 2006). The dissociation between (time-dependent) syntactic structure-building and…

The prevalence and use of antidepressant medication in pediatric cancer patients.

PubMed

Portteus, Andrew; Ahmad, Naveed; Tobey, Daniel; Leavey, Patrick

2006-08-01

During the period of cancer diagnosis and active treatment, several small case series have revealed high rates of psychiatric difficulty in pediatric patients. However, due to the methodological limitations in these studies, it remains impossible to determine accurately the true prevalence of mood disorders in pediatric cancer patients receiving cancer treatment. To date, no study has reported rates of antidepressant treatment in this population. The aims of this study were: (1) To determine the prevalence of the use of antidepressant medication (ADM) in children with cancer; (2) to identify a group of children being treated for cancer, that are likely to receive ADM, and who therefore may be eligible for a prospective observational or interventional clinical trial of depression during cancer therapy. We reviewed the medical records of 224 pediatric patients suspected for cancer in 2003 at the Children's Medical Center of Dallas. Of these, 6 proved non-oncologic and 2 were lost to follow up, leaving 216 charts for review. Within 1 year of diagnosis, 29 patients (13%) had received a psychiatric consultation. Twenty-two patients (10.2%) received ADM within 1 year of cancer diagnosis. Children >/= 12 years, children with acute lymphoblastic leukemia, and children receiving radiotherapy or opiate analgesics were more likely to receive ADM by multivariate analysis. Race, sex, bone marrow transplant, and surgery were not significantly associated with ADM use. The prevalence of ADM use in pediatric cancer patients (10.2%) was higher than the reported rates of depression (4-8%) and ADM treatment (1%) in the general pediatric population. Teenagers and those who received opiate analgesic medications during their cancer therapy represent a subgroup of children in whom further study of depression and cancer therapy may be valuable.

Disparities in Alcohol, Drug Use, and Mental Health Condition Prevalence and Access to Care in Rural, Isolated, and Reservation Areas: Findings From the South Dakota Health Survey.

PubMed

Davis, Melinda M; Spurlock, Margaret; Dulacki, Kristen; Meath, Thomas; Li, Hsin-Fang Grace; McCarty, Dennis; Warne, Donald; Wright, Bill; McConnell, K John

2016-06-01

Research on urban/rural disparities in alcohol, drug use, and mental health (ADM) conditions is inconsistent. This study describes ADM condition prevalence and access to care across diverse geographies in a predominantly rural state. Multimodal cross-sectional survey in South Dakota from November 2013 to October 2014, with oversampling in rural areas and American Indian reservations. Measures assessed demographic characteristics, ADM condition prevalence using clinical screenings and participant self-report, perceived need for treatment, health service usage, and barriers to obtaining care. We tested for differences among urban, rural, isolated, and reservation geographic areas, controlling for participant age and gender. We analyzed 7,675 surveys (48% response rate). Generally, ADM condition prevalence rates were not significantly different across geographies. However, respondents in isolated and reservation areas were significantly less likely to have access to primary care. Knowledge of treatment options was significantly lower in isolated regions and individuals in reservation areas had significantly lower odds of reporting receipt of all needed care. Across the sample there was substantial discordance between ADM clinical screenings and participant self-reported need; 98.1% of respondents who screened positive for alcohol or drug misuse and 63.8% of respondents who screened positive for a mental health condition did not perceive a need for care. In a predominantly rural state, geographic disparities in ADM conditions are related to differences in access as opposed to prevalence, particularly for individuals in isolated and reservation areas. Educational interventions about ADM condition characteristics may be as important as improving access to care. © 2015 National Rural Health Association.

Therapeutic efficacy of interleukin-2 activated killer cells against adriamycin resistant mouse B16-BL6 melanoma.

PubMed

Gautam, S C; Chikkala, N F; Lewis, I; Grabowski, D R; Finke, J H; Ganapathi, R

1992-01-01

Development of multidrug-resistance (MDR) remains a major cause of failure in the treatment of cancer with chemotherapeutic agents. In our efforts to explore alternative treatment regimens for multidrug-resistant tumors we have examined the sensitivity of MDR tumor cell lines to lymphokine activated killer (LAK) cells. Adriamycin (ADM) resistant B16-BL6 melanoma, L1210 and P388 leukemic cell lines were tested for sensitivity to lysis by LAK cells in vitro. While ADM-resistant B16-BL6 and L1210 sublines were found to exhibit at least 2-fold greater susceptibility to lysis by LAK cells, sensitivity of ADM-resistant P388 cell was similar to that of parental cells. Since ADM-resistant B16-BL6 cells were efficiently lysed by LAK cells in vitro, the efficacy of therapy with LAK cells against the ADM-resistant B16-BL6 subline in vivo was evaluated. Compared to mice bearing parental B16-BL6 tumor cells, the adoptive transfer of LAK cells and rIL2 significantly reduced formation of experimental metastases (P less than 0.009) and extended median survival time (P less than 0.001) of mice bearing ADM-resistant B16-BL6 tumor cells. Results suggest that immunotherapy with LAK cells and rIL2 may be a useful modality in the treatment of cancers with the MDR phenotype.

A new system for cultivation of human keratinocytes on acellular dermal matrix substitute with the use of human fibroblast feeder layer.

PubMed

Xiao, S; Zhu, S; Ma, B; Xia, Z-F; Yang, J; Wang, G

2008-01-01

To improve the proliferative potential of human keratinocytes (HK) cultured on acellular dermal matrix (ADM), HK and mitomycin C-treated human fibroblasts (MMC-HF) were seeded onto ADM to form four types of composite skin: type I, HK were seeded onto the epidermal side of ADM; type II, both HK and MMC-HF were seeded onto the epidermal side; type III, MMC-HF were preseeded onto the dermal side of ADM, and then HK were seeded onto the epidermal side, and type IV, where MMC-HF were preseeded onto both sides, and then HK were seeded onto the epidermal side. Compared with type I and III, the proliferative potential of HK of type II and IV was significantly higher on day 3, 5, 7 and 9 in vitro. In type I and III, HK grew into one layer on day 7-9, while in type II and IV keratinocytes grew into a confluent monolayer by day 4-6. The adherence to ADM of HK in types II and IV was stronger than that in type I and III. The take rate of type II and IV composite skin was also significantly higher. In conclusion, when MMC-HF and HK were cocultured on the epidermal side of ADM, MMC-HF could serve as excellent feeder cells. Copyright 2007 S. Karger AG, Basel.

The effect of porcine ADM to improve the burn wound healing

PubMed Central

Chen, Xiaodong; Shi, Yan; Shu, Bin; Xie, Xiaoxia; Yang, Ronghua; Zhang, Lijun; Ruan, Shubin; Lin, Yan; Lin, Zepeng; Shen, Rui; Zhang, Fenggang; Feng, Xiangsheng; Xie, Julin

2013-01-01

To study the effect of porcine acellular dermal matrix (ADM) on the burn wound healing. Seventy healthy Wistar rats were inflicted with 2 cm second degree burn and divided into 2 groups; one group was treated with porcine ADM and the other with Povidone Iodine Cream. Biopsies were taken on day 1, 3, 5, 7, 10, 14, 21 for histopathological and biochemical analysis to test PCNA, K19, Integrin-β1, PDGF, EGF and FGF. The results revealed relatively better and faster regeneration after treatment of porcine ADM, along with greatly increased synthesis in collagen in the experimental group. PCNA, K19, Integrin-β1 had an increase and then tapered down, and were stronger in the experimental group than in the contrast group during 21 days after burns. PDGF, EGF and FGF levels increased on day 3, peaked on day 5 and then started to decrease, while significantly enhanced expression of relevant growth factors were observed in the experimental group. Porcine ADM stimulate collagen synthesis, stem cells proliferation and differentiation, and the expression of relevant growth factors and ultimately improve the burn wound healing. PMID:24228089

Diffeomorphisms as symplectomorphisms in history phase space: Bosonic string model

NASA Astrophysics Data System (ADS)

Kouletsis, I.; Kuchař, K. V.

2002-06-01

The structure of the history phase space G of a covariant field system and its history group (in the sense of Isham and Linden) is analyzed on an example of a bosonic string. The history space G includes the time map T from the spacetime manifold (the two-sheet) Y to a one-dimensional time manifold T as one of its configuration variables. A canonical history action is posited on G such that its restriction to the configuration history space yields the familiar Polyakov action. The standard Dirac-ADM action is shown to be identical with the canonical history action, the only difference being that the underlying action is expressed in two different coordinate charts on G. The canonical history action encompasses all individual Dirac-ADM actions corresponding to different choices T of foliating Y. The history Poisson brackets of spacetime fields on G induce the ordinary Poisson brackets of spatial fields in the instantaneous phase space G0 of the Dirac-ADM formalism. The canonical history action is manifestly invariant both under spacetime diffeomorphisms Diff Y and temporal diffeomorphisms Diff T. Both of these diffeomorphisms are explicitly represented by symplectomorphisms on the history phase space G. The resulting classical history phase space formalism is offered as a starting point for projection operator quantization and consistent histories interpretation of the bosonic string model.

Recent developments in software tools for high-throughput in vitro ADME support with high-resolution MS.

PubMed

Paiva, Anthony; Shou, Wilson Z

2016-08-01

The last several years have seen the rapid adoption of the high-resolution MS (HRMS) for bioanalytical support of high throughput in vitro ADME profiling. Many capable software tools have been developed and refined to process quantitative HRMS bioanalysis data for ADME samples with excellent performance. Additionally, new software applications specifically designed for quan/qual soft spot identification workflows using HRMS have greatly enhanced the quality and efficiency of the structure elucidation process for high throughput metabolite ID in early in vitro ADME profiling. Finally, novel approaches in data acquisition and compression, as well as tools for transferring, archiving and retrieving HRMS data, are being continuously refined to tackle the issue of large data file size typical for HRMS analyses.

Numeric Modified Adomian Decomposition Method for Power System Simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimitrovski, Aleksandar D; Simunovic, Srdjan; Pannala, Sreekanth

This paper investigates the applicability of numeric Wazwaz El Sayed modified Adomian Decomposition Method (WES-ADM) for time domain simulation of power systems. WESADM is a numerical method based on a modified Adomian decomposition (ADM) technique. WES-ADM is a numerical approximation method for the solution of nonlinear ordinary differential equations. The non-linear terms in the differential equations are approximated using Adomian polynomials. In this paper WES-ADM is applied to time domain simulations of multimachine power systems. WECC 3-generator, 9-bus system and IEEE 10-generator, 39-bus system have been used to test the applicability of the approach. Several fault scenarios have been tested.more » It has been found that the proposed approach is faster than the trapezoidal method with comparable accuracy.« less

Non-parametric PCM to ADM conversion. [Pulse Code to Adaptive Delta Modulation

NASA Technical Reports Server (NTRS)

Locicero, J. L.; Schilling, D. L.

1977-01-01

An all-digital technique to convert pulse code modulated (PCM) signals into adaptive delta modulation (ADM) format is presented. The converter developed is shown to be independent of the statistical parameters of the encoded signal and can be constructed with only standard digital hardware. The structure of the converter is simple enough to be fabricated on a large scale integrated circuit where the advantages of reliability and cost can be optimized. A concise evaluation of this PCM to ADM translation technique is presented and several converters are simulated on a digital computer. A family of performance curves is given which displays the signal-to-noise ratio for sinusoidal test signals subjected to the conversion process, as a function of input signal power for several ratios of ADM rate to Nyquist rate.

Heterocyclic replacements for benzene: Maximising ADME benefits by considering individual ring isomers.

PubMed

Ritchie, Timothy J; Macdonald, Simon J F

2016-11-29

The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Excitability of the Primary Motor Cortex Increases More Strongly with Slow- than with Normal-Speed Presentation of Actions

PubMed Central

Moriuchi, Takefumi; Iso, Naoki; Sagari, Akira; Ogahara, Kakuya; Kitajima, Eiji; Tanaka, Koji; Tabira, Takayuki; Higashi, Toshio

2014-01-01

Introduction The aim of the present study was to investigate how the speed of observed action affects the excitability of the primary motor cortex (M1), as assessed by the size of motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS). Methods Eighteen healthy subjects watched a video clip of a person catching a ball, played at three different speeds (normal-, half-, and quarter-speed). MEPs were induced by TMS when the model's hand had opened to the widest extent just before catching the ball (“open”) and when the model had just caught the ball (“catch”). These two events were locked to specific frames of the video clip (“phases”), rather than occurring at specific absolute times, so that they could easily be compared across different speeds. MEPs were recorded from the thenar (TH) and abductor digiti minimi (ADM) muscles of the right hand. Results The MEP amplitudes were higher when the subjects watched the video clip at low speed than when they watched the clip at normal speed. A repeated-measures ANOVA, with the factor VIDEO-SPEED, showed significant main effects. Bonferroni's post hoc test showed that the following MEP amplitude differences were significant: TH, normal vs. quarter; ADM, normal vs. half; and ADM, normal vs. quarter. Paired t-tests showed that the significant MEP amplitude differences between TMS phases under each speed condition were TH, “catch” higher than “open” at quarter speed; ADM, “catch” higher than “open” at half speed. Conclusions These results indicate that the excitability of M1 was higher when the observed action was played at low speed. Our findings suggest that the action observation system became more active when the subjects observed the video clip at low speed, because the subjects could then recognize the elements of action and intention in others. PMID:25479161

Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

PubMed

Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

2018-05-22

Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine.

PubMed

Ravindran, Selvan; Suthar, Jitendra Kumar; Rokade, Rutuja; Deshpande, Pooja; Singh, Pooja; Pratinidhi, Ashutosh; Khambadkhar, Rajeshree; Utekar, Srushti

2018-01-01

Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Generic Authentication LoA Derivation Model

NASA Astrophysics Data System (ADS)

Yao, Li; Zhang, Ning

One way of achieving a more fine-grained access control is to link an authentication level of assurance (LoA) derived from a requester’s authentication instance to the authorisation decision made to the requester. To realise this vision, there is a need for designing a LoA derivation model that supports the use and quantification of multiple LoA-effecting attributes, and analyse their composite effect on a given authentication instance. This paper reports the design of such a model, namely a generic LoA derivation model (GEA- LoADM). GEA-LoADM takes into account of multiple authentication attributes along with their relationships, abstracts the composite effect by the multiple attributes into a generic value, authentication LoA, and provides algorithms for the run-time derivation of LoA. The algorithms are tailored to reflect the relationships among the attributes involved in an authentication instance. The model has a number of valuable properties, including flexibility and extensibility; it can be applied to different application contexts and support easy addition of new attributes and removal of obsolete ones.

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bidding farewell to outgoing commander, Rear Adm. Edward B. Cashman here, Tuesday, April 17, 2018. Joint , Rear Adm. Edward B. Cashman here, Tuesday, April 17, 2018. During the ceremony, Cashman read his orders

Utility of Army Design Methodology in U.S. Coast Guard Counter Narcotic Interdiction Strategy

DTIC Science & Technology

2017-06-09

UTILITY OF ARMY DESIGN METHODOLOGY IN U.S. COAST GUARD COUNTER NARCOTIC INTERDICTION STRATEGY A thesis presented to the...Thesis 3. DATES COVERED (From - To) AUG 2016 – JUN 2017 4. TITLE AND SUBTITLE Utility of Army Design Methodology in U.S. Coast Guard Counter...Distribution is Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT This study investigates the utility of using Army Design Methodology (ADM) to

Workshop on Aeronautical Decision Making (ADM). Volume 1. Executive Summary

DTIC Science & Technology

1992-08-01

expert and novice pilots when a real decision was required. Aeronautical Decision Making (ADM), Crew Resource Management (CRM), Advanced Qualification Program (AQP), Cognitive Task Analysis (CTA), Expert Decision Making (EDM)

Dynamic multiphoton imaging of acellular dermal matrix scaffolds seeded with mesenchymal stem cells in diabetic wound healing.

PubMed

Chu, Jing; Shi, Panpan; Deng, Xiaoyuan; Jin, Ying; Liu, Hao; Chen, Maosheng; Han, Xue; Liu, Hanping

2018-03-25

Significantly effective therapies need to be developed for chronic nonhealing diabetic wounds. In this work, the topical transplantation of mesenchymal stem cell (MSC) seeded on an acellular dermal matrix (ADM) scaffold is proposed as a novel therapeutic strategy for diabetic cutaneous wound healing. GFP-labeled MSCs were cocultured with an ADM scaffold that was decellularized from normal mouse skin. These cultures were subsequently transplanted as a whole into the full-thickness cutaneous wound site in streptozotocin-induced diabetic mice. Wounds treated with MSC-ADM demonstrated an increased percentage of wound closure. The treatment of MSC-ADM also greatly increased angiogenesis and rapidly completed the reepithelialization of newly formed skin on diabetic mice. More importantly, multiphoton microscopy was used for the intravital and dynamic monitoring of collagen type I (Col-I) fibers synthesis via second harmonic generation imaging. The synthesis of Col-I fibers during diabetic wound healing is of great significance for revealing wound repair mechanisms. In addition, the activity of GFP-labeled MSCs during wound healing was simultaneously traced via two-photon excitation fluorescence imaging. Our research offers a novel advanced nonlinear optical imaging method for monitoring the diabetic wound healing process while the ADM and MSCs interact in situ. Schematic of dynamic imaging of ADM scaffolds seeded with mesenchymal stem cells in diabetic wound healing using multiphoton microscopy. PMT, photo-multiplier tube. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Experience with the delegation of anaesthesia for disbudding and castration to trained and certified livestock owners

PubMed Central

2014-01-01

Background Anaesthesia is mandatory for disbudding and castrating calves and lambs of any age, in Switzerland. According to the “anaesthesia delegation model” (ADM), anaesthesia for disbudding calves <3 weeks of age and castrating calves and lambs <2 weeks of age may be administered by certified farmers. Experience with this unique model is not available. The aim was to evaluate the experience of the veterinary practitioners with the ADM. The response rate was 42%. The survey consisted of one questionnaire for each procedure. Procedure I was the delegation of anaesthesia for disbudding calves and procedures II and III were anaesthesia for castrating calves and lambs. Results Procedure I was performed with local anaesthesia in all farms of 51.8% of the veterinary practices, while this was only 39.3% and 7.6% for procedures II and III (p < 0.001). Anaesthesia for procedure I was administered technically correctly by farmers in at least 66% of the farms of 58.3% of the practitioners, while this was 45.4% and only 23.6% for procedures II and III (p < 0.001). The ADM was assessed as a moderate to very good model to reinforce the legal obligations for procedures I, II, or III by 74.8%, 76.5% and 62.0% of the veterinary practitioners (p < 0.005). Conclusions The delegation of anaesthesia to certified farmers may be a promising model to reinforce the obligation to provide local anaesthesia for disbudding and castrating calves, but to a lesser extent for castrating lambs. PMID:24495664

Teleradiology Via The Naval Remote Medical Diagnosis System (RMDS)

NASA Astrophysics Data System (ADS)

Rasmussen, Will; Stevens, Ilya; Gerber, F. H.; Kuhlman, Jayne A.

1982-01-01

Testing was conducted to obtain qualitative and quantitative (statistical) data on radiology performance using the Remote Medical Diagnosis System (RMDS) Advanced Development Models (ADMs)1. Based upon data collected during testing with professional radiologists, this analysis addresses the clinical utility of radiographic images transferred through six possible RMDS transmission modes. These radiographs were also viewed under closed-circuit television (CCTV) and lightbox conditions to provide a basis for comparison. The analysis indicates that the RMDS ADM terminals (with a system video resolution of 525 x 256 x 6) would provide satisfactory radiographic images for radiology consultations in emergency cases with gross pathological disorders. However, in cases involving more subtle findings, a system video resolution of 525 x 512 x 8 would be preferable.

Novel function of N,N-bis(2-chloroethyl)docos-13-enamide for reversal of multidrug resistance in tongue cancer.

PubMed

Qin, Qing; Ma, Peng-Fei; Kuang, Xiao-Cong; Gao, Ming-Xing; Mo, De-Huan; Xia, Shuang; Jin, Ning; Xia, Jun-Jie; Qi, Zhong-Quan; Lin, Cui-Wu

2013-12-05

Multidrug resistance (MDR) is a key element in the failure of chemotherapies, and development of agents to overcome MDR is crucial to improving cancer treatments. The overexpression of glutathione-S-transferases (GSTs) is one of the major mechanisms of MDR. Because some agents used in traditional Chinese medicine have strong antitumor effects coupled with low toxicity; we investigated the ability of N,N-bis(2-chloroethyl)docos-13-enamide (compound J), the synthesized analog of a highly unsaturated fatty acid from Isatis tinctoria L., to reverse the MDR induced by adriamycin (ADM) in TCA8113/ADM cells. We found that compound J significantly increased the cytotoxicity of ADM in TCA8113/ADM cells, with a reversal fold of 2.461. Analysis of the mechanisms through which compound J reversed MDR indicated that compound J significantly decreased the activity of GSTs and enhanced the depletion of GSH in TCA8113/ADM cells, but did not affect the P-glycoprotein (P-gp) efflux. Taken together, our data suggested that compound J was an excellent candidate for reversing MDR in cancer therapy. © 2013 Published by Elsevier B.V.

Uncertainty characterization and quantification in air pollution models. Application to the ADMS-Urban model.

NASA Astrophysics Data System (ADS)

Debry, E.; Malherbe, L.; Schillinger, C.; Bessagnet, B.; Rouil, L.

2009-04-01

Evaluation of human exposure to atmospheric pollution usually requires the knowledge of pollutants concentrations in ambient air. In the framework of PAISA project, which studies the influence of socio-economical status on relationships between air pollution and short term health effects, the concentrations of gas and particle pollutants are computed over Strasbourg with the ADMS-Urban model. As for any modeling result, simulated concentrations come with uncertainties which have to be characterized and quantified. There are several sources of uncertainties related to input data and parameters, i.e. fields used to execute the model like meteorological fields, boundary conditions and emissions, related to the model formulation because of incomplete or inaccurate treatment of dynamical and chemical processes, and inherent to the stochastic behavior of atmosphere and human activities [1]. Our aim is here to assess the uncertainties of the simulated concentrations with respect to input data and model parameters. In this scope the first step consisted in bringing out the input data and model parameters that contribute most effectively to space and time variability of predicted concentrations. Concentrations of several pollutants were simulated for two months in winter 2004 and two months in summer 2004 over five areas of Strasbourg. The sensitivity analysis shows the dominating influence of boundary conditions and emissions. Among model parameters, the roughness and Monin-Obukhov lengths appear to have non neglectable local effects. Dry deposition is also an important dynamic process. The second step of the characterization and quantification of uncertainties consists in attributing a probability distribution to each input data and model parameter and in propagating the joint distribution of all data and parameters into the model so as to associate a probability distribution to the modeled concentrations. Several analytical and numerical methods exist to perform an uncertainty analysis. We chose the Monte Carlo method which has already been applied to atmospheric dispersion models [2, 3, 4]. The main advantage of this method is to be insensitive to the number of perturbed parameters but its drawbacks are its computation cost and its slow convergence. In order to speed up this one we used the method of antithetic variable which takes adavantage of the symmetry of probability laws. The air quality model simulations were carried out by the Association for study and watching of Atmospheric Pollution in Alsace (ASPA). The output concentrations distributions can then be updated with a Bayesian method. This work is part of an INERIS Research project also aiming at assessing the uncertainty of the CHIMERE dispersion model used in the Prev'Air forecasting platform (www.prevair.org) in order to deliver more accurate predictions. (1) Rao, K.S. Uncertainty Analysis in Atmospheric Dispersion Modeling, Pure and Applied Geophysics, 2005, 162, 1893-1917. (2) Beekmann, M. and Derognat, C. Monte Carlo uncertainty analysis of a regional-scale transport chemistry model constrained by measurements from the Atmospheric Pollution Over the PAris Area (ESQUIF) campaign, Journal of Geophysical Research, 2003, 108, 8559-8576. (3) Hanna, S.R. and Lu, Z. and Frey, H.C. and Wheeler, N. and Vukovich, J. and Arunachalam, S. and Fernau, M. and Hansen, D.A. Uncertainties in predicted ozone concentrations due to input uncertainties for the UAM-V photochemical grid model applied to the July 1995 OTAG domain, Atmospheric Environment, 2001, 35, 891-903. (4) Romanowicz, R. and Higson, H. and Teasdale, I. Bayesian uncertainty estimation methodology applied to air pollution modelling, Environmetrics, 2000, 11, 351-371.

Principles and techniques in the design of ADMS+. [advanced data-base management system

NASA Technical Reports Server (NTRS)

Roussopoulos, Nick; Kang, Hyunchul

1986-01-01

'ADMS+/-' is an advanced data base management system whose architecture integrates the ADSM+ mainframe data base system with a large number of work station data base systems, designated ADMS-; no communications exist between these work stations. The use of this system radically decreases the response time of locally processed queries, since the work station runs in a single-user mode, and no dynamic security checking is required for the downloaded portion of the data base. The deferred update strategy used reduces overhead due to update synchronization in message traffic.

[EFFECTIVENESS OF VAGINOPLASTY WITH ACELLULAR DERMAL MATRIX AND MIXED PARTICLES GRAFT].

PubMed

Zhou, Yu; Li, Qiang; Ll, Senkai; Zhou, Chuande; Li, Fengyong; Cao, Yujiao; Zhang, Siya; Wei, Shuyi; Zhao, Yang

2015-06-01

To evaluate the effectiveness or acellular dermal matrix (ADM) with autologous buccal micro mucosa and micro skin graft in vaginoplasty. A retrospective analysis was made on the clinical data of 67 patients with vaginal agenesis treated between July 2006 and June 2013. ADM and mixed particles were used in 20 cases (ADM group) and mixed particles graft in 47 cases (control group) in vaginoplasty. There was no significant difference in age between 2 groups (t=0.233, P=0.816). The depth, diameter, and volume of neovagina, epithelization time, stent needing time, and female sexual function index (FSFI) score were compared between 2 groups. There was no significant difference in operation time and amount of bleeding between 2 groups (t = -1.922, P = 0.059; t = 0.398, P = 0.692). The patients were followed up 11-38 months (mean, 16.08 months). Fifteen cases in ADM group and 29 cases in control group had sexual life after operation. Bleeding after operation occurred in 6 cases (2 in ADM group and 4 in control group). No stenosis was observed. Difference in epithelization time was not statistically significant (t = -1.938, P = 0.057). However, the stent needing time of ADM group was significantly shorter than that of control group (t = 7.020, P = 0.000). The neovagina was ideal in wetness degree, smoothness, flexibility, and hairlessness during follow-up. The depth, diameter, and volume of vagina had no significant difference between 2 groups (P > 0.05) at last follow-up, which were close to normal vagina. The other patients had normal sexual function except 1 patient whose FSFI score was less than 23; no statistically significant difference was found in FSFI score between 2 groups (P > 0.05). On the basis of mixed particles grafting, the ADM could improve trestle structure for resisting contracture. The effectiveness is better than merely mixed particles graft. The procedure has satisfactory anatomical and functional results.

Characterizing the solar reflection from wildfire smoke plumes using airborne multiangle measurements

NASA Astrophysics Data System (ADS)

Gatebe, C. K.; Varnai, T.; Gautam, R.; Poudyal, R.; Singh, M. K.

2016-12-01

To help better understand forest fire smoke plumes, this study examines sunlight reflected from plumes that were observed over Canada during the ARCTAS campaign in summer 2008. In particular, the study analyzes multiangle and multispectral measurements of smoke scattering by the airborne Cloud Absorption Radiometer (CAR). In combination with other in-situ and remote sensing information and radiation modeling, CAR data is used for characterizing the radiative properties and radiative impact of smoke particles—which inherently depend on smoke particle properties that influence air quality. In addition to estimating the amount of reflected and absorbed sunlight, the work includes using CAR data to create spectral and broadband top-of-atmosphere angular distribution models (ADMs) of solar radiation reflected by smoke plumes, and examining the sensitivity of such angular models to scene parameters. Overall, the results help better understand the radiative properties and radiative effects of smoke particles, and are anticipated to help better interpret satellite data on smoke plumes.

75 FR 76482 - Federal Housing Administration (FHA): FHA Maximum Loan Limits for 2011

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-08

... http://www.hud.gov/offices/adm/hudclips/letters/mortgagee/ . FOR FURTHER INFORMATION CONTACT: Karin B... be found at http://www.hud.gov/offices/adm/hudclips/letters/mortgagee/ mortgagee/. Dated: November 29...

Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR-101/Nrf2 pathway

PubMed Central

Gao, Ai-Mei; Zhang, Xiao-Yu; Ke, Zun-Ping

2017-01-01

Chemo-resistance is one of the main obstacle in hepatocellular carcinoma therapy. Apigenin as a natural bioflavonoid has been exhibited anti-cancer properties in various malignant cancers. The aim of this study is to evaluate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM and to investigate its possible mechanism. We found that apigenin significantly reversed doxorubicin sensitivity and induced caspase-dependent apoptosis in BEL-7402/ADM cells. Furthermore, apigenin induced miR-101 expression, and overexpression of miR-101 mimicked the doxorubicin-sensitizing effect of apigenin. Importantly, we showed that miR-101 was able to target the 3′-UTR of Nrf2. The results suggested that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-101/Nrf2 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma. PMID:29137246

Notch3 negatively regulates chemoresistance in breast cancers.

PubMed

Gu, Xiaoting; Lu, Chunxiao; He, Dongxu; Lu, Yangfan; Jin, Jian; Liu, Dequan; Ma, Xin

2016-10-14

To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells. Increased Fra1 activated the EMT process. Finally, Notch3 expression was confirmed in clinically chemoresistant samples of breast cancers from patients receiving anthracycline-based chemotherapy. Low expression of Notch3 was an unfavorable predictor of distant relapse-free survival in ER positive breast cancers. Taken together, our findings demonstrate that the Notch3-Fra1 signaling pathway mediates chemoresistance via the EMT.

Prognostic performance of multiple biomarkers in patients with non-ST-segment elevation acute coronary syndrome: analysis from the MERLIN-TIMI 36 trial (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36).

PubMed

O'Malley, Ryan G; Bonaca, Marc P; Scirica, Benjamin M; Murphy, Sabina A; Jarolim, Petr; Sabatine, Marc S; Braunwald, Eugene; Morrow, David A

2014-04-29

The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year. A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF(copeptin: 13.2% vs. 5.0%, p < 0.001; MR-proADM: 15.8% vs. 4.1%, p < 0.001; MR-proANP: 17.7% vs. 3.5%, p < 0.001)as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001).These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year(all categorical NRI >10%, p < 0.001), and maintained independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus BNP, cTnI, ST2, PAPP-A, and MPO (each p≤0.01) [corrected]. Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

PubMed Central

Semedo, Patricia; Buscariollo, Bruna N.; Donizetti-Oliveira, Cassiano; Cenedeze, Marcos A.; Soares, Maria Fernanda; Pacheco-Silva, Alvaro; Savage, Paul B.; Câmara, Niels O. S.; Keller, Alexandre C.

2012-01-01

A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1α, IL-1β, IL-17, TNF-α, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-β, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-β through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management. PMID:22427838

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

PubMed Central

Kumar, Ramiya; Mota, Linda C.; Litoff, Elizabeth J.; Rooney, John P.; Boswell, W. Tyler; Courter, Elliott; Henderson, Charles M.; Hernandez, Juan P.; Corton, J. Christopher; Moore, David D.

2017-01-01

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice. PMID:28350814

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.

PubMed

Kumar, Ramiya; Mota, Linda C; Litoff, Elizabeth J; Rooney, John P; Boswell, W Tyler; Courter, Elliott; Henderson, Charles M; Hernandez, Juan P; Corton, J Christopher; Moore, David D; Baldwin, William S

2017-01-01

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

Pattern Differences of Small Hand Muscle Atrophy in Amyotrophic Lateral Sclerosis and Mimic Disorders.

PubMed

Fang, Jia; Liu, Ming-Sheng; Guan, Yu-Zhou; Du, Hua; Li, Ben-Hong; Cui, Bo; Ding, Qing-Yun; Cui, Li-Ying

2016-04-05

Amyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. We compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. The ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P < 0.001) than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (P < 0.001) and the HD patients (P < 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients (P = 0.004). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P < 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls (P = 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥4.5) were observed exclusively in the ALS patients. The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.

Cardiac biomarkers, mortality, and post-traumatic stress disorder in military veterans.

PubMed

Xue, Yang; Taub, Pam R; Iqbal, Navaid; Fard, Arrash; Wentworth, Bailey; Redwine, Laura; Clopton, Paul; Stein, Murray; Maisel, Alan

2012-04-15

Post-traumatic stress disorder (PTSD) is gaining increasing recognition as a risk factor for morbidity and mortality. The aim of this study was to examine the impact of PTSD and abnormal cardiovascular biomarkers on mortality in military veterans. Eight hundred ninety-one patients presenting for routine echocardiography were enrolled. Baseline clinical data and serum samples for biomarker measurement were obtained and echocardiography was performed at the time of enrollment. Patients were followed for up to 7.5 years for the end point of all-cause mortality. Ninety-one patients had PTSD at the time of enrollment. There were 33 deaths in patients with PTSD and 221 deaths in those without PTSD. Patients with PTSD had a trend toward worse survival on Kaplan-Meier analysis (p = 0.057). Among patients with elevated B-type natriuretic peptide (>60 pg/ml), those with PTSD had significantly increased mortality (p = 0.024). Among patients with PTSD, midregional proadrenomedullin (MR-proADM), creatinine, and C-terminal proendothelin-1 were significant univariate predictors of mortality (p = 0.006, p = 0.024, and p = 0.003, respectively). In a multivariate model, PTSD, B-type natriuretic peptide, and MR-proADM were independent predictors of mortality. In patients with PTSD, MR-proADM was a significant independent predictor of mortality after adjusting for B-type natriuretic peptide, cardiovascular risk factors, cancer, and sleep apnea. Adding MR-proADM to clinical predictors of mortality increased the C-statistic from 0.572 to 0.697 (p = 0.007). In conclusion, this study demonstrates an association among PTSD, abnormal cardiac biomarker levels, and increased mortality. Copyright © 2012 Elsevier Inc. All rights reserved.

Essential Set of Molecular Descriptors for ADME Prediction in Drug and Environmental Chemical Space

EPA Science Inventory

Historically, the disciplines of pharmacology and toxicology have embraced quantitative structure-activity relationships (QSAR) and quantitative structure-property relationships (QSPR) to predict ADME properties or biological activities of untested chemicals. The question arises ...

Effectiveness of Acellular Dermal Matrix on Autologous Split-Thickness Skin Graft in Treatment of Deep Tissue Defect: Esthetic Subjective and Objective Evaluation.

PubMed

Lee, Yoo Jung; Park, Myong Chul; Park, Dong Ha; Hahn, Hyung Min; Kim, Sue Min; Lee, Il Jae

2017-10-01

A split-thickness skin graft (STSG) is performed to cover a large full-thickness skin defect. Esthetic and functional deficits can result, and many studies have sought to overcome them. This study compared the effectiveness of the acellular dermal matrix (ADM) graft and STSG concerning esthetic and functional effectiveness of ADM on scar quality. Of the patients who underwent anterolateral thigh free flap from 2011 to 2015, patients who received skin graft only (n = 10) or skin graft with ADM (n = 20) for coverage of the donor site were enrolled. In all cases, autologous STSG was performed with 1:1.5 meshed 0.008-0.010-inch-thick skin. In the skin graft with ADM group, 0.008-0.013-inch-thick meshed ADM (CGderm ® ; CGBio, Inc., Seungnam, Korea) was co-grafted. Negative-pressure wound therapy (CuraVAC ® ; CGBio, Inc., Seungnam, Korea) was applied to both groups in continuous mode at -120 mmHg. We investigate early outcomes (skin loss rate, duration of negative-pressure wound therapy, days to removal of stitches, days to achieve complete healing, and complications) and late outcomes in terms of scar quality (vascularity, pigmentation, pliability and height) and graft-related symptoms (itching sensation and pain). Assessments used the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale. Skin fold was measured to evaluate the elasticity of scar tissue. In the Vancouver Scar Scale, vascularity subscore (p = 0.003) and total score (p = 0.016) were significantly lower in the skin graft with ADM group. In Patient and Observer Scar Assessment Scale, the pain (p = 0.037) and stiffness subscores (p = 0.002), and total score (p = 0.017) were significantly lower in the skin graft with ADM group. Skin graft with ADM results in better scar quality in objective and subjective aspects. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse/recurrence: results of a randomised controlled trial (the PREVENT study).

PubMed

Kuyken, Willem; Hayes, Rachel; Barrett, Barbara; Byng, Richard; Dalgleish, Tim; Kessler, David; Lewis, Glyn; Watkins, Edward; Morant, Nicola; Taylor, Rod S; Byford, Sarah

2015-09-01

Individuals with a history of recurrent depression have a high risk of repeated depressive relapse/recurrence. Maintenance antidepressant medication (m-ADM) for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to m-ADM. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce the risk of relapse/recurrence compared with usual care but has not yet been compared with m-ADM in a definitive trial. To establish whether MBCT with support to taper and/or discontinue antidepressant medication (MBCT-TS) is superior to and more cost-effective than an approach of m-ADM in a primary care setting for patients with a history of recurrent depression followed up over a 2-year period in terms of preventing depressive relapse/recurrence. Secondary aims examined MBCT's acceptability and mechanism of action. Single-blind, parallel, individual randomised controlled trial. UK general practices. Adult patients with a diagnosis of recurrent depression and who were taking m-ADM. Participants were randomised to MBCT-TS or m-ADM with stratification by centre and symptomatic status. Outcome data were collected blind to treatment allocation and the primary analysis was based on the principle of intention to treat. Process studies using quantitative and qualitative methods examined MBCT's acceptability and mechanism of action. The primary outcome measure was time to relapse/recurrence of depression. At each follow-up the following secondary outcomes were recorded: number of depression-free days, residual depressive symptoms, quality of life, health-related quality of life and psychiatric and medical comorbidities. In total, 212 patients were randomised to MBCT-TS and 212 to m-ADM. The primary analysis did not find any evidence that MBCT-TS was superior to m-ADM in terms of the primary outcome of time to depressive relapse/recurrence over 24 months [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.67 to 1.18] or for any of the secondary outcomes. Cost-effectiveness analysis did not support the hypothesis that MBCT-TS is more cost-effective than m-ADM in terms of either relapse/recurrence or quality-adjusted life-years. In planned subgroup analyses, a significant interaction was found between treatment group and reported childhood abuse (HR 1.89, 95% CI 1.06 to 3.38), with delayed time to relapse/recurrence for MBCT-TS participants with a more abusive childhood compared with those with a less abusive history. Although changes in mindfulness were specific to MBCT (and not m-ADM), they did not predict outcome in terms of relapse/recurrence at 24 months. In terms of acceptability, the qualitative analyses suggest that many people have views about (dis)/continuing their ADM, which can serve as a facilitator or a barrier to taking part in a trial that requires either continuation for 2 years or discontinuation. There is no support for the hypothesis that MBCT-TS is superior to m-ADM in preventing depressive relapse/recurrence among individuals at risk for depressive relapse/recurrence. Both treatments appear to confer protection against relapse/recurrence. There is an indication that MBCT may be most indicated for individuals at greatest risk of relapse/recurrence. It is important to characterise those most at risk and carefully establish if and why MBCT may be most indicated for this group. Current Controlled Trials ISRCTN26666654. This project was funded by the NIHR Health Technology Assessment programme and the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care South West Peninsula and will be published in full in Health Technology Assessment; Vol. 19, No. 73. See the NIHR Journals Library website for further project information.

In vivo drug metabolite identification in preclinical ADME studies by means of UPLC/TWIMS/high resolution-QTOF MS(E) and control comparison: cost and benefit of vehicle-dosed control samples.

PubMed

Fiebig, Lukas; Laux, Ralf; Binder, Rudolf; Ebner, Thomas

2016-10-01

1. Liquid chromatography (LC)-high resolution mass spectrometry (HRMS) techniques proved to be well suited for the identification of predicted and unexpected drug metabolites in complex biological matrices. 2. To efficiently discriminate between drug-related and endogenous matrix compounds, however, sophisticated postacquisition data mining tools, such as control comparison techniques are needed. For preclinical absorption, distribution, metabolism and excretion (ADME) studies that usually lack a placebo-dosed control group, the question arises how high-quality control data can be yielded using only a minimum number of control animals. 3. In the present study, the combination of LC-traveling wave ion mobility separation (TWIMS)-HRMS(E) and multivariate data analysis was used to study the polymer patterns of the frequently used formulation constituents polyethylene glycol 400 and polysorbate 80 in rat plasma and urine after oral and intravenous administration, respectively. 4. Complex peak patterns of both constituents were identified underlining the general importance of a vehicle-dosed control group in ADME studies for control comparison. Furthermore, the detailed analysis of administration route, blood sampling time and gender influences on both vehicle peak pattern as well as endogenous matrix background revealed that high-quality control data is obtained when (i) control animals receive an intravenous dose of the vehicle, (ii) the blood sampling time point is the same for analyte and control sample and (iii) analyte and control samples of the same gender are compared.

Modelling phosphorus (P), sulfur (S) and iron (Fe) interactions for dynamic simulations of anaerobic digestion processes.

PubMed

Flores-Alsina, Xavier; Solon, Kimberly; Kazadi Mbamba, Christian; Tait, Stephan; Gernaey, Krist V; Jeppsson, Ulf; Batstone, Damien J

2016-05-15

This paper proposes a series of extensions to functionally upgrade the IWA Anaerobic Digestion Model No. 1 (ADM1) to allow for plant-wide phosphorus (P) simulation. The close interplay between the P, sulfur (S) and iron (Fe) cycles requires a substantial (and unavoidable) increase in model complexity due to the involved three-phase physico-chemical and biological transformations. The ADM1 version, implemented in the plant-wide context provided by the Benchmark Simulation Model No. 2 (BSM2), is used as the basic platform (A0). Three different model extensions (A1, A2, A3) are implemented, simulated and evaluated. The first extension (A1) considers P transformations by accounting for the kinetic decay of polyphosphates (XPP) and potential uptake of volatile fatty acids (VFA) to produce polyhydroxyalkanoates (XPHA) by phosphorus accumulating organisms (XPAO). Two variant extensions (A2,1/A2,2) describe biological production of sulfides (SIS) by means of sulfate reducing bacteria (XSRB) utilising hydrogen only (autolithotrophically) or hydrogen plus organic acids (heterorganotrophically) as electron sources, respectively. These two approaches also consider a potential hydrogen sulfide ( [Formula: see text] inhibition effect and stripping to the gas phase ( [Formula: see text] ). The third extension (A3) accounts for chemical iron (III) ( [Formula: see text] ) reduction to iron (II) ( [Formula: see text] ) using hydrogen ( [Formula: see text] ) and sulfides (SIS) as electron donors. A set of pre/post interfaces between the Activated Sludge Model No. 2d (ASM2d) and ADM1 are furthermore proposed in order to allow for plant-wide (model-based) analysis and study of the interactions between the water and sludge lines. Simulation (A1 - A3) results show that the ratio between soluble/particulate P compounds strongly depends on the pH and cationic load, which determines the capacity to form (or not) precipitation products. Implementations A1 and A2,1/A2,2 lead to a reduction in the predicted methane/biogas production (and potential energy recovery) compared to reference ADM1 predictions (A0). This reduction is attributed to two factors: (1) loss of electron equivalents due to sulfate [Formula: see text] reduction by XSRB and storage of XPHA by XPAO; and, (2) decrease of acetoclastic and hydrogenotrophic methanogenesis due to [Formula: see text] inhibition. Model A3 shows the potential for iron to remove free SIS (and consequently inhibition) and instead promote iron sulfide (XFeS) precipitation. It also reduces the quantities of struvite ( [Formula: see text] ) and calcium phosphate ( [Formula: see text] ) that are formed due to its higher affinity for phosphate anions. This study provides a detailed analysis of the different model assumptions, the effect that operational/design conditions have on the model predictions and the practical implications of the proposed model extensions in view of plant-wide modelling/development of resource recovery strategies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Agricultural Drainage Management Systems Task Force (ADMSTF)

USDA-ARS?s Scientific Manuscript database

The Agricultural Drainage Management Systems (ADMS) Task Force was initiated during a Charter meeting in the fall of 2002 by dedicated professional employees of Federal, State, and Local Government Agencies and Universities. The Agricultural Drainage Management (ADM) Coalition was established in 200...

All-dielectric metamaterial frequency selective surface

NASA Astrophysics Data System (ADS)

Wang, Jun; Qu, Shaobo; Li, Liyang; Wang, Jiafu; Feng, Mingde; Ma, Hua; Du, Hongliang; Xu, Zhuo

Frequency selective surface (FSS) has been extensively studied due to its potential applications in radomes, antenna reflectors, high-impedance surfaces and absorbers. Recently, a new principle of designing FSS has been proposed and mainly studied in two levels. In the level of materials, dielectric materials instead of metallic patterns are capable of achieving more functional performance in FSS design. Moreover, FSSs made of dielectric materials can be used in different extreme environments, depending on their electrical, thermal or mechanical properties. In the level of design principle, the theory of metamaterial can be used to design FSS in a convenient and concise way. In this review paper, we provide a brief summary about the recent progress in all-dielectric metamaterial frequency selective surface (ADM-FSS). The basic principle of designing ADM-FSS is summarized. As significant tools, Mie theory and dielectric resonator (DR) theory are given which illustrate clearly how they are used in the FSS design. Then, several design cases including dielectric particle-based ADM-FSS and dielectric network-based ADM-FSS are introduced and reviewed. After a discussion of these two types of ADM-FSSs, we reviewed the existing fabrication techniques that are used in building the experiment samples. Finally, issues and challenges regarding the rapid fabrication techniques and further development aspects are discussed.

A two-year prospective study of coronally positioned flap with or without acellular dermal matrix graft.

PubMed

de Queiroz Côrtes, Antonieta; Sallum, Antonio Wilson; Casati, Marcio Z; Nociti, Francisco H; Sallum, Enilson A

2006-09-01

Evaluation of the treatment of gingival recessions with coronally positioned flap with or without acellular dermal matrix allograft (ADM) after a period of 24 months. Thirteen patients with bilateral gingival recessions were included. The defects were randomly assigned to one of the treatments: coronally positioned flap plus ADM or coronally positioned flap alone. The clinical measurements were taken before the surgeries and after 6, 12 and 24 months. At baseline, the mean values for recession height were 3.46 and 3.58 mm for the defects treated with and without the graft, respectively (p>0.05). No significant differences between the groups were observed after 6 and 12 months in this parameter. However, after 24 months, the group treated with coronally positioned flap alone showed a greater recession height when compared with the group treated with ADM (1.62 and 1.15 mm, respectively--p<0.05). A significant increase in the thickness of keratinized tissue was observed in the group treated with ADM as compared with coronally positioned flap alone (p<0.05). ADM may reduce the residual gingival recession observed after 24 months in defects treated with coronally positioned flap. In addition, a greater gingival thickness may be achieved when the graft is used.

The cost effectiveness of acellular dermal matrix in expander-implant immediate breast reconstruction.

PubMed

Krishnan, Naveen M; Chatterjee, Abhishek; Rosenkranz, Kari M; Powell, Stephen G; Nigriny, John F; Vidal, Dale C

2014-04-01

Expander-implant breast reconstruction is often supplemented with acellular dermal matrix (ADM). The use of acellular dermal matrix has allowed for faster, less painful expansions and improved aesthetics, but with increased cost. Our goal was to provide the first cost utility analysis of using acellular dermal matrix in two-stage, expander-implant immediate breast reconstruction following mastectomy. A comprehensive literature review was conducted to identify complication rates for two-stage, expander-implant immediate breast reconstruction with and without acellular dermal matrix. The probabilities of the most common complications were combined with Medicare Current Procedural Terminology reimbursement codes and expert utility estimates to fit into a decision model. The decision model evaluated the cost effectiveness of acellular dermal matrix relative to reconstructions without it. Retail costs for ADM were derived from the LifeCell 2012 company catalogue for Alloderm. The overall complication rates were 30% and 34.5% with and without ADM. The decision model revealed a baseline cost increase of $361.96 when acellular dermal matrix is used. The increase in Quality-Adjusted Life Years (QALYs) is 1.37 in the population with acellular dermal matrix. This yields a cost effective incremental cost-utility ratio (ICUR) of $264.20/QALY. Univariate sensitivity analysis confirmed that using acellular dermal matrix is cost effective even when using retail costs for unilateral and bilateral reconstructions. Our study shows that, despite an increased cost, acellular dermal matrix is a cost effective technology for patients undergoing two-stage, expander-implant immediate breast reconstruction due to its increased utility in successful procedures. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Multi-Segment Radius Measurement Using an Absolute Distance Meter Through a Null Assembly

NASA Technical Reports Server (NTRS)

Merle, Cormic; Wick, Eric; Hayden, Joseph

2011-01-01

This system was one of the test methods considered for measuring the radius of curvature of one or more of the 18 segmented mirrors that form the 6.5 m diameter primary mirror (PM) of the James Webb Space Telescope (JWST). The assembled telescope will be tested at cryogenic temperatures in a 17-m diameter by 27-m high vacuum chamber at the Johnson Space Center. This system uses a Leica Absolute Distance Meter (ADM), at a wavelength of 780 nm, combined with beam-steering and beam-shaping optics to make a differential distance measurement between a ring mirror on the reflective null assembly and individual PM segments. The ADM is located inside the same Pressure-Tight Enclosure (PTE) that houses the test interferometer. The PTE maintains the ADM and interferometer at ambient temperature and pressure so that they are not directly exposed to the telescope s harsh cryogenic and vacuum environment. This system takes advantage of the existing achromatic objective and reflective null assembly used by the test interferometer to direct four ADM beamlets to four PM segments through an optical path that is coincident with the interferometer beam. A mask, positioned on a linear slide, contains an array of 1.25 mm diameter circular subapertures that map to each of the 18 PM segments as well as six positions around the ring mirror. A down-collimated 4 mm ADM beam simultaneously covers 4 adjacent PM segment beamlets and one ring mirror beamlet. The radius, or spacing, of all 18 segments can be measured with the addition of two orthogonally-oriented scanning pentaprisms used to steer the ADM beam to any one of six different sub-aperture configurations at the plane of the ring mirror. The interferometer beam, at a wavelength of 687 nm, and the ADM beamlets, at a wavelength of 780 nm, pass through the objective and null so that the rays are normally incident on the parabolic PM surface. After reflecting off the PM, both the ADM and interferometer beams return to their respective instruments on nearly the same path. A fifth beamlet, acting as a differential reference, reflects off a ring mirror attached to the objective and null and returns to the ADM. The spacings between the ring mirror, objective, and null are known through manufacturing tolerances as well as through an in situ null wavefront alignment of the interferometer test beam with a reflective hologram located near the caustic of the null. Since total path length between the ring mirror and PM segments is highly deterministic, any ADM-measured departures from the predicted path length can be attributed to either spacing error or radius error in the PM. It is estimated that the path length measurement between the ring mirror and a PM segment is accurate to better than 100 m. The unique features of this invention include the differential distance measuring capability and its integration into an existing cryogenic and vacuum compatible interferometric optical test.

Distributed Common Ground System Army Increment 1 (DCGS-A Inc 1)

DTIC Science & Technology

2016-03-01

Acquisition Executive DoD - Department of Defense DoDAF - DoD Architecture Framework FD - Full Deployment FDD - Full Deployment Decision FY - Fiscal...updated prior to the FDD ITAB in December 2012 and provided additional COA analysis/validation referenced in the FDD ADM (December 14, 2012) and FDD ...required by 10 U.S.C. 2334(a)(6). The Army Cost Review Board developed the FDD Army Cost Position (ACP), dated October 19, 2012, through the update of

JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma.

PubMed

Maia, Lucas de Lima; Peterle, Gabriela Tonini; Dos Santos, Marcelo; Trivilin, Leonardo Oliveira; Mendes, Suzanny Oliveira; de Oliveira, Mayara Mota; Dos Santos, Joaquim Gasparini; Stur, Elaine; Agostini, Lidiane Pignaton; Couto, Cinthia Vidal Monteiro da Silva; Dalbó, Juliana; de Assis, Aricia Leone Evangelista Monteiro; Archanjo, Anderson Barros; Mercante, Ana Maria Da Cunha; Lopez, Rossana Veronica Mendoza; Nunes, Fábio Daumas; de Carvalho, Marcos Brasilino; Tajara, Eloiza Helena; Louro, Iúri Drumond; Álvares-da-Silva, Adriana Madeira

2018-01-01

Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. JMJD1A gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types. We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffin-embedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk. JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets.

JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma

PubMed Central

Peterle, Gabriela Tonini; dos Santos, Marcelo; Trivilin, Leonardo Oliveira; Mendes, Suzanny Oliveira; de Oliveira, Mayara Mota; dos Santos, Joaquim Gasparini; Stur, Elaine; Agostini, Lidiane Pignaton; Couto, Cinthia Vidal Monteiro da Silva; Dalbó, Juliana; de Assis, Aricia Leone Evangelista Monteiro; Archanjo, Anderson Barros; Mercante, Ana Maria Da Cunha; Lopez, Rossana Veronica Mendoza; Nunes, Fábio Daumas; de Carvalho, Marcos Brasilino; Tajara, Eloiza Helena; Louro, Iúri Drumond; Álvares-da-Silva, Adriana Madeira

2018-01-01

Aims Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. JMJD1A gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types. Methods and results We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffin-embedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk. Conclusion JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets. PMID:29590186

Comparative evaluation of free gingival graft and AlloDerm® in enhancing the width of attached gingival: A clinical study

PubMed Central

Agarwal, Chitra; Tarun Kumar, A. B.; Mehta, Dhoom Singh

2015-01-01

Background: The presence of an adequate width of keratinized tissue is important to maintain a healthy dentogingival junction. In case of inadequate width of attached gingiva, the gingival augmentation procedure has been performed classically using the patient's own masticatory mucosa and more recently, using an acellular dermal allograft as the donor material. Aims: The aim of the clinical study was to evaluate and compare the effectiveness of free gingival graft (FGG) and acellular dermal matrix (ADM) allograft in the ability to increase the zone of attached gingiva. Materials and Methods: Fifteen patients with 30 sites showing the inadequate width of attached gingiva (≤1 mm) were enrolled for the split-mouth study. The width of keratinized gingiva and other clinical parameters were recorded at baseline and 12th month postoperatively. Statistical Analysis: The difference in clinical parameters within the group was assessed by Wilcoxon signed rank test. However, Mann–Whitney U-test was used to analyze the differences between test and control groups. Results: The width of attached gingiva increased significantly (P < 0.01) following both the treatments but comparatively lesser gain with ADM allograft (2.13 mm vs. 4.8 mm). ADM site had significantly more shrinkage (76.6%) than FGG site (49.7%). Though FGG was found to be more effective, clinicians can prefer ADM allograft because of its certain advantages over the FGG. Conclusion: ADM allograft has resulted in sufficient increase in width of attached gingiva although lesser than FGG. Considering the disadvantages of FGG, it can be concluded that ADM allograft can be used as an alternative to FGG in increasing width of attached gingival in certain clinical situations. PMID:26681852

Label-free image-based detection of drug resistance with optofluidic time-stretch microscopy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kobayashi, Hirofumi; Lei, Cheng; Mao, Ailin; Jiang, Yiyue; Guo, Baoshan; Ozeki, Yasuyuki; Goda, Keisuke

2017-02-01

Acquired drug resistance is a fundamental predicament in cancer therapy. Early detection of drug-resistant cancer cells during or after treatment is expected to benefit patients from unnecessary drug administration and thus play a significant role in the development of a therapeutic strategy. However, the development of an effective method of detecting drug-resistant cancer cells is still in its infancy due to their complex mechanism in drug resistance. To address this problem, we propose and experimentally demonstrate label-free image-based drug resistance detection with optofluidic time-stretch microscopy using leukemia cells (K562 and K562/ADM). By adding adriamycin (ADM) to both K562 and K562/ADM (ADM-resistant K562 cells) cells, both types of cells express unique morphological changes, which are subsequently captured by an optofluidic time-stretch microscope. These unique morphological changes are extracted as image features and are subjected to supervised machine learning for cell classification. We hereby have successfully differentiated K562 and K562/ADM solely with label-free images, which suggests that our technique is capable of detecting drug-resistant cancer cells. Our optofluidic time-stretch microscope consists of a time-stretch microscope with a high spatial resolution of 780 nm at a 1D frame rate of 75 MHz and a microfluidic device that focuses and orders cells. We compare various machine learning algorithms as well as various concentrations of ADM for cell classification. Owing to its unprecedented versatility of using label-free image and its independency from specific molecules, our technique holds great promise for detecting drug resistance of cancer cells for which its underlying mechanism is still unknown or chemical probes are still unavailable.

[Effects of intrasplenic transplantation of IL-18 gene-modified fetal hepatocytes on mouse immune function

PubMed

Yao, Hang-Ping; Zhang, Li-Huang; Sun, Wen-Ji; Leng, Jian-Hang

2002-04-01

OBJECTIVE: To investigate the effects of IL-18 gene-modified fetal hepatocytes (AdmIL-18/MNL.CL2) intrasplenic transplantation on mouse immune function. METHODS: Forty mice were evenly divided into 4 groups of 10. Each group received an intrasplenic transplantation one of the following: AdmIL-18/BNL.CL2, Ad-LacZ/BNL.CL2 (virus control), BNL.CL2 (cell control) and PBS (blank control). After two weeks, the mice were sacrificed. Serum cytokine levels, Mpsi and splenic cell culture supernatant and liver tissue extracts supernatants were measured using ELISA. Hepatic cytokines mRNA expression were determined by RT-PCR. THe cytotoxicity of peritoneal Mpsi and NK activity of spienocytes were detected by LDH release assay. The proliferation of splenic lymphocytes was determined by MTT assay. RESULTS: The IL-18, IL-2,IFN-gamma, TNF-alpha levels of serum, Mpsi and splenocyte culture supernatant, liver tissue extracts supernatants in mice transplanted with AdmIL-18/BNL.CL2 were higher and the IL-4, IL-10 levels were lower compared to their levels in other 3 groups. The highest IL-18, IL-2, IFN-gamma, TNF-alpha and the lowest IL-4, IL-10 mRNA expressions in the liver were observed in mice transplanted with AdmIL-18/BNL.CL2. The mice transplanted with AdmIL-18/BNL.Cl2 showed significantly increases cytotoxicity of Mpsi, NK activity and splenic cell proliferation compared with the other 3 groups. CONCLUSION: AdmIL-18 can be effectively transfected into mice fetal heptocytes which subsequently IL-18. Intransplenic transplantation of IL-18 gene-modified fetal hepatocytes may augment mouse immune function and provide an useful basis for targeted gene therapy of liver disease.

Correlation of inflammatory and cardiovascular biomarkers with pneumonia severity scores.

PubMed

Lacoma, Alicia; Bas, Albert; Tudela, Pere; Giménez, Montse; Mòdol, Josep Maria; Pérez, Miguel; Ausina, Vicente; Dominguez, Jose; Prat-Aymerich, Cristina

2014-03-01

To assess the correlation of procalcitonin (PCT), C-reactive protein (CRP), neopterin, mid-regional pro-atrial natriuretic peptide (MR-proANP), and mid-regional pro-adrenomedullin (MR-proADM) with severity risk scores: severe CAP (SCAP) and SMART-COP in patients with community-acquired pneumonia (CAP), as well as short term prognosis and to determine the correlation with mortality risk scores. Eighty-five patients with a final diagnosis of pneumonia were consecutively included during a two month period. Epidemiological, clinical, microbiological, and radiological data were recorded. Patients were stratified according to the PSI, CURB-65, SCAP and SMART-COP. Complications were defined as respiratory failure/shock, need of ICU, and death. Plasma samples were collected at admission. MR-proANP and MR-proADM showed significantly higher levels in high risk SCAP group in comparison to low risk. When considering SMART-COP none of the biomarkers showed statistical differences. MR-proADM levels were high in patients with high risk of needing intensive respiratory or vasopressor support according to SMRT-CO. Neopterin and MR-proADM were significantly higher in patients that developed complications. PCT and MR-proADM showed significantly higher levels in cases of a definite bacterial diagnosis in comparison to probable bacterial, and unknown origin. MR-proANP and MR-proADM levels increased statistically according to PSI and CURB-65. Biomarker levels are higher in pneumonia patients with a poorer prognosis according to SCAP and SMART-COP indexes, and to the development of complications. Copyright © 2013 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Evidence that exercise-induced heat storage is dependent on adrenomedullary secretion.

PubMed

Rodrigues, A G; Lima, N R V; Coimbra, C C; Marubayashi, U

2008-06-09

To investigate the influence of medullary adrenal secretion on thermoregulation during exercise, Phy (Eserine, 5x10(-3) M) was injected into the lateral cerebral ventricle of normal (INT) or bilaterally adrenodemedullated (ADM) untrained rats. Body temperature (Tb) and metabolic rate were measured in the rats while they were exercising on a treadmill (20 m min(-1), 5% inclination) until fatigue or while they were at rest after drug injection. In resting rats, Phy increased oxygen consumption in both INT or ADM rats without any effect on core temperature. During the dynamic phase of exercise (first 20 min), ADM attenuated the exercise-induced increase in core temperature (0.86+/-0.12 degrees C ADM Sal vs 1.48+/-0.21 degrees C INT Sal), thus reducing heat storage (HS) levels. Icv injection of Phy in ADM rats significantly reduced the increase in Tb (0.012+/-0.10 degrees C min(-1) Phy vs 0.042+/-0.006 degrees C min(-1) Sal; p<0.02) and HS (65.8+/-56.1 cal Phy vs 207.7+/-32.7 cal Sal; p<0.04) compared to ADM Sal rats. In conclusion, the exercise-induced increase in heat storage was attenuated by adrenodemedullation in rats. Furthermore, the activation of heat loss mechanisms by the central cholinergic system during exercise occurs independently of adrenal medullary secretion suppression and can be improved by previous adrenodemedullation. Our data indicate the existence of a dual mechanism of heat loss control during the dynamic phase of exercise: one involving sympathoadrenal system activation that impairs heat loss and another that counteracts the increased sympathoadrenal activity through the hypothalamic cholinergic system to promote heat loss.

Effects of onion extract on endogenous vascular H2S and adrenomedulin in rat atherosclerosis.

PubMed

Li, Wei; Tang, Chaoshu; Jin, Hongfang; Du, Junbao

2011-09-01

This study aimed to explore the effect of onion extract on endogenous hydrogen sulfide (H2S) and adrenomedulin (ADM) and on atherosclerotic progression in rats with atherosclerosis (AS). Male Sprague-Dawley rats were randomly divided into control, AS and AS+onion groups. Ultrastructure of aorta and atherosclerotic lesions both in aorta and in coronary artery were detected. Plasma and aortic H2S were detected by using a sulfide- sensitive electrode. Plasma and aortic ADM was determined with radioimmunoassay. Cystathionine-γ-lyase (CSE), calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP1, RAMP2 and RAMP3) mRNA expressions were analysed. Glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and NO synthase (NOS) contents in plasma, SOD1, SOD2 and ICAM-1 expressions in aorta were detected. Rats in the AS group showed marked atherosclerotic lesions both in aorta and in coronary artery but decreased aortic H2S production. Decreased plasma and aortic ADM content, but increased levels of aortic CRLR, RAMP2 and RAMP3 mRNAs were observed. Plasma GSH-PX and SOD were reduced but MDA elevated. Plasma ICAM-1 and NO contents and iNOS activity were increased. Onion extract, however, lessened atherosclerotic lesions and increased endogenous aortic H2S production, but decreased plasma ADM content, aortic ADM content and aortic CRLR, RAMP2 and RAMP3 mRNAs. In addition, it increased plasma GSH-PX level and SOD activities but reduced MDA; it decreased inflammatory response but increased plasma eNOS activity and NO content. Onion extract exerted a marked antiatherogenic effect in association with the up-regulation of the endogenous CSE/H2S pathway but down-regulation of the ADM/CRLR family in atherosclerotic rats.

Root coverage using acellular dermal matrix and comparing a coronally positioned tunnel with and without platelet-rich plasma: a pilot study in humans.

PubMed

Shepherd, Neal; Greenwell, Henry; Hill, Margaret; Vidal, Ricardo; Scheetz, James P

2009-03-01

The primary aim of this randomized, controlled, blinded clinical pilot study was to compare the percentage of recession defect coverage obtained with a coronally positioned tunnel (CPT) plus an acellular dermal matrix allograft (ADM) to that of a CPT plus ADM and platelet-rich plasma (CPT/PRP) 4 months post-surgically. Eighteen patients with Miller Class I or II recession >or=3 mm at one site were treated and followed for 4 months. Nine patients received a CPT plus ADM and were considered the positive control group. The test group consisted of nine patients treated with a CPT plus ADM and PRP. Patients were randomly selected by a coin toss to receive the test or positive control treatment. The mean recession at the initial examination for the CPT group was 3.6 +/- 1.0 mm, which was reduced to 1.0 +/- 1.0 mm at the 4-month examination for a gain of 2.6 +/- 1.5 mm or 70% defect coverage (P <0.05). The mean recession at the initial examination for the CPT/PRP group was 3.3 +/- 0.7 mm, which was reduced to 0.4 +/- 0.7 mm at the 4-month examination for a gain of 2.9 +/- 0.5 mm or 90% defect coverage (P <0.05). There were no statistically significant differences between the groups (P >0.05). The CPT plus ADM and PRP produced defect coverage of 90%, whereas the CPT with ADM produced only 70% defect coverage. This difference was not statistically significant, but it may be clinically significant.

Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

PubMed Central

2014-01-01

A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitroP. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1. PMID:24689770

A review of nanoelectrospray ionization applications for drug metabolism and pharmacokinetics.

PubMed

Wickremsinhe, Enaksha R; Singh, Gurkeerat; Ackermann, Bradley L; Gillespie, Todd A; Chaudhary, Ajai K

2006-12-01

Although traditionally reserved for proteomic analysis, nanoESI has found increased use for small molecule applications related to drug metabolism/pharmacokinetics (DMPK). NanoESI, which refers to ESI performed at flow rates in the range of 200 to 1000 nL/min using smaller diameter emitters (10 to 100 microm id), produces smaller droplets than conventional ESI resulting in more efficient ionization. Benefits include greater sensitivity, enhanced dynamic range, and a reduced competition for ionization. These advantages may now be harnessed largely due to the introduction of a commercial system for automated nanoESI infusion. This development in turn has allowed ADME (absorption, distribution, metabolism, and excretion) scientists to consider novel approaches to mass spectrometric analysis without direct LC interfacing. While it is freely acknowledged that nanoESI infusion is not likely to supplant LC-MS as the primary analytical platform for ADME, nanoESI infusion has been successfully applied to both quantitative (bioanalysis) and qualitative (metabolite identification) applications. This review summarizes published applications of this technology and offers a perspective on where it fits best into the DMPK laboratory.

HIM-herbal ingredients in-vivo metabolism database.

PubMed

Kang, Hong; Tang, Kailin; Liu, Qi; Sun, Yi; Huang, Qi; Zhu, Ruixin; Gao, Jun; Zhang, Duanfeng; Huang, Chenggang; Cao, Zhiwei

2013-05-31

Herbal medicine has long been viewed as a valuable asset for potential new drug discovery and herbal ingredients' metabolites, especially the in vivo metabolites were often found to gain better pharmacological, pharmacokinetic and even better safety profiles compared to their parent compounds. However, these herbal metabolite information is still scattered and waiting to be collected. HIM database manually collected so far the most comprehensive available in-vivo metabolism information for herbal active ingredients, as well as their corresponding bioactivity, organs and/or tissues distribution, toxicity, ADME and the clinical research profile. Currently HIM contains 361 ingredients and 1104 corresponding in-vivo metabolites from 673 reputable herbs. Tools of structural similarity, substructure search and Lipinski's Rule of Five are also provided. Various links were made to PubChem, PubMed, TCM-ID (Traditional Chinese Medicine Information database) and HIT (Herbal ingredients' targets databases). A curated database HIM is set up for the in vivo metabolites information of the active ingredients for Chinese herbs, together with their corresponding bioactivity, toxicity and ADME profile. HIM is freely accessible to academic researchers at http://www.bioinformatics.org.cn/.

The Failing Campus Infrastructure: Is It Too Late?

ERIC Educational Resources Information Center

Medlin, E. Lander

2000-01-01

Discusses the extent of damage being caused to colleges and universities from accumulated deferred maintenance (ADM) and why it is happening. Public policy implications are discussed along with highlights from case studies of institutions that have used practical approaches to retire their ADMs. (GR)

Screening circular RNA related to chemotherapeutic resistance in breast cancer.

PubMed

Gao, Danfeng; Zhang, Xiufen; Liu, Beibei; Meng, Dong; Fang, Kai; Guo, Zijian; Li, Lihua

2017-09-01

We aimed to identify circular RNAs (circRNAs) associated with breast cancer chemoresistance. CircRNA microarray expression profiles were obtained from Adriamycin (ADM) resistant MCF-7 breast cancer cells (MCF-7/ADM) and parental MCF-7 cells and were validated using quantitative real-time reverse transcription PCR. The expression data were analyzed bioinformatically. We detected 3093 circRNAs and identified 18 circRNAs that are differentially expressed between MCF-7/ADM and MCF-7 cells; after validating by quantitative real-time reverse transcription PCR, we predicted the possible miRNAs and potential target genes of the seven upregulated circRNAs using TargetScan and miRanda. The bioinformatics analysis revealed several target genes related to cancer-related signaling pathways. Additionally, we discovered a regulatory role of the circ_0006528-miR-7-5p-Raf1 axis in ADM-resistant breast cancer. These results revealed that circRNAs may play a role in breast cancer chemoresistance and that hsa_circ_0006528 might be a promising candidate for further functional analysis.

Comparison of acellular dermal graft and palatal autograft in the reconstruction of keratinized gingiva around dental implants: a case report.

PubMed

Yan, Ji-Jong; Tsai, Alex Yi-Min; Wong, Man-Ying; Hou, Lein-Tuan

2006-06-01

The use of autogenous gingival grafts has proved to be an effective and predictable way to increase the amount of keratinized gingiva. However, discomfort and pain at the donor site are unavoidable. Acellular dermal matrix (ADM) allograft can be used as a donor tissue to eliminate the need for another surgical site and alleviate pain and trauma. The purpose of this study was to evaluate the effectiveness of ADM allograft in increasing the width of keratinized gingiva around dental implants. A patient with inadequate keratinized gingiva around dental implants in maxillary and mandibular anterior regions received either an ADM graft or palatal autograft by random allocation. The width of keratinized gingiva and other clinical periodontal parameters were recorded initially and at 3 and 6 months after surgery. Both grafts provided satisfactory results. The width of keratinized tissues was increased by using the ADM allograft, but by a lesser amount than seen with the autogenous gingival graft.

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models.

PubMed

Fortuna, Ana; Alves, Gilberto; Soares-da-Silva, Patrício; Falcão, Amílcar

2013-11-01

In silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models. For this purpose, a single dose of each compound (1.4mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure. The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (>0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05-0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma-protein bound fraction (>90%) herein revealed for the first time. The comparative in vivo pharmacokinetic data obtained in the present work might be usefully applied in the context of discovery of new antiepileptic drugs that are derivatives of CBZ. Copyright © 2013 Elsevier B.V. All rights reserved.

ADM-CLE Approach for Detecting Slow Variables in Continuous Time Markov Chains and Dynamic Data

DTIC Science & Technology

2015-04-01

Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, United Kingdom. E -mail: erban@maths.ox.ac.uk; Radek Erban would like to thank the Royal Society...more e cient than the ADM method for a large class of chemical reaction systems, because it replaces the computationally most expensive step of ADM...i.e., m = 4), given by ∅ k1 −→ X1 k2−→←− k3 X2 k4−→ ∅. (2.2) Throughout the rest of this paper, we shall refer to the chemical system (2.2) as CS-I (i.e

DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS

EPA Science Inventory

DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS
Pastoor, Timothy1, Barton, Hugh2
1 Syngenta Crop Protection, Greensboro, NC, USA.
2 EPA, Office of Research and Development-NHEERL, RTP, NC, USA.

A multi-stakeholder series of discussions d...

Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis.

PubMed

Bernal-Morell, Enrique; García-Villalba, Eva; Vera, Maria Del Carmen; Medina, Blanca; Martinez, Monica; Callejo, Victoria; Valero, Salvador; Cinesi, Cesar; Piñera, Pascual; Alcaraz, Antonia; Marin, Irene; Muñoz, Angeles; Cano, Alfredo

2018-03-01

Midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP) and sepsis. In this paper, we examined the ability of MR-proADM to predict organ damage and long-term mortality in sepsis patients, compared to that of procalcitonin, C-reactive protein and lactate. This was a prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to internal service department. The association between biomarkers and 90-day mortality was assessed by Cox regression analysis and Kaplan-Meier curves. The accuracy of biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. A total of 148 patients with severe sepsis, according to the criteria of the campaign to survive sepsis, were enrolled. Eighty-five (57.4%) had sepsis according to the new criteria of Sepsis-3. MR-proADM showed the best AUROC to predict sepsis as defined by the Sepsis-3 criteria (AUROC of 0.771, 95% CI 0.692-0.850, p <0.001) and was the only marker independently associated with Sepsis-3 criteria (OR = 4.78, 95% CI 2.25-10.14; p < 0.001) in multivariate analysis. MR-proADM was the biomarker with the best AUROC to predict mortality in 90 days (AUROC of 0.731, CI 95% 0.612-0.850, p <0.001) and was the only marker that kept its independence [hazard ratio (HR) of 1.4, 95% CI 1.2-1.64, p <0.001] in multivariate analysis. The cut-off point of MR-proADM of 1.8 nmol/L (HR of 4.65, 95% CI 6.79-10.1, p < 0.001) was the one that had greater discriminative capacity to predict 90 days mortality. All patients with MR-proADM concentrations ≤0.60 nmol/L survived up to 90 days. In patients with SOFA ≤ 6, the addition of MR-proADM to SOFA score increased the ability of SOFA to identify non-survivors, AUROC of 0.65 (CI 95% 0.537-0.764) and AUROC of 0.700 (CI 95% 0.594-0.800), respectively (p < 0.05 for both). MR-proADM is a good biomarker in the early identification of high risk septic patients and may contribute to improve the predictive capacity of SOFA scale, especially when scores are low. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

ADM3, TFF3 and LGALS3 are discriminative molecular markers in fine-needle aspiration biopsies of benign and malignant thyroid tumours

PubMed Central

Karger, S; Krause, K; Gutknecht, M; Schierle, K; Graf, D; Steinert, F; Dralle, H; Führer, D

2012-01-01

Background: Previously, we reported a six-marker gene set, which allowed a molecular discrimination of benign and malignant thyroid tumours. Now, we evaluated these markers in fine-needle aspiration biopsies (FNAB) in a prospective, independent series of thyroid tumours with proven histological outcome. Methods: Quantitative RT–PCR was performed (ADM3, HGD1, LGALS3, PLAB, TFF3, TG) in the needle wash-out of 156 FNAB of follicular adenoma (FA), adenomatous nodules, follicular and papillary thyroid cancers (TC) and normal thyroid tissues (NT). Results: Significant expression differences were found for TFF3, HGD1, ADM3 and LGALS3 in FNAB of TC compared with benign thyroid nodules and NT. Using two-marker gene sets, a specific FNAB distinction of benign and malignant tumours was achieved with negative predictive values (NPV) up to 0.78 and positive predictive values (PPV) up to 0.84. Two FNAB marker gene combinations (ADM3/TFF3; ADM3/ACTB) allowed the distinction of FA and malignant follicular neoplasia with NPV up to 0.94 and PPV up to 0.86. Conclusion: We demonstrate that molecular FNAB diagnosis of benign and malignant thyroid tumours including follicular neoplasia is possible with recently identified marker gene combinations. We propose multi-centre FNAB studies on these markers to bring this promising diagnostic tool closer to clinical practice. PMID:22223087

Hamiltonian dynamics of extended objects

NASA Astrophysics Data System (ADS)

Capovilla, R.; Guven, J.; Rojas, E.

2004-12-01

We consider relativistic extended objects described by a reparametrization-invariant local action that depends on the extrinsic curvature of the worldvolume swept out by the object as it evolves. We provide a Hamiltonian formulation of the dynamics of such higher derivative models which is motivated by the ADM formulation of general relativity. The canonical momenta are identified by looking at boundary behaviour under small deformations of the action; the relationship between the momentum conjugate to the embedding functions and the conserved momentum density is established. The canonical Hamiltonian is constructed explicitly; the constraints on the phase space, both primary and secondary, are identified and the role they play in the theory is described. The multipliers implementing the primary constraints are identified in terms of the ADM lapse and shift variables and Hamilton's equations are shown to be consistent with the Euler Lagrange equations.

Kinetic modelling of anaerobic hydrolysis of solid wastes, including disintegration processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

García-Gen, Santiago; Sousbie, Philippe; Rangaraj, Ganesh

2015-01-15

Highlights: • Fractionation of solid wastes into readily and slowly biodegradable fractions. • Kinetic coefficients estimation from mono-digestion batch assays. • Validation of kinetic coefficients with a co-digestion continuous experiment. • Simulation of batch and continuous experiments with an ADM1-based model. - Abstract: A methodology to estimate disintegration and hydrolysis kinetic parameters of solid wastes and validate an ADM1-based anaerobic co-digestion model is presented. Kinetic parameters of the model were calibrated from batch reactor experiments treating individually fruit and vegetable wastes (among other residues) following a new protocol for batch tests. In addition, decoupled disintegration kinetics for readily and slowlymore » biodegradable fractions of solid wastes was considered. Calibrated parameters from batch assays of individual substrates were used to validate the model for a semi-continuous co-digestion operation treating simultaneously 5 fruit and vegetable wastes. The semi-continuous experiment was carried out in a lab-scale CSTR reactor for 15 weeks at organic loading rate ranging between 2.0 and 4.7 g VS/L d. The model (built in Matlab/Simulink) fit to a large extent the experimental results in both batch and semi-continuous mode and served as a powerful tool to simulate the digestion or co-digestion of solid wastes.« less

Modelling the energy balance of an anaerobic digester fed with cattle manure and renewable energy crops.

PubMed

Lübken, Manfred; Wichern, Marc; Schlattmann, Markus; Gronauer, Andreas; Horn, Harald

2007-10-01

Knowledge of the net energy production of anaerobic fermenters is important for reliable modelling of the efficiency of anaerobic digestion processes. By using the Anaerobic Digestion Model No. 1 (ADM1) the simulation of biogas production and composition is possible. This paper shows the application and modification of ADM1 to simulate energy production of the digestion of cattle manure and renewable energy crops. The paper additionally presents an energy balance model, which enables the dynamic calculation of the net energy production. The model was applied to a pilot-scale biogas reactor. It was found in a simulation study that a continuous feeding and splitting of the reactor feed into smaller heaps do not generally have a positive effect on the net energy yield. The simulation study showed that the ratio of co-substrate to liquid manure in the inflow determines the net energy production when the inflow load is split into smaller heaps. Mathematical equations are presented to calculate the increase of biogas and methane yield for the digestion of liquid manure and lipids for different feeding intervals. Calculations of different kinds of energy losses for the pilot-scale digester showed high dynamic variations, demonstrating the significance of using a dynamic energy balance model.

Toward a Blended Ontology: Applying Knowledge Systems to Compare Therapeutic and Toxicological Nanoscale Domains

EPA Science Inventory

Bionanomedicine and environmental research share need common terms and ontologies. This study applied knowledge systems, data mining, and bibliometrics used in nano-scale ADME research from 1991 to 2011. The prominence of nano-ADME in environmental research began to exceed the pu...

25 CFR 39.204 - How does OIEP calculate ADM?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Administrative Procedures, Student Counts, and Verifications § 39.204 How does OIEP calculate ADM... each Bureau-funded school; and (b) Dividing the total enrollment for each school by the number of days...

75 FR 53718 - Notice of Lodging of Consent Decree Under the Comprehensive Environmental Response, Compensation...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-01

... States v. International Paper Company, et al., Civil Action No. 10-cv-03749-ADM-XXX. In this action, the... Action No.10-cv-03749-ADM-XXX, DJ 90-11-3-06790/2. The Consent Decrees may be examined at the Office of...

HELAC-PHEGAS: A generator for all parton level processes

NASA Astrophysics Data System (ADS)

Cafarella, Alessandro; Papadopoulos, Costas G.; Worek, Malgorzata

2009-10-01

The updated version of the HELAC-PHEGAS event generator is presented. The matrix elements are calculated through Dyson-Schwinger recursive equations using color connection representation. Phase-space generation is based on a multichannel approach, including optimization. HELAC-PHEGAS generates parton level events with all necessary information, in the most recent Les Houches Accord format, for the study of any process within the Standard Model in hadron and lepton colliders. New version program summaryProgram title: HELAC-PHEGAS Catalogue identifier: ADMS_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADMS_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 35 986 No. of bytes in distributed program, including test data, etc.: 380 214 Distribution format: tar.gz Programming language: Fortran Computer: All Operating system: Linux Classification: 11.1, 11.2 External routines: Optionally Les Houches Accord (LHA) PDF Interface library ( http://projects.hepforge.org/lhapdf/) Catalogue identifier of previous version: ADMS_v1_0 Journal reference of previous version: Comput. Phys. Comm. 132 (2000) 306 Does the new version supersede the previous version?: Yes, partly Nature of problem: One of the most striking features of final states in current and future colliders is the large number of events with several jets. Being able to predict their features is essential. To achieve this, the calculations need to describe as accurately as possible the full matrix elements for the underlying hard processes. Even at leading order, perturbation theory based on Feynman graphs runs into computational problems, since the number of graphs contributing to the amplitude grows as n!. Solution method: Recursive algorithms based on Dyson-Schwinger equations have been developed recently in order to overcome the computational obstacles. The calculation of the amplitude, using Dyson-Schwinger recursive equations, results in a computational cost growing asymptotically as 3 n, where n is the number of particles involved in the process. Off-shell subamplitudes are introduced, for which a recursion relation has been obtained allowing to express an n-particle amplitude in terms of subamplitudes, with 1-, 2-, … up to (n-1) particles. The color connection representation is used in order to treat amplitudes involving colored particles. In the present version HELAC-PHEGAS can be used to efficiently obtain helicity amplitudes, total cross sections, parton-level event samples in LHA format, for arbitrary multiparticle processes in the Standard Model in leptonic, pp¯ and pp collisions. Reasons for new version: Substantial improvements, major functionality upgrade. Summary of revisions: Color connection representation, efficient integration over PDF via the PARNI algorithm, interface to LHAPDF, parton level events generated in the most recent LHA format, k reweighting for Parton Shower matching, numerical predictions for amplitudes for arbitrary processes for phase-space points provided by the user, new user interface and the possibility to run over computer clusters. Running time: Depending on the process studied. Usually from seconds to hours. References:A. Kanaki, C.G. Papadopoulos, Comput. Phys. Comm. 132 (2000) 306. C.G. Papadopoulos, Comput. Phys. Comm. 137 (2001) 247. URL: http://www.cern.ch/helac-phegas.

Acellular dermal matrices in breast implant surgery: defining the problem and proof of concept.

PubMed

Baxter, Richard A

2012-04-01

The use of acellular dermal matrices (ADMs) has become a useful adjunct to implant-based breast reconstruction and revision of the augmented breast. In both instances, the goal is replacement or reinforcement of thinned or missing tissues for implant support and control of the implant pocket. This article reviews the factors that contribute to periprosthetic tissue thinning, and the advantages and limitations of the use of ADMs for revision breast surgery and breast reconstruction. Proof of concept for the use of ADMs in the periprosthetic space is detailed from early clinical experience and histologic analysis documenting vascular ingrowth and cellular repopulation. Copyright © 2012 Elsevier Inc. All rights reserved.

A Miniaturized QEPAS Trace Gas Sensor with a 3D-Printed Acoustic Detection Module.

PubMed

Yang, Xiaotao; Xiao, Youhong; Ma, Yufei; He, Ying; Tittel, Frank K

2017-07-31

A 3D printing technique was introduced to a quartz-enhanced photoacoustic spectroscopy (QEPAS) sensor and is reported for the first time. The acoustic detection module (ADM) was designed and fabricated using the 3D printing technique and the ADM volume was compressed significantly. Furthermore, a small grin lens was used for laser focusing and facilitated the beam adjustment in the 3D-printed ADM. A quartz tuning fork (QTF) with a low resonance frequency of 30.72 kHz was used as the acoustic wave transducer and acetylene (C₂H₂) was chosen as the analyte. The reported miniaturized QEPAS trace gas sensor is useful in actual sensor applications.

Sequestering ADM ethanol plant carbon dioxide

USGS Publications Warehouse

Finley, R.J.; Riddle, D.

2008-01-01

Archer Daniels Midland Co. (ADM) and the Illinois State Geological Survey (ISGS) are collaborating on a project in confirming that a rock formation can store carbon dioxide from the plant in its pores. The project aimed to sequester the gas underground permanently to minimize release of the greenhouse gas into the atmosphere. It is also designed to store one million tons of carbon dioxide over a three-year period. The project is worth $84.3M, funded by $66.7M from the US Department Energy, supplemented by co-funding from ADM and other corporate and state resources. The project will start drilling of wells to an expected depth over 6500 feet into the Mount Simon Sandstone formation.

ADM. Service Building (TAN603). Floor plan. Names of functional areas. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Service Building (TAN-603). Floor plan. Names of functional areas. Ralph M. Parsons 902-2-ANY-603-A 43. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 033-0603-00-693-106718 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Warehouse (TAN604). Elevations and sections. Ralph M. Parsons 9022ANP604A ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Warehouse (TAN-604). Elevations and sections. Ralph M. Parsons 902-2-ANP-604-A 56. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0604-00-693-106728 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Change House (TAN606). Elevations and floor plan. Room Names. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Change House (TAN-606). Elevations and floor plan. Room Names. Ralph M. Parsons 902-2-ANP-606-A 65. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0606-00-693-106733 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Warehouse (TAN604) Floor plan. General warehouse and chemical storage. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Warehouse (TAN-604) Floor plan. General warehouse and chemical storage. Ralph M. Parsons 902-2-ANP-604-A 55. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0604-00-693-106727 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Water System Pump House (TAN610). Elevations, plan, and sections. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Water System Pump House (TAN-610). Elevations, plan, and sections. Ralph M. Parsons 902-2-ANP-610-A 74. Date: February 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0610-00-693-106739 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Administration Building (TAN602). Early room layout, door and room ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Administration Building (TAN-602). Early room layout, door and room schedules. Ralph M. Parsons 902-2-ANP-602-A 31. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 033-0602-00-693-106710 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Change House (TAN606) as completed. Camera facing northerly. Note ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Change House (TAN-606) as completed. Camera facing northerly. Note proximity to shielding berm. Part of hot shop (A&M Building, TAN-607) at left of view beyond berm. Date: October 29, 1954. INEEL negative no. 12705 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

United States Pacific Command (USPACOM)

Science.gov Websites

sailors from the Royal Malaysian Navy during an office call with Vice Adm. Dato' Syed Zahiruddin Putra Bin Osman, commander of the Eastern Fleet of the Royal Malaysian Navy. Sawyers is visiting Kota Kinabalu to Malaysian Navy during an office call KOTA KINABALU, Malaysia (May 23, 2018) - Vice Adm. Phil Sawyer

Dermal Sensitization Potential of DIGL-RP Solid Propellant in Guinea Pigs

DTIC Science & Technology

1989-10-01

y ’,c. ADM$$S (ft, SWOt , &Wd ZIP Cod 7b. ADDRESS (City, State, arid ZIP Code) Letterman Army Institute of Research Fort Detrick Presidio of San...for contact sensitization. Toxicol Appl Pharmacol 1969; Suppl 3:90-102. 7. Buehler EV, Griffith JF. Experimental skin sensitization in the guinea pig

Modeling the anaerobic digestion of cane-molasses vinasse: extension of the Anaerobic Digestion Model No. 1 (ADM1) with sulfate reduction for a very high strength and sulfate rich wastewater.

PubMed

Barrera, Ernesto L; Spanjers, Henri; Solon, Kimberly; Amerlinck, Youri; Nopens, Ingmar; Dewulf, Jo

2015-03-15

This research presents the modeling of the anaerobic digestion of cane-molasses vinasse, hereby extending the Anaerobic Digestion Model No. 1 with sulfate reduction for a very high strength and sulfate rich wastewater. Based on a sensitivity analysis, four parameters of the original ADM1 and all sulfate reduction parameters were calibrated. Although some deviations were observed between model predictions and experimental values, it was shown that sulfates, total aqueous sulfide, free sulfides, methane, carbon dioxide and sulfide in the gas phase, gas flow, propionic and acetic acids, chemical oxygen demand (COD), and pH were accurately predicted during model validation. The model showed high (±10%) to medium (10%-30%) accuracy predictions with a mean absolute relative error ranging from 1% to 26%, and was able to predict failure of methanogenesis and sulfidogenesis when the sulfate loading rate increased. Therefore, the kinetic parameters and the model structure proposed in this work can be considered as valid for the sulfate reduction process in the anaerobic digestion of cane-molasses vinasse when sulfate and organic loading rates range from 0.36 to 1.57 kg [Formula: see text]  m(-3) d(-1) and from 7.66 to 12 kg COD m(-3) d(-1), respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

What happens to an acellular dermal matrix after implantation in the human body? A histological and electron microscopic study.

PubMed

Boháč, Martin; Danišovič, Ľuboš; Koller, Ján; Dragúňová, Jana; Varga, Ivan

2018-01-22

Acellular matrices are used for various purposes and they have been studied extensively for their potential roles in regenerating tissues or organs. The acellular matrix generates physiological cues that mimic the native tissue microenvironment. Acellular dermal matrix (ADM) is a soft connective tissue graft generated by a decellularization process that preserves the intact extracellular skin matrix. Upon implantation, this structure serves as a scaffold for donor-side cells to facilitate subsequent incorporation and revascularization. In breast reconstruction, ADM is used mainly for lower pole coverage and the shaping of a new breast. It helps control the positioning of the implant in the inframammary fold, and prevent the formation of contractile pseudocapsule around the breast implant. In this study, we provide a comprehensive histological description of ADM used for human breast reconstruction over the course of several months following implementation. Using immunohistochemical methods (a panel of 12 antibodies) coupled with optical and transmission electron microscopy, we confirmed that the original acellular dermal matrix became recolonized by fibroblasts and myofibroblasts, and also by various other free cells of the connective tissue (lymphocytes, macrophages and multinucleated giant cells, granulocytes, mast cells) after implantation into the patient's body. Within the implanted ADM, there was a relatively rapid ingrowth of blood vessels. Lymphatic vessels were only detected in one case 9 months after the implantation of the ADM. These results suggest that lymphangiogenesis is a longer process than angiogenesis.

Haploinsufficiency for Adrenomedullin Reduces Pinopodes and Diminishes Uterine Receptivity in Mice1

PubMed Central

Li, Manyu; Wu, Yongqin; Caron, Kathleen M.

2008-01-01

Adrenomedullin (AM) is a multifunctional peptide vasodilator that signals through a G-protein-coupled receptor when the receptor, called calcitonin receptor-like receptor (CL), is associated with a receptor activity-modifying protein 2 (RAMP2). We demonstrated previously that haploinsufficieny for each of these genes led to reduced maternal fertility, and that even a modest genetic reduction of AM peptide caused maternal defects in implantation, placentation, and fetal growth. Here, we further demonstrate that Adm+/− female mice displayed reduced pregnancy success rates that were not caused by defects in folliculogenesis, ovulation, or fertilization. The poor fertility of Adm+/− female mice could not be rescued by transfer of wild-type blastocysts, which suggested an underlying defect in uterine receptivity. In fact, we found that Adm, Calcrl, and Ramp2 gene expressions are tightly and spatiotemporally regulated in the luminal epithelial cells of the uterus during the estrus cycle and the peri-implantation period. RAMP3, which also generates an AM receptor when associated with CL, had a diametrically opposite expression pattern than that of Adm, Calcrl, and Ramp2 and was most robustly induced in the stroma of the uterus. Finally, we discovered that Adm+/− female mice have a substantially reduced number of pinopodes on the uterine luminal epithelial surface, which is indicative and possibly causative of the poor uterine receptivity. Taken together, our studies identify a new class of pharmacologically tractable proteins that are involved in establishing uterine receptivity through the regulation of pinopode formation. PMID:18716289

Induction of apoptosis and reversal of permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM by ginsenoside Rh2.

PubMed

Zhang, Hui; Gong, Jian; Zhang, Huilai; Kong, Di

2015-01-01

Multidrug resistance is a phenomenon that cancer cells develop a cross-resistant phenotype against several unrelated drugs, and permeability glycoprotein derived from the overexpression of multidrug resistance gene 1 has been taken as the most significant cause of multidrug resistance. In the present study, ginsenoside Rh2 was used to reverse permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM cell line. Effects of ginsenoside Rh2 on the apoptotic process and caspase-3 activity of MCF-7 and MCF-7/ADM cell lines were determined using flow cytometry and microplate reader. Methyl thiazolyl tetrazolium test was conducted to assess the IC50 values of ginsenoside Rh2 and adriamycin on MCF-7 and MCF-7/ADM cultures; Rhodamin 123 assay was used to assess the retention of permeability glycoprotein after ginsenoside Rh2 treatment; flow cytometry and real time polymerase chain reaction were used to determine the expression levels of permeability glycoprotein and multidrug resistance gene 1 in drug-resistant cells and their parental cells after exposure to ginsenoside Rh2. The results showed that ginsenoside Rh2, except for inducing apoptosis, had the ability to reverse multidrug resistance in MCF-7/ADM cell line without changing the expression levels of permeability glycoprotein and multidrug resistance gene 1. Our findings provided some valuable information for the application of ginsenoside Rh2 in cancer therapy, especially for multidrug resistance reversal in clinic.

Conservative mastectomies and immediate reconstruction with the use of ADMs.

PubMed

Govshievich, Alexander; Somogyi, Ron B; Brown, Mitchell H

2015-12-01

In recent years, a novel approach to immediate breast reconstruction has been introduced with the advent of acellular dermal matrix (ADM). In the setting of conservative mastectomies where the native skin envelope is preserved, placement of ADM at the lower pole in continuity with the pectoralis major muscle (PMM) provides additional support, allowing direct-to-implant breast reconstruction. The following manuscript presents the senior author's experience with ADM-assisted reconstruction and provides a detailed description of surgical technique along with a comprehensive discussion of patient selection and potential complications. A retrospective chart review of patients undergoing direct-to-implant breast reconstruction following skin sparing or nipple sparing mastectomy with the use of ADM (AlloDerm; LifeCell Corp., Branchburg, USA) was conducted at Women's College Hospital in Toronto over a 5-year period [2008-2013]. Demographic data, previous radiation therapy and post-operative complications were recorded. A total of 72 patients representing 119 breasts were identified. Average follow-up was 16 months (range, 3-51 months). Twenty-seven complications were recorded for a complication rate of 22.7% (27/119). Complications included six cases of capsular contracture (Baker III/IV), five cases of red skin syndrome, four cases of rippling, three cases of dehiscence and two cases of seroma. Overall, direct-to-implant reconstruction was successfully completed in 97.5% of breasts (116/119). One case of infection was treated with explantation and conversion to autogenous reconstruction. Two breasts with tissue necrosis or dehiscence had the implants removed and replaced with tissue expanders. Overall reoperation rate was 9.7% (7/72 patients). ADM assisted direct-to-implant breast reconstruction has been shown to be a safe option for women who are candidates for skin sparing or nipple sparing mastectomies. Judicious patient selection, effective collaboration between the oncologic and reconstructive surgeon, careful evaluation of post-mastectomy skin flaps and precise surgical technique are paramount to the success of this technique.

High Throughput Assay for Bacterial Adhesion on Acellular Dermal Matrices and Synthetic Surgical Materials

PubMed Central

Nyame, Theodore T.; Lemon, Katherine P.; Kolter, Roberto; Liao, Eric C.

2013-01-01

Background There has been increasing use of various synthetic and biologically derived materials in surgery. Biologic surgical materials are used in many plastic surgery procedures, ranging from breast reconstruction to hernia repairs. In particular, acellular dermal matrix (ADM) material has gained popularity in these applications. There is a paucity of data on how ADM compares to other surgical materials as a substrate for bacterial adhesion, the first step in formation biofilm, which occurs in prosthetic wound infections. We have designed a high throughput assay to evaluate Staphylococcus aureus adherence on various synthetic and biologically derived materials. Methods Clinical isolates of Staphylococcus aureus (strains SC-1 and UAMS-1) were cultured with different materials and bacterial adherence was measured using a resazurin cell vitality reporter microtiter assay. Four materials that are commonly utilized in reconstructive procedures were evaluated: prolene mesh, vicryl mesh, and two different ADM preparations (AlloDerm®, FlexHD®). We were able to develop a high throughput and reliable assay for quantifying bacterial adhesion on synthetic and biologically derived materials. Results The resazurin vitality assay can be reliably used to quantify bacterial adherence to acellular dermal matrix material, as well as synthetic material. S. aureus strains SC-1 and UAMS-1 both adhered better to ADM materials (AlloDerm® vs. FlexHD®) than to the synthetic material prolene. S. aureus also adhered better to vicryl than to prolene. Strain UAMS-1 adhered better to vicryl and ADM materials than did strain SC-1. Conclusion Our results suggest that S. aureus adheres more readily to ADM material than to synthetic material. We have developed an assay to rapidly test bacterial formation on surgical materials, using two S. aureus bacterial strains. This provides a standard method to evaluate existing and new materials with regard to bacterial adherence and potential propensity for infection. This assay is particularly important in the clinical context of the severe sequelae of post-operative infection. PMID:22030489

Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063.

PubMed

Tohyama, Kimio; Sudo, Miyako; Morohashi, Akio; Kato, Suguru; Takahashi, Junzo; Tagawa, Yoshihiko

2018-06-01

TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC 50 values of 8.4, 12 and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020). © 2018 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Field Demonstration of Active Desiccant Modules Designed to Integrate with Standard Unitary Rooftop Package Equipment - Final Report: Phase 3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fischer, J

2004-03-15

This report summarizes the investigation of two active desiccant module (ADM) pilot site installations initiated in 2001. Both pilot installations were retrofits at existing facilities served by conventional heating, ventilating, and air-conditioning (HVAC) systems that had encountered frequent humidity control, indoor air quality (IAQ), and other operational problems. Each installation involved combining a SEMCO, Inc., ADM (as described in Fischer and Sand 2002) with a standard packaged rooftop unit built by the Trane Company. A direct digital control (DDC) system integral to the ADM performed the dual function of controlling the ADM/rooftop combination and facilitating data collection, trending, and remotemore » performance monitoring. The first installation involved providing preconditioned outdoor air to replace air exhausted from the large kitchen hood and bathrooms of a Hooters restaurant located in Rome, Georgia. This facility had previously added an additional rooftop unit in an attempt to achieve occupant comfort without success. The second involved conditioning the outdoor air delivered to each room of a wing of the Mountain Creek Inn at the Callaway Gardens resort. This hotel, designed in the ''motor lodge'' format with each room opening to the outdoors, is located in southwest Georgia. Controlling the space humidity always presented a serious challenge. Uncomfortable conditions and musty odors had caused many guests to request to move to other areas within the resort. This is the first field demonstration performed by Oak Ridge National Laboratory where significant energy savings, operating cost savings, and dramatically improved indoor environmental conditions can all be claimed as the results of a retrofit desiccant equipment field installation. The ADM/rooftop combination installed at the restaurant resulted in a reduction of about 34% in the electricity used by the building's air-conditioning system. This represents a reduction of approximately 15% in overall electrical energy consumption and a 12.5-kW reduction in peak demand. The cost of gas used for regeneration of the desiccant wheel over this period of time is estimated to be only $740, using a gas cost of $0.50 per therm--the summer rate in 2001. The estimated net savings is $5400 annually, resulting in a 1-2 year payback. It is likely that similar energy/cost savings were realized at the Callaway Gardens hotel. In this installation, however, a central plant supplied the chilled water serving fan coil units in the hotel wing retrofitted with the ADM, so it was not metered separately. Consequently, the owner could not provide actual energy consumption data specific to the facility. The energy and operating cost savings at both sites are directly attributable to higher cooling-season thermostat settings and decreased conventional system run times. These field installations were selected as an immediate and appropriate response to correct indoor humidity and fresh air ventilation problems being experienced by building occupants and owners, so no rigorous baseline-building vs. test-building energy use/operating cost savings results can be presented. The report presents several simulated comparisons between the ADM/roof HVAC approach and other equipment combinations, where both desiccant and conventional systems are modeled to provide comparable fresh air ventilation rates and indoor humidity levels. The results obtained from these simulations demonstrate convincingly the energy and operating cost savings obtainable with this hybrid desiccant/vapor-compression technology, verifying those actually seen at the pilot installations. The ADM approach is less expensive than conventional alternatives providing similar performance and indoor air quality and provides a very favorable payback (1 year or so) compared with oversized rooftop units that cannot be operated effectively with the necessary high outdoor air percentages.« less

GridAPPS-D Conceptual Design v1.0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melton, Ronald B.; Schneider, Kevin P.; McDermott, Thomas E.

2017-05-31

The purpose of this document is to provide a conceptual design of the distribution system application development platform being developed for the U.S. Department of Energy’s Advanced Distribution Management System (ADMS) Program by the Grid Modernization Laboratory Consortium project GM0063. The platform will be referred to as GridAPPS-D. This document provides a high level, conceptual view of the platform and provides related background and contextual information. This document is intended to both educate readers about the technical work of the project and to serve as a point of reference for the project team. The document will be updated as themore » project progresses.« less

Acellular dermal matrix allografts to achieve increased attached gingiva. Part 2. A histological comparative study.

PubMed

Wei, Pein-Chi; Laurell, Lars; Lingen, Mark W; Geivelis, Milton

2002-03-01

In part 1 of this study, we compared the clinical efficacy of freeze-dried acellular dermal matrix (ADM) allograft in 6 patients with autogenous free gingival graft (FGG) in 6 patients for increasing the width of attached gingiva in the mandibular anterior area. The purpose of the present study was to histologically compare the microstructure of ADM and FGG treated sites from the same group. Biopsies were harvested from all 12 patients at 6 months postsurgery. The biopsies included the grafted sites with adjacent alveolar mucosa and gingiva propria and also donor palatal mucosa saved at the time of surgery. The 5 microm thick, neutral buffered formalin fixed, paraffin-embedded tissue sections were stained with hematoxylin and eosin (H&E), Masson's trichrome, and Verhoeff-van Gieson stains in order to investigate the density of collagen and elastic fibers. Additional sections were stained with periodic acid-Schiff (PAS) and Papanicolaou's stain to identify the presence of glycogen granules in the epithelial layer and to highlight the keratin layer respectively. The unique appearance of ADM-derived tissue did not parallel any known oral mucosa. The connective tissue portion contained dense to extremely dense collagen fibers along with scattered elastic fibers. The demarcations between the ADM graft and the coronal gingiva as well as the apical alveolar mucosa were usually not very defined. A moderate to thin epithelial layer, with heterogeneous expression of keratinization and flat epithelium-connective tissue interface, covered the lamina propria. Both the thickness of the epithelium and the degree of keratinization decreased in apical direction, being mostly para- or orthokeratinized in the area close to gingiva and non-keratinized adjacent to the alveolar mucosa. In the FGG-treated sites, the density of collagen fibers was less than in ADM-derived tissue, palatal mucosa, and gingiva. Elastic fibers were very sparse, comparable to gingiva, but much less than in ADM-derived tissue. The epithelium was moderate, somewhat thinner but the shape of the rete ridges resembled that of palatal mucosa. Similar to gingiva epithelium, the epithelium of the FGG-treated area was relatively uniform in both thickness and keratinization, mostly para-keratinized with a well defined border to the non-keratinized alveolar mucosa. Underneath the FGG-alveolar mucosa junction, a scar band composed of extremely dense collagen fibers consistently existed. The results of this 6-month histological evaluation suggest that: 1) the resultant tissue types of ADM grafts were similar to "scar" tissue; 2) the non-vital dermal matrix of ADM allograft lacked the capability of directing cyto-differentiation of the covering epithelium; 3) autogenous FGG-derived tissue was neither identical to donor palatal mucosa nor to adjacent gingiva propria; 4) the connective tissue of donor palatal mucosa only partially contributed to the differentiation of the epithelium covering the FGG-treated area; and 5) the epithelium/connective tissue microenvironment surrounding the recipient site influenced the epithelial differentiation of the graft; this may play a more critical role in ADM grafting than in the grafting of autogenous FGG.

Performance optimization and validation of ADM1 simulations under anaerobic thermophilic conditions.

PubMed

Atallah, Nabil M; El-Fadel, Mutasem; Ghanimeh, Sophia; Saikaly, Pascal; Abou-Najm, Majdi

2014-12-01

In this study, two experimental sets of data each involving two thermophilic anaerobic digesters treating food waste, were simulated using the Anaerobic Digestion Model No. 1 (ADM1). A sensitivity analysis was conducted, using both data sets of one digester, for parameter optimization based on five measured performance indicators: methane generation, pH, acetate, total COD, ammonia, and an equally weighted combination of the five indicators. The simulation results revealed that while optimization with respect to methane alone, a commonly adopted approach, succeeded in simulating methane experimental results, it predicted other intermediary outputs less accurately. On the other hand, the multi-objective optimization has the advantage of providing better results than methane optimization despite not capturing the intermediary output. The results from the parameter optimization were validated upon their independent application on the data sets of the second digester. Copyright © 2014 Elsevier Ltd. All rights reserved.

"Dispersion modeling approaches for near road | Science ...

EPA Pesticide Factsheets

Roadway design and roadside barriers can have significant effects on the dispersion of traffic-generated pollutants, especially in the near-road environment. Dispersion models that can accurately simulate these effects are needed to fully assess these impacts for a variety of applications. For example, such models can be useful for evaluating the mitigation potential of roadside barriers in reducing near-road exposures and their associated adverse health effects. Two databases, a tracer field study and a wind tunnel study, provide measurements used in the development and/or validation of algorithms to simulate dispersion in the presence of noise barriers. The tracer field study was performed in Idaho Falls, ID, USA with a 6-m noise barrier and a finite line source in a variety of atmospheric conditions. The second study was performed in the meteorological wind tunnel at the US EPA and simulated line sources at different distances from a model noise barrier to capture the effect on emissions from individual lanes of traffic. In both cases, velocity and concentration measurements characterized the effect of the barrier on dispersion.This paper presents comparisons with the two datasets of the barrier algorithms implemented in two different dispersion models: US EPA’s R-LINE (a research dispersion modelling tool under development by the US EPA’s Office of Research and Development) and CERC’s ADMS model (ADMS-Urban). In R-LINE the physical features reveal

Calculation and Identification of the Aerodynamic Parameters for Small-Scaled Fixed-Wing UAVs.

PubMed

Shen, Jieliang; Su, Yan; Liang, Qing; Zhu, Xinhua

2018-01-13

The establishment of the Aircraft Dynamic Model(ADM) constitutes the prerequisite for the design of the navigation and control system, but the aerodynamic parameters in the model could not be readily obtained especially for small-scaled fixed-wing UAVs. In this paper, the procedure of computing the aerodynamic parameters is developed. All the longitudinal and lateral aerodynamic derivatives are firstly calculated through semi-empirical method based on the aerodynamics, rather than the wind tunnel tests or fluid dynamics software analysis. Secondly, the residuals of each derivative are proposed to be identified or estimated further via Extended Kalman Filter(EKF), with the observations of the attitude and velocity from the airborne integrated navigation system. Meanwhile, the observability of the targeted parameters is analyzed and strengthened through multiple maneuvers. Based on a small-scaled fixed-wing aircraft driven by propeller, the airborne sensors are chosen and the model of the actuators are constructed. Then, real flight tests are implemented to verify the calculation and identification process. Test results tell the rationality of the semi-empirical method and show the improvement of accuracy of ADM after the compensation of the parameters.

Calculation and Identification of the Aerodynamic Parameters for Small-Scaled Fixed-Wing UAVs

PubMed Central

Shen, Jieliang; Su, Yan; Liang, Qing; Zhu, Xinhua

2018-01-01

The establishment of the Aircraft Dynamic Model (ADM) constitutes the prerequisite for the design of the navigation and control system, but the aerodynamic parameters in the model could not be readily obtained especially for small-scaled fixed-wing UAVs. In this paper, the procedure of computing the aerodynamic parameters is developed. All the longitudinal and lateral aerodynamic derivatives are firstly calculated through semi-empirical method based on the aerodynamics, rather than the wind tunnel tests or fluid dynamics software analysis. Secondly, the residuals of each derivative are proposed to be identified or estimated further via Extended Kalman Filter (EKF), with the observations of the attitude and velocity from the airborne integrated navigation system. Meanwhile, the observability of the targeted parameters is analyzed and strengthened through multiple maneuvers. Based on a small-scaled fixed-wing aircraft driven by propeller, the airborne sensors are chosen and the model of the actuators are constructed. Then, real flight tests are implemented to verify the calculation and identification process. Test results tell the rationality of the semi-empirical method and show the improvement of accuracy of ADM after the compensation of the parameters. PMID:29342856

Pharmacophore Identification, Molecular Docking, Virtual Screening, and In Silico ADME Studies of Non-Nucleoside Reverse Transcriptase Inhibitors.

PubMed

Pirhadi, Somayeh; Ghasemi, Jahan B

2012-12-01

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies used to treat HIV. In this study, chemical feature based pharmacophore models of different classes of NNRT inhibitors of HIV-1 have been developed. The best HypoRefine pharmacophore model, Hypo 1, which has the best correlation coefficient (0.95) and the lowest RMS (0.97), contains two hydrogen bond acceptors, one hydrophobic and one ring aromatic feature, as well as four excluded volumes. Hypo 1 was further validated by test set and Fischer validation method. The best pharmacophore model was then utilized as a 3D search query to perform a virtual screening to retrieve potential inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies by Libdock and Gold methods to refine the retrieved hits. Finally, 7 top ranked compounds based on Gold score fitness function were subjected to in silico ADME studies to investigate for compliance with the standard ranges. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mechanism of orientation of stimulating currents in magnetic brain stimulation (abstract)

NASA Astrophysics Data System (ADS)

Ueno, S.; Matsuda, T.

1991-04-01

We made a functional map of the human motor cortex related to the hand and foot areas by stimulating the human brain with a focused magnetic pulse. We observed that each functional area in the cortex has an optimum direction for which stimulating currents can produce neural excitation. The present report focuses on the mechanism which is responsible for producing this anisotropic response to brain stimulation. We first obtained a functional map of the brain related to the left ADM (abductor digiti minimi muscles). When the stimulating currents were aligned in the direction from the left to the right hemisphere, clear EMG (electromyographic) responses were obtained only from the left ADM to magnetic stimulation of both hemisphere. When the stimulating currents were aligned in the direction from the right to the left hemisphere, clear EMG signals were obtained only from the right ADM to magnetic stimulation of both hemisphere. The functional maps of the brain were sensitive to changes in the direction of the stimulating currents. To explain the phenomena obtained in the experiments, we developed a model of neural excitation elicited by magnetic stimulation. When eddy currents which are induced by pulsed magnetic fields flow in the direction from soma to the distal part of neural fiber, depolarized area in the distal part are excited, and the membrane excitation propagates along the nerve fiber. In contrast, when the induced currents flow in the direction from the distal part to soma, hyperpolarized parts block or inhibit neural excitation even if the depolarized parts near the soma can be excited. The model explains our observation that the orientation of the induced current vectors reflect both the functional and anatomical organization of the neural fibers in the brain.

Computational Prediction of Alzheimer’s and Parkinson’s Disease MicroRNAs in Domestic Animals

PubMed Central

Wang, Hai Yang; Lin, Zi Li; Yu, Xian Feng; Bao, Yuan; Cui, Xiang-Shun; Kim, Nam-Hyung

2016-01-01

As the most common neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two of the main health concerns for the elderly population. Recently, microRNAs (miRNAs) have been used as biomarkers of infectious, genetic, and metabolic diseases in humans but they have not been well studied in domestic animals. Here we describe a computational biology study in which human AD- and PD-associated miRNAs (ADM and PDM) were utilized to predict orthologous miRNAs in the following domestic animal species: dog, cow, pig, horse, and chicken. In this study, a total of 121 and 70 published human ADM and PDM were identified, respectively. Thirty-seven miRNAs were co-regulated in AD and PD. We identified a total of 105 unrepeated human ADM and PDM that had at least one 100% identical animal homolog, among which 81 and 54 showed 100% sequence identity with 241 and 161 domestic animal miRNAs, respectively. Over 20% of the total mature horse miRNAs (92) showed perfect matches to AD/PD-associated miRNAs. Pigs, dogs, and cows have similar numbers of AD/PD-associated miRNAs (63, 62, and 59). Chickens had the least number of perfect matches (34). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that humans and dogs are relatively similar in the functional pathways of the five selected highly conserved miRNAs. Taken together, our study provides the first evidence for better understanding the miRNA-AD/PD associations in domestic animals, and provides guidance to generate domestic animal models of AD/PD to replace the current rodent models. PMID:26954182

25 CFR 39.230 - How will the provisions of this subpart be phased in?

Code of Federal Regulations, 2010 CFR

2010-04-01

... SCHOOL EQUALIZATION PROGRAM Administrative Procedures, Student Counts, and Verifications Phase-in Period... rolling average of ADM for each school and for the entire Bureau-funded school system will be phased-in as shown in the following table. Time period How OIEP must calculate ADM (a) First school year after May 31...

ADM. Tanks: from left to right: fuel oil tank, fuel ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Tanks: from left to right: fuel oil tank, fuel pump house (TAN-611), engine fuel tank, water pump house, water storage tank. Camera facing northwest. Not edge of shielding berm at left of view. Date: November 25, 1953. INEEL negative no. 9217 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

Ready, Set, Go: EGFR at the pancreatic cancer starting line

PubMed Central

Perera, Rushika M.; Bardeesy, Nabeel

2012-01-01

Acinar-to-ductal metaplasia (ADM) results from pancreatic injury or KRAS activation, and is an early step in pancreatic cancer progression. In this Cancer Cell issue, Ardito et al. and Navas et al. demonstrate that ADM and KRAS-driven pancreatic cancer require EGFR signaling, revealing a mechanism for developmental reprogramming that primes tumorigenesis. PMID:22975369

Art Dialogue Methods: Phronèsis and Its Potential for Restoring an Embodied Moral Authority in Local Communities

ERIC Educational Resources Information Center

Muijen, Heidi S. C. A.; Brohm, René

2018-01-01

We put forward Art-Dialogue-Methods (ADM) as an inquiry for practical wisdom within communities. It draws from a series of methodological traditions like artistic inquiry, participatory action research and narrative research. The practice of ADM could facilitate healing processes in fractured communities and organisations in today's world. ADM…

Review on Prescription Compatibility of Shaoyao Gancao Decoction and Reflection on Pharmacokinetic Compatibility Mechanism of Traditional Chinese Medicine Prescription Based on In Vivo Drug Interaction of Main Efficacious Components

PubMed Central

Bi, Xiaolin; Gong, Meirong; Di, Liuqing

2014-01-01

Shaoyao Gancao Decoction (SGD) derived from Zhang Zhongjing's “Typhoid Theory” is composed of peony and licorice, having the efficacy of nourishing liver, relaxing spasm, and relieving pain. Modern compatibility studies of SGD on chemistry, pharmacology, and pharmacokinetics all demonstrate the reasonable compatibility of peony and licorice. However, the present research on pharmacokinetics is only descriptive and limited to the influence on in vivo dynamic process of certain ingredients; correspondingly, there is lack of studies on the essence of these efficacious substances' in vivo changes; that is, whether it is because there exists in vivo drug interaction in absorption, distribution, metabolism, and excretion (ADME) of active ingredients that leads to the improvement of bioavailability. We herein take SGD as an example and suggest that it is necessary to study in vivo drug interaction of main efficacious components mediated by metabolic enzymes, transport proteins, or plasma protein binding in the course of ADME, which is helpful to illustrate the principle of pharmacokinetic compatibility from the essence leading to the changes of effective substances in vivo. PMID:25147573

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.

PubMed

Arruda, Mônica Barcellos; Campagnari, Francine; de Almeida, Tailah Bernardo; Couto-Fernandez, José Carlos; Tanuri, Amilcar; Cardoso, Cynthia Chester

2016-01-01

Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.

Sucralose.

PubMed

AlDeeb, Omar A A; Mahgoub, Hoda; Foda, Nagwa H

2013-01-01

Sucralose is a nonnutritive, zero-calorie artificial sweetener. It is a chlorinated sugar substitute that is about 600 times as sweet as sucrose. It is produced from sucrose when three chlorine atoms replace three hydroxyl groups. It is consumed as tablets (Blendy) by diabetic and obese patients. It is also used as an excipient in drug manufacturing. Unlike other artificial sweeteners, it is stable when heated and can, therefore, be used in baked and fried foods. The FDA approved sucralose in 1998. This review presents a comprehensive profile for sucralose including physical, analytical, and ADME profiles and methods of its synthesis. Spectral data for X-ray powder diffraction and DSC of sucralose are recorded and presented. The authors also recorded FT-IR, (1)H- and (13)C NMR, and ESI-MS spectra. Interpretation with detailed spectral assignments is provided. The analytical profile of sucralose covered the compendial methods, spectroscopic, and different chromatographic analytical techniques. The ADME profile covered all absorption, distribution, metabolism, and elimination data in addition to pharmacokinetics and pharmacological effects of sucralose. Some nutritional aspects for sucralose in obesity and diabetes are also presented. Both chemical and microbiological synthesis schemes for sucralose are reviewed and included. Copyright © 2013 Elsevier Inc. All rights reserved.

Report from the EPAA workshop: in vitro ADME in safety testing used by EPAA industry sectors.

PubMed

Schroeder, K; Bremm, K D; Alépée, N; Bessems, J G M; Blaauboer, B; Boehn, S N; Burek, C; Coecke, S; Gombau, L; Hewitt, N J; Heylings, J; Huwyler, J; Jaeger, M; Jagelavicius, M; Jarrett, N; Ketelslegers, H; Kocina, I; Koester, J; Kreysa, J; Note, R; Poth, A; Radtke, M; Rogiers, V; Scheel, J; Schulz, T; Steinkellner, H; Toeroek, M; Whelan, M; Winkler, P; Diembeck, W

2011-04-01

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritization, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data. Copyright © 2010 Elsevier Ltd. All rights reserved.

Is glycated albumin useful for differential diagnosis between fulminant type 1 diabetes mellitus and acute-onset autoimmune type 1 diabetes mellitus?

PubMed

Koga, Masafumi; Kanehara, Hideo; Bando, Yukihiro; Morita, Shinya; Kasayama, Soji

2015-12-07

Markedly elevated plasma glucose and relatively low HbA1c compared to plasma glucose is one diagnostic criterion for fulminant type 1 diabetes mellitus (FT1DM). Glycated albumin (GA) is a glycemic control marker that reflects glycemic control in shorter period than HbA1c. This study investigated whether GA is useful for differential diagnosis between FT1DM and acute-onset autoimmune type 1 diabetes mellitus (T1ADM) or not. This study included 38 FT1DM patients and 31 T1ADM patients in whom both HbA1c and GA were measured at the time of diagnosis. In FT1DM patients, as compared to T1ADM patients, both HbA1c and GA were significantly lower (HbA1c; 6.6±0.9% vs. 11.7±2.6%, P<0.0001, GA; 22.9±4.8% vs. 44.3±8.3%, P<0.0001). For differential diagnosis between FT1DM and T1ADM, ROC analysis showed that the optimum cut-off value for GA was 33.5% with sensitivity and specificity of 97.4% and 96.8%, respectively, while the optimum cut-off value for HbA1c was 8.7% with sensitivity and specificity of 100% and 83.9%, respectively. GA also may be useful for the differential diagnosis between FT1DM and T1ADM when the cut-off value can be set at 33.5%. Copyright © 2015 Elsevier B.V. All rights reserved.

Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease.

PubMed

Tedroff, Joakim; Waters, Susanna; Barker, Roger A; Roos, Raymund; Squitieri, Ferdinando

2015-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies.

Incidence of Non-AIDS-Defining Malignancies in HIV-Infected Vs. Non-Infected Patients in the HAART Era: Impact of Immunosuppression

PubMed Central

Bedimo, Roger J.; McGinnis, Kathleen A.; Dunlap, Melinda; Rodriguez-Barradas, Maria C.; Justice, Amy C.

2009-01-01

Background The incidence of non-AIDS-defining malignancies (non-ADM) is reported as unchanged or increasing in the HAART era. Whether incidence of non-ADM is significantly higher in HIV-infected than in HIV-uninfected patients remains unclear. Methods Incidence rates of malignancies were calculated in a cohort of veterans in care for HIV-infected and age, race, and gender-matched uninfected patients from 1997 to 2004. For HIV-infected patients CD4 counts closest to first observation date were compared between those with and without cancer. Results 33,420 HIV-infected and 66,840 HIV-uninfected patients were followed for a median of 5.1 and 6.4 years. The Incidence rate ratio [IRR] of HIV-infected to HIV-uninfected was 1.6 (1260 vs. 841/100,000 person-years; 95% CI: 1.5–1.7). IRR for individual cancers was highest for anal cancer (14.9; CI: 10.1–22.1). Among HIV-infected patients, median CD4 counts were lower for those with non-ADM (249 vs. 270, p=0.02), anal cancer (154 vs. 270; p<0.001), and Hodgkin’s (217 vs. 270; p=0.03). Prostate cancer was associated with a higher CD4 count (310 vs. 270; p<0.001). Conclusions In the HAART era, the incidence of non-ADMs is higher among HIV-infected than HIV-uninfected patients, adjusting for age, race, and gender. Some non-ADMs do not appear to be associated with significantly lower CD4 counts. PMID:19617846

Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression

PubMed Central

Andrews, Paul W.; Kornstein, Susan G.; Halberstadt, Lisa J.; Gardner, Charles O.; Neale, Michael C.

2011-01-01

Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings. PMID:21779273

Document-Based and Message-Centric Security Using XML Authentication and Encryption for Coalition and Interagency Operations

DTIC Science & Technology

2009-09-01

Peruvian Navy Peru X X X X VADM Andrzej Karweta Commander-in-Chief, Polish Navy Poland X X ADM Fernando Jose Ribeiro de Melo Gomes...Chief of Naval Staff, Portuguese Navy Portugal X X X X X VADM J. Mudimu Chief, South African Navy South Africa X X X X X ADM Manuel Rebollo

ADM. Fuel Pump House (TAN611). Elevations, floor plan. Drawing includes ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Fuel Pump House (TAN-611). Elevations, floor plan. Drawing includes elevation and plans for "H.M." structures (Hose Storage?). Ralph M. Parsons 902-2-ANP-611-A 78 Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0611-00-693-106741 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Water well pump houses (TAN612 and TAN613). Plans, elevations, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Water well pump houses (TAN-612 and TAN-613). Plans, elevations, floor and other details. Ralph M. Parsons 902-2-ANP-612-613-A S & P 82. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 035-0612-00-693-106743 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

ADM. Administration Building (TAN602). Elevations, sections, details. Shows areas that ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Administration Building (TAN-602). Elevations, sections, details. Shows areas that were soon remodeled or added onto. Ralph M. Parsons 902-2-ANP-602-A 32 Date: August 1955. Approved by INEEL Classification Office for public release. INEEL index code no. 033-0602-00-693-106711 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

Electrophysiological diagnosis and patterns of response to treatment of botulism with neuromuscular respiratory failure.

PubMed

Kongsaengdao, Subsai; Samintarapanya, Kanoksri; Rusmeechan, Siwarit; Sithinamsuwan, Pasiri; Tanprawate, Surat

2009-08-01

In this study we describe the electrophysiological findings in botulism patients with neuromuscular respiratory failure from major botulism outbreaks in Thailand. High-rate repetitive nerve stimulation testing (RNST) of the abductor digiti minimi (ADM) muscle of 17 botulism patients with neuromuscular respiratory failure showed mostly incremental responses, especially in response to >20-HZ stimulation. In the most severe stage of neuromuscular respiratory failure, RNST failed to elicit a compound muscle action potential (CMAP) of the ADM muscle. In the moderately severe stage, the initial CMAPs were of very low amplitude, and a 3-HZ RNST elicited incremental or decremental responses. A 10-HZ RNST elicited mainly decremental responses. In the early recovery stage, the initial CMAP amplitudes of the ADM muscle improved, with initially low amplitudes and an incremental response to 3- and 10-HZ RNSTs. Improved electrophysiological patterns of the ADM muscle correlated with improved respiratory muscle function. Incremental responses to 20-HZ RNST were most useful for diagnosis. The initial electrodiagnostic sign of recovery following treatment of neuromuscular respiratory failure was an increased CMAP amplitude and an incremental response to 10-20-HZ RNST. Muscle Nerve 40: 271-278, 2009.

Development of an Experimental African Drought Monitoring and Seasonal Forecasting System: A First Step towards a Global Drought Information System

NASA Astrophysics Data System (ADS)

Wood, E. F.; Chaney, N.; Sheffield, J.; Yuan, X.

2012-12-01

Extreme hydrologic events in the form of droughts are a significant source of social and economic damage. Internationally, organizations such as UNESCO, the Group on Earth Observations (GEO), and the World Climate Research Programme (WCRP) have recognized the need for drought monitoring, especially for the developing world where drought has had devastating impacts on local populations through food insecurity and famine. Having the capacity to monitor droughts in real-time, and to provide drought forecasts with sufficient warning will help developing countries and international programs move from the management of drought crises to the management of drought risk. While observation-based assessments, such as those produced by the US Drought Monitor, are effective for monitoring in countries with extensive observation networks (of precipitation in particular), their utility is lessened in areas (e.g., Africa) where observing networks are sparse. For countries with sparse networks and weak reporting systems, remote sensing observations can provide the real-time data for the monitoring of drought. More importantly, these datasets are now available for at least a decade, which allows for the construction of a climatology against which current conditions can be compared. In this presentation we discuss the development of our multi-lingual experimental African Drought Monitor (ADM) (see http://hydrology.princeton.edu/~nchaney/ADM_ML). At the request of UNESCO, the ADM system has been installed at AGRHYMET, a regional climate and agricultural center in Niamey, Niger and at the ICPAC climate center in Nairobi, Kenya. The ADM system leverages off our U.S. drought monitoring and forecasting system (http://hydrology.princeton.edu/forecasting) that uses the NLDAS data to force the VIC land surface model (LSM) at 1/8th degree spatial resolution for the estimation of our soil moisture drought index (Sheffield et al., 2004). For the seasonal forecast of drought, CFSv2 climate forecasts are bias corrected, downscaled and used as inputs to the VIC LSM as well as forecasts based on ESP and CPC official seasonal outlook. For Africa, data from a combination of remote sensing (TMPA-based precipitation, land cover characteristics) and GFS analysis fields (temperature and wind) are used to monitor drought using our soil moisture drought index as well as 1, 3 and and 6-month SPI. River discharge is also estimated at over 900 locations. Seasonal forecasts have been developed using CFSv2 climate forecasts following the approaches used over CONUS. We will discuss the performance of the system to evaluate the depiction of drought over various scales, from regional to the African continent, and over a number of years to capture multiple drought events. Furthermore, the hindcasts from the seasonal drought forecast system are analyzed to assess the ability of seasonal climate models to detect drought on-set and its recovery. Finally, we will discuss whether our ADM provides a pathway to a Global Drought Information System, a goal of the WCRP Drought Task Force.

A Hybrid Stochastic-Neuro-Fuzzy Model-Based System for In-Flight Gas Turbine Engine Diagnostics

DTIC Science & Technology

2001-04-05

Margin (ADM) and (ii) Fault Detection Margin (FDM). Key Words: ANFIS, Engine Health Monitoring , Gas Path Analysis, and Stochastic Analysis Adaptive Network...The paper illustrates the application of a hybrid Stochastic- Fuzzy -Inference Model-Based System (StoFIS) to fault diagnostics and prognostics for both...operational history monitored on-line by the engine health management (EHM) system. To capture the complex functional relationships between different

Give Design a Chance: A Case for a Human Centered Approach to Operational Art

DTIC Science & Technology

2017-03-30

strategy development and operational art. This demands fuller integration of the Army Design Methodology (ADM) and the Military Decision Making Process...MDMP). This monograph proposes a way of thinking and planning that goes beyond current Army doctrinal methodologies to address the changing...between conceptual and detailed planning. 15. SUBJECT TERMS Design; Army Design Methodology (ADM); Human Centered; Strategy; Operational Art

76 FR 67207 - Certain Wiper Blades; Receipt of Complaint; Solicitation of Comments Relating to the Public Interest

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-31

... complaint names as respondents ADM21 Co., Ltd. of Korea; ADM21 Co. (North America) Ltd. of NJ; Alberee Products, Inc. of MD; API Korea Co., Ltd. of Korea; Cequent Consumer Products, Inc. of OH; Corea Autoparts Producing Corporation of South Korea; Danyang UPC Auto Parts Co., Ltd. of China; Fu-Gang Co., Ltd. of Taiwan...

JPRS Report, West Europe, Reference Aid, Glossary of Acronyms and Abbreviations of Norway

DTIC Science & Technology

1989-04-04

nuclear-biological- chemical [use NBC] ABC/S Forsvarets ABC-sekretariat Defense NBC Secretariat adj . adjutant adm administrasj on adm...institusj onens regneanlegg kjem kjemi(sk) kj. st. kj^restilling Kjeller Institute Computing Facility chemical driving position kjt kj...National Federation of the Chemical Mineral Industry Air Commander, North Norway LKR lett kontrollrom LKS Luftkommandor S0r-Norge LK-sjef

Defense.gov Special Report: Military Bids Farewell to Navy Adm. Mike Mullen

Science.gov Websites

Staff Sept. 26, 2011 "I leave humbled now by the performance and the resilience of men and women in Adm. Mike Mullen Chairman, Joint Chiefs of Staff Washington, D.C., Sept. 22, 2011 Obama Praises Mullen Mullen for his service as chairman of the Joint Chiefs of Staff during a hail and farewell ceremony, at

Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway.

PubMed

Zhang, Xueyan; Ai, Ziying; Chen, Jing; Yi, Juan; Liu, Zhuan; Zhao, Huaishun; Wei, Hulai

2017-04-01

In human leukaemia, resistance to chemotherapy leads to treatment ineffectiveness or failure. Previous studies have indicated that cancers with increased levels of aerobic glycolysis are insensitive to numerous forms of chemotherapy and respond poorly to radiotherapy. Whether glycolysis serves a key role in drug resistance of leukaemia cells remains unclear. The present study systematically investigated aerobic glycolytic alterations and regulation in K562/adriamycin (ADM) multidrug‑resistant (MDR) and ADM‑sensitive K562 leukaemia cells in normoxia, and the association between drug resistance and improper glycometabolism. The cell proliferating activity was assessed with an MTT colorimetric assay, glycolysis, including glucose consumption, lactate export and key‑enzyme activity was determined by corresponding commercial testing kits. The expression levels of hexokinase‑II (HK‑II), lactate dehydrogenase A (LDHA), glucose transporter‑4 (GLUT‑4), AKT, p‑AKT473/308, mammalian target of rapamycin (mTOR), p‑mTOR, c‑Myc and hypoxia‑inducible factor‑1α (HIF‑1α) were analyzed by western blot or reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). K562/ADM cells exhibited increased glucose consumption and lactate accumulation, increased lactate dehydrogenase, hexokinase and pyruvate kinase activities, and reduced phosphofructokinase activity. In addition, K562/ADM cells expressed significantly more HK‑II and GLUT‑4. Notably, inhibition of glycolysis effectively killed sensitive and resistant leukaemia cells and potently restored the sensitivity of MDR cells to the anticancer agent ADM. The AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway, a crucial regulator of glycometabolic homeostasis, mediated over‑activation and upregulation of c‑Myc expression levels in K562/ADM cells, which directly stimulated glucose consumption and enhanced glycolysis. In conclusion, the present study demonstrated that MDR leukaemia cells exhibit increased aerobic glycolytic activity and that this may be responsible for resistance to chemotherapeutics in leukaemia MDR cells via activation of the AKT‑mTOR‑c‑Myc signalling pathway. Therefore, inhibition of aerobic glycolysis may be a potential therapeutic strategy to efficiently treat multidrug resistance in relapsed or refractory leukaemia and cancers.

Four dimensional variational inversion of atmospheric chemical sources in WRFDA

NASA Astrophysics Data System (ADS)

Guerrette, J. J.

Atmospheric aerosols are known to affect health, weather, and climate, but their impacts on regional scales are uncertain due to heterogeneous source, transport, and transformation mechanisms. The Weather Research and Forecasting model with chemistry (WRF-Chem) can account for aerosol-meteorology feedbacks as it simultaneously integrates equations of dynamical and chemical processes. Here we develop and apply incremental four dimensional variational (4D-Var) data assimilation (DA) capabilities in WRF-Chem to constrain chemical emissions (WRFDA-Chem). We develop adjoint (ADM) and tangent linear (TLM) model descriptions of boundary layer mixing, emission, aging, dry deposition, and advection of black carbon (BC) aerosol. ADM and TLM model performance is verified against finite difference derivative approximations. A second order checkpointing scheme is used to reduce memory costs and enable simulations longer than six hours. We apply WRFDA-Chem to constraining anthropogenic and biomass burning sources of BC throughout California during the 2008 Arctic Research of the Composition of the Troposphere from Aircraft and Satellites (ARCTAS) field campaign. Manual corrections to the prior emissions and subsequent inverse modeling reduce the spread in total emitted BC mass between two biomass burning inventories from a factor of x10 to only x2 across three days of measurements. We quantify posterior emission variance using an eigendecomposition of the cost function Hessian matrix. We also address the limited scalability of 4D-Var, which traditionally uses a sequential optimization algorithm (e.g., conjugate gradient) to approximate these Hessian eigenmodes. The Randomized Incremental Optimal Technique (RIOT) uses an ensemble of TLM and ADM instances to perform a Hessian singular value decomposition. While RIOT requires more ensemble members than Lanczos requires iterations to converge to a comparable posterior control vector, the wall-time of RIOT is x10 shorter since the ensemble is executed in parallel. This work demonstrates that RIOT improves the scalability of 4D-Var for high-dimensional nonlinear problems. Overall, WRFDA-Chem and RIOT provide a framework for air quality forecasting, campaign planning, and emissions constraint that can be used to refine our understanding of the interplay between atmospheric chemistry, meteorology, climate, and human health.

Model-based design of an agricultural biogas plant: application of anaerobic digestion model no.1 for an improved four chamber scheme.

PubMed

Wett, B; Schoen, M; Phothilangka, P; Wackerle, F; Insam, H

2007-01-01

Different digestion technologies for various substrates are addressed by the generic process description of Anaerobic Digestion Model No. 1. In the case of manure or agricultural wastes a priori knowledge about the substrate in terms of ADM1 compounds is lacking and influent characterisation becomes a major issue. The actual project has been initiated for promotion of biogas technology in agriculture and for expansion of profitability also to rather small capacity systems. In order to avoid costly individual planning and installation of each facility a standardised design approach needs to be elaborated. This intention pleads for bio kinetic modelling as a systematic tool for process design and optimisation. Cofermentation under field conditions was observed, quality data and flow data were recorded and mass flow balances were calculated. In the laboratory different substrates have been digested separately in parallel under specified conditions. A configuration of four ADM1 model reactors was set up. Model calibration identified disintegration rate, decay rates for sugar degraders and half saturation constant for sugar as the three most sensitive parameters showing values (except the latter) about one order of magnitude higher than default parameters. Finally, the model is applied to the comparison of different reactor configurations and volume partitions. Another optimisation objective is robustness and load flexibility, i.e. the same configuration should be adaptive to different load situations only by a simple recycle control in order to establish a standardised design.

Reference intervals and longitudinal changes in copeptin and MR-proADM concentrations during pregnancy.

PubMed

Joosen, Annemiek M C P; van der Linden, Ivon J M; Schrauwen, Lianne; Theeuwes, Alisia; de Groot, Monique J M; Ermens, Antonius A M

2017-11-27

Vasopressin and adrenomedullin and their stable by-products copeptin and midregional part of proadrenomedullin (MR-proADM) are promising biomarkers for the development of preeclampsia. However, clinical use is hampered by the lack of trimester-specific reference intervals. We therefore estimated reference intervals for copeptin and MR-proADM in disease-free Dutch women throughout pregnancy. Apparently healthy low risk pregnant women were recruited. Exclusion criteria included current or past history of endocrine disease, multiple pregnancy, use of medication known to influence thyroid function and current pregnancy as a result of hormonal stimulation. Women who miscarried, developed hyperemesis gravidarum, hypertension, pre-eclampsia, hemolysis elevated liver enzymes and low platelets, diabetes or other disease, delivered prematurely or had a small for gestational age neonate were excluded from analyses. Blood samples were collected at 9-13 weeks (n=98), 27-29 weeks (n=94) and 36-39 weeks (n=91) of gestation and at 4-13 weeks post-partum (PP) (n=89). Sixty-two women had complete data during pregnancy and PP. All analyses were performed on a Kryptor compact plus. Copeptin increases during pregnancy, but 97.5th percentiles remain below the non-pregnant upper reference limit (URL) provided by the manufacturer. MR-proADM concentrations increase as well during pregnancy. In trimesters 2 and 3 the 97.5th percentiles are over three times the non-pregnant URL provided by the manufacturer. Trimester- and assay-specific reference intervals for copeptin and MR-proADM should be used. In addition, consecutive measurements and the time frame between measurements should be considered as the differences seen with or in advance of preeclampsia can be expected to be relatively small compared to the reference intervals.

Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease.

PubMed

Lake, April D; Novak, Petr; Fisher, Craig D; Jackson, Jonathan P; Hardwick, Rhiannon N; Billheimer, D Dean; Klimecki, Walter T; Cherrington, Nathan J

2011-10-01

Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.

Methylation of Notch3 modulates chemoresistance via P-glycoprotein.

PubMed

Gu, Xiaoting; Lu, Yangfan; He, Dongxu; Lu, Chunxiao; Jin, Jian; Lu, Xiaojie; Ma, Xin

2016-12-05

The global gene expression and DNA methylation of genes in adriamycin-resistant human breast cancer cells (MCF-7/ADM cells) are similar to those in paclitaxel-resistant MCF-7 cells (MCF-7/PTX) and are significantly different from those in wild-type MCF-7 cells. DNA methylation is associated with chemoresistance in breast cancer and changes the characteristics of chemoresistant and chemosensitive cells. Here, we showed that the tumor-suppressor gene Notch3 was inactivated due to epigenetic silencing DNA hypermethylation in MCF-7/ADM cells. In addition, the drug efflux pump P-glycoprotein was negatively regulated by Notch3 and highly expressed in MCF-7/ADM cells. Taken together, our findings demonstrated that hypermethylation of Notch3 causes activation of P-glycoprotein in adriamycin-resistant cells. Copyright © 2016 Elsevier B.V. All rights reserved.

Naval Aviation Costs: Targeting Operations and Support

DTIC Science & Technology

2013-12-01

Brian Jacobs n Cmdr. Craig Owen Aubrey Dennis n Michael Berkin n Roy Lancaster n Tim Simpson n Duane Mallicoat Farmer, AIR-6.0B, is the...Department. Jacobs , AIR-6.7B, is the military director, Logistics and Maintenance Planning Department. Owen is the COMFRC Produc- tion director. Dennis...Board Extended Members Vice Adm. McCoy , NAVSEA Vice Adm. Van Buskirk, CNP Lt. Gen. Ronling, MARFORPAC Lt. Gen. Paxton, MARFORCOM

Modelling anaerobic co-digestion in Benchmark Simulation Model No. 2: Parameter estimation, substrate characterisation and plant-wide integration.

PubMed

Arnell, Magnus; Astals, Sergi; Åmand, Linda; Batstone, Damien J; Jensen, Paul D; Jeppsson, Ulf

2016-07-01

Anaerobic co-digestion is an emerging practice at wastewater treatment plants (WWTPs) to improve the energy balance and integrate waste management. Modelling of co-digestion in a plant-wide WWTP model is a powerful tool to assess the impact of co-substrate selection and dose strategy on digester performance and plant-wide effects. A feasible procedure to characterise and fractionate co-substrates COD for the Benchmark Simulation Model No. 2 (BSM2) was developed. This procedure is also applicable for the Anaerobic Digestion Model No. 1 (ADM1). Long chain fatty acid inhibition was included in the ADM1 model to allow for realistic modelling of lipid rich co-substrates. Sensitivity analysis revealed that, apart from the biodegradable fraction of COD, protein and lipid fractions are the most important fractions for methane production and digester stability, with at least two major failure modes identified through principal component analysis (PCA). The model and procedure were tested on bio-methane potential (BMP) tests on three substrates, each rich on carbohydrates, proteins or lipids with good predictive capability in all three cases. This model was then applied to a plant-wide simulation study which confirmed the positive effects of co-digestion on methane production and total operational cost. Simulations also revealed the importance of limiting the protein load to the anaerobic digester to avoid ammonia inhibition in the digester and overloading of the nitrogen removal processes in the water train. In contrast, the digester can treat relatively high loads of lipid rich substrates without prolonged disturbances. Copyright © 2016 Elsevier Ltd. All rights reserved.

Microbial Internal Storage Alters the Carbon Transformation in Dynamic Anaerobic Fermentation.

PubMed

Ni, Bing-Jie; Batstone, Damien; Zhao, Bai-Hang; Yu, Han-Qing

2015-08-04

Microbial internal storage processes have been demonstrated to occur and play an important role in activated sludge systems under both aerobic and anoxic conditions when operating under dynamic conditions. High-rate anaerobic reactors are often operated at a high volumetric organic loading and a relatively dynamic profile, with large amounts of fermentable substrates. These dynamic operating conditions and high catabolic energy availability might also facilitate the formation of internal storage polymers by anaerobic microorganisms. However, so far information about storage under anaerobic conditions (e.g., anaerobic fermentation) as well as its consideration in anaerobic process modeling (e.g., IWA Anaerobic Digestion Model No. 1, ADM1) is still sparse. In this work, the accumulation of storage polymers during anaerobic fermentation was evaluated by batch experiments using anaerobic methanogenic sludge and based on mass balance analysis of carbon transformation. A new mathematical model was developed to describe microbial storage in anaerobic systems. The model was calibrated and validated by using independent data sets from two different anaerobic systems, with significant storage observed, and effectively simulated in both systems. The inclusion of the new anaerobic storage processes in the developed model allows for more successful simulation of transients due to lower accumulation of volatile fatty acids (correction for the overestimation of volatile fatty acids), which mitigates pH fluctuations. Current models such as the ADM1 cannot effectively simulate these dynamics due to a lack of anaerobic storage mechanisms.

Verification for robustness to laser-induced damage for the Aladin instrument on the ADM-Aeolus satellite

NASA Astrophysics Data System (ADS)

Wernham, Denny; Ciapponi, Alessandra; Riede, Wolfgang; Allenspacher, Paul; Era, Fabio; D'Ottavi, Alessandro; Thibault, Dominique

2016-12-01

The Aladin instrument will fly on the European Space Agency's ADM Aeolus satellite. The instrument is a Doppler wind LIDAR, primarily designed to measure global wind profiles to improve the accuracy of numerical weather prediction models. At the heart of the instrument is a frequency stabilized 355nm laser which will emit approximately 100mJ of energy in the form of 20ns pulses with a fluence around 1Jcm-2. The pulse repetition frequency is 50Hz meaning that Aladin will eventually have to accumulate 5Gshots over its 3 years planned lifetime in orbit. Due to anomalies that have occurred on previous spaceborne lasers, as well as a number of failures that we have observed in previous tests, an extensive development and verification campaign was undertaken in order to ensure that the Aladin instrument is robust enough to survive the mission. In this paper, we shall report the logic and the results of this verification campaign.

MUC1 and survivin combination tumor gene vaccine generates specific immune responses and anti-tumor effects in a murine melanoma model.

PubMed

Zhang, Haihong; Liu, Chenlu; Zhang, Fangfang; Geng, Fei; Xia, Qiu; Lu, Zhenzhen; Xu, Ping; Xie, Yu; Wu, Hui; Yu, Bin; Wu, Jiaxin; Yu, Xianghui; Kong, Wei

2016-05-23

MUC1 and survivin are ideal tumor antigens. Although many cancer vaccines targeting survivin or MUC1 have entered clinical trials, no vaccine combining MUC1 and survivin have been reported. Due to tumor heterogeneity, vaccines containing a combination of antigens may have improved efficacy and coverage of a broader spectrum of cancer targets. Here, cellular responses and anti-tumor activities induced by a combination of DNA vaccine targeting MUC1 and survivin (MS) were evaluated. Results showed that CTL activity and inhibition of tumor growth were obviously enhanced in mice immunized with the combined vaccine in a protection assay. However, in order to enhance the therapeutic effect in the treatment assay, a recombinant adenovirus (rAd) vaccine expressing MUC1 and survivin (Ad-MS) was used as a booster following the DNA vaccine prime. Meanwhile, IL-2 promoting T cell proliferation was used as an immunoadjuvant for the DNA vaccine. Results showed that the CTL activity response to the DNA vaccine was enhanced nearly 200% when boosted by the rAd vaccine and was further enhanced by nearly 60% when combined with the IL-2 adjuvant. Therefore, DNA prime combined with rAd boost and IL-2 (MS/IL2/Ad-MS) adjuvant was considered as the best strategy and further evaluated. Multiple cytokines promoting cellular immune responses were shown to be greatly enhanced in mice immunized with MS/IL2/Ad-MS. Moreover, in the treatment assay, the tumor inhibition rate of MS/IL2/Ad-MS reached up to 50.1%, which may be attributed to the enhancement of immune responses and reduction of immunosuppressive factors in tumor-bearing mice. These results suggested that immunization with the combination vaccine targeting MUC1 and survivin using a DNA prime-rAd boost strategy along with IL-2 adjuvant may be an effective method for breaking through immune tolerance to tumors expressing these antigens with potential therapeutic benefits in melanoma cancer. Copyright © 2016. Published by Elsevier Ltd.

Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon

2014-06-12

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinasemore » domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.« less

Design, Synthesis and Antifungal Activity Evaluation of New Thiazolin-4-ones as Potential Lanosterol 14α-Demethylase Inhibitors

PubMed Central

Stana, Anca; Vodnar, Dan C.; Tamaian, Radu; Pîrnău, Adrian; Vlase, Laurian; Ionuț, Ioana; Oniga, Ovidiu; Tiperciuc, Brînduşa

2017-01-01

Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), 1H NMR (proton nuclear magnetic resonance), 13C NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds’ lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds. PMID:28106743

ADM. Service Building (TAN603). Elevations of all facades with door ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Service Building (TAN-603). Elevations of all facades with door details and detail of kitchen. Section through garage area shows second level of steel decking. Equipment and laboratory furniture schedule. Ralph M. Parsons 902-2-ANP-603-A 44. Date: December 1952. Approved by INEEL Classification Office for public release. INEEL index code no. 033-0603-00-693-106719 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

Kranc: a Mathematica package to generate numerical codes for tensorial evolution equations

NASA Astrophysics Data System (ADS)

Husa, Sascha; Hinder, Ian; Lechner, Christiane

2006-06-01

We present a suite of Mathematica-based computer-algebra packages, termed "Kranc", which comprise a toolbox to convert certain (tensorial) systems of partial differential evolution equations to parallelized C or Fortran code for solving initial boundary value problems. Kranc can be used as a "rapid prototyping" system for physicists or mathematicians handling very complicated systems of partial differential equations, but through integration into the Cactus computational toolkit we can also produce efficient parallelized production codes. Our work is motivated by the field of numerical relativity, where Kranc is used as a research tool by the authors. In this paper we describe the design and implementation of both the Mathematica packages and the resulting code, we discuss some example applications, and provide results on the performance of an example numerical code for the Einstein equations. Program summaryTitle of program: Kranc Catalogue identifier: ADXS_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADXS_v1_0 Program obtainable from: CPC Program Library, Queen's University of Belfast, N. Ireland Distribution format: tar.gz Computer for which the program is designed and others on which it has been tested: General computers which run Mathematica (for code generation) and Cactus (for numerical simulations), tested under Linux Programming language used: Mathematica, C, Fortran 90 Memory required to execute with typical data: This depends on the number of variables and gridsize, the included ADM example requires 4308 KB Has the code been vectorized or parallelized: The code is parallelized based on the Cactus framework. Number of bytes in distributed program, including test data, etc.: 1 578 142 Number of lines in distributed program, including test data, etc.: 11 711 Nature of physical problem: Solution of partial differential equations in three space dimensions, which are formulated as an initial value problem. In particular, the program is geared towards handling very complex tensorial equations as they appear, e.g., in numerical relativity. The worked out examples comprise the Klein-Gordon equations, the Maxwell equations, and the ADM formulation of the Einstein equations. Method of solution: The method of numerical solution is finite differencing and method of lines time integration, the numerical code is generated through a high level Mathematica interface. Restrictions on the complexity of the program: Typical numerical relativity applications will contain up to several dozen evolution variables and thousands of source terms, Cactus applications have shown scaling up to several thousand processors and grid sizes exceeding 500 3. Typical running time: This depends on the number of variables and the grid size: the included ADM example takes approximately 100 seconds on a 1600 MHz Intel Pentium M processor. Unusual features of the program: based on Mathematica and Cactus

Modelling the anaerobic digestion of solid organic waste - Substrate characterisation method for ADM1 using a combined biochemical and kinetic parameter estimation approach.

PubMed

Poggio, D; Walker, M; Nimmo, W; Ma, L; Pourkashanian, M

2016-07-01

This work proposes a novel and rigorous substrate characterisation methodology to be used with ADM1 to simulate the anaerobic digestion of solid organic waste. The proposed method uses data from both direct substrate analysis and the methane production from laboratory scale anaerobic digestion experiments and involves assessment of four substrate fractionation models. The models partition the organic matter into a mixture of particulate and soluble fractions with the decision on the most suitable model being made on quality of fit between experimental and simulated data and the uncertainty of the calibrated parameters. The method was tested using samples of domestic green and food waste and using experimental data from both short batch tests and longer semi-continuous trials. The results showed that in general an increased fractionation model complexity led to better fit but with increased uncertainty. When using batch test data the most suitable model for green waste included one particulate and one soluble fraction, whereas for food waste two particulate fractions were needed. With richer semi-continuous datasets, the parameter estimation resulted in less uncertainty therefore allowing the description of the substrate with a more complex model. The resulting substrate characterisations and fractionation models obtained from batch test data, for both waste samples, were used to validate the method using semi-continuous experimental data and showed good prediction of methane production, biogas composition, total and volatile solids, ammonia and alkalinity. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Algorithm To Architecture Mapping Model (ATAMM) multicomputer operating system functional specification

NASA Technical Reports Server (NTRS)

Mielke, R.; Stoughton, J.; Som, S.; Obando, R.; Malekpour, M.; Mandala, B.

1990-01-01

A functional description of the ATAMM Multicomputer Operating System is presented. ATAMM (Algorithm to Architecture Mapping Model) is a marked graph model which describes the implementation of large grained, decomposed algorithms on data flow architectures. AMOS, the ATAMM Multicomputer Operating System, is an operating system which implements the ATAMM rules. A first generation version of AMOS which was developed for the Advanced Development Module (ADM) is described. A second generation version of AMOS being developed for the Generic VHSIC Spaceborne Computer (GVSC) is also presented.

The Army Study Program.

DTIC Science & Technology

1980-10-09

STUDDIES BY CATEGORY STUDY TITLE SPONSOR NMtTHOO PPA ADM RE:MOTE LINK PRUG DARCOM CONTRACT ADV TECH MODEL FULL DARCON CONTRACT ARMY COMMAND ANDi CONTROL...HOUUSE NUN -RLCURRIN 1 LMANUS DARCON I"-HUSL FF-TH-hLLI TM~k ECUNLNI(. ANALYSIS DARCOM CUNTRALT FOR SFELTKUM ANALYZERS UPLRA1IUN&L FLt)AI/EKPSL TKADL...TECHNULOGY A5 AESM:NT TRADOC bUTH *TEN YEAR INSTRUMENTATIOft ANALYSkIS OCSA ot" PHASE I TERRAIN MODELS DARCOM bUTH lEST CRITLRIA FUOR NUN -IIILLL-K WEAPUN

Biomarkers from distinct biological pathways improve early risk stratification in medical emergency patients: the multinational, prospective, observational TRIAGE study.

PubMed

Schuetz, Philipp; Hausfater, Pierre; Amin, Devendra; Amin, Adina; Haubitz, Sebastian; Faessler, Lukas; Kutz, Alexander; Conca, Antoinette; Reutlinger, Barbara; Canavaggio, Pauline; Sauvin, Gabrielle; Bernard, Maguy; Huber, Andreas; Mueller, Beat

2015-10-29

Early risk stratification in the emergency department (ED) is vital to reduce time to effective treatment in high-risk patients and to improve patient flow. Yet, there is a lack of investigations evaluating the incremental usefulness of multiple biomarkers measured upon admission from distinct biological pathways for predicting fatal outcome and high initial treatment urgency in unselected ED patients in a multicenter and multinational setting. We included consecutive, adult, medical patients seeking ED care into this observational, cohort study in Switzerland, France and the USA. We recorded initial clinical parameters and batch-measured prognostic biomarkers of inflammation (pro-adrenomedullin [ProADM]), stress (copeptin) and infection (procalcitonin). During a 30-day follow-up, 331 of 7132 (4.6 %) participants reached the primary endpoint of death within 30 days. In logistic regression models adjusted for conventional risk factors available at ED admission, all three biomarkers strongly predicted the risk of death (AUC 0.83, 0.78 and 0.75), ICU admission (AUC 0.67, 0.69 and 0.62) and high initial triage priority (0.67, 0.66 and 0.58). For the prediction of death, ProADM significantly improved regression models including (a) clinical information available at ED admission (AUC increase from 0.79 to 0.84), (b) full clinical information at ED discharge (AUC increase from 0.85 to 0.88), and (c) triage information (AUC increase from 0.67 to 0.83) (p <0.01 for each comparison). Similarly, ProADM also improved clinical models for prediction of ICU admission and high initial treatment urgency. Results were robust in regard to predefined patient subgroups by center, main diagnosis, presenting symptoms, age and gender. Combination of clinical information with results of blood biomarkers measured upon ED admission allows early and more adequate risk stratification in individual unselected medical ED patients. A randomized trial is needed to answer the question whether biomarker-guided initial patient triage reduces time to initial treatment of high-risk patients in the ED and thereby improves patient flow and clinical outcomes. ClinicalTrials.gov NCT01768494 . Registered January 9, 2013.

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein

PubMed Central

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression. PMID:29121121

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein.

PubMed

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression.

High-Temperature Electrical Insulation Behavior of Alumina Films Prepared at Room Temperature by Aerosol Deposition and Influence of Annealing Process and Powder Impurities

NASA Astrophysics Data System (ADS)

Schubert, Michael; Leupold, Nico; Exner, Jörg; Kita, Jaroslaw; Moos, Ralf

2018-04-01

Alumina (Al2O3) is a widely used material for highly insulating films due to its very low electrical conductivity, even at high temperatures. Typically, alumina films have to be sintered far above 1200 °C, which precludes the coating of lower melting substrates. The aerosol deposition method (ADM), however, is a promising method to manufacture ceramic films at room temperature directly from the ceramic raw powder. In this work, alumina films were deposited by ADM on a three-electrode setup with guard ring and the electrical conductivity was measured between 400 and 900 °C by direct current measurements according to ASTM D257 or IEC 60093. The effects of film annealing and of zirconia impurities in the powder on the electrical conductivity were investigated. The conductivity values of the ADM films correlate well with literature data and can even be improved by annealing at 900 °C from 4.5 × 10-12 S/cm before annealing up to 5.6 × 10-13 S/cm after annealing (measured at 400 °C). The influence of zirconia impurities is very low as the conductivity is only slightly elevated. The ADM-processed films show a very good insulation behavior represented by an even lower electrical conductivity than conventional alumina substrates as they are commercially available for thick-film technology.

Preparation and characterization of an advanced collagen aggregate from porcine acellular dermal matrix.

PubMed

Liu, Xinhua; Dan, Nianhua; Dan, Weihua

2016-07-01

The objective of this study was to extract and characterize an advanced collagen aggregate (Ag-col) from porcine acellular dermal matrix (pADM). Based on histological examination, scanning electron microscopy (SEM) and atomic force microscope (AFM), Ag-col was composed of the D-periodic cross-striated collagen fibrils and thick collagen fiber bundles with uneven diameters and non-orientated arrangement. Fourier transform infrared (FTIR) spectra of pADM, Ag-col and Col were similar and revealed the presence of the triple helix. Circular dichroism (CD) analysis exhibited a slightly higher content of α-helix but inappreciably less amount of random coil structure in Ag-col compared to Col. Moreover, imino acid contents of pADM, Ag-col and Col were 222.43, 218.30 and 190.01 residues/1000 residues, respectively. From zeta potential analysis, a net charge of zero was found at pH 6.45 and 6.11 for Ag-col and Col, respectively. Differential scanning calorimetry (DSC) study suggested that the Td of Ag-col was 20°C higher than that of Col as expected, and dynamic mechanical analysis (DMA) indicated that Ag-col possessed a higher storage modulus but similar loss factor compared to Col. Therefore, the collagen aggregate from pADM could serve as a better alternative source of collagens for further applications in food and biological industries. Copyright © 2016 Elsevier B.V. All rights reserved.

Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis.

PubMed

Kang, E H; Lee, E B; Shin, K C; Im, C H; Chung, D H; Han, S K; Song, Y W

2005-10-01

To assess the prevalence, characteristics and prognostic factors of interstitial lung disease (ILD) in Korean patients with polymyositis (PM), dermatomyositis (DM) and amyopathic dermatomyositis (ADM). We reviewed the medical records of 72 consecutive PM and DM patients, including six patients with ADM, who were seen at the Rheumatology Clinic of Seoul National University Hospital between 1984 and 2003. Twenty-nine PM/DM patients (40.3%) developed ILD. Anti-Jo-1 antibody and arthralgia were associated with the presence of ILD (P = 0.022 and P = 0.041, respectively), whereas dysphagia was more frequently found in patients without ILD (P = 0.041). Lung biopsies revealed diffuse alveolar damage (DAD) (n = 2), usual interstitial pneumonia (UIP) with DAD (n = 2), UIP (n = 1), and non-specific interstitial pneumonia (n = 2). Of the 29 patients, 11 (37.9%) died. The mean survival time in ILD patients was significantly shorter than in those without ILD (13.8+/-1.8 vs 19.2+/-0.9 yr, P = 0.017). Poor survival in ILD patients was associated with a Hamman-Rich-like presentation (P = 0.0000), ADM features (P = 0.0001) and an initial forced vital capacity (FVC) < or =60% (P = 0.024). ILD was observed in 40.3% of Korean PM/DM patients and was associated with poor survival. A Hamman-Rich-like presentation, ADM features and an initial FVC < or =60% were associated with poor survival in ILD.

Effects of spermatozoa-oviductal cell coincubation time and oviductal cell age on spermatozoa-oviduct interactions.

PubMed

Aldarmahi, Ahmed; Elliott, Sarah; Russell, Jean; Fazeli, Alireza

2014-01-01

The oviduct plays a crucial role in sperm storage, maintenance of sperm viability and sperm transport to the site of fertilisation. The aim of the present study was to investigate the effects of oviductal cell culture passage number, oviductal cell age and spermatozoa-oviduct coincubation times on gene expression in oviductal cells. Immortalised oviductal epithelial cells (OPEC) obtained from two different cell passages (36 and 57) were subcultured three times with and without spermatozoa for 24 h (control group). In a second study, OPEC were cocultured with spermatozoa for different time intervals (0, 4, 12 and 24 h). Expression of adrenomedullin (ADM), heat shock 70 kDa protein 8 (HSPA8) and prostaglandin E synthase (PGES) in OPEC was measured by quantitative polymerase chain reaction. The expression of ADM and HSPA8 was decreased significantly in OPEC cells from Passage 57, particularly in the later subculture group. These effects on HSPA8, but not ADM, expression in OPEC were further altered after coculture with spermatozoa for 24 h. We also demonstrated that spermatozoa-oviduct coculture for 12 and 24 h resulted in significantly higher expression of ADM, HSPA8 and PGES in OPEC. Overall, the data suggest that the OPEC lose some of their properties as a result of oviductal cell aging and that there are spermatozoa-oviduct interactions leading to increased oviductal cell gene expression.

Healing rate and autoimmune safety of full-thickness wounds treated with fish skin acellular dermal matrix versus porcine small-intestine submucosa: a noninferiority study.

PubMed

Baldursson, Baldur Tumi; Kjartansson, Hilmar; Konrádsdóttir, Fífa; Gudnason, Palmar; Sigurjonsson, Gudmundur F; Lund, Sigrún Helga

2015-03-01

A novel product, the fish skin acellular dermal matrix (ADM) has recently been introduced into the family of biological materials for the treatment of wounds. Hitherto, these products have been produced from the organs of livestock. A noninferiority test was used to compare the effect of fish skin ADM against porcine small-intestine submucosa extracellular matrix in the healing of 162 full-thickness 4-mm wounds on the forearm of 81 volunteers. The fish skin product was noninferior at the primary end point, healing at 28 days. Furthermore, the wounds treated with fish skin acellular matrix healed significantly faster. These results might give the fish skin ADM an advantage because of its environmental neutrality when compared with livestock-derived products. The study results on these acute full-thickness wounds might apply for diabetic foot ulcers and other chronic full-thickness wounds, and the shorter healing time for the fish skin-treated group could influence treatment decisions. To test the autoimmune reactivity of the fish skin, the participants were tested with the following ELISA (enzyme-linked immunosorbent assay) tests: RF, ANA, ENA, anti ds-DNA, ANCA, anti-CCP, and anticollagen I and II. These showed no reactivity. The results demonstrate the claims of safety and efficacy of fish skin ADM for wound care. © The Author(s) 2015.

A novel dermal matrix generated from burned skin as a promising substitute for deep-degree burns therapy

PubMed Central

YU, GUANYING; YE, LAN; TAN, WEI; ZHU, XUGUO; LI, YAONAN; JIANG, DUYIN

2016-01-01

The extensive skin defects induced by severe burns are dangerous and can be fatal. Currently, the most common therapy is tangential excision to remove the necrotic or denatured areas of skin, followed by skin grafting. Xenogeneic dermal substitutes, such as porcine acellular dermal matrix (ADM), are typically used to cover the burn wounds, and may accelerate wound healing. It is assumed that burned skin that still maintains partial biological activity may be recycled to construct an autologous acellular dermal matrix, termed 'deep-degree burned dermal matrix (DDBDM)'. In theory, DDBDM may avoid the histoincompatibility issues associated with foreign or xenogeneic dermal matrices, and reduce therapy costs by making full use of discarded skin. In the present study, the collagens within prepared DDBDM were thickened, disorganized and partially fractured, however, they still maintained their reticular structure and tensile strength (P<0.01). Through microarray analysis of the cytokines present in ADM and DDBDM, it was determined that the DDBDM did not produce excessive levels of harmful burn toxins. Following 4 weeks of subcutaneous implantation, ADM and DDBDM were incompletely degraded and maintained good integrity. No significant inflammatory reaction or rejection were observed, which indicated that ADM and DDBDM have good histocompatibility. Therefore, DDBDM may be a useful material for the treatment of deep-degree burns. PMID:26846279

Attachment, proliferation and collagen type I mRNA expression of human gingival fibroblasts on different biodegradable membranes.

PubMed

Hakki, Sema S; Korkusuz, Petek; Purali, Nuhan; Bozkurt, Buket; Kus, Mahmut; Duran, Ismet

2013-01-01

The purpose of this study was to investigate adhesion, proliferation and type I collagen (COL I) mRNA expression of gingival fibroblasts on different membranes used in periodontal applications. Collagen (C), acellular dermal matrix (ADM) and polylactic acid; polyglycolic acid; lactide/glycolide copolymer (PLGA) biodegradable membranes were combined with gingival fibroblasts in culture and incubated for 48 h. Cell adhesion was examined with scanning electron and confocal microscopy. MTT assay was used to measure proliferation. COL I mRNA expression was assessed using quantitative-polymerase chain reaction (QPCR). The PLGA group exhibited the lowest cell survival on day 5 and 10, and lowest cell proliferation on days 5, 10 and 14. While cell proliferation was similar in C and ADM groups, the C membrane showed a slightly greater increase in viable cells to day 10. Confocal and scanning electron microscopy confirmed the results of proliferation and MTT assays. The highest COL I mRNA expression was noted in the PLGA membrane group when compared to the C (p < 0.01) and ADM (p < 0.05) membrane groups. These data revealed that adherence and proliferation of primary gingival fibroblasts on collagen-based C and ADM membranes is better than that seen with PLGA membranes, and thus may be preferable in the treatment of gingival recession defects.

A novel technique to solve nonlinear higher-index Hessenberg differential-algebraic equations by Adomian decomposition method.

PubMed

Benhammouda, Brahim

2016-01-01

Since 1980, the Adomian decomposition method (ADM) has been extensively used as a simple powerful tool that applies directly to solve different kinds of nonlinear equations including functional, differential, integro-differential and algebraic equations. However, for differential-algebraic equations (DAEs) the ADM is applied only in four earlier works. There, the DAEs are first pre-processed by some transformations like index reductions before applying the ADM. The drawback of such transformations is that they can involve complex algorithms, can be computationally expensive and may lead to non-physical solutions. The purpose of this paper is to propose a novel technique that applies the ADM directly to solve a class of nonlinear higher-index Hessenberg DAEs systems efficiently. The main advantage of this technique is that; firstly it avoids complex transformations like index reductions and leads to a simple general algorithm. Secondly, it reduces the computational work by solving only linear algebraic systems with a constant coefficient matrix at each iteration, except for the first iteration where the algebraic system is nonlinear (if the DAE is nonlinear with respect to the algebraic variable). To demonstrate the effectiveness of the proposed technique, we apply it to a nonlinear index-three Hessenberg DAEs system with nonlinear algebraic constraints. This technique is straightforward and can be programmed in Maple or Mathematica to simulate real application problems.

Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle

PubMed Central

Vernetti, Lawrence; Gough, Albert; Baetz, Nicholas; Blutt, Sarah; Broughman, James R.; Brown, Jacquelyn A.; Foulke-Abel, Jennifer; Hasan, Nesrin; In, Julie; Kelly, Edward; Kovbasnjuk, Olga; Repper, Jonathan; Senutovitch, Nina; Stabb, Janet; Yeung, Catherine; Zachos, Nick C.; Donowitz, Mark; Estes, Mary; Himmelfarb, Jonathan; Truskey, George; Wikswo, John P.; Taylor, D. Lansing

2017-01-01

Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements. PMID:28176881

Use of porcine acellular dermal matrix following early dermabrasion reduces length of stay in extensive deep dermal burns.

PubMed

Guo, Zhi-Qian; Qiu, Le; Gao, You; Li, Jin-Hu; Zhang, Xin-He; Yang, Xin-Lei; Peszel, April; Chen, Xu-Lin

2016-05-01

Extensive deep partial-thickness burns still seriously challenge the surgeon's abilities. This study aimed to assess the impact of early dermabrasion combined with porcine acellular dermal matrix (ADM) in extensive deep dermal burns. From September 2009 to September 2013, a total of 60 adult patients sustained greater than 50% total body surface area (TBSA) burn by hot water or gas explosion were divided into three groups based on dermabrasion: group A (early dermabrasion and porcine ADM), group B (early dermabrasion and nano-silver dressings), and group C (conservative group). The wound healing time and length of hospital stay were analyzed. Scar assessment was performed at 3 and 12 months after the injury with a modified Vancouver Scar Scale linked with TBSA (mVSS-TBSA). No significant difference was found in mean burn size, burn depth, age, male-to-female ratio, or incidence of inhalation injury between the patients in the three groups (p>0.05). Compared with groups B and C, the patients that received early dermabrasion combined with porcine ADM had a shorter wound healing time (p<0.01). The burn patients treated with early dermabrasion and porcine ADM coverage had a mean length of hospital stay of 28.3 days (±7.2), which was significantly shorter than that of groups B and C (p<0.05-0.01). The mVSS-TBSA of patients in group A was significantly improved in comparison with groups B and C at 3 and 12 months after the injury. There was no significant difference in the mortality rate between the three groups (p>0.05). Early dermabrasion combined with porcine ADM coverage facilitates wound healing, reduces the length of hospital stay, and improves esthetic and functional results in extensive deep dermal burns with burn size over 50% TBSA. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Effect of age and gender on the number of motor units in healthy subjects estimated by the multipoint incremental MUNE method.

PubMed

Gawel, Malgorzata; Kostera-Pruszczyk, Anna

2014-06-01

Motor unit number estimation (MUNE) is a tool for estimating the number of motor units. The aim was to evaluate the multipoint incremental MUNE method in a healthy population, to analyze whether aging, gender, and the dominant hand side influence the motor unit number, and to assess reproducibility of MUNE with the Shefner modification. We studied 60 volunteers (mean age, 47 ± 17.7 years) in four groups aged 18 to 30, 31 to 45, 46 to 60, and above 60 years. Motor unit number estimation was calculated in the abductor pollicis brevis (APB) and the abductor digiti minimi (ADM) by dividing the single motor unit action potential amplitude into the maximal compound motor action potential amplitude. Test-retest variability was 7%. The mean value of MUNE for APB was 133.2 ± 43 and for ADM was 157.1 ± 39.4. Significant differences in MUNE results were found between groups aged 18 to 30 and 60 years or older and between groups aged 31 to 45 and 60 years or older. Motor unit number estimation results correlated negatively with the age of subjects for both APB and ADM. Single motor unit action potential, reflecting the size of motor unit, increased with the age of subjects only in APB. Compound motor action potential amplitude correlated negatively with the age of subjects in APB and ADM. Significant correlations were seen between MUNE in APB or ADM and compound motor action potential amplitude in these muscles and the age of female subjects. A similar relationship was not found in males. Multipoint incremental MUNE method with the Shefner modification is a noninvasive, easy to perform method with high reproducibility. The loss of motor neurons because of aging could be confirmed by our MUNE study and seems to be more pronounced in females.

Leakage Risk Assessment of CO{sub 2} Transportation by Pipeline at the Illinois Basin Decatur Project, Decatur, Illinois

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazzoldi, A.; Oldenburg, C. M.

The Illinois Basin Decatur Project (IBDP) is designed to confirm the ability of the Mt. Simon Sandstone, a major regional saline-water-bearing formation in the Illinois Basin, to store 1 million tons of carbon dioxide (CO{sub 2}) injected over a period of three years. The CO{sub 2} will be provided by Archer Daniels Midland (ADM) from its Decatur, Illinois, ethanol plant. In order to transport CO{sub 2} from the capture facility to the injection well (also located within the ADM plant boundaries), a high-pressure pipeline of length 3,200 ft (975 m) has been constructed, running above the ground surface within themore » ADM plant footprint. We have qualitatively evaluated risks associated with possible pipeline failure scenarios that lead to discharge of CO{sub 2} within the real-world environment of the ADM plant in which there are often workers and visitors in the vicinity of the pipeline. There are several aspects of CO{sub 2} that make its transportation and potential leakage somewhat different from other substances, most notable is its non-flammability and propensity to change to solid (dry ice) upon strong decompression. In this study, we present numerical simulations using Computational Fluid Dynamics (CFD) methods of the release and dispersion of CO{sub 2} from individual hypothetical pipeline failures (i.e., leaks). Failure frequency of the various components of a pipeline transportation system over time are taken from prior work on general pipeline safety and leakage modeling and suggest a 4.65% chance of some kind of pipeline failure over the three-years of operation. Following the Precautionary Principle (see below), we accounted for full-bore leakage scenarios, where the temporal evolution of the mass release rate from the high-pressure pipeline leak locations was simulated using a state-of-the-art Pipe model which considers the thermodynamic effects of decompression in the entire pipeline. Failures have been simulated at four representative locations along the pipeline route within the ADM plant. Leakage scenarios at sites along the route of the pipeline, where plant operations (e.g., vehicular and train transportation) seem to present a higher likelihood of accidental failure, for example due to vehicles or equipment crashing into the pipeline and completely severing it, were modeled by allowing them to have a double source consistent with the pipeline releasing high-pressure CO{sub 2} from both ends of the broken pipe after a full-bore offset rupture. Simulation results show that the built environment of the plant plays a significant role in the dispersion of the gas as leaking CO{sub 2} can impinge upon buildings and other infrastructure. In all scenarios simulated, the region of very high-concentration of CO{sub 2} is limited to a small area around the pipeline failure, suggesting the likelihood of widespread harmful CO{sub 2} exposure to plant personnel from pipeline leakage is low. An additional risk is posed by the blast wave that emanates from a high-pressure pipeline when it is breached quickly. We estimate the blast wave risk as low because it occurs only for a short time in the immediate vicinity of the rupture, and requires an instantaneous large-scale rupture to occur. We recommend consideration of signage and guard rails and posts to mitigate the likelihood of vehicles crashing into the pipeline. A standardized emergency response plan applicable to capture plants within industrial sites could be developed based on the IBDP that would be useful for other capture plants. Finally, we recommend carrying out coupled wellbore-reservoir blowout scenario modeling to understand the potential for hazardous conditions arising from an unexpected blowout at the wellhead.« less

Full-mouth esthetic rehabilitation with acellular dermal matrix.

PubMed

Clozza, Emanuele; Suzuki, Takanori; Engebretson, Steven P

2014-01-01

Treatment of multiple recession defects with the adjunct use of a connective tissue graft (CTG) represents a challenge when diagnosed in several teeth of the mouth. The amount of CTG harvested from the palate may not be adequate to address this condition. In such scenarios, alternative sources such as acellular dermal matrix (ADM) are preferred due to the unlimited availability. A case report is presented, dealing with the treatment of multiple gingival recessions affecting the majority of dentition using ADM, with a 6-month follow-up.

Aerosol optical properties retrieved from the future space lidar mission ADM-aeolus

NASA Astrophysics Data System (ADS)

Martinet, Pauline; Flament, Thomas; Dabas, Alain

2018-04-01

The ADM-Aeolus mission, to be launched by end of 2017, will enable the retrieval of aerosol optical properties (extinction and backscatter coefficients essentially) for different atmospheric conditions. A newly developed feature finder (FF) algorithm enabling the detection of aerosol and cloud targets in the atmospheric scene has been implemented. Retrievals of aerosol properties at a better horizontal resolution based on the feature finder groups have shown an improvement mainly on the backscatter coefficient compared to the common 90 km product.

Navy Littoral Combat Ship (LCS) Program: Background and Issues for Congress

DTIC Science & Technology

2014-02-05

Surface Fleet,” submitted late last year by the head of Naval Surface Forces, Vice Adm. Tom Copeman, to Chief of Naval Operations Adm. Jon Greenert...with Farragut at Mobile Bay. They took part in the Red River campaigns of the West and proved ideal for coastal blockading work. A Monitor even served...too slow, too vulnerable. It couldn’t defend itself, they argued. The 76mm gun was little more than a pea- shooter . The Phalanx system, poorly situated

Application of 2D-Nonlinear Shallow Water Model of Tsunami by using Adomian Decomposition Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waewcharoen, Sribudh; Boonyapibanwong, Supachai; Koonprasert, Sanoe

2008-09-01

One of the most important questions in tsunami modeling is the estimation of tsunami run-up heights at different points along a coastline. Methods for numerical simulation of tsunami wave propagation in deep and shallow seas are well developed and have been widely used by many scientists (2001-2008). In this paper, we consider a two-dimensional nonlinear shallow water model of tsunami given by Tivon Jacobson is work [1]. u{sub t}+uu{sub x}+{nu}u{sub y} -c{sup 2}(h{sub x}+(h{sub b}){sub x}) {nu}{sub t}+u{nu}{sub x}+{nu}{nu}{sub y} = -c{sup 2}(h{sub y}+(h{sub b}){sub y}) h{sub t}+(hu){sub x}+(h{nu}){sub y} = 0 g-shore, h is surface elevation and s, tmore » is time, u is velocity of cross-shore, {nu} is velocity of along-shore, h is surface elevation and h{sub b} is function of shore. This is a nondimensionalized model with the gravity g and constant reference depth H factored into c = {radical}(gH). We apply the Adomian Decompostion Method (ADM) to solve the tsunami model. This powerful method has been used to obtain explicit and numerical solutions of three types of diffusion-convection-reaction (DECR) equations. The ADM results for the tsunami model yield analytical solutions in terms of a rapidly convergent infinite power series. Symbolic computation, numerical results and graphs of solutions are obtained by Maple program.« less

Metabolic stability for drug discovery and development: pharmacokinetic and biochemical challenges.

PubMed

Masimirembwa, Collen M; Bredberg, Ulf; Andersson, Tommy B

2003-01-01

Metabolic stability refers to the susceptibility of compounds to biotransformation in the context of selecting and/or designing drugs with favourable pharmacokinetic properties. Metabolic stability results are usually reported as measures of intrinsic clearance, from which secondary pharmacokinetic parameters such as bioavailability and half-life can be calculated when other data on volume of distribution and fraction absorbed are available. Since these parameters are very important in defining the pharmacological and toxicological profile of drugs as well as patient compliance, the pharmaceutical industry has a particular interest in optimising for metabolic stability during the drug discovery and development process. In the early phases of drug discovery, new chemical entities cannot be administered to humans; hence, predictions of these properties have to be made from in vivo animal, in vitro cellular/subcellular and computational systems. The utility of these systems to define the metabolic stability of compounds that is predictive of the human situation will be reviewed here. The timing of performing the studies in the discovery process and the impact of recent advances in research on drug absorption, distribution, metabolism and excretion (ADME) will be evaluated with respect to the scope and depth of metabolic stability issues. Quantitative prediction of in vivo clearance from in vitro metabolism data has, for many compounds, been shown to be poor in retrospective studies. One explanation for this may be that there are components used in the equations for scaling that are missing or uncertain and should be an area of more research. For example, as a result of increased biochemical understanding of drug metabolism, old assumptions (e.g. that the liver is the principal site of first-pass metabolism) need revision and new knowledge (e.g. the relationship between transporters and drug metabolising enzymes) needs to be incorporated into in vitro-in vivo correlation models. With ADME parameters increasingly being determined on automated platforms, instead of using results from high throughput screening (HTS) campaigns as simple go/no-go filters, the time saved and the many compounds analysed using the robots should be invested in careful processing of the data. A logical step would be to investigate the potential to construct computational models to understand the factors governing metabolic stability. A rational approach to the use of HTS assays should aim to screen for many properties (e.g. physicochemical parameters, absorption, metabolism, protein binding, pharmacokinetics in animals and pharmacology) in an integrated manner rather than screen against one property on many compounds, since it is likely that the final drug will represent a global average of these properties.

Measuring Training ROI: Silver Bullet or Urban Legend

DTIC Science & Technology

2008-06-01

unlimited 13. SUPPLEMENTARY NOTES See also ADM202527. Military Operations Research Society Symposium (76th) Held in New London, Connecticut on June... new markets and innovation) than the bottom line (the accounting fiction of profits).” Jay Cross, CEO of Internet Time Group, “A Fresh Look at ROI...AFAMS. Return on Investment oF Modeling and Simulation (M&S) Workshop Briefing, April 2008 ALTERNATIVES? MATERIAL NEW SYSTEMS SOFTWARE COURSWARE

Non-invasive assessment of muscle stiffness in patients with Duchenne muscular dystrophy.

PubMed

Lacourpaille, Lilian; Hug, François; Guével, Arnaud; Péréon, Yann; Magot, Armelle; Hogrel, Jean-Yves; Nordez, Antoine

2015-02-01

Assessment of muscle mechanical properties may provide clinically valuable information for follow-up of patients with Duchenne muscular dystrophy (DMD) through the course of their disease. In this study we aimed to assess the effect of DMD on stiffness of relaxed muscles using elastography (supersonic shear imaging). Fourteen DMD patients and 13 control subjects were studied. Six muscles were measured at 2 muscle lengths (shortened and stretched): gastrocnemius medialis (GM); tibialis anterior (TA); vastus lateralis (VL); biceps brachii (BB); triceps brachii (TB); and abductor digiti minimi (ADM). Stiffness was significantly higher in DMD patients compared with controls for all the muscles (main effect for population, P < 0.033 in all cases), except for ADM. The effect size was small (d = 0.33 for ADM at both muscle lengths) to large (d = 0.86 for BB/stretched). Supersonic shear imaging is a sensitive non-invasive technique to assess the increase in muscle stiffness associated with DMD. © 2014 Wiley Periodicals, Inc.

Energy in higher-dimensional spacetimes

NASA Astrophysics Data System (ADS)

Barzegar, Hamed; Chruściel, Piotr T.; Hörzinger, Michael

2017-12-01

We derive expressions for the total Hamiltonian energy of gravitating systems in higher-dimensional theories in terms of the Riemann tensor, allowing a cosmological constant Λ ∈R . Our analysis covers asymptotically anti-de Sitter spacetimes, asymptotically flat spacetimes, as well as Kaluza-Klein asymptotically flat spacetimes. We show that the Komar mass equals the Arnowitt-Deser-Misner (ADM) mass in stationary asymptotically flat spacetimes in all dimensions, generalizing the four-dimensional result of Beig, and that this is no longer true with Kaluza-Klein asymptotics. We show that the Hamiltonian mass does not necessarily coincide with the ADM mass in Kaluza-Klein asymptotically flat spacetimes, and that the Witten positivity argument provides a lower bound for the Hamiltonian mass—and not for the ADM mass—in terms of the electric charge. We illustrate our results on the five-dimensional Rasheed metrics, which we study in some detail, pointing out restrictions that arise from the requirement of regularity, which have gone seemingly unnoticed so far in the literature.

Can one ADM quantize relativistic bosonicstrings and membranes?

NASA Astrophysics Data System (ADS)

Moncrief, Vincent

2006-04-01

The standard methods for quantizing relativistic strings diverge significantly from the Dirac-Wheeler-DeWitt program for quantization of generally covariant systems and one wonders whether the latter could be successfully implemented as an alternative to the former. As a first step in this direction, we consider the possibility of quantizing strings (and also relativistic membranes) via a partially gauge-fixed ADM (Arnowitt, Deser and Misner) formulation of the reduced field equations for these systems. By exploiting some (Euclidean signature) Hamilton-Jacobi techniques that Mike Ryan and I had developed previously for the quantization of Bianchi IX cosmological models, I show how to construct Diff( S 1)-invariant (or Diff(Σ)-invariant in the case of membranes) ground state wave functionals for the cases of co-dimension one strings and membranes embedded in Minkowski spacetime. I also show that the reduced Hamiltonian density operators for these systems weakly commute when applied to physical (i.e. Diff( S 1) or Diff(Σ)-invariant) states. While many open questions remain, these preliminary results seem to encourage further research along the same lines.

Alternatives to connective tissue graft in the treatment of localized gingival recessions: A systematic review.

PubMed

Amine, K; El Amrani, Y; Chemlali, S; Kissa, J

2018-02-01

The aim of this Systematic Review (SR) was to assess the clinical efficacy of alternatives procedures; Acellular Dermal Matrix (ADM), Xenogeneic Collagen Matrix (XCM), Enamel Matrix Derivative (EMD) and Platelet Rich Fibrin (PRF), compared to conventional procedures in the treatment of localized gingival recessions. Electronic searches were performed to identify randomized clinical trials (RCTs) on treatment of single gingival recession with at least 6 months of follow-up. Applying guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA). The risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool. Eighteen randomized controlled trials (RCTs) with a total of 390 treated patients (606 recessions) were included. This systematic review showed that: Coronally Advanced Flap (CAF) in conjunction with ADM was significantly better than CAF alone, while the comparison between CAF+ADM and CTG was affected by large uncertainty. The CAF+EMD was significantly better than CAF alone, whereas the comparison between CAF+EMD and CTG was affected by large uncertainty. No significant difference was recorded when comparing CAF+XCM with CAF alone, and the comparison between CAF+XCM and CTG was affected by large uncertainty. The comparison between PRF and others technique was affected by large uncertainty. ADM, XCM and EMD assisted to CAF might be considered alternatives of CTG in the treatment of Miller class I and II gingival recession. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evaluation of STAT medication ordering process in a community hospital.

PubMed

Abdelaziz, Hani; Richardson, Sandra; Walsh, Kim; Nodzon, Jessica; Schwartz, Barbara

2016-01-01

In most health care facilities, problems related to delays in STAT medication order processing time are of common concern. The purpose of this study was to evaluate processing time for STAT orders at Kimball Medical Center. All STAT orders were reviewed to determine processing time; order processing time was also stratified by physician order entry (physician entered (PE) orders vs. non-physician entered (NPE) orders). Collected data included medication ordered, indication, time ordered, time verified by pharmacist, time sent from pharmacy, and time charted as given to the patient. A total of 502 STAT orders were reviewed and 389 orders were included for analysis. Overall, median time was 29 minutes, IQR 16-63; p<0.0001.). The time needed to process NPE orders was significantly less than that needed for PE orders (median 27 vs. 34 minutes; p=0.026). In terms of NPE orders, the median total time required to process STAT orders for medications available in the Automated Dispensing Devices (ADM) was within 30 minutes, while that required to process orders for medications not available in the ADM was significantly greater than 30 minutes. For PE orders, the median total time required to process orders for medications available in the ADM (i.e., not requiring pharmacy involvement) was significantly greater than 30 minutes. [Median time = 34 minutes (p<0.001)]. We conclude that STAT order processing time may be improved by increasing the availability of medications in ADM, and pharmacy involvement in the verification process.

Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P-gp and MRP-1.

PubMed

Yi, Ying-Jie; Jia, Xiu-Hong; Wang, Jian-Yong; Li, You-Jie; Wang, Hong; Xie, Shu-Yang

2016-05-01

Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.

A comparative study of root coverage using two different acellular dermal matrix products.

PubMed

Barker, Thomas S; Cueva, Marco A; Rivera-Hidalgo, Francisco; Beach, M Miles; Rossmann, Jeffrey A; Kerns, David G; Crump, T Bradley; Shulman, Jay D

2010-11-01

Gingival recession remains an important problem in dental esthetics. A new dermal matrix material has been introduced, but its effectiveness has not been studied and compared to current dermal matrix material. The aim of this study is to compare the healing associated with a coronally advanced flap for root coverage in areas of localized tissue recession when using Alloderm (ADM) and Puros Dermis (PDM). A split-mouth design was used for this study, with 52 contralateral sites in 14 patients with Miller Class I or III facial tissue recession. Twenty-six sites were treated with coronally advanced flap using PDM, and 26 sites were treated with coronally advanced flap using ADM, all followed for 6 months. Clinical measurements of vertical recession, keratinized tissue, probing depths, and attachment levels were made initially, at 3 months, and at 6 months. Both groups had significant improvement in the amount of recession coverage with means of 2.83 mm for the PDM and 3.13 mm for the ADM. The percentage of root coverage was 81.4% for the PDM and 83.4% for the ADM; differences between the materials were not statistically significant. Based on the results of this study, there was no statistical or clinical difference in the amount of root coverage, probing depth, or keratinized tissue in coronally advanced flaps for root coverage with either of the two acellular dermal matrix materials. Both materials were successful in achieving root coverage.

Application of Design of Experiments and Surrogate Modeling within the NASA Advanced Concepts Office, Earth-to-Orbit Design Process

NASA Technical Reports Server (NTRS)

Zwack, Mathew R.; Dees, Patrick D.; Holt, James B.

2016-01-01

Decisions made during early conceptual design have a large impact upon the expected life-cycle cost (LCC) of a new program. It is widely accepted that up to 80% of such cost is committed during these early design phases. Therefore, to help minimize LCC, decisions made during conceptual design must be based upon as much information as possible. To aid in the decision making for new launch vehicle programs, the Advanced Concepts Office (ACO) at NASA Marshall Space Flight Center (MSFC) provides rapid turnaround pre-phase A and phase A concept definition studies. The ACO team utilizes a proven set of tools to provide customers with a full vehicle mass breakdown to tertiary subsystems, preliminary structural sizing based upon worst-case flight loads, and trajectory optimization to quantify integrated vehicle performance for a given mission. Although the team provides rapid turnaround for single vehicle concepts, the scope of the trade space can be limited due to analyst availability and the manpower requirements for manual execution of the analysis tools. In order to enable exploration of a broader design space, the ACO team has implemented an advanced design methods (ADM) based approach. This approach applies the concepts of design of experiments (DOE) and surrogate modeling to more exhaustively explore the trade space and provide the customer with additional design information to inform decision making. This paper will first discuss the automation of the ACO tool set, which represents a majority of the development effort. In order to fit a surrogate model within tolerable error bounds a number of DOE cases are needed. This number will scale with the number of variable parameters desired and the complexity of the system's response to those variables. For all but the smallest design spaces, the number of cases required cannot be produced within an acceptable timeframe using a manual process. Therefore, automation of the tools was a key enabler for the successful application of an ADM approach to an ACO design study. Following the overview of the tool set automation, an example problem will be given to illustrate the implementation of the ADM approach. The example problem will first cover the inclusion of ground rules and assumptions (GR&A) for a study. The GR&A are very important to the study as they determine the constraints within which a trade study can be conducted. These trades must ultimately reconcile with the customer's desired output and any anticipated "what if" questions. The example problem will then illustrate the setup and execution of a DOE through the automated ACO tools. This process is accomplished more efficiently in this work by splitting the tools into two separate environments. The first environment encompasses the structural optimization and mass estimation tools, while the second is focused on trajectory optimization. Surrogate models are fit to the outputs of each environment and are "integrated" via connection of the surrogate equations. Throughout this process, checks are implemented to compare the output of the surrogates to the output of manually run cases to ensure that the error of the final surrogates is at an acceptable level. The conclusion of the example problem demonstrates the utility of the ADM based approach. Using surrogate models gives the ACO team the ability to visualize vehicle sensitivities to various design parameters and identify regions of interest within the design space. The ADM approach can thus be used to inform concept down selection and isolate promising vehicle configurations to be explored in more detail through the manual design process. In addition it provides the customer with an almost instantaneous turnaround on any ''what if" questions that may arise within the bounds of the surrogate model. This approach ultimately expands the ability of the ACO team to provide its customer with broad and rapid turnaround trade studies for launch vehicle conceptual design. The ability to identify a selection of designs which can meet the customer requirements will help ensure lower LCC of launch vehicle designs originating from ACO.

Application of Design of Experiments and Surrogate Modeling within the NASA Advanced Concepts Office, Earth-to-Orbit Design Process

NASA Technical Reports Server (NTRS)

Zwack, Mathew R.; Dees, Patrick D.; Holt, James B.

2016-01-01

Decisions made during early conceptual design have a large impact upon the expected life-cycle cost (LCC) of a new program. It is widely accepted that up to 80% of such cost is committed during these early design phases.1 Therefore, to help minimize LCC, decisions made during conceptual design must be based upon as much information as possible. To aid in the decision making for new launch vehicle programs, the Advanced Concepts Office (ACO) at NASA Marshall Space Flight Center (MSFC) provides rapid turnaround pre-phase A and phase A concept definition studies. The ACO team utilizes a proven set of tools to provide customers with a full vehicle mass breakdown to tertiary subsystems, preliminary structural sizing based upon worst-case flight loads, and trajectory optimization to quantify integrated vehicle performance for a given mission.2 Although the team provides rapid turnaround for single vehicle concepts, the scope of the trade space can be limited due to analyst availability and the manpower requirements for manual execution of the analysis tools. In order to enable exploration of a broader design space, the ACO team has implemented an Advanced Design Methods (ADM) based approach. This approach applies the concepts of Design of Experiments (DOE) and surrogate modeling to more exhaustively explore the trade space and provide the customer with additional design information to inform decision making. This paper will first discuss the automation of the ACO tool set, which represents a majority of the development e ort. In order to t a surrogate model within tolerable error bounds a number of DOE cases are needed. This number will scale with the number of variable parameters desired and the complexity of the system's response to those variables. For all but the smallest design spaces, the number of cases required cannot be produced within an acceptable timeframe using a manual process. Therefore, automation of the tools was a key enabler for the successful application of an ADM approach to an ACO design study. Following the overview of the tool set automation, an example problem will be given to illustrate the implementation of the ADM approach. The example problem will first cover the inclusion of Ground Rules and Assumptions (GR&A) for a study. The GR&A are very important to the study as they determine the constraints within which a trade study can be conducted. These trades must ultimately reconcile with the customer's desired output and any anticipated \\what if" questions. The example problem will then illustrate the setup and execution of a DOE through the automated ACO tools. This process is accomplished more efficiently in this work by splitting the tools into two separate environments. The first environment encompasses the structural optimization and mass estimation tools, while the second is focused on trajectory optimization. Surrogate models are t to the outputs of each environment and are integrated via connection of the surrogate equations. Throughout this process, checks are implemented to compare the output of the surrogates to the output of manually run cases to ensure that the error of the final surrogates is at an acceptable level. The conclusion of the example problem demonstrates the utility of the ADM based approach. Using surrogate models gives the ACO team the ability to visualize vehicle sensitivities to various design parameters and identify regions of interest within the design space. The ADM approach can thus be used to inform concept down selection and isolate promising vehicle configurations to be explored in more detail through the manual design process. In addition it provides the customer with an almost instantaneous turnaround on any \\what if" questions that may arise within the bounds of the surrogate model. This approach ultimately expands the ability of the ACO team to provide its customer with broad and rapid turnaround trade studies for launch vehicle conceptual design. The ability to identify a selection of designs which can meet the customer requirements will have the potential to lower LCC of launch vehicle designs originating from ACO.

Construction of a Matched Global Cloud and Radiance Product from LEO/GEO and EPIC Observations to Estimate Daytime Earth Radiation Budget from DSCOVR

NASA Technical Reports Server (NTRS)

Duda, David P.; Khlopenkov, Konstantin V.; Thiemann, Mandana; Palikonda, Rabindra; Sun-Mack, Sunny; Minnis, Patrick; Su, Wenying

2016-01-01

With the launch of the Deep Space Climate Observatory (DSCOVR), new estimates of the daytime Earth radiation budget can be computed from a combination of measurements from the two Earth-observing sensors onboard the spacecraft, the Earth Polychromatic Imaging Camera (EPIC) and the National Institute of Standards and Technology Advanced Radiometer (NISTAR). Although these instruments can provide accurate top-of-atmosphere (TOA) radiance measurements, they lack sufficient resolution to provide details on small-scale surface and cloud properties. Previous studies have shown that these properties have a strong influence on the anisotropy of the radiation at the TOA, and ignoring such effects can result in large TOA-flux errors. To overcome these effects, high-resolution scene identification is needed for accurate Earth radiation budget estimation. Selected radiance and cloud property data measured and derived from several low earth orbit (LEO, including NASA Terra and Aqua MODIS, NOAA AVHRR) and geosynchronous (GEO, including GOES (east and west), METEOSAT, INSAT-3D, MTSAT-2, and HIMAWARI-8) satellite imagers were collected to create hourly 5-km resolution global composites of data necessary to compute angular distribution models (ADM) for reflected shortwave (SW) and longwave (LW) radiation. The satellite data provide an independent source of radiance measurements and scene identification information necessary to construct ADMs that are used to determine the daytime Earth radiation budget. To optimize spatial matching between EPIC measurements and the high-resolution composite cloud properties, LEO/GEO retrievals within the EPIC fields of view (FOV) are convolved to the EPIC point spread function (PSF) in a similar manner to the Clouds and the Earth's Radiant Energy System (CERES) Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product. Examples of the merged LEO/GEO/EPIC product will be presented, describing the chosen radiance and cloud properties and details of how data from the multi-satellite measurements are selected.

Construction of a Matched Global Cloud and Radiance Product from LEO/GEO and EPIC Observations to Estimate Daytime Earth Radiation Budget from DSCOVR

NASA Astrophysics Data System (ADS)

Duda, D. P.; Khlopenkov, K. V.; Palikonda, R.; Khaiyer, M. M.; Minnis, P.; Su, W.; Sun-Mack, S.

2016-12-01

With the launch of the Deep Space Climate Observatory (DSCOVR), new estimates of the daytime Earth radiation budget can computed from a combination of measurements from the two Earth-observing sensors onboard the spacecraft, the Earth Polychromatic Imaging Camera (EPIC) and the National Institute of Standards and Technology Advanced Radiometer (NISTAR). Although these instruments can provide accurate top-of-atmosphere (TOA) radiance measurements, they lack sufficient resolution to provide details on small-scale surface and cloud properties. Previous studies have shown that these properties have a strong influence on the anisotropy of the radiation at the TOA, and ignoring such effects can result in large TOA-flux errors. To overcome these effects, high-resolution scene identification is needed for accurate Earth radiation budget estimation. Selected radiance and cloud property data measured and derived from several low earth orbit (LEO, including NASA Terra and Aqua MODIS, NOAA AVHRR) and geosynchronous (GEO, including GOES (east and west), METEOSAT, INSAT-3D, MTSAT-2, and HIMAWARI-8) satellite imagers were collected to create hourly 5-km resolution global composites of data necessary to compute angular distribution models (ADM) for reflected shortwave (SW) and longwave (LW) radiation. The satellite data provide an independent source of radiance measurements and scene identification information necessary to construct ADMs that are used to determine the daytime Earth radiation budget. To optimize spatial matching between EPIC measurements and the high-resolution composite cloud properties, LEO/GEO retrievals within the EPIC fields of view (FOV) are convolved to the EPIC point spread function (PSF) in a similar manner to the Clouds and the Earth's Radiant Energy System (CERES) Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product. Examples of the merged LEO/GEO/EPIC product will be presented, describing the chosen radiance and cloud properties and details of how data from the multi-satellite measurements are selected.

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability.

PubMed

Clarke, John D; Cherrington, Nathan J

2015-07-01

There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model.

PubMed

Ham, Sangwoo; Lee, Yun-Il; Jo, Minkyung; Kim, Hyojung; Kang, Hojin; Jo, Areum; Lee, Gum Hwa; Mo, Yun Jeong; Park, Sang Chul; Lee, Yun Song; Shin, Joo-Ho; Lee, Yunjong

2017-04-03

Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frusciante, Noemi; Papadomanolakis, Georgios; Silvestri, Alessandra, E-mail: fruscian@iap.fr, E-mail: papadomanolakis@lorentz.leidenuniv.nl, E-mail: silvestri@lorentz.leidenuniv.nl

We present a generalization of the effective field theory (EFT) formalism for dark energy and modified gravity models to include operators with higher order spatial derivatives. This allows the extension of the EFT framework to a wider class of gravity theories such as Hořava gravity. We present the corresponding extended action, both in the EFT and the Arnowitt-Deser-Misner (ADM) formalism, and proceed to work out a convenient mapping between the two, providing a self contained and general procedure to translate a given model of gravity into the EFT language at the basis of the Einstein-Boltzmann solver EFTCAMB. Putting this mappingmore » at work, we illustrate, for several interesting models of dark energy and modified gravity, how to express them in the ADM notation and then map them into the EFT formalism. We also provide for the first time, the full mapping of GLPV models into the EFT framework. We next perform a thorough analysis of the physical stability of the generalized EFT action, in absence of matter components. We work out viability conditions that correspond to the absence of ghosts and modes that propagate with a negative speed of sound in the scalar and tensor sector, as well as the absence of tachyonic modes in the scalar sector. Finally, we extend and generalize the phenomenological basis in terms of α-functions introduced to parametrize Horndeski models, to cover all theories with higher order spatial derivatives included in our extended action. We elaborate on the impact of the additional functions on physical quantities, such as the kinetic term and the speeds of propagation for scalar and tensor modes.« less

Effectiveness of imatinib mesylate over etoposide in the treatment of sensitive and resistant chronic myeloid leukaemia cells in vitro.

PubMed

Husaini, Roslina; Ahmad, Munirah; Zakaria, Zubaidah

2017-06-01

Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin-resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492±0.024 and 0.378±0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6±16.5 and 194±8.46 µM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3±0.2 and 31.9±16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3±8.35%) relative to K562/ADM cells (5.17±3.3%). In addition, the MDR genes in K562/ADM cells were knocked down by short interfering RNAs. The percentage knockdowns were 15.4% for MRP1, 17.8% for MDR and 30.7% for BCL-2, which resulted in a non-significant difference in the half maximal inhibitory concentration value of K562/ADM cells relative to K562 cells upon treatment with etoposide.

Cardiac natriuretic peptides in plasma increase after dietary induced weight loss in obesity.

PubMed

Kistorp, Caroline; Bliddal, Henning; Goetze, Jens P; Christensen, Robin; Faber, Jens

2014-01-01

Cardiac natriuretic peptides are established biomarkers in heart disease, but are also affected by body mass index (BMI). The purpose of the present study was to examine the impact of weight loss and changes in body composition following dietary intervention on plasma concentrations of the prohormones to A- and B-type natriuretic peptides (proANP and proBNP) and adrenomedullin (proADM). A total of 52 healthy obese subjects, 47 women and 5 men (BMI 36.5 ± 5.6 kg/m(2)) were randomised to either an intensive weight reduction programme using a combination of very low calorie diet (810 kcal/day) and conventional hypo-energetic diet (1200 kcal/day) for 52 weeks, or to a control group that was offered diet-related counselling. N-terminal proBNP (NT-proBNP), mid-regional proANP (MR-proANP) and proADM (MR-proADM) and body composition using dual-energy x-ray absorptiometry (DEXA) scanning were determined at baseline and after 52 weeks. Comparisons between groups were analysed using t-tests. Changes from the baseline within the groups were analysed with paired tests. Changes in the variables, delta (∆), were calculated as 52 weeks minus the baseline. In the intervention group, BMI decreased by almost 20% (31.6 ± 6.2 vs. 37.1 ± 6.1 kg/m(2); P <0.001) with a loss of body fat of 23.5 ± 15.5% (P < 0.001). Plasma concentrations of NT-proBNP and MR-proANP increased (from 55 ± 31 to 97 ± 55 pg/ml; P < 0.001, and from 59 ± 21 to 74 ± 26 pmol/L; P < 0.001), whereas MR-proADM decreased (from 573 ± 153 to 534 ± 173 pmol/L; P <0.001). Changes (Δ) in MR-proANP correlated with Δfat mass (r = -0.359; P = 0.011) and Δglucose (r = -0.495; P <0.001), while increases in NT-proBNP were primarily associated with reduced plasma glucose (r = -0.462; P <0.001). A modest but significant weight loss of 6% (P < 0.001) was found in the control group with no changes in plasma concentrations of NT-proBNP or MR-proANP, and a minor change in MR-proADM. Plasma NT-proBNP and MR-proANP concentrations increase and MR-proADM concentration decreases during weight loss, underlining the dynamic impact of BMI, body composition and glucose metabolism on these cardiovascular biomarkers.

The Spectrum of Malignancies among Adult HIV Cohort in Poland between 1995 and 2012: A Retrospective Analysis of 288 Cases.

PubMed

Kowalski, Jacek; Cholewińska, Grażyna; Pyziak-Kowalska, Karolina; Jabłonowska, Elżbieta; Barałkiewicz, Grażyna; Grzeszczuk, Anna; Leszczyszyn-Pynka, Magdalena; Olczak, Anita; Jankowska, Maria; Mikuła, Tomasz; Bociąga-Jasik, Monika; Firląg-Burkacka, Ewa; Horban, Andrzej

2015-01-01

The aim of the study was to evaluate the spectrum of AIDS-defining malignancies (ADMs) and non-AIDS-defining malignancies (NADMs) in HIV-infected patients in Poland. A retrospective observational study was conducted among HIV-infected adult patients who developed a malignancy between 1995 and 2012 in a Polish cohort. Malignancies were divided into ADMs and NADMs. Non-AIDS-defining malignancies were further categorised as virus-related (NADMs-VR) and unrelated (NADMs-VUR). Epidemiological data was analysed according to demographic data, medical history, and HIV-related information. Results were analysed by OR, EPITools package parameters and Fisher's exact test. In this study 288 malignancies were discovered. The mean age at diagnosis was 41.25 years (IQR20-81); for ADMs 38.05 years, and for NADMs-VURs 46.42 years; 72.22% were male, 40.28% were co-infected with HCV. The risk behaviours were: 37.85% IDU, 33.33% MSM, and 24.31% heterosexual. Mean CD4+ at the diagnosis was 282 cells/mm(3) (for ADMs 232 and for NADMs-VUR 395). Average duration of HIV infection at diagnosis was 5.69 years. There were 159 (55.2%) ADMs and 129 (44.8%) NADMs, among whom 58 (44.96%) NADMs-VR and 71 (55.04%) NADMs-VUR. The most frequent malignancies were: NHL (n = 76; 26.39%), KS (n = 49; 17.01%), ICC (n = 34; 11.81%), HD (n = 23; 7.99%), lung cancer (n = 18; 6.25%) and HCC (n = 14; 4.86%). The amount of NADMs, NADMs-VURs in particular, is increasing at present. Male gender (OR = 1.889; 95% CI: 1.104-3.233; p = 0.024), advanced age: 50-60 years (OR = 3.022; 95% CI: 1.359-6.720; p = 0.01) and ≥ 60 years (OR = 15.111; 95% CI: 3.122-73.151; p < 0.001), longer duration of HIV-infection and successful HAART (OR = 2.769; 95% CI: 1.675-4.577; p = 0) were independent predictors of NADMs overall, respectively. In a Polish cohort NHL was the most frequent malignancy among ADMs, whereas HD was the most frequent among NADMs. Increased incidence of NADMs appearing in elderly men with longer duration of HIV-infection and with better virological and immunological control was confirmed. As HIV-infected individuals live longer, better screening strategies, especially for NADMs-VUR, are needed. The spectrum of cancer diagnoses in Poland currently does not appear dissimilar to that observed in other European populations.

Stratigraphy and Surface Ages of Dwarf Planet (1) Ceres: Results from Geologic and Topographic Mapping in Survey, HAMO and LAMO Data of the Dawn Framing Camera Images

NASA Astrophysics Data System (ADS)

Wagner, R. J.; Schmedemann, N.; Stephan, K.; Jaumann, R.; Neesemann, A.; Preusker, F.; Kersten, E.; Roatsch, T.; Hiesinger, H.; Williams, D. A.; Yingst, R. A.; Crown, D. A.; Mest, S. C.; Raymond, C. A.; Russell, C. T.

2017-12-01

Since March 6, 2015, the surface of dwarf planet (1) Ceres is being imaged by the FC framing camera aboard the Dawn spacecraft from orbit at various altitudes [1]. For this study we focus on images from the Survey orbit phase (4424 km altitude) with spatial resolutions of 400 m/pxl and use images and topographic data from DTMs (digital terrain models) for global geologic mapping. On Ceres' surface cratered plains are ubiquitous, with variations in superimposed crater frequency indicating different ages and processes. Here, we take the topography into account for geologic mapping and discriminate cratered plains units according to their topographic level - high-standing, medium, or low-lying - in order to examine a possible correlation between topography and surface age. Absolute model ages (AMAs) are derived from two impact cratering chronology models discussed in detail by [2] (henceforth termed LDM: lunar-derived model, and ADM: asteroid-derived model). We also apply an improved method to obtain relative ages and AMAs from crater frequency measurements termed Poisson timing analysis [3]. Our ongoing analysis shows no trend that the topographic level has an influence on the age of the geologic units. Both high-standing and low-lying cratered plains have AMAs ranging from 3.5 to 1.5 Ga (LDM), versus 4.2 to 0.5 Ga (ADM). Some areas of measurement within these units, however, show effects of resurfacing processes in their crater distributions and feature an older and a younger age. We use LAMO data (altitude: 375 km; resolution 30 m/pxl) and/or HAMO data (altitude: 1475 km; resolution 140 m/pxl) to study local geologic units and their ages, e.g., smaller impact craters, especially those not dated so far with crater measurements and/or those with specific spectral properties [4], deposits of mass wasting (e.g., landslides), and mountains, such as Ahuna Mons. Crater frequencies are used to set these geologic units into the context of Ceres' time-stratigraphic system and chronologic periods [5]. References: [1] Russell C. T., et al. (2016), Science 353, doi:10.1126/science.aaf4219. [2] Hiesinger H. H. et al. (2016), Science 353, doi:10.1126/science.aaf4759. [3] Michael G. G. et al. (2016), Icarus 277, 279-285. [4] Stephan K. et al. (2017), submitted to Icarus. [5] Mest S. C. et al. (2017), LPSC XLVIII, abstr. No. 2512.

Calibration and Initialization of the NPS Modified Infrared Search and Target Designation (IRSTD) System.

DTIC Science & Technology

1987-12-01

level of performance comparable to the original ADM configuration. ’p, OTIC CPY Acesion For NTiS CRA&I UTNY’ TAB [ arinc ,:,cced 0 C yfi.’ hb .vC.Je i...levels below standard. This modified system was found to be operating at a level of performance comparable to the original ADM configuration. 4’ TABLE OF...requirements for systems that function under conditions of emissions control (EMCON). The AN/SAR-8, currently in the Engineering Development Phase , is an

Three types of dermal grafts in rats: the importance of mechanical property and structural design.

PubMed

You, Chuangang; Wang, Xingang; Zheng, Yurong; Han, Chunmao

2013-12-04

To determine how the mechanical property and micro structure affect tissue regeneration and angiogenesis, three types of scaffolds were studied. Acellular dermal matrices (ADM), produced from human skin by removing the epidermis and cells, has been widely used in wound healing because of its high mechanical strength. Collagen scaffolds (CS) incorporated with poly(glycolide-co-L-lactide) (PLGA) mesh forms a well-supported hybrid dermal equivalent poly(glycolide-co-L-lactide) mesh/collagen scaffolds (PMCS). We designed this scaffold to enhance the CS mechanical property. These three different dermal substitutes-ADM, CS and PMCSs are different in the tensile properties and microstructure. Several basic physical characteristics of dermal substitutes were investigated in vitro. To characterize the angiogenesis and tissue regeneration, the materials were embedded subcutaneously in Sprague-Dawley (SD) rats. At weeks 1, 2, 4 and 8 post-surgery, the tissue specimens were harvested for histology, immunohistochemistry and real-time quantitative PCR (RT-qPCR). In vitro studies demonstrated ADM had a higher Young's modulus (6.94 MPa) rather than CS (0.19 MPa) and PMCS (3.33 MPa) groups in the wet state. Compared with ADMs and CSs, PMCSs with three-dimensional porous structures resembling skin and moderate mechanical properties can promote tissue ingrowth more quickly after implantation. In addition, the vascularization of the PMCS group is more obvious than that of the other two groups. The incorporation of a PLGA knitted mesh in CSs can improve the mechanical properties with little influence on the three-dimensional porous microstructure. After implantation, PMCSs can resist the contraction and promote cell infiltration, neotissue formation and blood vessel ingrowth, especially from the mesh side. Although ADM has high mechanical strength, its vascularization is poor because the pore size is too small. In conclusion, the mechanical properties of scaffolds are important for maintaining the three-dimensional microarchitecture of constructs used to induce tissue regeneration and vascularization. The results illustrated that tissue regeneration requires the proper pore size and an appropriate mechanical property like PMCS which could satisfy these conditions to sustain growth.

Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS.

PubMed

Frøssing, Signe; Nylander, Malin; Kistorp, Caroline; Skouby, Sven O; Faber, Jens

2018-01-01

Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease (CVD), and biomarkers can be used to detect early subclinical CVD. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial natriuretic peptide (MR-proANP) and copeptin are all associated with CVD and part of the delicate system controlling fluid and hemodynamic homeostasis through vascular tonus and diuresis. The GLP-1 receptor agonist liraglutide, developed for treatment of type 2 diabetes (T2D), improves cardiovascular outcomes in patients with T2D including a decrease in particular MR-proANP. To investigate if treatment with liraglutide in women with PCOS reduces levels of the cardiovascular biomarkers MR-proADM, MR-proANP and copeptin. Seventy-two overweight women with PCOS were treated with 1.8 mg/day liraglutide or placebo for 26 weeks in a placebo-controlled RCT. Biomarkers, anthropometrics, insulin resistance, body composition (DXA) and visceral fat (MRI) were examined. Baseline median (IQR) levels were as follows: MR-proADM 0.52 (0.45-0.56) nmol/L, MR-proANP 44.8 (34.6-56.7) pmol/L and copeptin 4.95 (3.50-6.50) pmol/L. Mean percentage differences (95% CI) between liraglutide and placebo group after treatment were as follows: MR-proADM -6% (-11 to 2, P  = 0.058), MR-proANP -25% (-37 to -11, P  = 0.001) and copeptin +4% (-13 to 25, P  = 0.64). Reduction in MR-proANP concentration correlated with both increased heart rate and diastolic blood pressure in the liraglutide group. Multiple regression analyses with adjustment for BMI, free testosterone, insulin resistance, visceral fat, heart rate and eGFR showed reductions in MR-proANP to be independently correlated with an increase in the heart rate. In an RCT, liraglutide treatment in women with PCOS reduced levels of the cardiovascular risk biomarkers MR-proANP with 25% and MR-proADM with 6% (borderline significance) compared with placebo. The decrease in MR-proANP was independently associated with an increase in the heart rate. © 2018 The authors.

Three types of dermal grafts in rats: the importance of mechanical property and structural design

PubMed Central

2013-01-01

Background To determine how the mechanical property and micro structure affect tissue regeneration and angiogenesis, three types of scaffolds were studied. Acellular dermal matrices (ADM), produced from human skin by removing the epidermis and cells, has been widely used in wound healing because of its high mechanical strength. Collagen scaffolds (CS) incorporated with poly(glycolide-co-L-lactide) (PLGA) mesh forms a well-supported hybrid dermal equivalent poly(glycolide-co-L-lactide) mesh/collagen scaffolds (PMCS). We designed this scaffold to enhance the CS mechanical property. These three different dermal substitutes—ADM, CS and PMCSs are different in the tensile properties and microstructure. Methods Several basic physical characteristics of dermal substitutes were investigated in vitro. To characterize the angiogenesis and tissue regeneration, the materials were embedded subcutaneously in Sprague–Dawley (SD) rats. At weeks 1, 2, 4 and 8 post-surgery, the tissue specimens were harvested for histology, immunohistochemistry and real-time quantitative PCR (RT-qPCR). Results In vitro studies demonstrated ADM had a higher Young’s modulus (6.94 MPa) rather than CS (0.19 MPa) and PMCS (3.33 MPa) groups in the wet state. Compared with ADMs and CSs, PMCSs with three-dimensional porous structures resembling skin and moderate mechanical properties can promote tissue ingrowth more quickly after implantation. In addition, the vascularization of the PMCS group is more obvious than that of the other two groups. The incorporation of a PLGA knitted mesh in CSs can improve the mechanical properties with little influence on the three-dimensional porous microstructure. After implantation, PMCSs can resist the contraction and promote cell infiltration, neotissue formation and blood vessel ingrowth, especially from the mesh side. Although ADM has high mechanical strength, its vascularization is poor because the pore size is too small. In conclusion, the mechanical properties of scaffolds are important for maintaining the three-dimensional microarchitecture of constructs used to induce tissue regeneration and vascularization. Conclusion The results illustrated that tissue regeneration requires the proper pore size and an appropriate mechanical property like PMCS which could satisfy these conditions to sustain growth. PMID:24304500

A method for reducing the sloughing of thick blood films for malaria diagnosis.

PubMed

Norgan, Andrew P; Arguello, Heather E; Sloan, Lynne M; Fernholz, Emily C; Pritt, Bobbi S

2013-07-08

The gold standard for malaria diagnosis is the examination of thick and thin blood films. Thick films contain 10 to 20 times more blood than thin films, correspondingly providing increased sensitivity for malaria screening. A potential complication of thick film preparations is sloughing of the blood droplet from the slide during staining or rinsing, resulting in the loss of sample. In this work, two methods for improving thick film slide adherence ('scratch' (SCM) and 'acetone dip' (ADM) methods) were compared to the 'standard method' (SM) of thick film preparation. Standardized blood droplets from 26 previously examined EDTA whole blood specimens (22 positive and four negative) were concurrently spread on glass slides using the SM, ADM, and SCM. For the SM and ADM prepared slides, the droplet was gently spread to an approximate 22 millimeters in diameter spot on the slide using the edge of a second glass slide. For the SCM, the droplet was spread by carefully grinding (or scratching) it into the slide with the point of a second glass slide. Slides were dried for one hour in a laminar flow hood. For the ADM, slides were dipped once in an acetone filled Coplin jar and allowed to air dry. All slides were then Giemsa-stained and examined in a blinded manner. Adherence was assessed by blinded reviewers. No significant or severe defects were observed for slides prepared with the SCM. In contrast, 8 slides prepared by the ADM and 3 prepared using the SM displayed significant or severe defects. Thick films prepared by the three methods were microscopically indistinguishable and concordant results (positive or negative) were obtained for the three methods. Estimated parasitaemia of the blood samples ranged from 25 to 429,169 parasites/μL of blood. The SCM is an inexpensive, rapid, and simple method that improves the adherence of thick blood films to standard glass slides without altering general slide preparation, microscopic appearance or interpretability. Using the SCM, thick films can be reliably examined less than two hours after sample receipt. This represents a significant diagnostic improvement over protocols requiring extended drying periods.

Including policy and management in socio-hydrology models: initial conceptualizations

NASA Astrophysics Data System (ADS)

Hermans, Leon; Korbee, Dorien

2017-04-01

Socio-hydrology studies the interactions in coupled human-water systems. So far, the use of dynamic models that capture the direct feedback between societal and hydrological systems has been dominant. What has not yet been included with any particular emphasis, is the policy or management layer, which is a central element in for instance integrated water resources management (IWRM) or adaptive delta management (ADM). Studying the direct interactions between human-water systems generates knowledges that eventually helps influence these interactions in ways that may ensure better outcomes - for society and for the health and sustainability of water systems. This influence sometimes occurs through spontaneous emergence, uncoordinated by societal agents - private sector, citizens, consumers, water users. However, the term 'management' in IWRM and ADM also implies an additional coordinated attempt through various public actors. This contribution is a call to include the policy and management dimension more prominently into the research focus of the socio-hydrology field, and offers first conceptual variables that should be considered in attempts to include this policy or management layer in socio-hydrology models. This is done by drawing on existing frameworks to study policy processes throughout both planning and implementation phases. These include frameworks such as the advocacy coalition framework, collective learning and policy arrangements, which all emphasis longer-term dynamics and feedbacks between actor coalitions in strategic planning and implementation processes. A case about longter-term dynamics in the management of the Haringvliet in the Netherlands is used to illustrate the paper.

Comparison of ADM and Connective Tissue Graft as the Membrane in Class II Furcation Defect Regeneration: A Randomized Clinical Trial

PubMed Central

Esfahanian, Vahid; Farhad, Shirin; Sadighi Shamami, Mehrnaz

2014-01-01

Background and aims. Furcally-involved teeth present unique challenges to the success of periodontal therapy and influence treatment outcomes. This study aimed to assess to compare use of ADM and connective tissue membrane in class II furcation defect regeneration. Materials and methods. 10 patient with 2 bilaterally class II furcation defects in first and/or second maxilla or man-dibular molar without interproximal furcation involvement, were selected. Four weeks after initial phase of treatment, before and thorough the surgery pocket depth (PD), clinical attachment level to stent (CAL-S), free gingival margin to stent(FGM-S) , crestal bone to stent (Crest-S), horizontal defect depth to stent (HDD-S) and vertical defect depth to stent (VDD-S) and crestal bone to defect depth measured from stent margin. Thereafter, one side randomly treated using connective tissue and DFDBA (study group) and opposite side received ADM and DFDBA (control group). After 6 months, soft and hard tissue parameters measured again in re-entry. Results. Both groups presented improvements after therapies (P & 0.05). No inter-group differences were seen in PD re-duction (P = 0.275), CAL gain (P = 0.156), free gingival margin (P = 0.146), crest of the bone (P = 0.248), reduction in horizontal defects depth (P = 0.139) and reduction in vertical defects depth (P = 0.149). Conclusion. Both treatments modalities have potential of regeneration without any adverse effect on healing process. Connective tissue grafts did not have significant higher bone fill compared to that of ADM. PMID:25093054

Comparison of the clinical outcomes of connective tissue and acellular dermal matrix in combination with double papillary flap for root coverage: A 6-month trial

PubMed Central

Gholami, Gholam Ali; Saberi, Arezoo; Kadkhodazadeh, Mahdi; Amid, Reza; Karami, Daryoosh

2013-01-01

Background: Different techniques have been proposed for the treatment of gingival recession. The majority of current procedures use autogenous soft-tissue grafts, which are associated with morbidity at the donor sites. Acellular dermal matrix (ADM) Alloderm is an alternative donor material presented to reduce related morbidity and provide more volume of the donor tissue. This study aimed to evaluate the effectiveness of an ADM allograft for root coverage and to compare it with a connective tissue graft (CTG), when used with a double papillary flap. Materials and Methods: Sixteen patients with bilateral class I or II gingival recessions were selected. A total of 32 recessions were treated and randomly assigned into the test and contralateral recessions into the control group. In the control group, the exposed root surfaces were treated by the placement of a CTG in combination with a double papillary flap; and in the test group, an ADM allograft was used as a substitute for palatal donor tissue. Probing depth, clinical attachment level, width of keratinized tissue (KT), recession height and width were measured before, and after 2 weeks and 6 months of surgery. Results: There were no statistically significant differences between the test and control groups in terms of recession reduction, clinical attachment gain, and reduction in probing depth. The control group had a statistically significant increased area of KT after 6 months compared to the test group. Conclusion: ADM allograft can be considered as a substitute for palatal donor tissue in root coverage procedure. PMID:24130587

Is there a rationale to use a dual mobility poly insert for failed Birmingham metal-on-metal hip replacements? A retrieval analysis.

PubMed

Renner, Lisa; Faschingbauer, Martin; Boettner, Friedrich

2015-08-01

Previous studies showed poor outcomes for patients undergoing revision of failed metal-on-metal total hip arthroplasty (MoM-THA) and resurfacing (RS) with an increased risk of dislocation. Dual mobility inserts are an option to retain the acetabular component and change the metal-on-metal bearing to plastic-on-metal. The current study analyzes the rationale for the off-label use of a dual mobility poly insert (MDM X3, Stryker, Mahwah, NJ) in a Birmingham metal shell (Smith & Nephew, Memphis, TN). Based on retrievals from the implant database the study compared the clearance between 20 BHR shells, 31 MDM poly inserts and 24 ADM acetabular components of different sizes. The radial clearance was calculated for each possible combination of implants [n = 81 (MDM/BHR) and n = 119 (MDM/ADM)]. An MDM mobile bearing poly insert in an ADM shell has an average clearance of 0.314 mm (SD 0.031) compared to 0.234 mm (SD 0.030) in a BHR shell (p < 0.01). The minimal clearance is 0.246 and 0.163 mm, respectively. 30.9 % of the MDM/BHR clearances were within the range of the MDM/ADM bearing and 88.9 % had a clearance of more than 0.2 mm. Clearances of the MDM poly insert in a BHR shell are reduced, and although the majority of combinations appear safe, the indication needs to be made on an individual base carefully considering alternative treatment options.

Evaluation of STAT medication ordering process in a community hospital

PubMed Central

Walsh., Kim; Schwartz., Barbara

Background: In most health care facilities, problems related to delays in STAT medication order processing time are of common concern. Objective: The purpose of this study was to evaluate processing time for STAT orders at Kimball Medical Center. Methods: All STAT orders were reviewed to determine processing time; order processing time was also stratified by physician order entry (physician entered (PE) orders vs. non-physician entered (NPE) orders). Collected data included medication ordered, indication, time ordered, time verified by pharmacist, time sent from pharmacy, and time charted as given to the patient. Results: A total of 502 STAT orders were reviewed and 389 orders were included for analysis. Overall, median time was 29 minutes, IQR 16–63; p<0.0001.). The time needed to process NPE orders was significantly less than that needed for PE orders (median 27 vs. 34 minutes; p=0.026). In terms of NPE orders, the median total time required to process STAT orders for medications available in the Automated Dispensing Devices (ADM) was within 30 minutes, while that required to process orders for medications not available in the ADM was significantly greater than 30 minutes. For PE orders, the median total time required to process orders for medications available in the ADM (i.e., not requiring pharmacy involvement) was significantly greater than 30 minutes. [Median time = 34 minutes (p<0.001)]. Conclusion: We conclude that STAT order processing time may be improved by increasing the availability of medications in ADM, and pharmacy involvement in the verification process. PMID:27382418

Moral Injury, Religiosity, and Suicide Risk in U.S. Veterans and Active Duty Military with PTSD Symptoms.

PubMed

Ames, Donna; Erickson, Zachary; Youssef, Nagy A; Arnold, Irina; Adamson, Chaplain Sam; Sones, Alexander C; Yin, Justin; Haynes, Kerry; Volk, Fred; Teng, Ellen J; Oliver, John P; Koenig, Harold G

2018-06-15

There is growing evidence that moral injury (MI) is related to greater suicide risk among Veterans and Active Duty Military (V/ADM). This study examines the relationship between MI and suicide risk and the moderating effect of religiosity on this relationship in V/ADM with post-traumatic stress disorder (PTSD) symptoms. This was a cross-sectional multi-site study involving 570 V/ADM from across the USA. Inclusion criteria were having served in a combat theater and the presence of PTSD symptoms. Multidimensional measures assessed MI, religiosity, PTSD symptoms, anxiety, and depression. In this secondary data analysis, a suicide risk index was created based on 10 known risk factors. Associations between MI and the suicide risk index were examined, controlling for demographic, religious, and military characteristics, and the moderating effects of religiosity were explored. MI overall was correlated strongly with suicide risk (r = 0.54), as were MI subscales (ranging from r = 0.19 for loss of trust to 0.48 for self-condemnation). Controlling for other characteristics had little effect on this relationship (B = 0.016, SE = 0.001, p < 0.0001). Religiosity was unrelated to suicide risk and did not moderate the relationship between suicide risk and MI or any of its subscales. MI is strongly and independently associated with risk factors for suicide among V/ADM with PTSD symptoms, and religiosity does not mediate or moderate this relationship. Whether interventions that target MI reduce risk of suicide or suicidal ideation remains unknown and needs further study.

Effe0cts of porcine acellular dermal matrix treatment on wound healing and scar formation: role of Jag1 expression in epidermal stem cells.

PubMed

Chen, Xiao-Dong; Ruan, Shu-Bin; Lin, Ze-Peng; Zhou, Ziheng; Zhang, Feng-Gang; Yang, Rong-Hua; Xie, Ju-Lin

2018-02-08

Skin wound healing involves Notch/Jagged1 signaling. However, little is known how Jag1 expression level in epidermal stem cells (ESCs) contributes to wound healing and scar formation. We applied multiple cellular and molecular techniques to examine how Jag1 expression in ESCs modulates ESCs differentiation to myofibroblasts (MFB) in vitro, interpret how Jag1 expression in ESCs is involved in wound healing and scar formation in mice, and evaluate the effects of porcine acellular dermal matrix (ADM) treatment on wound healing and scar formation. We found that Jag1, Notch1 and Hes1 expression was up-regulated in the wound tissue during the period of wound healing. Furthermore, Jag1 expression level in the ESCs was positively associated with the level of differentiation to MFB. ESC-specific knockout of Jag1 delayed wound healing and promoted scar formation in vivo. In addition, we reported that porcine ADM treatment after skin incision could accelerate wound closure and reduce scar formation in vivo. This effect was associated with decreased expression of MFB markers, including α-SMA Col-1 and Col-III in wound tissues. Finally, we confirmed that porcine ADM treatment could increase Jag1, Notch1 and Hesl expression in wound tissues. Taken together, our results suggested that ESC-specific Jag1 expression levels are critical for wound healing and scar formation, and porcine ADM treatment would be beneficial in promoting wound healing and preventing scar formation by enhancing Notch/Jagged1 signaling pathway in ESCs.

Association of Circulating Biomarkers (Adrenomedullin, TNFR1, and NT-proBNP) With Renal Function Decline in Patients With Type 2 Diabetes: A French Prospective Cohort.

PubMed

Saulnier, Pierre-Jean; Gand, Elise; Velho, Gilberto; Mohammedi, Kamel; Zaoui, Philippe; Fraty, Mathilde; Halimi, Jean Michel; Roussel, Ronan; Ragot, Stéphanie; Hadjadj, Samy

2017-03-01

We explored the prognostic value of three circulating candidate biomarkers-midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)-for change in renal function in patients with type 2 diabetes. Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <-5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA 1c , blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors. Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope -1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34-1.89], P < 0.0001; 1.33 [1.14-1.55], P = 0.0003; and 1.22 [1.07-1.40], P = 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7-2.09], P = 0.003; 1.72 [1.33-2.22], P < 0.0001; and 1.28 [1.03-1.59], P = 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, P < 0.0001; 0.067, P < 0.0001 for RFL; and 0.027, P < 0.0001 for RRFD). In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes. © 2017 by the American Diabetes Association.

Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis

PubMed Central

Garcia-Carracedo, Dario; Yu, Chih-Chieh; Akhavan, Nathan; Fine, Stuart A.; Schönleben, Frank; Maehara, Naoki; Karg, Dillon C.; Xie, Chuangao; Qiu, Wanglong; Fine, Robert L.; Remotti, Helen E.; Su, Gloria H.

2015-01-01

Aims While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. Methods The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. Results Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. Conclusion We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer. PMID:25803032

Yeasts from skin colonization are able to cross the acellular dermal matrix.

PubMed

Jarros, Isabele Carrilho; Okuno, Érika; Costa, Maiara Ignacio; Veiga, Flávia Franco; de Souza Bonfim-Mendonça, Patricia; Negri, Melyssa Fernanda Norman; Svidzinski, Terezinha Inez Estivalet

2018-04-01

In recent decades, the prognosis for burn patients has improved considerably with the development of specialized care. The acellular dermal matrix (ADM) is a totally artificial acellular device that functions to control water loss, prevent penetration by bacteria and allow migration of endothelial cells and fibroblasts from patient tissues. However, little is known about its effectiveness against yeasts. The present study evaluated the capacity of colonization and migration of some human commensal yeasts. Three clinical isolates from skin scales, identified as Candida parapsilosis, Candida glabrata and Rhodotorula mucilaginosa, were used. Their ability to cross the ADM was evaluated. After three days, all isolates had crossed the ADM. C. parapsilosis showed the lowest growth, while R. mucilaginosa showed intermediate and C. glabrata the highest growth. In the plates incubated for seven days, the growth of C. parapsilosis and C. glabrata increased by 1 log over the third day. All isolates have the capacity to colonize and migrate through the matrix, increasing the potential risk to burn patients, who can develop severe and even fatal infections by invasive fungi. Copyright © 2018 Elsevier Ltd. All rights reserved.

Remarks on the "Non-canonicity Puzzle": Lagrangian Symmetries of the Einstein-Hilbert Action

NASA Astrophysics Data System (ADS)

Kiriushcheva, N.; Komorowski, P. G.; Kuzmin, S. V.

2012-07-01

Given the non-canonical relationship between variables used in the Hamiltonian formulations of the Einstein-Hilbert action (due to Pirani, Schild, Skinner (PSS) and Dirac) and the Arnowitt-Deser-Misner (ADM) action, and the consequent difference in the gauge transformations generated by the first-class constraints of these two formulations, the assumption that the Lagrangians from which they were derived are equivalent leads to an apparent contradiction that has been called "the non-canonicity puzzle". In this work we shall investigate the group properties of two symmetries derived for the Einstein-Hilbert action: diffeomorphism, which follows from the PSS and Dirac formulations, and the one that arises from the ADM formulation. We demonstrate that unlike the diffeomorphism transformations, the ADM transformations (as well as others, which can be constructed for the Einstein-Hilbert Lagrangian using Noether's identities) do not form a group. This makes diffeomorphism transformations unique (the term "canonical" symmetry might be suggested). If the two Lagrangians are to be called equivalent, canonical symmetry must be preserved. The interplay between general covariance and the canonicity of the variables used is discussed.

Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis.

PubMed

Gao, Ai-Mei; Zhang, Xiao-Yu; Hu, Juan-Ni; Ke, Zun-Ping

2018-01-25

Chemo-resistance is a serious obstacle for successful treatment of cancer. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in various malignant cancers. This study aimed to investigate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM. We observed that apigenin significantly enhanced doxorubicin sensitivity, induced miR-520b expression and inhibited ATG7-dependent autophagy in BEL-7402/ADM cells. In addition, we also showed that miR-520b mimics increased doxorubicin sensitivity and inhibited ATG7-dependent autophagy. Meanwhile, we indicated that ATG7 was a potential target of miR-520b. Furthermore, APG inhibited the growth of hepatocellar carcinoma xenografts in nude mice by up-regulating miR-520b and inhibiting ATG7. Our finding provides evidence that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-520b/ATG7 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Tunneling procedure for root coverage using acellular dermal matrix: a case series.

PubMed

Modaressi, Marmar; Wang, Hom-Lay

2009-08-01

This study was designed to demonstrate the use of the relatively novel tunneling technique for root coverage with acellular dermal matrix (ADM) to treat Miller Class I and II gingival recession defects. Five subjects with two to five adjacent buccal gingival recession defects were treated with ADM using the tunneling technique for root coverage. A calibrated, blinded examiner measured clinical parameters, including probing depth, clinical attachment level, width of keratinized tissue, recession depth, recession width at 1 mm apical to the cementoenamel junction, gingival tissue thickness at 1 mm and 3 mm apical to the gingival margin, Plaque Index, Gingival Index, and Wound Healing Index, at different time intervals. Patient discomfort was recorded 14 days postoperatively, and an overall quality assessment was recorded 180 days postoperatively. Results showed an average of 61% defect coverage (equal to 93.5% root coverage), and a 0.15-mm gain in tissue thickness was achieved 1 year postoperatively. This suggested that root coverage with ADM using the tunneling technique can be a viable alternative to traditional techniques, especially for multiple recession defects in maxillary premolar and anterior teeth.

Introduction to cognitive processes of expert pilots.

PubMed

Adams, R J; Ericsson, A E

2000-10-01

This report addresses the historical problem that a very high percentage of accidents have been classified as involving "pilot error." Through extensive research since 1977, the Federal Aviation Administration determined that the predominant underlying cause of these types of accidents involved decisional problems or cognitive information processing. To attack these problems, Aeronautical Decision Making (ADM) training materials were developed and tested for ten years. Since the publication of the ADM training manuals in 1987, significant reductions in human performance error (HPE) accidents have been documented both in the U.S. and world wide. However, shortcomings have been observed in the use of these materials for recurrency training and in their relevance to more experienced pilots. The following discussion defines the differences between expert and novice decision makers from a cognitive information processing perspective, correlates the development of expert pilot cognitive processes with training and experience, and reviews accident scenarios which exemplify those processes. This introductory material is a necessary prerequisite to an understanding of how to formulate expert pilot decision making training innovations; and, to continue the record of improved safety through ADM training.

Integrated Electronic Warfare System Advanced Development Model (ADM); Appendix 26 - Signal Sorter (SS) Supervisor Design Specification & Flow Diagrams.

DTIC Science & Technology

1977-10-01

These modules make up a multi-task priority real - time operating system in which each of the functions of the Supervisor is performed by one or more tasks. The Initialization module performs the initialization of the Supervisor software and hardware including the Input Buffer, the FIFO, and the Track Correlator This module is used both at initial program load time and upon receipt of a SC Initialization Command.

Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators.

PubMed

Yellapu, Nanda Kumar; Kilaru, Ravendra Babu; Chamarthi, Nagaraju; Pvgk, Sarma; Matcha, Bhaskar

2017-06-01

Glucokinase (GK) is a potential therapeutic target of type 2 diabetes and GK activators (GKAs) represent a promising class of small organic molecules which enhance GK activity. Based on the configuration and conformation of the allosteric site of GK, we have designed a novel class of amino phosphonate derivatives in order to develop potent GKAs. The QSAR model developed using numerous descriptors revealed its potential with the best effective statistical values of RMSE=1.52 and r 2 =0.30. Moreover, application of this model on the present test set GKAs proved to be worthy to predict their activities as a better linear relationship was observed with RMSE=0.14 and r 2 =0.88. ADME studies and Lipinski filters encouraged them as safer therapeutics. The molecular dynamics and docking studies against the GK allosteric site revealed that all GKAs bind with best affinities and the complexes are strengthened by H-bonding, phosphonate salt bridges, hydrophobic and arene cat ionic interactions. Finally, in vitro evaluation with human liver GK revealed their potential to increase the GK activity by different folds. The results from QSAR, ADME, molecular docking and in vitro assays strongly suggested that the present molecules could be used as effective and safer therapeutics to control and manage type 2 diabetes. Copyright © 2017. Published by Elsevier Ltd.

Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors

PubMed Central

Verma, Sant Kumar

2017-01-01

Aldose reductase (ALR2) inhibition is the most legitimate approach for the management of diabetic complications. The limited triumph in the drug development against ALR2 is mainly because of its close structural similarity with the other members of aldo-keto reductase (AKR) superfamily viz. ALR1, AKR1B10; and lipophilicity problem i.e. poor diffusion of synthetic aldose reductase inhibitors (ARIs) to target tissues. The literature evidenced that naturally occurring curcumin demonstrates relatively specific and non-competitive inhibition towards human recombinant ALR2 over ALR1 and AKR1B10; however β-diketone moiety of curcumin is a specific substrate for liver AKRs and accountable for it’s rapid in vivo metabolism. In the present study, structure based comprehensive modelling studies were used to map the pharmacophoric features/spatial fingerprints of curcumin analogues responsible for their ALR2 specificity along with potency on a data set of synthetic curcumin analogues and naturally occurring curcuminoids. The data set molecules were also screened for drug-likeness or ADME parameters, and the screening data strongly support that curcumin analogues could be proposed as a good drug candidate for the development of ALR2 inhibitors with improved pharmacokinetic profile compared to curcuminoids due to the absence of β-diketone moiety in their structural framework. PMID:28399135

Integrating Crystallography into Early Metabolism Studies

NASA Astrophysics Data System (ADS)

Cruciani, Gabriele; Aristei, Yasmin; Goracci, Laura; Carosati, Emanuele

Since bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information to be produced early in the discovery phase. Once obtained, researchers can judge whether or not a potential candidate should be eliminated from the pipeline, or modified to improve chemical stability or safety. The use of in silico methods to predict the site of metabolism in Phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, which provides the site of metabolism for any CYP-mediated reaction acting on unknown substrates. The methodology can be applied automatically to all the cytochromes whose Xray 3D structure is known, but can be also applied to homology model 3D structures. The fully automated procedure can be used to detect positions that should be protected in order to avoid metabolic degradation, or to check the suitability of a new scaffold or pro-drug. Therefore the procedure is also a valuable new tool in early ADME-Tox, where drug-safety and metabolic profile patterns must be evaluated as soon, and as early, as possible.

RANS Simulation (Actuator Disk Model[ADM]) of the NREL Phase VI wind turbine modeled as MHK Turbine

DOE Data Explorer

Javaherchi, Teymour

2016-06-08

Attached are the .cas and .dat files for the Reynolds Averaged Navier-Stokes (RANS) simulation of a single lab-scaled DOE RM1 turbine implemented in ANSYS FLUENT CFD-package. In this case study the flow field around and in the wake of the NREL Phase VI wind turbine, modeled is MHK turbine, is simulated using Actuator Disk Model (a.k.a Porous Media) by solving RANS equations coupled with a turbulence closure model. It should be highlighted that in this simulation the actual geometry of the rotor blade is not modeled. The effect of turbine rotating blades are modeled using the Actuator Disk Theory (see the stated section of attached M.Sc. thesis for more details).

Epigenetic Testing for Breast Cancer Risk Stratification

DTIC Science & Technology

2012-10-01

The genes selected for this validation were: ER-POS: GSTP1 , HBA2, BNC1, and WDR66 ER-NEG: IRF7, PECI, ARTN, VCAN, ADM, LIPG, and PLAU Figure 1...6 maintained in only a small fraction of the tumor cells. Only BNC1, CCNA1, and GSTP1 show noticeable expansion of the methylated population in...ADM 0.820 0.609 ARTN 0.192 0.138 GSTP1 0.218 0.070 LIPG 0.090 0.011 CCNA1 0.655 0.428 VCAN 0.301 0.128 IRF7 0.483 0.496 HBA2 cND ND PLAU ND ND

Communication system analysis for manned space flight

NASA Technical Reports Server (NTRS)

Schilling, D. L.

1977-01-01

One- and two-dimensional adaptive delta modulator (ADM) algorithms are discussed and compared. Results are shown for bit rates of two bits/pixel, one bit/pixel and 0.5 bits/pixel. Pictures showing the difference between the encoded-decoded pictures and the original pictures are presented. The effect of channel errors on the reconstructed picture is illustrated. A two-dimensional ADM using interframe encoding is also presented. This system operates at the rate of two bits/pixel and produces excellent quality pictures when there is little motion. The effect of large amounts of motion on the reconstructed picture is described.

A modified tensionless gingival grafting technique using acellular dermal matrix.

PubMed

Taylor, John B; Gerlach, Robert C; Herold, Robert W; Bisch, Frederick C; Dixon, Douglas R

2010-10-01

Conventional surgical procedures designed for autogenous tissue material may not be appropriate when using acellular dermal matrix (ADM) for the treatment of gingival recessions. This article describes a new surgical technique that addresses the unique and sensitive aspects of ADM specifically to improve esthetic outcomes and gain increased clinical predictability when treating Miller Class I and II gingival recession defects. In this paper, a root coverage case is described and the specific steps and rationale for this new technique are explained. This technique has been predictable clinically, with results comparable to those achieved using autogenous tissue.

ESA's spaceborne lidar mission ADM-Aeolus; project status and preparations for launch

NASA Astrophysics Data System (ADS)

Straume, Anne Grete; Elfving, Anders; Wernham, Denny; de Bruin, Frank; Kanitz, Thomas; Schuettemeyer, Dirk; Bismarck, Jonas von; Buscaglione, Fabio; Lecrenier, O.; McGoldrick, Phil

2018-04-01

ESA's Doppler Wind lidar mission, the Atmospheric Dynamics Mission (ADM-Aeolus, hereafter abbreviated to Aeolus), was chosen as an Earth Explorer Core mission within the Living Planet Programme in 1999. It shall demonstrate the potential of space-based Doppler Wind lidars for operational measurements of wind profiles and their use in Numerical Weather Prediction (NWP) and climate research. Spin-off products are profiles of cloud and aerosol optical properties. Aeolus carries the novel Doppler Wind lidar instrument ALADIN. The mission prime is Airbus Defence & Space UK (ADS-UK), and the instrument prime is Airbus Defence & Space France (ADS-F).

[Exploiture and application of an internet-based Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine].

PubMed

Xu, Hai-Yu; Liu, Zhen-Ming; Fu, Yan; Zhang, Yan-Qiong; Yu, Jian-Jun; Guo, Fei-Fei; Tang, Shi-Huan; Lv, Chuan-Yu; Su, Jin; Cui, Ru-Yi; Yang, Hong-Jun

2017-09-01

Recently, integrative pharmacology(IP) has become a pivotal paradigm for the modernization of traditional Chinese medicines(TCM) and combinatorial drugs discovery, which is an interdisciplinary science for establishing the in vitro and in vivo correlation between absorption, distribution, metabolism, and excretion/pharmacokinetic(ADME/PK) profiles of TCM and the molecular networks of disease by the integration of the knowledge of multi-disciplinary and multi-stages. In the present study, an internet-based Computation Platform for IP of TCM(TCM-IP, www.tcmip.cn) is established to promote the development of the emerging discipline. Among them, a big data of TCM is an important resource for TCM-IP including Chinese Medicine Formula Database, Chinese Medical Herbs Database, Chemical Database of Chinese Medicine, Target Database for Disease and Symptoms, et al. Meanwhile, some data mining and bioinformatics approaches are critical technology for TCM-IP including the identification of the TCM constituents, ADME prediction, target prediction for the TCM constituents, network construction and analysis, et al. Furthermore, network beautification and individuation design are employed to meet the consumer's requirement. We firmly believe that TCM-IP is a very useful tool for the identification of active constituents of TCM and their involving potential molecular mechanism for therapeutics, which would wildly applied in quality evaluation, clinical repositioning, scientific discovery based on original thinking, prescription compatibility and new drug of TCM, et al. Copyright© by the Chinese Pharmaceutical Association.

Modelling an industrial anaerobic granular reactor using a multi-scale approach.

PubMed

Feldman, H; Flores-Alsina, X; Ramin, P; Kjellberg, K; Jeppsson, U; Batstone, D J; Gernaey, K V

2017-12-01

The objective of this paper is to show the results of an industrial project dealing with modelling of anaerobic digesters. A multi-scale mathematical approach is developed to describe reactor hydrodynamics, granule growth/distribution and microbial competition/inhibition for substrate/space within the biofilm. The main biochemical and physico-chemical processes in the model are based on the Anaerobic Digestion Model No 1 (ADM1) extended with the fate of phosphorus (P), sulfur (S) and ethanol (Et-OH). Wastewater dynamic conditions are reproduced and data frequency increased using the Benchmark Simulation Model No 2 (BSM2) influent generator. All models are tested using two plant data sets corresponding to different operational periods (#D1, #D2). Simulation results reveal that the proposed approach can satisfactorily describe the transformation of organics, nutrients and minerals, the production of methane, carbon dioxide and sulfide and the potential formation of precipitates within the bulk (average deviation between computer simulations and measurements for both #D1, #D2 is around 10%). Model predictions suggest a stratified structure within the granule which is the result of: 1) applied loading rates, 2) mass transfer limitations and 3) specific (bacterial) affinity for substrate. Hence, inerts (X I ) and methanogens (X ac ) are situated in the inner zone, and this fraction lowers as the radius increases favouring the presence of acidogens (X su ,X aa , X fa ) and acetogens (X c4 ,X pro ). Additional simulations show the effects on the overall process performance when operational (pH) and loading (S:COD) conditions are modified. Lastly, the effect of intra-granular precipitation on the overall organic/inorganic distribution is assessed at: 1) different times; and, 2) reactor heights. Finally, the possibilities and opportunities offered by the proposed approach for conducting engineering optimization projects are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of OSA on hypoxic and inflammatory markers during CPAP withdrawal: Further evidence from three randomized control trials.

PubMed

Turnbull, Chris D; Rossi, Valentina A; Santer, Peter; Schwarz, Esther I; Stradling, John R; Petousi, Nayia; Kohler, Malcolm

2017-05-01

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF). Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed. A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF. Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM. © 2016 Asian Pacific Society of Respirology.

A Meta-analysis of Studies Comparing Outcomes of Diverse Acellular Dermal Matrices for Implant-Based Breast Reconstruction.

PubMed

Lee, Kyeong-Tae; Mun, Goo-Hyun

2017-07-01

The current diversity of the available acellular dermal matrix (ADM) materials for implant-based breast reconstruction raises the issue of whether there are any differences in postoperative outcomes according to the kind of ADM used. The present meta-analysis aimed to investigate whether choice of ADM products can affect outcomes. Studies that used multiple kinds of ADM products for implant-based breast reconstruction and compared outcomes between them were searched. Outcomes of interest were rates of postoperative complications: infection, seroma, mastectomy flap necrosis, reconstruction failure, and overall complications. A total of 17 studies met the selection criteria. There was only 1 randomized controlled trial, and the other 16 studies had retrospective designs. Comparison of FlexHD, DermaMatrix, and ready-to-use AlloDerm with freeze-dried AlloDerm was conducted in multiple studies and could be meta-analyzed, in which 12 studies participated. In the meta-analysis comparing FlexHD and freeze-dried AlloDerm, using the results of 6 studies, both products showed similar pooled risks for all kinds of complications. When comparing DermaMatrix and freeze-dried AlloDerm with the results from 4 studies, there were also no differences between the pooled risks of complications of the two. Similarly, the meta-analysis of 4 studies comparing ready-to-use and freeze-dried AlloDerm demonstrated that the pooled risks for the complications did not differ. This meta-analysis demonstrates that the 3 recently invented, human cadaveric skin-based products of FlexHD, DermaMatrix, and ready-to-use AlloDerm have similar risks of complications compared with those of freeze-dried AlloDerm, which has been used for longer. However, as most studies had low levels of evidence, further investigations are needed.

Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations.

PubMed

Jin, Xiannu; Luong, Thu-Lan; Reese, Necole; Gaona, Heather; Collazo-Velez, Vanessa; Vuong, Chau; Potter, Brittney; Sousa, Jason C; Olmeda, Raul; Li, Qigui; Xie, Lisa; Zhang, Jing; Zhang, Ping; Reichard, Greg; Melendez, Victor; Marcsisin, Sean R; Pybus, Brandon S

2014-01-01

Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These "drug-like" characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays. The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses. Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine-Chloroquine drug-drug interactions in comparison with in vivo pharmacokinetic changes. This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption/distribution. Published by Elsevier Inc.

Numerical relativity and the early Universe

NASA Astrophysics Data System (ADS)

Mironov, Sergey

2016-10-01

We consider numerical simulations in general relativity in ADM formalism with cosmological ansatz for the metric. This ansatz is convenient for investigations of the Universe creation in laboratory with Galileons. Here we consider toy model for the software: spherically symmetric scalar field minimally coupled to the gravity with asymmetric double well potential. We studied the dependence of radius of critical bubble on the parameters of the theory. It demonstrates the wide applicability of thin-wall approximation. We did not find any kind of stable bubble solution.

Predicting human liver microsomal stability with machine learning techniques.

PubMed

Sakiyama, Yojiro; Yuki, Hitomi; Moriya, Takashi; Hattori, Kazunari; Suzuki, Misaki; Shimada, Kaoru; Honma, Teruki

2008-02-01

To ensure a continuing pipeline in pharmaceutical research, lead candidates must possess appropriate metabolic stability in the drug discovery process. In vitro ADMET (absorption, distribution, metabolism, elimination, and toxicity) screening provides us with useful information regarding the metabolic stability of compounds. However, before the synthesis stage, an efficient process is required in order to deal with the vast quantity of data from large compound libraries and high-throughput screening. Here we have derived a relationship between the chemical structure and its metabolic stability for a data set of in-house compounds by means of various in silico machine learning such as random forest, support vector machine (SVM), logistic regression, and recursive partitioning. For model building, 1952 proprietary compounds comprising two classes (stable/unstable) were used with 193 descriptors calculated by Molecular Operating Environment. The results using test compounds have demonstrated that all classifiers yielded satisfactory results (accuracy > 0.8, sensitivity > 0.9, specificity > 0.6, and precision > 0.8). Above all, classification by random forest as well as SVM yielded kappa values of approximately 0.7 in an independent validation set, slightly higher than other classification tools. These results suggest that nonlinear/ensemble-based classification methods might prove useful in the area of in silico ADME modeling.

A systems-pharmacology analysis of herbal medicines used in health improvement treatment: predicting potential new drugs and targets.

PubMed

Liu, Jianling; Pei, Mengjie; Zheng, Chunli; Li, Yan; Wang, Yonghua; Lu, Aiping; Yang, Ling

2013-01-01

For thousands of years, tonic herbs have been successfully used all around the world to improve health, energy, and vitality. However, their underlying mechanisms of action in molecular/systems levels are still a mystery. In this work, two sets of tonic herbs, so called Qi-enriching herbs (QEH) and Blood-tonifying herbs (BTH) in TCM, were selected to elucidate why they can restore proper balance and harmony inside body, organ and energy system. Firstly, a pattern recognition model based on artificial neural network and discriminant analysis for assessing the molecular difference between QEH and BTH was developed. It is indicated that QEH compounds have high lipophilicity while BTH compounds possess high chemical reactivity. Secondly, a systematic investigation integrating ADME (absorption, distribution, metabolism, and excretion) prediction, target fishing and network analysis was performed and validated on these herbs to obtain the compound-target associations for reconstructing the biologically-meaningful networks. The results suggest QEH enhance physical strength, immune system and normal well-being, acting as adjuvant therapy for chronic disorders while BTH stimulate hematopoiesis function in body. As an emerging approach, the systems pharmacology model might facilitate to understand the mechanisms of action of the tonic herbs, which brings about new development for complementary and alternative medicine.

Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: dose-volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy

PubMed Central

2016-01-01

Purpose/Objective(s) We sought to identify swallowing muscle dose-response thresholds associated with chronic radiation-associated dysphagia (RAD) after IMRT for oropharyngeal cancer. Materials/Methods T1-4 N0-3 M0 oropharyngeal cancer patients who received definitive IMRT and systemic therapy were examined. Chronic RAD was coded as any of the following ≥ 12 months post-IMRT: videofluoroscopy/endoscopy detected aspiration or stricture, gastrostomy tube and/or aspiration pneumonia. DICOM-RT plan data were autosegmented using a custom region-of-interest (ROI) library and included inferior, middle and superior constrictors (IPC, MPC, and SPC), medial and lateral pterygoids (MPM, LPM), anterior and posterior digastrics (ADM, PDM), intrinsic tongue muscles (ITM), mylo/geniohyoid complex (MHM), genioglossus (GGM), ), masseter (MM), Buccinator (BM), palatoglossus (PGM), and cricopharyngeus (CPM), with ROI dose-volume histograms (DVHs) calculated. Recursive partitioning analysis (RPA) was used to identify dose-volume effects associated with chronic-RAD, for use in a multivariate (MV) model. Results Of 300 patients, 34 (11%) had chronic-RAD. RPA showed DVH-derived MHM V69 (i.e. the volume receiving ≥69Gy), GGM V35, ADM V60, MPC V49, and SPC V70 were associated with chronic-RAD. A model including age in addition to MHM V69 as continuous variables was optimal among tested MV models (AUC 0.835). Conclusion In addition to SPCs, dose to MHM should be monitored and constrained, especially in older patients (>62-years), when feasible. PMID:26897515

Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: Dose-volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy.

PubMed

2016-02-01

We sought to identify swallowing muscle dose-response thresholds associated with chronic radiation-associated dysphagia (RAD) after IMRT for oropharyngeal cancer. T1-4 N0-3 M0 oropharyngeal cancer patients who received definitive IMRT and systemic therapy were examined. Chronic RAD was coded as any of the following ⩾12months post-IMRT: videofluoroscopy/endoscopy detected aspiration or stricture, gastrostomy tube and/or aspiration pneumonia. DICOM-RT plan data were autosegmented using a custom region-of-interest (ROI) library and included inferior, middle and superior constrictors (IPC, MPC, and SPC), medial and lateral pterygoids (MPM, LPM), anterior and posterior digastrics (ADM, PDM), intrinsic tongue muscles (ITM), mylo/geniohyoid complex (MHM), genioglossus (GGM), masseter (MM), buccinator (BM), palatoglossus (PGM), and cricopharyngeus (CPM), with ROI dose-volume histograms (DVHs) calculated. Recursive partitioning analysis (RPA) was used to identify dose-volume effects associated with chronic-RAD, for use in a multivariate (MV) model. Of 300 patients, 34 (11%) had chronic-RAD. RPA showed DVH-derived MHM V69 (i.e. the volume receiving⩾69Gy), GGM V35, ADM V60, MPC V49, and SPC V70 were associated with chronic-RAD. A model including age in addition to MHM V69 as continuous variables was optimal among tested MV models (AUC 0.835). In addition to SPCs, dose to MHM should be monitored and constrained, especially in older patients (>62-years), when feasible. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol.

PubMed

Williams, Leanne M; Rush, A John; Koslow, Stephen H; Wisniewski, Stephen R; Cooper, Nicholas J; Nemeroff, Charles B; Schatzberg, Alan F; Gordon, Evian

2011-01-05

Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators. The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm. First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide. International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849. URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1

On the Global and Linear Convergence of the Generalized Alternating Direction Method of Multipliers

DTIC Science & Technology

2012-08-01

the less exact one is solved later — assigned as step 4 of Algorithm 2 — because at each iteration , the ADM updates the variables in the Gauss - Seidel ...k) and that of an accelerated version descends at O(1/k2). Then, work [14] establishes the same rates on a Gauss - Seidel version and requires only one... iteration Fig. 5.1. Convergence curves of ADM for the elastic net problem. 17 0 50 100 150 200 0.75 0.8 0.85 0.9 0.95 1 Iteration ‖u k + 1 − u ∗ ‖ 2 G / ‖u k

Development of a Blood Pressure Measurement Instrument with Active Cuff Pressure Control Schemes.

PubMed

Kuo, Chung-Hsien; Wu, Chun-Ju; Chou, Hung-Chyun; Chen, Guan-Ting; Kuo, Yu-Cheng

2017-01-01

This paper presents an oscillometric blood pressure (BP) measurement approach based on the active control schemes of cuff pressure. Compared with conventional electronic BP instruments, the novelty of the proposed BP measurement approach is to utilize a variable volume chamber which actively and stably alters the cuff pressure during inflating or deflating cycles. The variable volume chamber is operated with a closed-loop pressure control scheme, and it is activated by controlling the piston position of a single-acting cylinder driven by a screw motor. Therefore, the variable volume chamber could significantly eliminate the air turbulence disturbance during the air injection stage when compared to an air pump mechanism. Furthermore, the proposed active BP measurement approach is capable of measuring BP characteristics, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), during the inflating cycle. Two modes of air injection measurement (AIM) and accurate dual-way measurement (ADM) were proposed. According to the healthy subject experiment results, AIM reduced 34.21% and ADM reduced 15.78% of the measurement time when compared to a commercial BP monitor. Furthermore, the ADM performed much consistently (i.e., less standard deviation) in the measurements when compared to a commercial BP monitor.

Osthole shows the potential to overcome P-glycoprotein‑mediated multidrug resistance in human myelogenous leukemia K562/ADM cells by inhibiting the PI3K/Akt signaling pathway.

PubMed

Wang, Hong; Jia, Xiu-Hong; Chen, Jie-Ru; Wang, Jian-Yong; Li, You-Jie

2016-06-01

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has been reported to play a pivotal role in tumor chemotherapy failure. Study after study has illustrated that the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with P-gp expression in many human malignancies. In the present study, osthole, an O-methylated coumarin, exhibited potent reversal capability of MDR in myelogenous leukemia K562/ADM cells. Simultaneously, the uptake and efflux of Rhodamine-123 (Rh-123) and the accumulation of doxorubicin assays combined with flow cytometric analysis suggested that osthole could increase intracellular drug accumulation. Furthermore, osthole decreased the expression of multidrug resistance gene 1 (MDR1) at both the mRNA and protein levels. Further experiments elucidated that osthole could suppress P-gp expression by inhibiting the PI3K/Akt signaling pathway which might be the main mechanism accounting for the reversal potential of osthole in the MDR in K562/ADM cells. In conclusion, osthole combats MDR and could be a promising candidate for the development of novel MDR reversal modulators.

Nanoscale observation of the natural structure of milk-fat globules and casein micelles in the liquid condition using a scanning electron assisted dielectric microscopy.

PubMed

Ogura, Toshihiko; Okada, Tomoko

2017-09-30

Recently, aqueous nanoparticles have been used in drug-delivery systems for new type medicines. In particular, milk-casein micelles have been used as drug nanocarriers for targeting cancer cells. Therefore, nanostructure observation of particles and micelles in their native liquid condition is indispensable for analysing their function and mechanisms. However, traditional optical and scanning electron microscopy have difficulty observing the nanostructures of aqueous micelles. Recently, we developed a novel imaging technique called scanning electron-assisted dielectric microscopy (SE-ADM) that enables observation of various biological specimens in water with very little radiation damage and high-contrast imaging without staining or fixation at an 8-nm spatial resolution. In this study, for the first time, we show that the SE-ADM system is capable of high-resolution observation of whole-milk specimens in their natural state. Moreover, we successfully observe the casein micelles and milk-fat globules in an intact liquid condition. Our SE-ADM system can be applied to various biological particles and micelles in a native liquid state. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Effect of Paired Muscle Stimulation on Preparation for Movement.

PubMed

Brownjohn, Philip W; Blakemore, Rebekah L; Fox, Jonathan A; Shemmell, Jonathan

2018-06-07

Paired muscle stimulation is used clinically to facilitate the performance of motor tasks for individuals with motor dysfunction. However, the optimal temporal relationship between stimuli for enhancing movement remains unknown. We hypothesized that synchronous, muscle stimulation would increase the extent to which stimulated muscles are concurrently prepared for movement. We validated a measure of muscle-specific changes in corticomotor excitability prior to movement. We used this measure to examine the preparation of the first dorsal interosseous (FDI), abductor digiti minimi (ADM), abductor pollicis brevis (APB) muscles prior to voluntary muscle contractions before and after paired muscle stimulation at four interstimulus intervals (0, 5, 10, and 75 ms). Paired muscle stimulation increased premovement excitability in the stimulated FDI, but not in the ADM muscle. Interstimulus interval was not a significant factor in determining efficacy of the protocol. Paired stimulation, therefore, did not result in a functional association being formed between the stimulated muscles. Somatosensory potentials evoked by the muscle stimuli were small compared to those commonly elicited by stimulation of peripheral nerves, suggesting that the lack of functional association formation between muscles may be due to the small magnitude of afferent volleys from the stimulated muscles, particularly the ADM, reaching the cortex.

Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development.

PubMed

Mátyus, Péter; Chai, Christina L L

2016-06-20

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Carbon Isotopes Profiles of Human Whole Blood, Plasma, Red Blood Cells, Urine and Feces for Biological/Biomedical 14C-Accelerator Mass Spectrometry Applications

PubMed Central

Kim, Seung-Hyun; Chuang, Jennifer C.; Kelly, Peter B.; Clifford, Andrew J.

2011-01-01

Radiocarbon (14C) is an ideal tracer for in vivo human ADME (absorption, distribution, metabolism, elimination) and PBPK (physiological-based pharmacokinetic) studies. Living plants preferentially incorporate atmospheric 14CO2, vs 13CO2, vs 12CO2, which result in unique signature. Furthermore, plants and the food chains they support also have unique carbon isotope signatures. Humans, at the top of the food chain, consequently acquire isotopic concentrations in the tissues and body fluids depending on their dietary habits. In preparation of ADME and PBPK studies, 12 healthy subjects were recruited. The human baseline (specific to each individual and their diet) total carbon (TC) and carbon isotope 13C (δ13C) and 14C (Fm) were quantified in whole blood (WB), plasma, washed red blood cell (RBC), urine, and feces. TC (mg of C/100μL) in WB, plasma, RBC, urine, and feces were 11.0, 4.37, 7.57, 0.53, and 1.90, respectively. TC in WB, RBC, and feces was higher in men over women, P < 0.05. Mean δ13C were ranked low to high as follows, feces < WB = plasma = RBC = urine, P < 0.0001. δ13C was not affected by gender. Our analytic method shifted δ13C by only ± 1.0 ‰ ensuring our Fm measurements were accurate and precise. Mean Fm were ranked low to high as follows, plasma = urine < WB = RBC = feces, P < 0.05. Fm in feces was higher for men over women, P < 0.05. Only in WB, 14C levels (Fm) and TC were correlated with one another (r = 0.746, P < 0.01). Considering the lag time to incorporate atmospheric 14C into plant foods (vegetarian) and or then into animal foods (non-vegetarian), the measured Fm of WB in our population (recruited April 2009) was 1.0468 ± 0.0022 (mean±SD), the Fm of WB matched the (extrapolated) atmospheric Fm of 1.0477 in 2008. This study is important in presenting a procedure to determine a baseline for a study group for human ADME and PBPK studies using 14C as a tracer. PMID:21452856

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor.

PubMed

Chitta, Aparna; Jatavath, Mohan Babu; Fatima, Sabiha; Manga, Vijjulatha

2012-02-01

To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.

A study of 15-year aerosol optical thickness and direct shortwave aerosol radiative effect trends using MODIS, MISR, CALIOP and CERES

NASA Astrophysics Data System (ADS)

Alfaro-Contreras, Ricardo; Zhang, Jianglong; Reid, Jeffrey S.; Christopher, Sundar

2017-11-01

By combining Collection 6 Moderate Resolution and Imaging Spectroradiometer (MODIS) and Version 22 Multi-angle Imaging Spectroradiometer (MISR) aerosol products with Cloud and Earth's Radiant Energy System (CERES) flux products, the aerosol optical thickness (AOT, at 0.55 µm) and shortwave (SW) aerosol radiative effect (SWARE) trends are studied over ocean for the near-full Terra (2000-2015) and Aqua (2002-2015) data records. Despite differences in sampling methods, regional SWARE and AOT trends are highly correlated with one another. Over global oceans, weak SWARE (cloud-free SW flux) and AOT trends of 0.5-0.6 W m-2 (-0.5 to -0.6 W m-2) and 0.002 AOT decade-1 are found using Terra data. Near-zero AOT and SWARE trends are also found for using Aqua data, regardless of the angular distribution models (ADMs) used. Regionally, positive AOT and cloud-free SW flux (negative SWARE) trends are found over the Bay of Bengal, the Arabian Sea, the Arabian/Persian Gulf and the Red Sea, while statistically significant negative trends are derived over the Mediterranean Sea and the eastern US coast. In addition, the global mean instantaneous SW aerosol direct forcing efficiencies are found to be ˜ -60 W m-2 AOT-1, with corresponding SWARE values of ˜ -7 W m-2 from both Aqua and Terra data, again regardless of CERES ADMs used. Regionally, SW aerosol direct forcing efficiency values of ˜ -40 W m-2 AOT-1 are found over the southwest coast of Africa where smoke aerosol particles dominate in summer. Larger (in magnitude) SW aerosol direct forcing efficiency values of -50 to -80 W m-2 AOT-1 are found over several other dust- and pollutant-aerosol-dominated regions. Lastly, the AOT and SWARE trends from this study are also intercompared with aerosol trends (such as active-based ones) from several previous studies. Findings suggest that a cohesive understanding of the changing aerosol skies can be achieved through the analysis of observations from both passive- and active-based analyses, as well as from both narrowband and broadband datasets.

Application of Design of Experiments and Surrogate Modeling within the NASA Advanced Concepts Office, Earth-to-Orbit Design Process

NASA Technical Reports Server (NTRS)

Zwack, Mathew R.; Dees, Patrick D.; Holt, James B.

2016-01-01

Decisions made during early conceptual design have a large impact upon the expected life-cycle cost (LCC) of a new program. It is widely accepted that up to 80% of such cost is committed during these early design phases [1]. Therefore, to help minimize LCC, decisions made during conceptual design must be based upon as much information as possible. To aid in the decision making for new launch vehicle programs, the Advanced Concepts Office (ACO) at NASA Marshall Space Flight Center (MSFC) provides rapid turnaround pre-phase A and phase A concept definition studies. The ACO team utilizes a proven set of tools to provide customers with a full vehicle mass breakdown to tertiary subsystems, preliminary structural sizing based upon worst-case flight loads, and trajectory optimization to quantify integrated vehicle performance for a given mission [2]. Although the team provides rapid turnaround for single vehicle concepts, the scope of the trade space can be limited due to analyst availability and the manpower requirements for manual execution of the analysis tools. In order to enable exploration of a broader design space, the ACO team has implemented an advanced design methods (ADM) based approach. This approach applies the concepts of design of experiments (DOE) and surrogate modeling to more exhaustively explore the trade space and provide the customer with additional design information to inform decision making. This paper will first discuss the automation of the ACO tool set, which represents a majority of the development effort. In order to fit a surrogate model within tolerable error bounds a number of DOE cases are needed. This number will scale with the number of variable parameters desired and the complexity of the system's response to those variables. For all but the smallest design spaces, the number of cases required cannot be produced within an acceptable timeframe using a manual process. Therefore, automation of the tools was a key enabler for the successful application of an ADM approach to an ACO design study. Following the overview of the tool set automation, an example problem will be given to illustrate the implementation of the ADM approach. The example problem will first cover the inclusion of ground rules and assumptions (GR&A) for a study. The GR&A are very important to the study as they determine the constraints within which a trade study can be conducted. These trades must ultimately reconcile with the customer's desired output and any anticipated "what if" questions.

ADM. Aerial view of administration area. Camera facing westerly. From ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ADM. Aerial view of administration area. Camera facing westerly. From left to right in foregound: Substation (TAN-605), Warehouse (TAN-628), Gate House (TAN-601), Administration Building (TAN-602). Left to right middle ground: Service Building (TAN-603), Warehouse (later known as Maintenance Shop or Craft Shop, TAN-604), Water Well Pump Houses, Fuel Tanks and Fuel Pump Houses, and Water Storage Tanks. Change House (TAN-606) on near side of berm. Large building beyond berm is A&M. Building, TAN-607. Railroad tracks beyond lead from (unseen) turntable to the IET. Date: June 6, 1955. INEEL negative no. 13201 - Idaho National Engineering Laboratory, Test Area North, Scoville, Butte County, ID

Optimal space communications techniques. [discussion of video signals and delta modulation

NASA Technical Reports Server (NTRS)

Schilling, D. L.

1974-01-01

The encoding of video signals using the Song Adaptive Delta Modulator (Song ADM) is discussed. The video signals are characterized as a sequence of pulses having arbitrary height and width. Although the ADM is suited to tracking signals having fast rise times, it was found that the DM algorithm (which permits an exponential rise for estimating an input step) results in a large overshoot and an underdamped response to the step. An overshoot suppression algorithm which significantly reduces the ringing while not affecting the rise time is presented along with formuli for the rise time and the settling time. Channel errors and their effect on the DM encoded bit stream were investigated.

High resolution kilometric range optical telemetry in air by radio frequency phase measurement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guillory, Joffray; García-Márquez, Jorge; Truong, Daniel

2016-07-15

We have developed an optical Absolute Distance Meter (ADM) based on the measurement of the phase accumulated by a Radio Frequency wave during its propagation in the air by a laser beam. In this article, the ADM principle will be described and the main results will be presented. In particular, we will emphasize how the choice of an appropriate photodetector can significantly improve the telemeter performances by minimizing the amplitude to phase conversion. Our prototype, tested in the field, has proven its efficiency with a resolution better than 15 μm for a measurement time of 10 ms and distances upmore » to 1.2 km.« less

Galerkin-collocation domain decomposition method for arbitrary binary black holes

NASA Astrophysics Data System (ADS)

Barreto, W.; Clemente, P. C. M.; de Oliveira, H. P.; Rodriguez-Mueller, B.

2018-05-01

We present a new computational framework for the Galerkin-collocation method for double domain in the context of ADM 3 +1 approach in numerical relativity. This work enables us to perform high resolution calculations for initial sets of two arbitrary black holes. We use the Bowen-York method for binary systems and the puncture method to solve the Hamiltonian constraint. The nonlinear numerical code solves the set of equations for the spectral modes using the standard Newton-Raphson method, LU decomposition and Gaussian quadratures. We show convergence of our code for the conformal factor and the ADM mass. Thus, we display features of the conformal factor for different masses, spins and linear momenta.

Hybrid Higgs inflation: The use of disformal transformation

NASA Astrophysics Data System (ADS)

Sato, Seiga; Maeda, Kei-ichi

2018-04-01

We propose a hybrid type of the conventional Higgs inflation and new Higgs inflation models. We perform a disformal transformation into the Einstein frame and analyze the background dynamics and the cosmological perturbations in the truncated model, in which we ignore the higher-derivative terms of the Higgs field. From the observed power spectrum of the density perturbations, we obtain the constraint on the nonminimal coupling constant ξ and the mass parameter M in the derivative coupling. Although the primordial tilt ns in the hybrid model barely changes, the tensor-to-scalar ratio r moves from the value in the new Higgs inflationary model to that in the conventional Higgs inflationary model as |ξ | increases. We confirm our results by numerical analysis by ADM formalism of the full theory in the Jordan frame.

Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department.

PubMed

Di Somma, Salvatore; Magrini, Laura; Travaglino, Francesco; Lalle, Irene; Fiotti, Nicola; Cervellin, Grianfranco; Avanzi, Gian Carlo; Lupia, Enrico; Maisel, Alan; Hein, Frauke; Wagner, Florian; Lippi, Giuseppe

2013-06-01

Sepsis is a leading healthcare problem, accounting for the vast majority of fatal events in critically ill patients. Beyond early diagnosis and appropriate treatment, this condition requires a multifaceted approach for monitoring the severity, the potential organ failure as well as the risk of death. Monitoring of the efficacy of treatment is also a major issue in the emergency department (ED). The assessment of critically ill conditions and the prognosis of patients with sepsis is currently based on some scoring systems, which are, however, inefficient to provide definite clues about organ failure and prognosis in general. The discretionary and appropriate use of some selected biomarkers such as procalcitonin, inducible protein 10 (IP10), Group IV phospholipase A2 type II (PLA2 II), neutrophil gelatinase-associated lipocalin (NGAL), natriuretic peptides, mature adrenomedullin (ADM), mid-regional pro-adrenomedullin (MR-proADM), copeptin, thrombopoietin, Mer receptor and even red blood cell distribution width (RDW) represent thereby an appealing perspective in the diagnosis and management of patients with sepsis. Nevertheless, at the moment, it is not still clear if it is better to use a multimarkers approach or if a single, most appropriate, biomarker exists. This collective opinion paper is aimed at providing an overview about the potential clinical usefulness of some innovative biomarkers of sepsis in its diagnosis and prognosis, but also in the treatment management of the disease. This manuscript represents a synopsis of the lectures of Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012.

Using DAS for reflection seismology - lessons learned from three field studies

NASA Astrophysics Data System (ADS)

Freifeld, B. M.; Dou, S.; Ajo Franklin, J. B.; Robertson, M.; Wood, T.; Daley, T. M.; White, D. J.; Worth, K.; Pevzner, R.; Yavuz, S.; dos Santos Maia Correa, J.; McDonald, S.

2017-12-01

Distributed acoustic sensing (DAS) has rapidly gained recognition for its potential for seismic imaging. For surface reflection seismology, the wide spatial aperture afforded by DAS is a primary motivation for its application, however the lower SNR of DAS has proven to be a significant impediment to acquiring data that can replace conventional receiver arrays. A further limitation of DAS cables is that the strain-dependent response is insensitive to acoustic energy which arrives orthogonal to the cable axis, reducing its effectiveness at seeing energy reflected from the deep subsurface. To enhance the sensitivity of DAS cables for reflection seismology, we have trialed at three field sites DAS cables with helical construction in which there is a significant component of optical fiber that is coincident with arriving broadside energy. We have installed helically wound DAS cables at the PTRC Aquistore Project in Saskatchewan, Canada and the CO2CRC Otway Project in Nirranda South, Victoria, Australia in shallow trenches. For the ADM Intelligent Monitoring Systems Project in Decatur, Illinois, USA we used a horizontal directional drilling method to install DAS cables at a depth that is greater than can be achieved using trenched installation. At the Otway and ADM sites we operated surface orbital vibrators (SOVs) at fixed locations to enhance sensitivity by stacking large numbers of sweeps. We present survey results from the three sites. Analysis of both vibroseis survey and SOV results show that the helical cable design achieves its primary objective of improving sensitivity to reflected energy, with further gains needed to achieve the sensitivity of conventional geophones.

Modification of S-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation

PubMed Central

Tambunan, Usman Sumo Friend; Nasution, Mochammad Arfin Fardiansyah; Azhima, Fauziah; Parikesit, Arli Aditya; Toepak, Erwin Prasetya; Idrus, Syarifuddin; Kerami, Djati

2017-01-01

Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world’s population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S-adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2′OH, resulting in S-adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔGbinding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever. PMID:28469408

Traumatic laryngotracheal stenosis treated by hyoid–sternohyoid osseomuscular flap combined with xenogenic acellular dermal matrix: A case report and literature review

PubMed Central

Yang, Hang; Chen, Zhe; Wang, Qin-Yin; Weng, Li-Xia; Wang, Fang; Wu, Ting-Ting; Zhou, Min-Li; Bao, Yang-Yang

2017-01-01

Objective The treatment of laryngotracheal stenosis is a major therapeutic challenge. Various treatments include observation, medical management, and surgical management. The most effective surgical management is resection and reconstruction. To the authors’ knowledge, no reports have described the use of xenogenic acellular dermal matrix (ADM) for laryngotracheal stenosis. Methods A 27-year-old man presented with hemoptysis of the neck due to a traffic accident. Emergency orotracheal intubation was performed. Tracheostomy was then performed under local anesthesia. Computed tomography revealed fractures of the right thyroid cartilage and posterior arc of the cricoid cartilage and stenosis of the subglottis and first and second tracheal rings. We used a composite hyoid–sternohyoid osseomuscular flap with xenogenic ADM and a straight silicone tube as a lumen stent to reconstruct the laryngotracheal stenosis. Results Surgical recovery was uneventful. The tracheotomy opening was changed to a metal tube 5 days postoperatively. Four months postoperatively, the silicone tube was endoscopically removed under local anesthesia. The patient was decannulated 20 days later. The patient satisfied with his voice, respiration, and deglutition at the 16-month postoperative follow-up. Conclusion The use of ADM for laryngotracheal stenosis may reduce the growth of granulation tissues and promote the repair process. PMID:28480810

Traumatic laryngotracheal stenosis treated by hyoid-sternohyoid osseomuscular flap combined with xenogenic acellular dermal matrix: A case report and literature review.

PubMed

Yang, Hang; Chen, Zhe; Zhou, Shui-Hong; Wang, Qin-Yin; Weng, Li-Xia; Wang, Fang; Wu, Ting-Ting; Zhou, Min-Li; Bao, Yang-Yang

2017-10-01

Objective The treatment of laryngotracheal stenosis is a major therapeutic challenge. Various treatments include observation, medical management, and surgical management. The most effective surgical management is resection and reconstruction. To the authors' knowledge, no reports have described the use of xenogenic acellular dermal matrix (ADM) for laryngotracheal stenosis. Methods A 27-year-old man presented with hemoptysis of the neck due to a traffic accident. Emergency orotracheal intubation was performed. Tracheostomy was then performed under local anesthesia. Computed tomography revealed fractures of the right thyroid cartilage and posterior arc of the cricoid cartilage and stenosis of the subglottis and first and second tracheal rings. We used a composite hyoid-sternohyoid osseomuscular flap with xenogenic ADM and a straight silicone tube as a lumen stent to reconstruct the laryngotracheal stenosis. Results Surgical recovery was uneventful. The tracheotomy opening was changed to a metal tube 5 days postoperatively. Four months postoperatively, the silicone tube was endoscopically removed under local anesthesia. The patient was decannulated 20 days later. The patient satisfied with his voice, respiration, and deglutition at the 16-month postoperative follow-up. Conclusion The use of ADM for laryngotracheal stenosis may reduce the growth of granulation tissues and promote the repair process.

Toward a Blended Ontology: Applying Knowledge Systems to ...

EPA Pesticide Factsheets

Bionanomedicine and environmental research share need common terms and ontologies. This study applied knowledge systems, data mining, and bibliometrics used in nano-scale ADME research from 1991 to 2011. The prominence of nano-ADME in environmental research began to exceed the publication rate in medical research in 2006. That trend appears to continue as a result of the growing products in commerce using nanotechnology, that is, 5-fold growth in number of countries with nanomaterials research centers. Funding for this research virtually did not exist prior to 2002, whereas today both medical and environmental research is funded globally. Key nanoparticle research began with pharmacology and therapeutic drug-delivery and contrasting agents, but the advances have found utility in the environmental research community. As evidence ultrafine aerosols and aquatic colloids research increased 6-fold, indicating a new emphasis on environmental nanotoxicology. User-directed expert elicitation from the engineering and chemical/ADME domains can be combined with appropriate Boolean logic and queries to define the corpus of nanoparticle interest. The study combined pharmacological expertise and informatics to identify the corpus by building logical conclusions and observations. Publication records informatics can lead to an enhanced understanding the connectivity between fields, as well as overcoming the differences in ontology between the fields. The National Exposure Resea

Increased adipogenicity of cells from regenerating skeletal muscle.

PubMed

Yamanouchi, Keitaro; Yada, Erica; Ishiguro, Naomi; Hosoyama, Tohru; Nishihara, Masugi

2006-09-10

Adipose tissue development is observed in some muscle pathologies, however, mechanisms that induce accumulation of this tissue as well as its cellular origin are unknown. The adipogenicity of cells from bupivacaine hydrochloride (BPVC)-treated and untreated muscle was compared in vitro. Culturing cells from both BPVC-treated and untreated muscles in adipogenic differentiation medium (ADM) for 10 days resulted in the appearance of mature adipocytes, but their number was 3.5-fold higher in cells from BPVC-treated muscle. Temporal expressions of PPARgamma and the presence of lipid droplets during adipogenic differentiation were examined. On day 2 of culture in ADM, only cells from BPVC-treated muscle were positive both for PPARgamma and lipid droplets. Pref-1 was expressed in cells from untreated muscle, whereas its expression was absent in cells from BPVC-treated muscle. In ADM, the presence of insulin, which negates an inhibitory effect of Pref-1 on adipogenic differentiation, was required for PPARgamma2 expression in cells from untreated muscle, but not for cells from BPVC-treated muscle. These results indicate that BPVC-induced degenerative/regenerative changes in muscle lead to increased adipogenicity of cells, and suggest that this increased adipogenicity not only involves an increase in the number of cells having adipogenic potential, but also contributes to the progression of these cells toward adipogenic differentiation.

Combined usage of extracorporeal membrane oxygenation and double filtration plasmapheresis in amyopathic dermatomyositis patient with severe interstitial lung disease: A case report.

PubMed

Huang, Jiequn; Liu, Changzhi; Zhu, Ruiqiu; Su, Yongpeng; Lin, Jingcheng; Lu, Jianhai; Wen, Shuchao; Zuo, Liuer

2018-06-01

We report a man with amyopathic dermatomyositis (ADM) complicated by severe interstitial lung disease (ILD) received extracorporeal membrane oxygenation (ECMO) in combination with double filtration plasmapheresis (DFPP). This is the first report of the utility of ECMO in combination with DFPP in ADM related ILD in adults. A 48-year-old man who was previously healthy had a 2-month history of cough and shortness of breath, which aggravated in 5 days. Amyopathic dermatomyositis and complicated by severe interstitial lung disease. ECMO was giving when the patient suffered acute respiratory failure. Though corticosteroids was giving, primary disease was still developing with relapses of spontaneous pneumomediastinum and pneumothorax. Then, DFPP treatment was initiated. After the treatments above, the patient's clinical condition improved with the reduction of bilateral interstitial infiltrates and improvement of lung compliance. Unfortunately, he discontinued the treatment because of the financial problem. When get a rapid progressive interstitial lung disease for no apparent reason, amyopathic dermatomyositis should be considered, especially with suspected skin lesions. ECMO, in combination with DFPP, should be considered as a supportive therapy and initiated early in patients in acute respiratory failure secondary to ADM-ILD. Prompt initiation of DFPP in dermatomyositis patients with ILD might help reduce the occurrence of spontaneous pneumomediastinum or pneumothorax.

Remote Medical Diagnosis System (RMDS) Advanced Development Model (ADM) Radiology Performance Test Results.

DTIC Science & Technology

1981-12-01

necrosis of lunate 6 6 Skull Nasal spine Fx D 1 4 Chest Pancoast tumor j 2 5 Skull Multiple myeloma 3 2 Abdomen Air under (R) diaphragm 4 6 Appendage...of lunate 6 6 Skull Nasal spine Fx D 1 4 Chest Pancoast tumor 2 5 Skull Multiple myeloma 3 2 Abdomen Air under (R) diaphragm 4 6 Appendage...nose and maxilla FINDINGS: Fx - inferior nasal spine (P) DIAGNOSES: Fx - inferior nasal spine (P) 86 I I I I I I RADIOGRAPH: D-1 HISTORY: 57-year old

Integrated Electronic Warfare System Advanced Development Model (ADM); Appendix 1 - Functional Requirement Specification.

DTIC Science & Technology

1977-10-01

APPROVED DATE FUNCTION APPROVED jDATE WRITER J . K-olanek 2/6/76 REVISIONS CHK DESCRIPTION REV CHK DESCRIPTION IREV REVISION jJ ~ ~ ~~~ _ II SHEET NO...DOCUMENT (CDBDD) 45 5.5 COMPUTER PROGRAM PACKAGE (CPP)- j 45 5.6 COMPUTER PROGRAM OPERATOR’S MANUAL (CPOM) 45 5.7 COMPUTER PROGRAM TEST PLAN (CPTPL) 45...I LIST OF FIGURES Number Page 1 JEWS Simplified Block Diagram 4 2 System Controller Architecture 5 SIZE CODE IDENT NO DRAWING NO. A 49956 SCALE REV J

Commander Naval Air Forces (CNAF) Flight Hour Program: Budgeting and Execution Response to the Implementation of the Fleet Response Plan and OP-20 Pricing Model Changes

DTIC Science & Technology

2005-06-01

seat ratio ( CSR ). The wartime CSR is the result of wartime manning levels divided by Primary Aircraft Authorized (PAA). The Aircrew Manning Factor...justifies the FHP.59 As ADM Mallon suggested, let us look at two simple examples of today’s best business practices with Starbucks and Southwest Airlines...focusing on efforts to achieve optimal efficiency in routine tasks of their operation. The Starbucks example involves redesigning ice scoops and

Outcomes of abdominal wall reconstruction with acellular dermal matrix are not affected by wound contamination.

PubMed

Garvey, Patrick B; Martinez, Roberto A; Baumann, Donald P; Liu, Jun; Butler, Charles E

2014-11-01

The optimal type of mesh for complex abdominal wall reconstruction has not been elucidated. We hypothesized that AWRs using acellular dermal matrix (ADM) experience low rates of surgical site occurrence (SSO) and surgical site infection, despite increasing degrees of wound contamination. We retrospectively reviewed prospectively collected data from consecutive abdominal wall reconstructions with ADM over a 9-year period. Outcomes of abdominal wall reconstructions were compared between patients with different CDC wound classifications. Univariate and multivariate logistic regression and Cox proportional hazard regression analyses identified potential associations and predictive/protective factors. The 359 patients had a mean follow-up of 28.3 ± 19.0 months. Reconstruction of clean wounds (n = 171) required fewer reoperations than that of combined contaminated (n = 188) wounds (2.3% vs 11.2%; p = 0.001) and trended toward experiencing fewer SSOs (19.9% vs 28.7%, p = 0.052). There were no significant differences between clean and combined contaminated cases in 30-day SSI (8.8% vs 8.0%), hernia recurrence (9.9% vs 10.1%), and mesh removal (1.2% vs 1.1%) rates. Independent predictors of SSO included body mass index ≥30 kg/m(2) (odds ratio [OR] 3.6; p < 0.001), 1 or more comorbidities (OR 2.5; p = 0.008), and defect width ≥15 cm (OR 1.8; p = 0.02). Complex abdominal wall reconstructions using ADM demonstrated similar rates of complications between the different CDC wound classifications. This is in contradistinction to published outcomes for abdominal wall reconstruction using synthetic mesh that show progressively higher complication rates with increasing degrees of contamination. These data support the use of ADM rather than synthetic mesh for complex abdominal wall reconstruction in the setting of wound contamination. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Intercellular transfer of P-glycoprotein from the drug resistant human bladder cancer cell line BIU-87 does not require cell-to-cell contact.

PubMed

Zhou, Hui-liang; Zheng, Yong-jun; Cheng, Xiao-zhi; Lv, Yi-song; Gao, Rui; Mao, Hou-ping; Chen, Qin

2013-09-01

The efflux activity of transmembrane P-glycoprotein prevents various therapeutic drugs from reaching lethal concentrations in cancer cells, resulting in multidrug resistance. We investigated whether drug resistant bladder cancer cells could transfer functional P-glycoprotein to sensitive parental cells. Drug sensitive BIU-87 bladder cancer cells were co-cultured for 48 hours with BIU-87/ADM, a doxorubicin resistant derivative of the same cell line, in a Transwell® system that prevented cell-to-cell contact. The presence of P-glycoprotein in recipient cell membranes was established using fluorescein isothiocyanate, laser scanning confocal microscopy and Western blot. P-glycoprotein mRNA levels were compared between cell types. Rhodamine 123 efflux assay was done to confirm that P-glycoprotein was biologically active. The amount of P-glycoprotein protein in BIU-87 cells co-cultured with BIU-87/ADM was significantly higher than in BIU-87 cells (0.44 vs 0.25) and BIU-87/H33342 cells (0.44 vs 0.26, each p <0.001), indicating P-glycoprotein transfer. P-glycoprotein mRNA expression was significantly higher in BIU-87/ADM cells than in co-cultured BIU-87 cells (1.28 vs 0.30), BIU-87/H33342 (0.28) and BIU-87 cells (0.25, each p <0.001), ruling out a genetic mechanism. After 30 minutes of efflux, rhodamine 123 fluorescence intensity was significantly lower in BIU-87/ADM cells (5.55 vs 51.45, p = 0.004) and co-cultured BIU-87 cells than in BIU-87 cells (14.22 vs 51.45, p <0.001), indicating that P-glycoprotein was functional. Bladder cancer cells can acquire functional P-glycoprotein through a nongenetic mechanism that does not require direct cell contact. This mechanism is consistent with a microparticle mediated process. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction.

PubMed

Aversa, Antonio; Letizia, Claudio; Francomano, Davide; Bruzziches, Roberto; Natali, Marco; Lenzi, Andrea

2012-10-18

It is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. 20 men complaining vascular ED (mean IIEF5=12 ± 6 and peak systolic velocity-PSV=24 ± 2 cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59 ± 11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). Patients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r(2)=0.22; p<0.005). The proportion of patients with an IIEF5 score of ≥ 22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline. We demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

[Glycemic variability and short-term outcome in critically ill].

PubMed

Zhang, L P; Guo, Y B; Zhou, L H

2016-06-07

To analyze the association of blood glucose variability and short-term outcome in critically ill. The retrospective study including 552 patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to March 2015. The initial blood glucose (GluAdm), the first 24 hours average blood glucose(GluMV1d) and glycemic lability index(GLI1d), 72-hour average blood glucose (GluMV3d) and glycemic lability index(GLI3d) were recorded. The receiver operating characteristic curve (ROC curve) was applied to evaluate the association between GluAdm, GLI1d, GLI3d and APACHE Ⅱ score and prognosis. The levels of APACHE Ⅱ, GluAdm, GLI 1d, GLI 3d of nonsurvivors were higher than those of survivors[(23.2±5.2) vs (16.7±4.4), (12.3±5.2)mmol/L vs(9.2±2.2)mmol/L, (23.3±12.2)vs(12.3±11.1), (21.6±19.3)vs(13.2±9.9), P<0.05]; there was no statistically significant difference between GluMV1d and GluMV3d; when ROC was applied, and the area under the curve (AUC) of APACHEⅡ, GLI1d and GLI3d were 0.826±0.035, 0.726±0.052 and 0.786±0.046, which were significantly higher than the GluMV1d and GluMV3d (0.412±0.031, 0.425±0.026, P<0.05) .It is correlated between GluAdm, GLI1d, GLI3d and the 28-day mortality, ICU days and total time of hospitalization. Blood glucose variability is closely related with the mortality in critical ill patients, GLI1d, GLI3d and APACHEⅡ score of critically ill patients have a similar predictive value in the short-term prognosis.

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

PubMed Central

Makarov, Vadim; Neres, João; Hartkoorn, Ruben C.; Ryabova, Olga B.; Kazakova, Elena; Šarkan, Michal; Huszár, Stanislav; Piton, Jérémie; Kolly, Gaëlle S.; Vocat, Anthony; Conroy, Trent M.; Mikušová, Katarína

2015-01-01

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency. PMID:25987616

Development and application of a UPLC-MS/MS method for P-glycoprotein quantification in human tumor cells.

PubMed

Qiu, Zhaohui; Peng, Jie; Mou, Lingli; Li, Xiao; Meng, Fanqi; Yu, Peng

2018-05-01

Multidrug resistance (MDR) of tumors occurs when tumor cells exhibit reduced sensitivity to a large number of unrelated drugs. The molecular mechanism of MDR commonly involves overexpression of the plasma membrane drug efflux pump P-glycoprotein (P-gp). Overexpression of P-gp may be induced by the selection and/or adaptation of cells during exposure to chemotherapeutic drugs, referred to as acquired P-gp-mediated MDR. This study aimed to establish a P-gp quantification method by Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC-MS/MS) to better understand the regulation of P-gp expression and its relationship with the level of drug resistance. Absolute P-gp expression was determined in the human tumor cells MCF-7, HepG-2, and SMMC-7721 and their corresponding drug-resistant subclones MCF-7/ADMs, MCF-7/MXs, MCF-7/MTXs, HepG-2/ADMs, HepG-2/MXs, HepG-2/MTXs, SMMC-7721/ADMs, SMMC-7721/MXs and SMMC-7721/MTXs. A unique 10-mer tryptic peptide (IATEAIENFR) of P-gp was synthesized for developing the quantitative UPLC-MS/MS method with the stable isotope labeled signature peptide IATEAI ( 13 C 6, 15 N 1 ) ENFR as the internal standard (IS). The detection signal was linear in the range of 0.1-100 ng mL -1 . Quality control (QC) data showed that the within-run and between-run precision (%RSD) and accuracy (%RE) conformed to acceptable criteria of ±15% for the calibration standards and QCs (±20% at the LLOQ). The UPLC-MS/MS method was first applied to quantify P-gp in HepG-2 and SMMC-7721 cells and their drug-resistant subclones. The results confirmed that P-gp expression in most drug-resistant subclones increase significantly compared to parental tumor cells but varied among different types of drugs or tumor cells. This outcome was then compared with published reports and discrepancy was observed in HepG2 cell lines mainly due to different sample types and samples sources. Additionally, P-gp mRNA results ascertained that overexpression of P-gp in subclones was not only regulated by MDR1. The linear correlation between RI and logarithm-transformed P-gp expression was moderate or high and statistically significantly different in subclones, except for SMMC-7721/ADMs. The present study is the first to demonstrate the quantitative relationship between RI and P-gp expression by linear regression modeling and expanded the number of efflux transporters related to MDR quantifiable by LC-MS/MS to better understand the biological significance of effluent transporter expression. Copyright © 2018 Elsevier B.V. All rights reserved.

Comparison of different modeling approaches to better evaluate greenhouse gas emissions from whole wastewater treatment plants.

PubMed

Corominas, Lluís; Flores-Alsina, Xavier; Snip, Laura; Vanrolleghem, Peter A

2012-11-01

New tools are being developed to estimate greenhouse gas (GHG) emissions from wastewater treatment plants (WWTPs). There is a trend to move from empirical factors to simple comprehensive and more complex process-based models. Thus, the main objective of this study is to demonstrate the importance of using process-based dynamic models to better evaluate GHG emissions. This is tackled by defining a virtual case study based on the whole plant Benchmark Simulation Model Platform No. 2 (BSM2) and estimating GHG emissions using two approaches: (1) a combination of simple comprehensive models based on empirical assumptions and (2) a more sophisticated approach, which describes the mechanistic production of nitrous oxide (N(2) O) in the biological reactor (ASMN) and the generation of carbon dioxide (CO(2) ) and methane (CH(4) ) from the Anaerobic Digestion Model 1 (ADM1). Models already presented in literature are used, but modifications compared to the previously published ASMN model have been made. Also model interfaces between the ASMN and the ADM1 models have been developed. The results show that the use of the different approaches leads to significant differences in the N(2) O emissions (a factor of 3) but not in the CH(4) emissions (about 4%). Estimations of GHG emissions are also compared for steady-state and dynamic simulations. Averaged values for GHG emissions obtained with steady-state and dynamic simulations are rather similar. However, when looking at the dynamics of N(2) O emissions, large variability (3-6 ton CO(2) e day(-1) ) is observed due to changes in the influent wastewater C/N ratio and temperature which would not be captured by a steady-state analysis (4.4 ton CO(2) e day(-1) ). Finally, this study also shows the effect of changing the anaerobic digestion volume on the total GHG emissions. Decreasing the anaerobic digester volume resulted in a slight reduction in CH(4) emissions (about 5%), but significantly decreased N(2) O emissions in the water line (by 14%). Copyright © 2012 Wiley Periodicals, Inc.

Semisynthesis, Characterization and Evaluation of New Adenosine Derivatives as Antiproliferative Agents.

PubMed

Valdés Zurita, Francisco; Brown Vega, Nelson; Gutiérrez Cabrera, Margarita

2018-05-08

We describe the semisynthesis and biological effects of adenosine derivatives, which were anticipated to function as agonists for the A₃ receptor. Molecular docking was used to select candidate compounds. Fifteen nucleoside derivatives were obtained through nucleophilic substitutions of the N ⁶-position of the nucleoside precursor 6-chloropurine riboside by amines of different origin. All compounds were purified by column chromatography and further characterized by spectroscopic and spectrometric techniques, showing moderate yield. These molecules were then evaluated for their antiproliferative activity in human gastric cancer cells expressing the A₃ receptor. We found that the compounds obtained have antiproliferative activity and that new structural modifications can enhance their biological activity. The ADME (Absorption, Distribution, Metabolism and Excretion) properties of the most active compounds were also evaluated theoretically.

A virtual university Web system for a medical school.

PubMed

Séka, L P; Duvauferrier, R; Fresnel, A; Le Beux, P

1998-01-01

This paper describes a Virtual Medical University Web Server. This project started in 1994 by the development of the French Radiology Server. The main objective of our Medical Virtual University is to offer not only an initial training (for students) but also the Continuing Professional Education (for practitioners). Our system is based on electronic textbooks, clinical cases (around 4000) and a medical knowledge base called A.D.M. ("Aide au Diagnostic Medical"). We have indexed all electronic textbooks and clinical cases according to the ADM base in order to facilitate the navigation on the system. This system base is supported by a relational database management system. The Virtual Medical University, available on the Web Internet, is presently in the process of external evaluations.

Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa

PubMed Central

Manda, Vamshi K.; Avula, Bharathi; Ali, Zulfiqar; Wong, Yan-Hong; Smillie, Troy J.; Khan, Ikhlas A.; Khan, Shabana I.

2017-01-01

Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women’s health as well as to treat inflammation, muscle spasm, and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9, and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8), and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3% in SGF and 12.4% in SIF, which could be accounted for by its conversion to diosgenin (24.2%. in SGF and 2.4% in SIF). The depletion of diosgenin in SGF and SIF was < 10%. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux, while diosgenin was subjected to efflux mediated by P-glycoprotein. Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 17 and 33 μM, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism. PMID:23970424

Review: Hamiltonian Linearization of the Rest-Frame Instant Form of Tetrad Gravity in a Completely Fixed 3-Orthogonal Gauge: A Radiation Gauge for Background-Independent Gravitational Waves in a Post-Minkowskian Einstein Spacetime

NASA Astrophysics Data System (ADS)

Agresti, Juri; De Pietri, Roberto; Lusanna, Luca; Martucci, Luca

2004-05-01

In the framework of the rest-frame instant form of tetrad gravity, where the Hamiltonian is the weak ADM energy {\\hat E}ADM, we define a special completely fixed 3-orthogonal Hamiltonian gauge, corresponding to a choice of non-harmonic 4-coordinates, in which the independent degrees of freedom of the gravitational field are described by two pairs of canonically conjugate Dirac observables (DO) r_{\\bar a}(\\tau ,\\vec \\sigma ), \\pi_{\\bar a}(\\tau ,\\vec \\sigma ), \\bar a = 1,2. We define a Hamiltonian linearization of the theory, i.e. gravitational waves, without introducing any background 4-metric, by retaining only the linear terms in the DO's in the super-hamiltonian constraint (the Lichnerowicz equation for the conformal factor of the 3-metric) and the quadratic terms in the DO's in {\\hat E}ADM. We solve all the constraints of the linearized theory: this amounts to work in a well defined post-Minkowskian Christodoulou-Klainermann space-time. The Hamilton equations imply the wave equation for the DO's r_{\\bar a}(\\tau ,\\vec \\sigma ), which replace the two polarizations of the TT harmonic gauge, and that linearized Einstein's equations are satisfied. Finally we study the geodesic equation, both for time-like and null geodesics, and the geodesic deviation equation.

PEGylated graphene oxide-mediated quercetin-modified collagen hybrid scaffold for enhancement of MSCs differentiation potential and diabetic wound healing.

PubMed

Chu, Jing; Shi, Panpan; Yan, Wenxia; Fu, Jinping; Yang, Zhi; He, Chengmin; Deng, Xiaoyuan; Liu, Hanping

2018-05-24

Nanoscale delivery based on polyethylene glycol (PEG)ylated graphene oxide (GO-PEG) merits attention for biomedical applications owing to its functional surface modification, superior solubility/biocompatibility and controllable drug release capability. However, impaired skin regeneration in applications of these fascinating nanomaterials in diabetes is still limited, and critical issues need to be addressed regarding insufficient collagen hyperplasia and inadequate blood supply. Therefore, a high-performance tissue engineering scaffold with biocompatible and biodegradable properties is essential for diabetic wound healing. Natural and artificial acellular dermal matrix (ADM) scaffolds with spatially organized collagen fibers can provide a suitable architecture and environment for cell attachment and proliferation. Here, a novel collagen-nanomaterial-drug hybrid scaffold was constructed from GO-PEG-mediated quercetin (GO-PEG/Que)-modified ADM (ADM-GO-PEG/Que). The resulting unique and versatile hybrid scaffold exhibited multiple advantages, including the following: a biocompatible, cell-adhesive surface for accelerating mesenchymal stem cell (MSC) attachment and proliferation; superior stability and adjustability of the conduction potential of quercetin for inducing the differentiation of MSCs into adipocytes and osteoblasts; and a biodegradable nanofiber interface for promoting collagen deposition and angiogenesis in diabetic wound repair. This study provides new prospects for the design of innovative GO-PEG-based collagen hybrid scaffolds for application in efficient therapeutic drug delivery, stem cell-based therapies, tissue engineering and regenerative medicine.

Network pharmacology-based prediction of active compounds and molecular targets in Yijin-Tang acting on hyperlipidaemia and atherosclerosis.

PubMed

Lee, A Yeong; Park, Won; Kang, Tae-Wook; Cha, Min Ho; Chun, Jin Mi

2018-07-15

Yijin-Tang (YJT) is a traditional prescription for the treatment of hyperlipidaemia, atherosclerosis and other ailments related to dampness phlegm, a typical pathological symptom of abnormal body fluid metabolism in Traditional Korean Medicine. However, a holistic network pharmacology approach to understanding the therapeutic mechanisms underlying hyperlipidaemia and atherosclerosis has not been pursued. To examine the network pharmacological potential effects of YJT on hyperlipidaemia and atherosclerosis, we analysed components, performed target prediction and network analysis, and investigated interacting pathways using a network pharmacology approach. Information on compounds in herbal medicines was obtained from public databases, and oral bioavailability and drug-likeness was screened using absorption, distribution, metabolism, and excretion (ADME) criteria. Correlations between compounds and genes were linked using the STITCH database, and genes related to hyperlipidaemia and atherosclerosis were gathered using the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Network analysis identified 447 compounds in five herbal medicines that were subjected to ADME screening, and 21 compounds and 57 genes formed the main pathways linked to hyperlipidaemia and atherosclerosis. Among them, 10 compounds (naringenin, nobiletin, hesperidin, galangin, glycyrrhizin, homogentisic acid, stigmasterol, 6-gingerol, quercetin and glabridin) were linked to more than four genes, and are bioactive compounds and key chemicals. Core genes in this network were CASP3, CYP1A1, CYP1A2, MMP2 and MMP9. The compound-target gene network revealed close interactions between multiple components and multiple targets, and facilitates a better understanding of the potential therapeutic effects of YJT. Pharmacological network analysis can help to explain the potential effects of YJT for treating dampness phlegm-related diseases such as hyperlipidaemia and atherosclerosis. Copyright © 2018 Elsevier B.V. All rights reserved.

32 CFR 191.6 - Procedures.

Code of Federal Regulations, 2010 CFR

2010-07-01

... include Dr. Martin Luther King Jr.'s Birthday, Black History Month, National Women's History Week, Women's... Council on Accessible Technology in accordance with General Services Administration Order ADM 5420.71A...

A genetic variant in the gene encoding adrenomedullin predicts the development of dysglycemia over 6.4 years in Chinese.

PubMed

Ong, Kwok Leung; Tso, Annette W K; Leung, Raymond Y H; Cherny, Stacey S; Sham, Pak Chung; Lam, Tai Hing; Cheung, Bernard M Y; Lam, Karen S L

2011-01-30

Adrenomedullin, a vasodilatory peptide, facilitates the differentiation of pre-adipocytes, and affects lipolysis and glucose uptake. We investigated the association of common single nucleotide polymorphisms (SNPs) in the gene encoding adrenomedullin (ADM) with dysglycemia in the Hong Kong Chinese population. Four SNPs were genotyped in 1391 subjects without dysglycemia at baseline from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, which had a median follow-up time of 6.4 years. Dysglycemia included impaired fasting glucose, impaired glucose tolerance, and diabetes according to the WHO 1998 criteria. At follow-up, 382 subjects had developed dysglycemia. In stepwise logistic regression, the SNP rs11042725 was a significant independent predictor of the development of dysglycemia (OR=1.31, P=0.012), together with baseline age (P<0.001), plasma triglycerides (P<0.001), body mass index (P=0.004), 2-h glucose after oral glucose tolerance test (P<0.001), homeostasis model assessment of insulin resistance index (P=0.045), and follow-up duration (P=0.009). The association was more significant in women (P=0.002) and in subjects without regular exercise (P=0.001). Our study suggests a potential role of genetic variants in the ADM gene in the development of dysglycemia in our local Chinese population. Copyright © 2010 Elsevier B.V. All rights reserved.

The Of?p stars of the Magellanic Clouds: Are they strongly magnetic?

NASA Astrophysics Data System (ADS)

Munoz, M.; Wade, G. A.; Nazé, Y.; Bagnulo, S.; Puls, J.

2018-01-01

All known Galactic Of?p stars have been shown to host strong, organized, magnetic fields. Recently, five Of?p stars have been discovered in the Magellanic Clouds. They posses photometric (Nazé et al., 2015) and spectroscopic (Walborn et al., 2015) variability compatible with the Oblique Rotator Model (ORM). However, their magnetic fields have yet to be directly detected. We have developed an algorithm allowing for the synthesis of photometric observables based on the Analytic Dynamical Magnetosphere (ADM) model by Owocki et al. (2016). We apply our model to OGLE photometry in order to constrain their magnetic geometries and surface dipole strengths. We predict that the field strengths for some of theses candidate extra-Galactic magnetic stars may be within the detection limits of the FORS2 instrument

Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

PubMed Central

2013-01-01

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. PMID:24900709

How drug-like are 'ugly' drugs: do drug-likeness metrics predict ADME behaviour in humans?

PubMed

Ritchie, Timothy J; Macdonald, Simon J F

2014-04-01

Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring drugs were compared to determine how well the score correlated with their actual pharmaceutical and pharmacokinetic (PK) profiles in humans. Drugs with high QED scores exhibit higher absorption and bioavailability, are administered at lower doses and have fewer drug-drug interaction warnings, P-glycoprotein interactions and absorption issues due to a food effect. By contrast, the high-scoring drugs exhibit similar behaviour to low-scoring drugs with respect to free fraction in plasma, extent of gut-wall metabolism, first-pass hepatic extraction, elimination half-life, clearance, volume of distribution and frequency of dosing. Copyright © 2014 Elsevier Ltd. All rights reserved.

eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells

PubMed Central

Yeh, Johannes T.-H.; Nam, Kwangho; Yeh, Joshua T.-H.; Perrimon, Norbert

2017-01-01

The absorption, distribution, metabolism and excretion (ADME) of metabolites and toxic organic solutes are orchestrated by the ATP-binding cassette (ABC) transporters and the organic solute carrier family (SLC) proteins. A large number of ABC and SLC transpoters exist; however, only a small number have been well characterized. To facilitate the analysis of these transporters, which is important for drug safety and physiological studies, we developed a sensitive genetically encoded bilirubin (BR)-inducible fluorescence sensor (eUnaG) to detect transporter-coupled influx/efflux of organic compounds. This sensor can be used in live cells to measure transporter activity, as excretion of BR depends on ABC and SLC transporters. Applying eUnaG in functional RNAi screens, we characterize l(2)03659 as a Drosophila multidrug resistant-associated ABC transporter. PMID:28176814