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Sample records for vivo direct correlation

  1. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control.

    Directory of Open Access Journals (Sweden)

    Adam R Hersperger

    2010-05-01

    Full Text Available Many immune correlates of CD8(+ T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8(+ T-cells to rapidly upregulate perforin--an essential molecule for cell-mediated cytotoxicity--following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35, viremic controllers (n = 29, chronic progressors (n = 27, and viremic nonprogressors (n = 6. Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8(+ T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8(+ T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8(+ T-cells to rapidly express perforin defines a novel correlate of control in HIV infection.

  2. Anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: direct correlation between reduction of established metastases and cytolytic activity of lymphokine-activated killer cells

    International Nuclear Information System (INIS)

    Mule, J.J.; Yang, J.; Shu, S.; Rosenberg, S.A.

    1986-01-01

    Our previous studies demonstrated that the incubation of human peripheral blood lymphocytes or murine splenocytes in recombinant interleukin 2 (RIL 2) resulted in the generation of lymphokine-activated killer (LAK) cells capable of lysing a broad spectrum of fresh tumors in short-term chromium-release assays. Moreover, injections of LAK cells plus RIL 2 were highly effective in eliminating established 3 day metastases in the lung and liver. We have examined several parameters to define whether or not the cytolytic activity of LAK cells as measured in vitro correlated directly with the in vivo anti-tumor efficacy of adoptively transferred LAK cells. LAK cells plus RIL 2 could mediate marked reductions of established pulmonary metastases in mice rendered T cell deficient by adult thymectomy and lethal, total body irradiation followed by reconstitution with T cell-depleted bone marrow and spleen cells. Thus there was no requirement for additional T lymphocytes of host origin for successful therapy with adoptively transferred LAK cells plus RIL 2. Fresh splenocytes depleted of T cells by anti-Thy-1.2 monoclonal antibody plus complement generated LAK cells that were as highly lytic to fresh tumor in vitro and were as effective in reducing established pulmonary metastases as those generated from untreated or complement-treated splenocytes. Thus, the precursor to LAK cells with anti-tumor activity in vitro and in vivo did not express the Thy-1 antigenic marker. In contrast, treatment of LAK effector cells (those generated from a 3-day incubation of fresh, normal splenocytes in RIL 2) with anti-Thy-1.2 antibody plus complement reduced or abolished their in vitro cytolytic activity

  3. High precision studies of directional correlations

    International Nuclear Information System (INIS)

    El-khosht, M.

    1980-01-01

    Two applications of the method of directional correlations are described. The first part deals with gamma-gamma directional correlations measurements. A total of 27 cascades have been studied in 97 Tc, 206 Pb and 206 Bi. Information is obtained on the angular momenta of levels, multipolarities of electromagnetic transitions and further, reduced transition probabilities. The later part of this thesis describes a determination of anisotropic directional correlation between gamma-rays and LX-rays in 160 Dy. To the authors' knowledge this is the first observation of an anisotropic correlation between gamma rays and X-rays following internal conversion. (Auth.)

  4. In vitro-in vivo correlation in skin permeation.

    Science.gov (United States)

    Mohammed, D; Matts, P J; Hadgraft, J; Lane, M E

    2014-02-01

    In vitro skin permeation studies have been used extensively in the development and optimisation of delivery of actives in vivo. However, there are few reported correlations of such in vitro studies with in vivo data. The aim of this study was to investigate the skin permeation of a model active, niacinamide, both in vitro and in vivo. Conventional diffusion cell studies were conducted in human skin to determine niacinamide permeation from a range of vehicles which included dimethyl isosorbide (DMI), propylene glycol (PG), propylene glycol monolaurate (PGML), N-methyl 2-pyrrolidone (NMP), Miglyol 812N® (MG), and mineral oil (MO). Single, binary or ternary systems were examined. The same vehicles were subsequently examined to investigate niacinamide delivery in vivo. For this proof-of-concept study one donor was used for the in vitro studies and one volunteer for the in vivo investigations to minimise biovariability. Analysis of in vitro samples was conducted using HPLC and in vivo uptake of niacinamide was evaluated using Confocal Raman spectroscopy (CRS). The amount of niacinamide permeated through skin in vitro was linearly proportional to the intensity of the niacinamide signal determined in the stratum corneum in vivo. A good correlation was observed between the signal intensities of selected vehicles and niacinamide signal intensity. The findings provide further support for the use of CRS to monitor drug delivery into and across the skin. In addition, the results highlight the critical role of the vehicle and its disposition in skin for effective dermal delivery.

  5. Temporal correlation coefficient for directed networks.

    Science.gov (United States)

    Büttner, Kathrin; Salau, Jennifer; Krieter, Joachim

    2016-01-01

    Previous studies dealing with network theory focused mainly on the static aggregation of edges over specific time window lengths. Thus, most of the dynamic information gets lost. To assess the quality of such a static aggregation the temporal correlation coefficient can be calculated. It measures the overall possibility for an edge to persist between two consecutive snapshots. Up to now, this measure is only defined for undirected networks. Therefore, we introduce the adaption of the temporal correlation coefficient to directed networks. This new methodology enables the distinction between ingoing and outgoing edges. Besides a small example network presenting the single calculation steps, we also calculated the proposed measurements for a real pig trade network to emphasize the importance of considering the edge direction. The farm types at the beginning of the pork supply chain showed clearly higher values for the outgoing temporal correlation coefficient compared to the farm types at the end of the pork supply chain. These farm types showed higher values for the ingoing temporal correlation coefficient. The temporal correlation coefficient is a valuable tool to understand the structural dynamics of these systems, as it assesses the consistency of the edge configuration. The adaption of this measure for directed networks may help to preserve meaningful additional information about the investigated network that might get lost if the edge directions are ignored.

  6. Electron-gamma directional correlations; Correlations directionnelles electron-gamma

    Energy Technology Data Exchange (ETDEWEB)

    Gerholm, T R [Commissariat a l' Energie Atomique, Centre d' Etudes Nucleaires de Saclay, 91 - Gif-sur-Yvette (France)

    1966-10-01

    of internal conversion process containing the dynamic effects appears to be coherent and well understood. The penetration matrix effects can then be used as independent and complementary sources of information for the study of problems on nuclear structure. (author) [French] Dans le premier chapitre, l'auteur demontre l'interet des correlations angulaires electrons de conversion-gamma en spectrometric nucleaire et souligne la presence ''d'elements de matrice de penetration'' et l'importance de corrections ''dynamiques'', causees par la dimension finie du noyau. Dans le chapitre 2, l'auteur expose les methodes experimentales pour l'etude de la correlation electron-gamma. Une etude comparative est faite entre la correlation angulaire electron de conversion-gamma et la correlation angulaire gamma-gamma. Il est demontre qu'une mesure simultanee de ces deux fonctions de correlation permet d'eliminer les facteurs d'attenuations dus a l'action des champs extranucleaires. Une etude complete de ces champs est menee dans le chapitre 3 avec, principalement, la mise en evidence des effets ''de trou'' correspondant a une interaction de structure hyperfine entre le spin du noyau et celui de son atome. Pour une periode du niveau intermediaire de l'ordre de la nanoseconde, les attenuations creees par la formation de trou ne peuvent pas etre negligees, chaque fois que les atomes radioactifs sont inclus dans un milieu isolant. Les experiences permettant la determination des coefficients b{sub 2}(E{sub 2}) et {alpha}{sub K}(E{sub 2}) du {sup 198}Hg sont decrits chapitre 4. Dans le chapitre 5, l'auteur applique la determination des elements de matrice de penetration dans le processus de conversion M{sub 1} a l'etude des problemes sur la structure nucleaire. Dans le chapitre 6 sont decrites des experiences mettant en evidence le mode de transition E{sub 0} en competition directe avec la conversion interne M{sub 1} et E{sub 2}. (auteur)

  7. Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: I. Principles and some general algorithms.

    Science.gov (United States)

    Langenbucher, Frieder

    2002-01-01

    Most computations in the field of in vitro/in vivo correlations can be handled directly by Excel worksheets, without the need for specialized software. Following a summary of Excel features, applications are illustrated for numerical computation of AUC and Mean, Wagner-Nelson and Loo-Riegelman absorption plots, and polyexponential curve fitting.

  8. The correlation of in vivo and ex vivo tissue dielectric properties to validate electromagnetic breast imaging: initial clinical experience

    International Nuclear Information System (INIS)

    Halter, Ryan J; Zhou, Tian; Meaney, Paul M; Hartov, Alex; Barth, Richard J Jr; Rosenkranz, Kari M; Wells, Wendy A; Kogel, Christine A; Borsic, Andrea; Rizzo, Elizabeth J; Paulsen, Keith D

    2009-01-01

    Electromagnetic (EM) breast imaging provides low-cost, safe and potentially a more specific modality for cancer detection than conventional imaging systems. A primary difficulty in validating these EM imaging modalities is that the true dielectric property values of the particular breast being imaged are not readily available on an individual subject basis. Here, we describe our initial experience in seeking to correlate tomographic EM imaging studies with discrete point spectroscopy measurements of the dielectric properties of breast tissue. The protocol we have developed involves measurement of in vivo tissue properties during partial and full mastectomy procedures in the operating room (OR) followed by ex vivo tissue property recordings in the same locations in the excised tissue specimens in the pathology laboratory immediately after resection. We have successfully applied all of the elements of this validation protocol in a series of six women with cancer diagnoses. Conductivity and permittivity gauged from ex vivo samples over the frequency range 100 Hz–8.5 GHz are found to be similar to those reported in the literature. A decrease in both conductivity and permittivity is observed when these properties are gauged from ex vivo samples instead of in vivo. We present these results in addition to a case study demonstrating how discrete point spectroscopy measurements of the tissue can be correlated and used to validate EM imaging studies

  9. Lifetime information from correlation functions selected by directional cuts

    International Nuclear Information System (INIS)

    Gelbke, C.K.

    1995-01-01

    Two-particle correlation functions provide information on the space-time characteristics of the emitting source. In many cases, ambiguities of the relative magnitudes of source radius and lifetime can be reduced by analysis of correlation functions evaluated for specific directional cuts on the relative velocity of the coincident particle pair. Information on non-spherical breakup geometries is more difficult to extract. Examples of two-proton correlation functions in which directional cuts are employed to reduce existing space-time ambiguities for the emitting system are presented. (author). 50 refs., 10 figs

  10. Correlation between the dielectric properties and biological activities of human ex vivo hepatic tissue

    International Nuclear Information System (INIS)

    Wang, Hang; You, Fusheng; Fu, Feng; Dong, Xiuzhen; Shi, Xuetao; He, Yong; Yang, Min; Yan, Qingguo

    2015-01-01

    Dielectric properties are vital biophysical features of biological tissues, and biological activity is an index to ascertain the active state of tissues. This study investigated the potential correlation between the dielectric properties and biological activities of human hepatic tissue with prolonged ex vivo time through correlation and regression analyses. The dielectric properties of 26 cases of normal human hepatic tissue at 10 Hz to 100 MHz were measured from 15 min after isolation to 24 h at 37 °C with 90% humidity. Cell morphologies, including nucleus area (NA) and alteration rate of intercellular area (ICAR), were analyzed as indicators of biological activities. Conductivity, complex resistivity, and NA exhibited opposing changes 1 h after isolation. Relative permittivity and ex vivo time were not closely correlated (p > 0.05). The dielectric properties measured at low frequencies (i.e. <1 MHz) were more sensitive than those measured at high frequencies in reflecting the biological activity of ex vivo tissue. Highly significant correlations were found between conductivity, resistivity and the ex vivo time (p < 0.05) as well as conductivity and the cell morphology (p < 0.05). The findings indicated that establishing the correlation between the dielectric properties and biological activities of human hepatic tissue is of great significance for promoting the role of dielectric properties in biological science, particularly in human biology. (paper)

  11. Direct detection and quantification of abasic sites for in vivo studies of DNA damage and repair

    International Nuclear Information System (INIS)

    Wang Yanming; Liu Lili; Wu Chunying; Bulgar, Alina; Somoza, Eduardo; Zhu Wenxia; Gerson, Stanton L.

    2009-01-01

    Use of chemotherapeutic agents to induce cytotoxic DNA damage and programmed cell death is a key strategy in cancer treatments. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway resulted in formation of abasic or apurinic/apyrimidinic (AP) sites, and blockage of AP sites led to a significant enhancement of drug sensitivity due to reduction of DNA base excision repair. Since a number of chemotherapeutic agents also induce formation of AP sites, monitoring of these sites as a clinical correlate of drug effect will provide a useful tool in the development of DNA-targeted chemotherapies aimed at blocking abasic sites from repair. Here we report an imaging technique based on positron emission tomography (PET) that allows for direct quantification of AP sites in vivo. For this purpose, positron-emitting carbon-11 has been incorporated into methoxyamine ([ 11 C]MX) that binds covalently to AP sites with high specificity. The binding specificity of [ 11 C]MX for AP sites was demonstrated by in vivo blocking experiments. Using [ 11 C]MX as a radiotracer, animal PET studies have been conducted in melanoma and glioma xenografts for quantification of AP sites. Following induction of AP sites by temozolomide, both tumor models showed significant increase of [ 11 C]MX uptake in tumor regions in terms of radioactivity concentration as a function of time, which correlates well with conventional aldehyde reactive probe (ARP)-based bioassays for AP sites.

  12. Histologic correlation of in vivo optical coherence tomography images of the human retina

    NARCIS (Netherlands)

    Chen, T.; Cense, B.; Miller, J.S.; Rubin, P. A. D.; Deschler, D. G.; Gragoudas, E. S.; de Boer, J.F.

    2006-01-01

    Purpose: To correlate in vivo human retina optical coherence tomography (OCT)3 images with histology. Design: Case series. Methods: Linear OCT3 scans through the macula and optic nerve were obtained in three eyes of three patients who then underwent exenteration surgery for orbital cancers. OCT3

  13. Personality Correlates of Self-Report, Role-Playing, and In Vivo Measures of Assertiveness.

    Science.gov (United States)

    Green, Samuel B.; And Others

    1979-01-01

    Undergraduates completed self-report inventories of assertiveness, participated in behavior role-playing tasks and in vivo measures of assertiveness, and completed the Personality Research Form E (PRF-E). Of 22 PRF-E scales, 11 had at least one significant correlation with assertiveness measures. Some composites of PRF-E scales were related to…

  14. Direct comparison of in vivo versus postmortem second-order motion-compensated cardiac diffusion tensor imaging.

    Science.gov (United States)

    Stoeck, Christian T; von Deuster, Constantin; Fleischmann, Thea; Lipiski, Miriam; Cesarovic, Nikola; Kozerke, Sebastian

    2018-04-01

    To directly compare in vivo versus postmortem second-order motion-compensated spin-echo diffusion tensor imaging of the porcine heart. Second-order motion-compensated spin-echo cardiac diffusion tensor imaging was performed during systolic contraction in vivo and repeated upon cardiac arrest by bariumchloride without repositioning of the study animal or replaning of imaging slices. In vivo and postmortem reproducibility was assessed by repeat measurements. Comparison of helix, transverse, and sheet (E2A) angulation as well as mean diffusivity and fractional anisotropy was performed. Intraclass correlation coefficients for repeated measurements (postmortem/in vivo) were 0.95/0.96 for helix, 0.70/0.66 for transverse, and 0.79/0.72 for E2A angulation; 0.83/0.72 for mean diffusivity; and 0.78/0.76 for fractional anisotropy. The corresponding 95% levels of agreement across the left ventricle were: helix 14 to 18°/12 to 15°, transverse 9 to 10°/10 to 11°, E2A 15 to 20°/16 to 18°. The 95% levels of agreement across the left ventricle for the comparison of postmortem versus in vivo were 20 to 22° for helix, 13 to 19° for transverse, and 24 to 31° for E2A angulation. Parameters derived from in vivo second-order motion-compensated spin-echo diffusion tensor imaging agreed well with postmortem imaging, indicating sufficient suppression of motion-induced signal distortions of in vivo cardiac diffusion tensor imaging. Magn Reson Med 79:2265-2276, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  15. Correlation of the Auger electrons direction of movement with the internal electron conversion direction of movement

    International Nuclear Information System (INIS)

    Mitrokhovich, N.F.; Kupryashkin, V.T.; Sidorenko, L.P.

    2013-01-01

    On installation of coincidences of γ-quanta with electrons and with law energy electrons about zero area the spatial correlation of the direction emitting Auger-electrons and electron of internal conversion was investigated at the 152 Eu decay. Auger-electrons were registered on e 0 -electrons of the secondary electron emission (γ e IC e 0 -coincidences). It was established, that Auger-electrons of M-series, as well as electrons 'shake-off' at β-decay and internal conversion, are strongly correlated at the direction of movement with the direction of movement of basic particle (β -particle, conversion electron), moving together mainly in the forward hemisphere. The intensity of correlated M-Auger radiation in range energy 1000 - 1700 eV is equal to intensity of correlated radiation 'shake-off' electron from internal conversion in this range. The assumption, that the presence of spatial correlating Auger-electron and conversion electron caused by cur-rent components of electron-electron interaction of particles in the final state is made

  16. Gastric ulcer localization by direct in vivo labeling of sucralfate: work in progress

    Energy Technology Data Exchange (ETDEWEB)

    Pera, A.; Seevers, R.H.; Meyer, K.; Hall, C.; Bekerman, C.; Anderson, T.M.; Katzen, H.; Laakso, L.; Pinsky, S.M.

    1985-09-01

    The authors developed and evaluated a new procedure for imaging gastric ulcer disease with technetium 99m - labeled sucralfate. The new method employs direct in vivo labeling of sucralfate instead of in vitro labeling using human serum albumin, as previously reported in the literature. In 26 studies using humans with sucralfate labeled directly in vivo, 15 gave true-negative results. Of 14 studies using humans with in vitro labeled sucralfate, three gave true-negative results, three gave true-positive results, and the results of eight were either false-negative or could not be interpreted because of high levels of activity remaining in the stomach. They suggest that the direct in vivo labeling method significantly improves the sucralfate gastric ulcer imaging technique.

  17. Gastric ulcer localization by direct in vivo labeling of sucralfate: work in progress

    International Nuclear Information System (INIS)

    Pera, A.; Seevers, R.H.; Meyer, K.; Hall, C.; Bekerman, C.; Anderson, T.M.; Katzen, H.; Laakso, L.; Pinsky, S.M.

    1985-01-01

    The authors developed and evaluated a new procedure for imaging gastric ulcer disease with technetium 99m - labeled sucralfate. The new method employs direct in vivo labeling of sucralfate instead of in vitro labeling using human serum albumin, as previously reported in the literature. In 26 studies using humans with sucralfate labeled directly in vivo, 15 gave true-negative results. Of 14 studies using humans with in vitro labeled sucralfate, three gave true-negative results, three gave true-positive results, and the results of eight were either false-negative or could not be interpreted because of high levels of activity remaining in the stomach. They suggest that the direct in vivo labeling method significantly improves the sucralfate gastric ulcer imaging technique

  18. In vitro and in vivo suppository studies with perturbed angular correlation and external scintigraphy

    International Nuclear Information System (INIS)

    Jay, M.; Beihn, R.M.; Snyder, G.A.; McClanahan, J.S.; Digenis, G.A.; Caldwell, L.; Mlodozeniec, A.

    1983-01-01

    Recently, there has been an increased interest in the rectal delivery of drugs as an alternative to parenteral administration. Because of their complexity, little is known about the release behavior of drugs from suppositories in vivo, and the universal applicability of most in vitro tests developed to date awaits broad acceptance. A novel technique has recently been utilized for the measurement of both in vitro and in vivo dissolution profiles of solid oral dosage forms. This technique, known as perturbed angular correlation (PAC), utilizes the property of cascading decay exhibited by indium-111. The authors now wish to report on the application of this technique for in vitro studies measuring the dissolution of an [ 111 In]salicylate coprecipitate incorporated in a suppository base. The PAC technique was also used in combination with external scintigraphic techniques for the in vivo measurement of the deformation and liquefaction of a suppository containing 111 In in humans in a totally non-invasive manner. (Auth.)

  19. In vitro and in vivo suppository studies with perturbed angular correlation and external scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Jay, M.; Beihn, R.M.; Snyder, G.A.; McClanahan, J.S.; Digenis, G.A. (Kentucky Univ., Lexington (USA). College of Pharmacy and Medicine); Caldwell, L.; Mlodozeniec, A. (INTER Research Corporation, Lawrence, KS (USA). Merck, Sharp and Dohme Research Laboratories)

    1983-04-01

    Recently, there has been an increased interest in the rectal delivery of drugs as an alternative to parenteral administration. Because of their complexity, little is known about the release behavior of drugs from suppositories in vivo, and the universal applicability of most in vitro tests developed to date awaits broad acceptance. A novel technique has recently been utilized for the measurement of both in vitro and in vivo dissolution profiles of solid oral dosage forms. This technique, known as perturbed angular correlation (PAC), utilizes the property of cascading decay exhibited by indium-111. The authors now wish to report on the application of this technique for in vitro studies measuring the dissolution of an (/sup 111/In)salicylate coprecipitate incorporated in a suppository base. The PAC technique was also used in combination with external scintigraphic techniques for the in vivo measurement of the deformation and liquefaction of a suppository containing /sup 111/In in humans in a totally non-invasive manner.

  20. Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

    Directory of Open Access Journals (Sweden)

    Brian C. Wilson

    2015-01-01

    Full Text Available Excited-state singlet oxygen (1O2, generated during photodynamic therapy (PDT, is believed to be the primary cytotoxic agent with a number of clinically approved photosensitizers. Its relative concentration in cells or tissues can be measured directly through its near-infrared (NIR luminescence emission, which has correlated well with in vitro cell and in vivo normal skin treatment responses. Here, its correlation with the response of tumor tissue in vivo is examined, using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC in an animal model comprising luciferase- and green fluorescent protein (GFP-transduced gliosarcoma grown in a dorsal window chamber. The change in the bioluminescence signal, imaged pretreatment and at 2, 5 and 9 d post treatment, was used as a quantitative measure of the tumor response, which was classified in individual tumors as "non", "moderate" and "strong" in order to reduce the variance in the data. Plotting the bioluminescence-based response vs the 1O2 counts demonstrated clear correlation, indicating that 1O2 luminescence provides a valid dosimetric technique for PDT in tumor tissue.

  1. Correlation of total, diffuse, and direct solar radiation

    Science.gov (United States)

    Buyco, E. H.; Namkoong, D.

    1977-01-01

    Present requirements for realistic solar energy system evaluations necessitate a comprehensive body of solar-radition data. The data should include both diffuse and direct solar radiation as well as their total on an hourly (or shorter) basis. In general, however, only the total solar radiation values were recorded. This report presents a correlation that relates the diffuse component of an hourly total solar radiation value to the total radiation ratio of the maximum value attainable. The data used were taken at the Blue Hill Observatory in Milton, Massachusetts, for the period 1952. The relation - in the form of the data plots - can be used in situations in which only the hourly total radiation data are available but the diffuse component is desired.

  2. Development of andrographolide loaded PLGA microspheres: optimization, characterization and in vitro-in vivo correlation.

    Science.gov (United States)

    Jiang, Yunxia; Wang, Fang; Xu, Hui; Liu, Hui; Meng, Qingguo; Liu, Wanhui

    2014-11-20

    The purpose of this study was to develop a sustained-release drug delivery system based on the injectable PLGA microspheres loaded with andrographolide. The andrographolide loaded PLGA microspheres were prepared by emulsion solvent evaporation method with optimization of formulation using response surface methodology (RSM). Physicochemical characterization, in vitro release behavior and in vivo pharmacokinetics of the optimized formulation were then evaluated. The percent absorbed in vivo was determined by deconvolution using the Loo-Riegelman method, and then the in vitro-in vivo correlation (IVIVC) was established. Results showed that the microspheres were spherical with a smooth surface. Average particle size, entrapment efficiency and drug loading were found to be 53.18±2.11 μm, 75.79±3.02% and 47.06±2.18%, respectively. In vitro release study showed a low initial burst release followed by a prolonged release up to 9 days and the release kinetics followed the Korsmeyer-Peppas model. After a single intramuscular injection, the microspheres maintained relatively high plasma concentration of andrographolide over one week. A good linear relationship was observed between the in vitro and in vivo release behavior (R(2)=0.9951). These results suggest the PLGA microspheres could be developed as a potential delivery system for andrographolide with high drug loading capacity and sustained drug release. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Applications of the direct photon absorption technique for measuring bone mineral content in vivo. Determination of body composition in vivo

    Science.gov (United States)

    Cameron, J. R.

    1972-01-01

    The bone mineral content, BMC, determined by monoenergetic photon absorption technique, of 29 different locations on the long bones and vertebral columns of 24 skeletons was measured. Compressive tests were made on bone from these locations in which the maximum load and maximum stress were measured. Also the ultimate strain, modulus of elasticity and energy absorbed to failure were determined for compact bone from the femoral diaphysis and cancellous bone from the eighth through eleventh thoracic vertebrae. Correlations and predictive relationships between these parameters were examined to investigate the applicability of using the BMC at sites normally measured in vivo, i.e. radius and ulna in estimating the BMC and/or strength of the spine or femoral neck. It was found that the BMC at sites on the same bone were highly correlated r = 0.95 or better; the BMC at sites on different bones were also highly interrelated, r = 0.85. The BMC at various sites on the long bones could be estimated to between 10 and 15 per cent from the BMC of sites on the radius or ulna.

  4. Handling of computational in vitro/in vivo correlation problems by Microsoft Excel II. Distribution functions and moments.

    Science.gov (United States)

    Langenbucher, Frieder

    2003-01-01

    MS Excel is a useful tool to handle in vitro/in vivo correlation (IVIVC) distribution functions, with emphasis on the Weibull and the biexponential distribution, which are most useful for the presentation of cumulative profiles, e.g. release in vitro or urinary excretion in vivo, and differential profiles such as the plasma response in vivo. The discussion includes moments (AUC and mean) as summarizing statistics, and data-fitting algorithms for parameter estimation.

  5. Generation of arbitrary two-point correlated directed networks with given modularity

    International Nuclear Information System (INIS)

    Zhou Jie; Xiao Gaoxi; Wong, Limsoon; Fu Xiuju; Ma, Stefan; Cheng, Tee Hiang

    2010-01-01

    In this Letter, we introduce measures of correlation in directed networks and develop an efficient algorithm for generating directed networks with arbitrary two-point correlation. Furthermore, a method is proposed for adjusting community structure in directed networks without changing the correlation. Effectiveness of both methods is verified by numerical results.

  6. Mutagenic Organized Recombination Process by Homologous IN vivo Grouping (MORPHING) for directed enzyme evolution.

    Science.gov (United States)

    Gonzalez-Perez, David; Molina-Espeja, Patricia; Garcia-Ruiz, Eva; Alcalde, Miguel

    2014-01-01

    Approaches that depend on directed evolution require reliable methods to generate DNA diversity so that mutant libraries can focus on specific target regions. We took advantage of the high frequency of homologous DNA recombination in Saccharomyces cerevisiae to develop a strategy for domain mutagenesis aimed at introducing and in vivo recombining random mutations in defined segments of DNA. Mutagenic Organized Recombination Process by Homologous IN vivo Grouping (MORPHING) is a one-pot random mutagenic method for short protein regions that harnesses the in vivo recombination apparatus of yeast. Using this approach, libraries can be prepared with different mutational loads in DNA segments of less than 30 amino acids so that they can be assembled into the remaining unaltered DNA regions in vivo with high fidelity. As a proof of concept, we present two eukaryotic-ligninolytic enzyme case studies: i) the enhancement of the oxidative stability of a H2O2-sensitive versatile peroxidase by independent evolution of three distinct protein segments (Leu28-Gly57, Leu149-Ala174 and Ile199-Leu268); and ii) the heterologous functional expression of an unspecific peroxygenase by exclusive evolution of its native 43-residue signal sequence.

  7. Analysis of antigen-specific B-cell memory directly ex vivo.

    Science.gov (United States)

    McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G

    2004-01-01

    Helper T-cell-regulated B-cell memory develops in response to initial antigen priming as a cellular product of the germinal center (GC) reaction. On antigen recall, memory response precursors expand rapidly with exaggerated differentiation into plasma cells to produce the high-titer, high-affinity antibody(Ab) that typifies the memory B-cell response in vivo. We have devised a high-resolution flow cytometric strategy to quantify the emergence and maintenance of antigen-specific memory B cells directly ex vivo. Extended cell surface phenotype establishes a level of cellular diversity not previously appreciated for the memory B-cell compartment. Using an "exclusion transfer" strategy, we ascertain the capacity of two distinct memory B-cell populations to transfer antigen-specific memory into naive adoptive hosts. Finally, we sequence expressed messenger ribonucleic acid (mRNA) from single cells within the population to estimate the level of somatic hypermutation as the best molecular indicator of B-cell memory. In this chapter, we describe the methods used in each of these four sections that serve to provide high-resolution quantification of antigen-specific B-cell memory responses directly ex vivo.

  8. In vivo analysis of trapeziometacarpal joint arthrokinematics during multi-directional thumb motions.

    Science.gov (United States)

    Su, Fong-Chin; Lin, Chien-Ju; Wang, Chien-Kuo; Chen, Guan-Po; Sun, Yung-Nien; Chuang, Alan K; Kuo, Li-Chieh

    2014-11-01

    The investigation of the joint arthrokinematics of the trapeziometacarpal joint is critical to comprehend the causative mechanism underlying this common form of osteoarthritis. Therefore, the purpose of this study is to evaluate the arthrokinematics of the trapeziometacarpal joint during thumb postures in vivo. Fifteen healthy participants were enrolled in this study. Static computed tomography images of the 1st metacarpal bone and trapezium were taken at specific thumb postures during thumb flexion-extension, abduction-adduction, and circumduction motions. Images were analyzed to examine the joint gliding, expressed as displacement of the centroid of the articular surface of the 1st metacarpal bone, relative to the trapezium. The gliding ratio, defined as joint gliding in each direction normalized to the dimension of the trapezium joint surface in the given direction, was computed and compared between different thumb motions. The results indicate that thumb motions influenced joint gliding. The centroids of the articular surface of the 1st metacarpal bone were primarily located at the central and dorsal-radial regions while executing these motions. The maximum joint gliding of the 1st metacarpal bone occurred in the radial-ulnar direction when performing abduction-adduction, and in the dorsal-volar direction while performing flexion-extension and circumduction, with the gliding ratio values of 42.35%, 51.65%, and 51.85%, respectively. Activities that involved abduction-adduction in the trapeziometacarpal joint caused greater joint gliding in the ulnar-radial direction, while flexion-extension resulted in greater joint gliding in the dorsal-volar and distal-proximal directions. Understanding normal joint kinematics in vivo may provide insights into the possible mechanism leading to osteoarthritis of the trapeziometacarpal joint, and help to improve the design of implants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Cell cycle-dependent mobility of Cdc45 determined in vivo by fluorescence correlation spectroscopy.

    Directory of Open Access Journals (Sweden)

    Ronan Broderick

    Full Text Available Eukaryotic DNA replication is a dynamic process requiring the co-operation of specific replication proteins. We measured the mobility of eGFP-Cdc45 by Fluorescence Correlation Spectroscopy (FCS in vivo in asynchronous cells and in cells synchronized at the G1/S transition and during S phase. Our data show that eGFP-Cdc45 mobility is faster in G1/S transition compared to S phase suggesting that Cdc45 is part of larger protein complex formed in S phase. Furthermore, the size of complexes containing Cdc45 was estimated in asynchronous, G1/S and S phase-synchronized cells using gel filtration chromatography; these findings complemented the in vivo FCS data. Analysis of the mobility of eGFP-Cdc45 and the size of complexes containing Cdc45 and eGFP-Cdc45 after UVC-mediated DNA damage revealed no significant changes in diffusion rates and complex sizes using FCS and gel filtration chromatography analyses. This suggests that after UV-damage, Cdc45 is still present in a large multi-protein complex and that its mobility within living cells is consistently similar following UVC-mediated DNA damage.

  10. Ex Vivo Produced Oral Mucosa Equivalent by Using the Direct Explant Cell Culture Technique

    Directory of Open Access Journals (Sweden)

    Kamile Öztürk

    2012-09-01

    Full Text Available Objective: The aim of this study is the histological and immunohistochemical evaluation of ex vivo produced oral mucosal equivalents using keratinocytes cultured by direct explant technique.Material and Methods: Oral mucosa tissue samples were obtained from the keratinized gingival tissues of 14 healthy human subjects. Human oral mucosa keratinocytes from an oral mucosa biopsy specimen were dissociated by the explant technique. Once a sufficient population of keratinocytes was reached, they were seeded onto the type IV collagen coated “AlloDerm” and taken for histological and immunohistochemical examinations at 11 days postseeding of the keratinocytes on the cadaveric human dermal matrix.Results: Histopathologically and immunohistochemically, 12 out of 14 successful ex vivo produced oral mucosa equivalents (EVPOME that consisted of a stratified epidermis on a dermal matrix have been developed with keratinocytes cultured by the explant technique.Conclusion: The technical handling involved in the direct explant method at the beginning of the process has fewer steps than the enzymatic method and use of the direct explant technique protocol for culturing of human oral mucosa keratinocyte may be more adequate for EVPOME production.

  11. The in vivo toxicity of hydroxyurea depends on its direct target catalase.

    Science.gov (United States)

    Juul, Trine; Malolepszy, Anna; Dybkaer, Karen; Kidmose, Rune; Rasmussen, Jan Trige; Andersen, Gregers Rom; Johnsen, Hans Erik; Jørgensen, Jan-Elo; Andersen, Stig Uggerhøj

    2010-07-09

    Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia, offering a possible explanation for the efficacy of HU against this malignancy.

  12. Direct determination of the redox status of cysteine residues in proteins in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Satoshi [Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta 4259-R1-8, Midori-ku, Yokohama 226-8503 (Japan); Tatenaka, Yuki; Ohuchi, Yuya [Dojindo Laboratories, 2025-5 Tabaru, Mashiki-machi, Kumamoto 861-2202 (Japan); Hisabori, Toru, E-mail: thisabor@res.titech.ac.jp [Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta 4259-R1-8, Midori-ku, Yokohama 226-8503 (Japan); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075 (Japan)

    2015-01-02

    Highlights: • A new DNA-maleimide which is cleaved by UV irradiation, DNA-PCMal, was developed. • DNA-PCMal can be used like DNA-Mal to analyze the redox state of cysteine residues. • It is useful for detecting the thiol redox status of a protein in vivo by Western blotting method. • Thus, DNA-PCMal can be a powerful tool for redox proteomics analysis. - Abstract: The redox states of proteins in cells are key factors in many cellular processes. To determine the redox status of cysteinyl thiol groups in proteins in vivo, we developed a new maleimide reagent, a photocleavable maleimide-conjugated single stranded DNA (DNA-PCMal). The DNA moiety of DNA-PCMal is easily removed by UV-irradiation, allowing DNA-PCMal to be used in Western blotting applications. Thereby the state of thiol groups in intracellular proteins can be directly evaluated. This new maleimide compound can provide information concerning redox proteins in vivo, which is important for our understanding of redox networks in the cell.

  13. In vivo reprogramming for heart regeneration: A glance at efficiency, environmental impacts, challenges and future directions.

    Science.gov (United States)

    Ebrahimi, Behnam

    2017-07-01

    Replacing dying or diseased cells of a tissue with new ones that are converted from patient's own cells is an attractive strategy in regenerative medicine. In vivo reprogramming is a novel strategy that can circumvent the hurdles of autologous/allogeneic cell injection therapies. Interestingly, studies have demonstrated that direct injection of cardiac transcription factors or specific miRNAs into the infarct border zone of murine hearts following myocardial infarction converts resident cardiac fibroblasts into functional cardiomyocytes. Moreover, in vivo cardiac reprogramming not only drives cardiac tissue regeneration, but also improves cardiac function and survival rate after myocardial infarction. Thanks to the influence of cardiac microenvironment and the same developmental origin, cardiac fibroblasts seem to be more amenable to reprogramming toward cardiomyocyte fate than other cell sources (e.g. skin fibroblasts). Thus, reprogramming of cardiac fibroblasts to functional induced cardiomyocytes in the cardiac environment holds great promises for induced regeneration and potential clinical purposes. Application of small molecules in future studies may represent a major advancement in this arena and pharmacological reprogramming would convey reprogramming technology to the translational medicine paradigm. This study reviews accomplishments in the field of in vitro and in vivo mouse cardiac reprogramming and then deals with strategies for the enhancement of the efficiency and quality of the process. Furthermore, it discusses challenges ahead and provides suggestions for future research. Human cardiac reprogramming is also addressed as a foundation for possible application of in vivo cardiac reprogramming for human heart regeneration in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. On the directional dependence of Bose-Einstein correlations

    International Nuclear Information System (INIS)

    Kvatadze, R.A.; Moeller, R.; Loerstad, B.

    1987-11-01

    A simple method to measure the shape of the particle emission region in high energy particle collisions by interferometry is discussed. Results from an application to data on inelastic pp scattering are compared with results based on determinations of the radial extensions of the source. Both show that in the c.m.s., the source is elongated in the beam direction. (orig.)

  15. Dorsal root ganglia hypertrophy as in vivo correlate of oxaliplatin-induced polyneuropathy.

    Directory of Open Access Journals (Sweden)

    Leonidas Apostolidis

    Full Text Available To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP by magnetic resonance neurography (MRN.Twenty patients (7 female, 13 male, 58.9±10.0 years with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7±15.6 years were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG, sciatic nerve normalized T2 (nT2 signal and caliber, and fractional anisotropy (FA, mean diffusivity (MD, axial (AD and radial diffusivity (RD. Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions.DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001 was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3±6.7mm2 vs. 27.4±7.4mm2, p = 0.80 and nT2 signal were not significantly changed in patients (1.32±0.22 vs. 1.22±0.26, p = 0.16. AD, RD, and MD showed a non-significant decrease in patients, while FA was unchanged.OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies.

  16. Neural Correlates of Direct and Indirect Suppression of Autobiographical Memories.

    Science.gov (United States)

    Noreen, Saima; O'Connor, Akira R; MacLeod, Malcolm D

    2016-01-01

    Research indicates that there are two possible mechanisms by which particular target memories can be intentionally forgotten. Direct suppression, which involves the suppression of the unwanted memory directly, and is dependent on a fronto-hippocampal modulatory process, and, memory substitution, which includes directing one's attention to an alternative memory in order to prevent the unwanted memory from coming to mind, and involves engaging the caudal prefrontal cortex (cPFC) and the mid-ventrolateral prefrontal cortex (VLPFC) regions. Research to date, however, has investigated the neural basis of memory suppression of relatively simple information. The aim of the current study was to use fMRI to identify the neural mechanisms associated with the suppression of autobiographical memories. In the present study, 22 participants generated memories in response to a series of cue words. In a second session, participants learnt these cue-memory pairings, and were subsequently presented with a cue word and asked either to recall (think) or to suppress (no-think) the associated memory, or to think of an alternative memory in order to suppress the original memory (memory-substitution). Our findings demonstrated successful forgetting effects in the no-think and memory substitution conditions. Although we found no activation in the dorsolateral prefrontal cortex, there was reduced hippocampal activation during direct suppression. In the memory substitution condition, however, we failed to find increased activation in the cPFC and VLPFC regions. Our findings suggest that the suppression of autobiographical memories may rely on different neural mechanisms to those established for other types of material in memory.

  17. Neural Correlates of Direct and Indirect Suppression of Autobiographical Memories

    Directory of Open Access Journals (Sweden)

    Saima eNoreen

    2016-03-01

    Full Text Available Research indicates that there are two possible mechanisms by which particular target memories can be intentionally forgotten. Direct suppression, which involves the suppression of the unwanted memory directly, and is dependent on a fronto-hippocampal modulatory process, and, memory substitution, which includes directing one's attention to an alternative memory in order to prevent the unwanted memory from coming to mind, and involves engaging the caudal prefrontal cortex (cPFC and the mid-ventrolateral prefrontal cortex (VLPFC regions. Research to date, however, has investigated the neural basis of memory suppression of relatively simple information. The aim of the current study was to use fMRI to identify the neural mechanisms associated with the suppression of autobiographical memories. In the present study, 22 participants generated memories in response to a series of cue words. In a second session, participants learnt these cue-memory pairings, and were subsequently presented with a cue word and asked either to recall (think or to suppress (no-think the associated memory, or to think of an alternative memory in order to suppress the original memory (memory-substitution. Our findings demonstrated successful forgetting effects in the no-think and memory substitution conditions. Although we found no activation in the dorsolateral prefrontal cortex there was reduced hippocampal activation during direct suppression. In the memory substitution condition, however, we failed to find increased activation in the cPFC and VLPFC regions. Our findings suggest that the suppression of autobiographical memories may rely on different neural mechanisms to those established for other types of material in memory.

  18. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of {sup 111}In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

    Energy Technology Data Exchange (ETDEWEB)

    Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Reilly, Raymond M. [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Toronto General Research Institute, University Health Network Toronto, Toronto, ON, M5S 3M2 (Canada)], E-mail: raymond.reilly@utoronto.ca

    2008-08-15

    Introduction: Our objective was to define the relationships between tumor uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10{sup 4}, 1.4x10{sup 4}, 4.0x10{sup 4} and 1.0x10{sup 5} IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 {mu}g) or IGFBP-3 (2 or 25 {mu}g) was studied. The relationship between tumor uptake of [{sup 111}In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [{sup 111}In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 {mu}g/ml) in the absence/presence of IGFBP-3 (1 {mu}g/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 {mu}g/ml), was determined. Results: [{sup 111}In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9{+-}0.1 vs. 1.0{+-}0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [{sup 111}In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r{sup 2}=0.99) between the tumor uptake of {sup 111}In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4{+-}0.05 %ID/g for H2N to 2.5{+-}0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC

  19. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

    International Nuclear Information System (INIS)

    Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle; Reilly, Raymond M.

    2008-01-01

    Introduction: Our objective was to define the relationships between tumor uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10 4 , 1.4x10 4 , 4.0x10 4 and 1.0x10 5 IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 μg) or IGFBP-3 (2 or 25 μg) was studied. The relationship between tumor uptake of [ 111 In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [ 111 In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 μg/ml) in the absence/presence of IGFBP-3 (1 μg/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 μg/ml), was determined. Results: [ 111 In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9±0.1 vs. 1.0±0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [ 111 In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r 2 =0.99) between the tumor uptake of 111 In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4±0.05 %ID/g for H2N to 2.5±0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC cells to trastuzumab was directly associated with IGF-1R expression, despite co

  20. PGE2 suppresses NK activity in vivo directly and through adrenal hormones: Effects that cannot be reflected by ex-vivo assessment of NK cytotoxicity

    Science.gov (United States)

    Meron, G.; Tishler, Y.; Shaashua, L.; Rosenne, E.; Levi, B.; Melamed, R.; Gotlieb, N.; Matzner, P.; Sorski, L.; Ben-Eliyahu, S.

    2013-01-01

    Surgery can suppress in vivo levels of NK cell cytotoxicity (NKCC) through various mechanisms, including catecholamine-, glucocorticoid (CORT)-, and prostaglandin (PG)-mediated responses. However, PGs are synthesized locally following tissue damage, driving proinflammatory and CORT responses, while their systemic levels are often unaffected. Thus, we herein studied the role of adrenal factors in mediating in vivo effects of PGs on NKCC, using adrenalectomized and sham-operated F344 rats subjected to surgery or PGE2 administration. In vivo and ex-vivo approaches were employed, based on intravenous administration of the NK-sensitive MADB106 tumor line, and based on ex-vivo assessment of YAC-1 and MADB106 target-line lysis. Additionally, in vitro studies assessed the kinetics of the impact of epinephrine, CORT, and PGE2 on NKCC. The results indicated that suppression of NKCC by epinephrine and PGE2 are short lasting, and cannot be evident when these compounds are removed from the in vitro assay milieu, or in the context of ex-vivo assessment of NKCC. In contrast, the effects of CORT are long-lasting and are reflected in both conditions even after its removal. Marginating-pulmonary NKCC was less susceptible to suppression than circulating NKCC, when tested against the xenogeneic YAC-1 target line, but not against the syngeneic MADB106 line, which seems to involve different cytotoxicity mechanisms. Overall, these findings indicate that elevated systemic PG levels can directly suppress NKCC in vivo, but following laparotomy adrenal hormones mediate most of the effects of endogenously-released PGs. Additionally, the ex-vivo approach seems limited in reflecting the short-lasting NK-suppressive effects of catecholamines and PGs. PMID:23153554

  1. PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity.

    Science.gov (United States)

    Meron, G; Tishler, Y; Shaashua, L; Rosenne, E; Levi, B; Melamed, R; Gotlieb, N; Matzner, P; Sorski, L; Ben-Eliyahu, S

    2013-02-01

    Surgery can suppress in vivo levels of NK cell cytotoxicity (NKCC) through various mechanisms, including catecholamine-, glucocorticoid (CORT)-, and prostaglandin (PG)-mediated responses. However, PGs are synthesized locally following tissue damage, driving proinflammatory and CORT responses, while their systemic levels are often unaffected. Thus, we herein studied the role of adrenal factors in mediating in vivo effects of PGs on NKCC, using adrenalectomized and sham-operated F344 rats subjected to surgery or PGE(2) administration. In vivo and ex vivo approaches were employed, based on intravenous administration of the NK-sensitive MADB106 tumor line, and based on ex vivo assessment of YAC-1 and MADB106 target-line lysis. Additionally, in vitro studies assessed the kinetics of the impact of epinephrine, CORT, and PGE(2) on NKCC. The results indicated that suppression of NKCC by epinephrine and PGE(2) are short lasting, and cannot be evident when these compounds are removed from the in vitro assay milieu, or in the context of ex vivo assessment of NKCC. In contrast, the effects of CORT are long-lasting and are reflected in both conditions even after its removal. Marginating-pulmonary NKCC was less susceptible to suppression than circulating NKCC, when tested against the xenogeneic YAC-1 target line, but not against the syngeneic MADB106 line, which seems to involve different cytotoxicity mechanisms. Overall, these findings indicate that elevated systemic PG levels can directly suppress NKCC in vivo, but following laparotomy adrenal hormones mediate most of the effects of endogenously-released PGs. Additionally, the ex vivo approach seems limited in reflecting the short-lasting NK-suppressive effects of catecholamines and PGs. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Direct parametric reconstruction in dynamic PET myocardial perfusion imaging: in vivo studies

    Science.gov (United States)

    Petibon, Yoann; Rakvongthai, Yothin; El Fakhri, Georges; Ouyang, Jinsong

    2017-05-01

    Dynamic PET myocardial perfusion imaging (MPI) used in conjunction with tracer kinetic modeling enables the quantification of absolute myocardial blood flow (MBF). However, MBF maps computed using the traditional indirect method (i.e. post-reconstruction voxel-wise fitting of kinetic model to PET time-activity-curves-TACs) suffer from poor signal-to-noise ratio (SNR). Direct reconstruction of kinetic parameters from raw PET projection data has been shown to offer parametric images with higher SNR compared to the indirect method. The aim of this study was to extend and evaluate the performance of a direct parametric reconstruction method using in vivo dynamic PET MPI data for the purpose of quantifying MBF. Dynamic PET MPI studies were performed on two healthy pigs using a Siemens Biograph mMR scanner. List-mode PET data for each animal were acquired following a bolus injection of ~7-8 mCi of 18F-flurpiridaz, a myocardial perfusion agent. Fully-3D dynamic PET sinograms were obtained by sorting the coincidence events into 16 temporal frames covering ~5 min after radiotracer administration. Additionally, eight independent noise realizations of both scans—each containing 1/8th of the total number of events—were generated from the original list-mode data. Dynamic sinograms were then used to compute parametric maps using the conventional indirect method and the proposed direct method. For both methods, a one-tissue compartment model accounting for spillover from the left and right ventricle blood-pools was used to describe the kinetics of 18F-flurpiridaz. An image-derived arterial input function obtained from a TAC taken in the left ventricle cavity was used for tracer kinetic analysis. For the indirect method, frame-by-frame images were estimated using two fully-3D reconstruction techniques: the standard ordered subset expectation maximization (OSEM) reconstruction algorithm on one side, and the one-step late maximum a posteriori (OSL-MAP) algorithm on the other

  3. Direct parametric reconstruction in dynamic PET myocardial perfusion imaging: in-vivo studies

    Science.gov (United States)

    Petibon, Yoann; Rakvongthai, Yothin; Fakhri, Georges El; Ouyang, Jinsong

    2017-01-01

    Dynamic PET myocardial perfusion imaging (MPI) used in conjunction with tracer kinetic modeling enables the quantification of absolute myocardial blood flow (MBF). However, MBF maps computed using the traditional indirect method (i.e. post-reconstruction voxel-wise fitting of kinetic model to PET time-activity-curves -TACs) suffer from poor signal-to-noise ratio (SNR). Direct reconstruction of kinetic parameters from raw PET projection data has been shown to offer parametric images with higher SNR compared to the indirect method. The aim of this study was to extend and evaluate the performance of a direct parametric reconstruction method using in-vivo dynamic PET MPI data for the purpose of quantifying MBF. Dynamic PET MPI studies were performed on two healthy pigs using a Siemens Biograph mMR scanner. List-mode PET data for each animal were acquired following a bolus injection of ~7-8 mCi of 18F-flurpiridaz, a myocardial perfusion agent. Fully-3D dynamic PET sinograms were obtained by sorting the coincidence events into 16 temporal frames covering ~5 min after radiotracer administration. Additionally, eight independent noise realizations of both scans - each containing 1/8th of the total number of events - were generated from the original list-mode data. Dynamic sinograms were then used to compute parametric maps using the conventional indirect method and the proposed direct method. For both methods, a one-tissue compartment model accounting for spillover from the left and right ventricle blood-pools was used to describe the kinetics of 18F-flurpiridaz. An image-derived arterial input function obtained from a TAC taken in the left ventricle cavity was used for tracer kinetic analysis. For the indirect method, frame-by-frame images were estimated using two fully-3D reconstruction techniques: the standard Ordered Subset Expectation Maximization (OSEM) reconstruction algorithm on one side, and the One-Step Late Maximum a Posteriori (OSL-MAP) algorithm on the other

  4. The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts.

    Directory of Open Access Journals (Sweden)

    Lucia Pagani

    Full Text Available BACKGROUND: Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls", clock properties measured in human fibroblasts correlated with extreme diurnal behavior. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. CONCLUSIONS/SIGNIFICANCE: We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness.

  5. Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye.

    Science.gov (United States)

    Awwad, Sahar; Day, Richard M; Khaw, Peng T; Brocchini, Steve; Fadda, Hala M

    2017-04-30

    Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50μL volume of TIPS microparticles resulted in a clearance t 1/2 of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t 1/2 of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye. Copyright © 2017. Published by Elsevier B.V.

  6. Correlation of regional disease and in vivo PO2 in rat mammary adenocarcinoma.

    Science.gov (United States)

    Cole, M A; Crawford, D W; Warner, N E; Puffer, H W

    1983-07-01

    A knowledge of the distribution of oxygen tension (PO2) and vascularization in neoplasia has been fundamental to understanding relationships between tumor growth, hypoxia, and therapy. We have combined recessed oxygen microcathode and freeze-substitution techniques to correlate in situ PO2 profiles and morphologic features in 7,12-dimethylbenz(a)anthracene (DMBA) tumors in rats. Overlying connective tissue of transplanted tumor was exposed by a 1-2 mm incision and a cross-stitch pattern demarcated electrode puncture sites for histologic reference. Three buffered salt solutions (BSS) with different PO2 were each allowed to flow through a well over the tumor where electrodes were placed for calibration. Zero electrode oxygen current was recorded from a buffered yeast-agar mixture of zero torr. PO2 was recorded at 5-mu intervals to approximately 1-2 mm. Atmospheric contamination was eliminated by continuous well flow of BSS, 30 torr. Finally, the tumor and surrounding tissues were quick-frozen in vivo with Freon 22 and liquid nitrogen. The tissue block was freeze-substituted and sectioned. PO2 profiles were superimposed onto correspondingly scaled photomicrographs. A viable periphery with a PO2 range of 50-82 torr and a transition to necrotic areas of PO2, 2-13 torr were observed. This transition was characterized by PO2 gradients within distances of 50-300 mu at variable puncture depths. This technique should be useful in further studies of growth, necrosis, and therapy.

  7. Blood vessel damage correlated with irradiance for in vivo vascular targeted photodynamic therapy

    Science.gov (United States)

    Zhang, Jinde; Tan, Zou; Niu, Xiangyu; Lin, Linsheng; Lin, Huiyun; Li, Buhong

    2016-10-01

    Vascular targeted photodynamic therapy (V-PDT) has been widely utilized for the prevention or treatment of vascular-related diseases, including age-related macular degeneration, port-wine stains and prostate cancer. In order to quantitative assessment the blood vessel damage during V-PDT, nude mice were implanted with Titanium dorsal skin window chambers for in vivo V-PDT studies. For treatments, various irradiances including 50, 75, 100 and 200 mW/cm2 provided by a 532 nm semiconductor laser were performed with the same total light dose of 30 J/cm2 after the mice were intravenously injection of Rose Bengal for 25 mg/Kg body weight. Laser speckle imaging and microscope were used to monitor blood flow dynamics and vessel constriction during and after V-PDT, respectively. The V-PDT induced vessel damages between different groups were compared. The results show that significant difference in blood vessel damage was found between the lower irradiances (50, 75 and 100 mW/cm2) and higher irradiance (200 mW/cm2), and the blood vessel damage induced by V-PDT is positively correlated with irradiance. This study implies that the optimization of irradiance is required for enhancing V-PDT therapeutic efficiency.

  8. The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions

    Directory of Open Access Journals (Sweden)

    Jaeil Han

    2016-09-01

    Full Text Available The RNA exosome is a 3′–5′ ribonuclease complex that is composed of nine core subunits and an essential catalytic subunit, Rrp44. Two distinct conformations of Rrp44 were revealed in previous structural studies, suggesting that Rrp44 may change its conformation to exert its function. In the channeling conformation, (Rrp44ch, RNA accesses the active site after traversing the central channel of the RNA exosome, whereas in the other conformation, (Rrp44da, RNA gains direct access to the active site. Here, we show that the Rrp44da exosome is important for nuclear function of the RNA exosome. Defects caused by disrupting the direct access conformation are distinct from those caused by channel-occluding mutations, indicating specific functions for each conformation. Our genetic analyses provide in vivo evidence that the RNA exosome employs a direct-access route to recruit specific substrates, indicating that the RNA exosome uses alternative conformations to act on different RNA substrates.

  9. Biologically-directed modeling reflects cytolytic clearance of SIV-infected cells in vivo in macaques.

    Directory of Open Access Journals (Sweden)

    W David Wick

    Full Text Available The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8⁺ T lymphocytes (CTLs has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4⁺ and CD8⁺ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic.

  10. Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: III. Convolution and deconvolution.

    Science.gov (United States)

    Langenbucher, Frieder

    2003-11-01

    Convolution and deconvolution are the classical in-vitro-in-vivo correlation tools to describe the relationship between input and weighting/response in a linear system, where input represents the drug release in vitro, weighting/response any body response in vivo. While functional treatment, e.g. in terms of polyexponential or Weibull distribution, is more appropriate for general survey or prediction, numerical algorithms are useful for treating actual experimental data. Deconvolution is not considered an algorithm by its own, but the inversion of a corresponding convolution. MS Excel is shown to be a useful tool for all these applications.

  11. Effects of Metalloporphyrins on Heme Oxygenase-1 Transcription: Correlative Cell Culture Assays Guide in Vivo Imaging

    Directory of Open Access Journals (Sweden)

    Monica Hajdena-Dawson

    2003-07-01

    Full Text Available Heme oxygenase (HO is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps, a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP and zinc bis glycol porphyrin (ZnBG, were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.

  12. Automatic frequency and phase alignment of in vivo J-difference-edited MR spectra by frequency domain correlation.

    Science.gov (United States)

    Wiegers, Evita C; Philips, Bart W J; Heerschap, Arend; van der Graaf, Marinette

    2017-12-01

    J-difference editing is often used to select resonances of compounds with coupled spins in 1 H-MR spectra. Accurate phase and frequency alignment prior to subtracting J-difference-edited MR spectra is important to avoid artefactual contributions to the edited resonance. In-vivo J-difference-edited MR spectra were aligned by maximizing the normalized scalar product between two spectra (i.e., the correlation over a spectral region). The performance of our correlation method was compared with alignment by spectral registration and by alignment of the highest point in two spectra. The correlation method was tested at different SNR levels and for a broad range of phase and frequency shifts. In-vivo application of the proposed correlation method showed reduced subtraction errors and increased fit reliability in difference spectra as compared with conventional peak alignment. The correlation method and the spectral registration method generally performed equally well. However, better alignment using the correlation method was obtained for spectra with a low SNR (down to ~2) and for relatively large frequency shifts. Our correlation method for simultaneously phase and frequency alignment is able to correct both small and large phase and frequency drifts and also performs well at low SNR levels.

  13. In vivo observation of transient photoreceptor movement correlated with oblique light stimulation

    Science.gov (United States)

    Lu, Yiming; Liu, Changgeng; Yao, Xincheng

    2018-02-01

    Rod-dominated transient retinal phototropism (TRP) has been observed in freshly isolated retinas, promising a noninvasive biomarker for high resolution assessment of retinal physiology. However, in vivo mapping of TRP is challenging due to its fast time course and sub-cellular signal magnitude. By developing a line-scanning and virtually structured detection based super-resolution ophthalmoscope, we report here in vivo observation of TRP in frog retina. In vivo characterization of TRP time course and magnitude were implemented by using variable light stimulus intensities.

  14. Visualizing Transcranial Direct Current Stimulation (tDCS) in vivo using Magnetic Resonance Imaging

    Science.gov (United States)

    Jog, Mayank Anant

    Transcranial Direct Current Stimulation (tDCS) is a low-cost, non-invasive neuromodulation technique that has been shown to treat clinical symptoms as well as improve cognition. However, no techniques exist at the time of research to visualize tDCS currents in vivo. This dissertation presents the theoretical framework and experimental implementations of a novel MRI technique that enables non-invasive visualization of the tDCS electric current using magnetic field mapping. The first chapter establishes the feasibility of measuring magnetic fields induced by tDCS currents. The following chapter discusses the state of the art implementation that can measure magnetic field changes in individual subjects undergoing concurrent tDCS/MRI. The final chapter discusses how the developed technique was integrated with BOLD fMRI-an established MRI technique for measuring brain function. By enabling a concurrent measurement of the tDCS current induced magnetic field as well as the brain's hemodynamic response to tDCS, our technique opens a new avenue to investigate tDCS mechanisms and improve targeting.

  15. Direct tissue oxygen monitoring by in vivo photoacoustic lifetime imaging (PALI)

    Science.gov (United States)

    Shao, Qi; Morgounova, Ekaterina; Ashkenazi, Shai

    2014-03-01

    Tissue oxygen plays a critical role in maintaining tissue viability and in various diseases, including response to therapy. Images of oxygen distribution provide the history of tissue hypoxia and evidence of oxygen availability in the circulatory system. Currently available methods of direct measuring or imaging tissue oxygen all have significant limitations. Previously, we have reported a non-invasive in vivo imaging modality based on photoacoustic lifetime. The technique maps the excited triplet state of oxygen-sensitive dye, thus reflects the spatial and temporal distribution of tissue oxygen. We have applied PALI on tumor hypoxia in small animals, and the hypoxic region imaged by PALI is consistent with the site of the tumor imaged by ultrasound. Here, we present two studies of applying PALI to monitor changes of tissue oxygen by modulations. The first study involves an acute ischemia model using a thin thread tied around the hind limb of a normal mouse to reduce the blood flow. PALI images were acquired before, during, and after the restriction. The drop of muscle pO2 and recovery from hypoxia due to reperfusion were observed by PALI tracking the same region. The second study modulates tissue oxygen by controlling the percentage of oxygen the mouse inhales. We demonstrate that PALI is able to reflect the change of oxygen level with respect to both hyperbaric and hypobaric conditions. We expect this technique to be very attractive for a range of clinical applications in which tissue oxygen mapping would improve therapy decision making and treatment planning.

  16. Direct anthelmintic effects of Cereus jamacaru (Cactaceae) on trichostrongylid nematodes of sheep: in vivo studies.

    Science.gov (United States)

    Vatta, A F; Kandu-Lelo, C; Ademola, I O; Eloff, J N

    2011-08-25

    Following claims of anthelmintic activity of Cereus jamacaru DC (Cactaceae) by a commercial farmer, in vivo studies were conducted to determine the possible direct anthelmintic effects of the plant on ovine gastrointestinal nematodes. Eighteen sheep were infected with 4000 Haemonchus contortus and 6000 Trichostrongylus colubriformis larvae given in three divided doses over a period of three days. Once the infections were patent, the sheep were allocated to three groups and were drenched once a week for six weeks with fresh blended C. jamacaru plant material at a single (32.3g/sheep) or double dose (64.6g/sheep) or they remained as undrenched controls. Faeces were collected from individual animals on the day of treatment and three days thereafter on a weekly basis for seven weeks for faecal egg count. While there were no statistically significant differences in the egg counts between the groups, a double dose of C. jamacaru was effective in reducing the egg counts in the sheep by 18-65% over the 49 days of the experiment. Given that all animals remained in good health throughout the course of the experiment, with no adverse events occurring during the study, further experiments using higher doses or administering the plant material for a longer period of time than in the present study would be warranted. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease

    Science.gov (United States)

    Bieganowska, Katarzyna D.; Ausubel, Lara J.; Modabber, Yalda; Slovik, Elissa; Messersmith, Wells; Hafler, David A.

    1997-01-01

    The frequency of clonally expanded and persistent T cells recognizing the immunodominant autoantigenic peptide of myelin basic protein (MBP)p85-99 was directly measured ex vivo in subjects with typical relapsing remitting multiple sclerosis (MS). T cells expressing mRNA transcripts encoding T cell receptor (TCR)-α and -β chains found in T cell clones previously isolated from these subjects recognizing the MBPp85-99 epitope were examined. In contrast to frequencies of 1 in 105–106 as measured by limiting dilution analysis, estimates of the T cell frequencies expressing MBPp85-99–associated TCR chain transcripts were as high as 1 in 300. These high frequencies were confirmed by performing PCR on single T cells isolated by flow cytometry. MBPp85-99 TCR transcripts were present in IL-2 receptor α–positive T cells which were induced to undergo Fas-mediated cell death upon antigen stimulation. These data demonstrate that at least a subpopulation of patients with MS can have a very high frequency of activated autoreactive T cells. PMID:9151896

  18. Determination of velocity vector angles using the directional cross-correlation method

    DEFF Research Database (Denmark)

    Kortbek, Jacob; Jensen, Jørgen Arendt

    2005-01-01

    and then select the angle with the highest normalized correlation between directional signals. The approach is investigated using Field II simulations and data from the experimental ultrasound scanner RASMUS and with a parabolic flow having a peak velocity of 0.3 m/s. A 7 MHz linear array transducer is used......A method for determining both velocity magnitude and angle in any direction is suggested. The method uses focusing along the velocity direction and cross-correlation for finding the correct velocity magnitude. The angle is found from beamforming directional signals in a number of directions......-time ) between signals to correlate, and a proper choice varies with flow angle and flow velocity. One performance example is given with a fixed value of k tprf for all flow angles. The angle estimation on measured data for flow at 60 ◦ to 90 ◦ , yields a probability of valid estimates between 68% and 98...

  19. Ex vivo fracture resistance of direct resin composite complete crowns with and without posts on maxillary premolars.

    NARCIS (Netherlands)

    Fokkinga, W.A.; Bell, A.M. Le; Kreulen, C.M.; Lassila, L.V.; Vallittu, P.K.; Creugers, N.H.J.

    2005-01-01

    AIM: To investigate ex vivo the fracture resistance and failure mode of direct resin composite complete crowns with and without various root canal posts made on maxillary premolars. METHODOLOGY: The clinical crowns of 40 human extracted single-rooted maxillary premolars were sectioned at the

  20. The evolution of trade-offs under directional and correlational selection.

    Science.gov (United States)

    Roff, Derek A; Fairbairn, Daphne J

    2012-08-01

    Using quantitative genetic theory, we develop predictions for the evolution of trade-offs in response to directional and correlational selection. We predict that directional selection favoring an increase in one trait in a trade-off will result in change in the intercept but not the slope of the trade-off function, with the mean value of the selected trait increasing and that of the correlated trait decreasing. Natural selection will generally favor an increase in some combination of trait values, which can be represented as directional selection on an index value. Such selection induces both directional and correlational selection on the component traits. Theory predicts that selection on an index value will also change the intercept but not the slope of the trade-off function but because of correlational selection, the direction of change in component traits may be in the same or opposite directions. We test these predictions using artificial selection on the well-established trade-off between fecundity and flight capability in the cricket, Gryllus firmus and compare the empirical results with a priori predictions made using genetic parameters from a separate half-sibling experiment. Our results support the predictions and illustrate the complexity of trade-off evolution when component traits are subject to both directional and correlational selection. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

  1. Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study.

    Science.gov (United States)

    Soeteman-Hernández, Lya G; Fellows, Mick D; Johnson, George E; Slob, Wout

    2015-12-01

    In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement). © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.

  2. Estimation of velocity vector angles using the directional cross-correlation method

    DEFF Research Database (Denmark)

    Kortbek, Jacob; Jensen, Jørgen Arendt

    2006-01-01

    and then select the angle with the highest normalized correlation between directional signals. The approach is investigated using Field II simulations and data from the experimental ultrasound scanner RASMUS and a circulating flow rig with a parabolic flow having a peak velocity of 0.3 m/s. A 7 MHz linear array......A method for determining both velocity magnitude and angle in any direction is suggested. The method uses focusing along the velocity direction and cross-correlation for finding the correct velocity magnitude. The angle is found from beamforming directional signals in a number of directions...... transducer is used with a normal transmission of a focused ultrasound field. In the simulations the relative standard deviation of the velocity magnitude is between 0.7% and 7.7% for flow angles between 45 deg and 90 deg. The study showed that angle estimation by directional beamforming can be estimated...

  3. In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems.

    Science.gov (United States)

    Blakney, Anna K; Little, Adam B; Jiang, Yonghou; Woodrow, Kim A

    2016-11-01

    Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a dimethyl sulfoxide extraction protocol and high-performance liquid chromatography analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R 2 =   0.80), but the correlation was not significant for MVC or TFV. For the sustained-release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel-tissue mimic may be a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures.

  4. Cortical microinfarcts detected in vivo on 3 tesla MRI : Clinical and radiological correlates

    NARCIS (Netherlands)

    Van Dalen, Jan Willem; Scuric, Eva E M; Van Veluw, Susanne J.; Caan, Matthan W A; Nederveen, Aart J.; Biessels, Geert Jan; Van Gool, Willem A.; Richard, Edo

    2015-01-01

    Background and Purpose-Cortical microinfarcts (CMIs) are a common postmortem finding associated with vascular risk factors, cognitive decline, and dementia. Recently, CMIs identified in vivo on 7 Tesla MRI also proved retraceable on 3 Tesla MRI. Methods-We evaluated CMIs on 3 Tesla MRI in a

  5. Cortical microinfarcts detected in vivo on 3 Tesla MRI: clinical and radiological correlates

    NARCIS (Netherlands)

    Dalen, J.W. van; Scuric, E.E.; Veluw, S.J. van; Caan, M.W.; Nederveen, A.J.; Biessels, G.J.; Gool, W.A. van; Richard, E.

    2015-01-01

    BACKGROUND AND PURPOSE: Cortical microinfarcts (CMIs) are a common postmortem finding associated with vascular risk factors, cognitive decline, and dementia. Recently, CMIs identified in vivo on 7 Tesla MRI also proved retraceable on 3 Tesla MRI. METHODS: We evaluated CMIs on 3 Tesla MRI in a

  6. In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides

    Energy Technology Data Exchange (ETDEWEB)

    Taxvig, Camilla, E-mail: camta@food.dtu.dk [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark); Hadrup, Niels; Boberg, Julie; Axelstad, Marta [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark); Bossi, Rossana [Department of Environmental Science, Aarhus University, DK-4000 Roskilde (Denmark); Bonefeld-Jørgensen, Eva Cecilie [Department of Public Health, University of Aarhus, DK-8000 Aarhus C (Denmark); Vinggaard, Anne Marie [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark)

    2013-11-01

    Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone were seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, either of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects. - Highlights: • The study examines the endocrine disrupting potential of mixtures of pesticides. • All single pesticides and both mixtures affected steroidogenesis in vitro. • Potential aromatase induction was found for Mix 5 both in vitro and in vivo. • The hormonal responses in vitro were only partly reflected in vivo.

  7. Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

    Science.gov (United States)

    Yoo, Junsang; Lee, Euiyeon; Kim, Hee Young; Youn, Dong-Ho; Jung, Junghyun; Kim, Hongwon; Chang, Yujung; Lee, Wonwoong; Shin, Jaein; Baek, Soonbong; Jang, Wonhee; Jun, Won; Kim, Soochan; Hong, Jongki; Park, Hi-Joon; Lengner, Christopher J.; Moh, Sang Hyun; Kwon, Youngeun; Kim, Jongpil

    2017-10-01

    Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinson's disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders.

  8. In vivo measurements background estimation of low energy trough the anthropometric parameters correlation and with the potassium body content

    International Nuclear Information System (INIS)

    Sousa, Wanderson O.; Dantas, Ana Leticia A.; Dantas, Bernardo M.

    2002-01-01

    The occupational monitoring of individuals with potential risk of incorporation of radionuclides such as Am-241, U-238, U-235 and Ra-226 by inhalation in workplaces where particulates in suspension can be present, is frequently performed by in vivo measurements of the lungs. The activity calculation involves a comparison of the acquired spectrum with a reference spectrum. The accuracy of the background prediction is critical when the expected activities are close to the minimum detection limit. This is the case of occupational monitoring where most of the activities observed are bellow or very close the detection limit. The use of a inappropriate reference spectrum can lead to false-positive or false-negative results. The variability of potassium content among individuals in one of the major factors in the fluctuation of the count rate in the low energy region of the spectrum. This contribution is associated with the Compton effect due to the interaction of 1461 keV photons emitted by K-40. In order to verify the correlation between the background count rate in the various regions of interest of the low energy spectra with the potassium mass in the body it was designed an experimental procedure consisting of measuring a thoracic phantom containing known amounts of potassium. The strong correlation observed motivated the continuity of this work which consisted in the analysis of real low energy in vivo spectra with the aim of verifying the correlation between anthropometric parameters (sex, age, weight and height) and the count rates in the region of K-40 with the count rates in the low energy regions of interest. The results obtained show a significant correlation between the selected parameters with the count rate of the background. This allows a more reliable estimation of activity of low energy radionuclides in individuals monitored through in vivo measurements. The occupational monitoring. (author)

  9. Spatiotemporal correlation of optical coherence tomography in-vivo images of rabbit airway for the diagnosis of edema

    Science.gov (United States)

    Kang, DongYel; Wang, Alex; Volgger, Veronika; Chen, Zhongping; Wong, Brian J. F.

    2015-07-01

    Detection of an early stage of subglottic edema is vital for airway management and prevention of stenosis, a life-threatening condition in critically ill neonates. As an observer for the task of diagnosing edema in vivo, we investigated spatiotemporal correlation (STC) of full-range optical coherence tomography (OCT) images acquired in the rabbit airway with experimentally simulated edema. Operating the STC observer on OCT images generates STC coefficients as test statistics for the statistical decision task. Resulting from this, the receiver operating characteristic (ROC) curves for the diagnosis of airway edema with full-range OCT in-vivo images were extracted and areas under ROC curves were calculated. These statistically quantified results demonstrated the potential clinical feasibility of the STC method as a means to identify early airway edema.

  10. In vivo reactive neural plasticity investigation by means of correlative two photon: electron microscopy

    Science.gov (United States)

    Allegra Mascaro, A. L.; Cesare, P.; Sacconi, L.; Grasselli, G.; Mandolesi, G.; Maco, B.; Knott, G.; Huang, L.; De Paola, V.; Strata, P.; Pavone, F. S.

    2013-02-01

    In the adult nervous system, different populations of neurons correspond to different regenerative behavior. Although previous works showed that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Time lapse two-photon imaging has been combined to laser nanosurgery2, 3 to define a temporal pattern of the degenerative event and to follow the structural rearrangement after injury. To characterize the damage and to elucidate the possible formation of new synaptic contacts on the sprouted branches of the lesioned CF, we combined two-photon in vivo imaging with block face scanning electron microscopy (FIB-SEM). Here we describe the approach followed to characterize the reactive plasticity after injury.

  11. In vitro-in vivo correlation study for the dermatopharmacokinetics of terbinafine hydrochloride topical cream.

    Science.gov (United States)

    Saeheng, Suwadee; Nosoongnoen, Wichit; Varothai, Supenya; Sathirakul, Korbtham

    2013-09-01

    To investigate the relationship between dermatopharmacokinetic (DPK) tape stripping from in vitro and in vivo using 1% terbinafine hydrochloride topical cream as the model formulation. In vitro and in vivo tape strippings were conducted on separated pig ear skin used as a biological membrane for franz diffusion cell testing and the non-hairy skin area at the ventral forearms of healthy volunteers, respectively. Terbinafine (1%) topical cream was applied to the skin for 0.5, 2, and 4 h. The drug profiles of terbinafine across the stratum corneum were determined immediately (time 0 h), and at 0.5, 1, 2, and 4 h after removing the formulation. The amounts of terbinafine were analyzed by a validated high-performance liquid chromatography-ultraviolet method. The area under the curve (AUC) and the maximum amounts of terbinafine absorption (Q(max)) were obtained from pharmacokinetic software. Partition coefficient (K(SC/veh)) and diffusion parameter (D/L²) were derived from the Fick's second law equation. During the schedule time of 8 h, the deviations of in vitro and in vivo data were 6.61 and 30.46% for AUC and Q(max), respectively. There was insignificant difference of the K(SC/veh) and the D/L² between excised pig ear and human skin. In addition, K(SC/veh) and D/L² at T(max) of 2 h were used to predict the AUC presented the value of 4.7481 %h whereas the true value calculated from pharmacokinetic software provided the value of 5.9311 %h differing from each other in approximate of 20%. In vitro tape stripping using the separated pig ear skin as a viable membrane of the franz diffusion cell testing demonstrates the potential to represent in vivo tape stripping in human for topical bioavailability/bioequivalence study of terbinafine hydrochloride 1% topical cream.

  12. A medaka model of cancer allowing direct observation of transplanted tumor cells in vivo at a cellular-level resolution.

    Science.gov (United States)

    Hasegawa, Sumitaka; Maruyama, Kouichi; Takenaka, Hikaru; Furukawa, Takako; Saga, Tsuneo

    2009-08-18

    The recent success with small fish as an animal model of cancer with the aid of fluorescence technique has attracted cancer modelers' attention because it would be possible to directly visualize tumor cells in vivo in real time. Here, we report a medaka model capable of allowing the observation of various cell behaviors of transplanted tumor cells, such as cell proliferation and metastasis, which were visualized easily in vivo. We established medaka melanoma (MM) cells stably expressing GFP and transplanted them into nonirradiated and irradiated medaka. The tumor cells were grown at the injection sites in medaka, and the spatiotemporal changes were visualized under a fluorescence stereoscopic microscope at a cellular-level resolution, and even at a single-cell level. Tumor dormancy and metastasis were also observed. Interestingly, in irradiated medaka, accelerated tumor growth and metastasis of the transplanted tumor cells were directly visualized. Our medaka model provides an opportunity to visualize in vivo tumor cells "as seen in a culture dish" and would be useful for in vivo tumor cell biology.

  13. Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems.

    Science.gov (United States)

    Yang, Yang; Manda, Prashanth; Pavurala, Naresh; Khan, Mansoor A; Krishnaiah, Yellela S R

    2015-07-28

    The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100μg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X-0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100μg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100μg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100μg/day. Published by Elsevier B.V.

  14. Coherent effects on two-photon correlation and directional emission of two two-level atoms

    International Nuclear Information System (INIS)

    Ooi, C. H. Raymond; Kim, Byung-Gyu; Lee, Hai-Woong

    2007-01-01

    Sub- and superradiant dynamics of spontaneously decaying atoms are manifestations of collective many-body systems. We study the internal dynamics and the radiation properties of two atoms in free space. Interesting results are obtained when the atoms are separated by less than half a wavelength of the atomic transition, where the dipole-dipole interaction gives rise to new coherent effects, such as (a) coherence between two intermediate collective states, (b) oscillations in the two-photon correlation G (2) , (c) emission of two photons by one atom, and (d) the loss of directional correlation. We compare the population dynamics during the two-photon emission process with the dynamics of single-photon emission in the cases of a Λ and a V scheme. We compute the temporal correlation and angular correlation of two successively emitted photons using the G (2) for different values of atomic separation. We find antibunching when the atomic separation is a quarter wavelength λ/4. Oscillations in the temporal correlation provide a useful feature for measuring subwavelength atomic separation. Strong directional correlation between two emitted photons is found for atomic separation larger than a wavelength. We also compare the directionality of a photon spontaneously emitted by the two atoms prepared in phased-symmetric and phased-antisymmetric entangled states vertical bar ±> k 0 =e ik 0 ·r 1 vertical bar a 1 ,b 2 >±e ik 0 ·r 2 vertical bar b 1 ,a 2 > by a laser pulse with wave vector k 0 . Photon emission is directionally suppressed along k 0 for the phased-antisymmetric state. The directionality ceases for interatomic distances less than λ/2

  15. Differential binding of Lef1 and Msx1/2 transcription factors to Dkk1 CNEs correlates with reporter gene expression in vivo.

    Directory of Open Access Journals (Sweden)

    Oliver Lieven

    Full Text Available Besides the active Wnt signalling itself, the extracellular inhibition by Dkk1 is important for various embryonic developmental processes, such as optic vesicle differentiation and facial outgrowth. Although a feedback crosstalk of the active Wnt/β-catenin signaling and Dkk1 regulation has been suggested, the control of Dkk1 transcription by the Tcf/Lef1 mediated Wnt signalling and its connection to additional signalling factors has not been elucidated in vivo. Here, we used a combination of transgenic mouse approaches and biochemical analyses to unravel the direct Dkk1 transcriptional regulation via Tcf/Lefs. By using site directed mutagenesis, we tested several conserved Tcf/Lef1 binding sites within Dkk1 conserved non-coding elements (CNEs and found that these are required for tissue specific reporter expression. In addition a conserved Msx1/2 binding site is required for retinal reporter expression and Msx2 but not Msx1 binds its conserved binding site within CNE195 in the optic cups. Within craniofacial expression domains, Lef1 interferes with Dkk1 directly via two conserved Tcf/Lef1 binding sites in the craniofacial enhancer CNE114, both of which are required for the general craniofacial Dkk1 reporter activation. Furthermore, these Tcf/Lef1 sites are commonly bound in the whisker hair bud mesenchyme but specifically Tcf/Lef1 (no. 2 is required for mandibular activation and repression of maxillar Dkk1 activation. Lastly, we tested the Tcf/Lef1 binding capacities of the Dkk1 promoter and found that although Lef1 binds the Dkk1 promoter, these sites are not sufficient for tissue specific Dkk1 activation. Together, we here present the importance of conserved Tcf/Lef1 and Msx1/2 sites that are required for differential Dkk1 transcriptional reporter activation in vivo. This requirement directly correlates with Lef1 and Msx1/2 interaction with these genomic loci.

  16. Three-dimensional optical micro-angiography maps directional blood perfusion deep within microcirculation tissue beds in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ruikang K [Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97237 (United States)

    2007-12-07

    Optical micro-angiography (OMAG) is a recently developed method of imaging localized blood perfusion at capillary level resolution within microcirculatory beds. This paper reports that the OMAG is capable of directional blood perfusion mapping in vivo. This is achieved simply by translating the mirror located in the reference arm back and forth while 3D imaging is performed. The mirror which moves toward the incident beam gives the blood perfusion that flows away from the beam direction and vice versa. The approach is experimentally demonstrated by imaging of a flow phantom and then cerebro-vascular perfusion of a live mouse with cranium intact.

  17. Spatial Vertical Directionality and Correlation of Low-Frequency Ambient Noise in Deep Ocean Direct-Arrival Zones

    Directory of Open Access Journals (Sweden)

    Qiulong Yang

    2018-01-01

    Full Text Available Wind-driven and distant shipping noise sources contribute to the total noise field in the deep ocean direct-arrival zones. Wind-driven and distant shipping noise sources may significantly and simultaneously affect the spatial characteristics of the total noise field to some extent. In this work, a ray approach and parabolic equation solution method were jointly utilized to model the low-frequency ambient noise field in a range-dependent deep ocean environment by considering their calculation accuracy and efficiency in near-field wind-driven and far-field distant shipping noise fields. The reanalysis databases of National Center of Environment Prediction (NCEP and Volunteer Observation System (VOS were used to model the ambient noise source intensity and distribution. Spatial vertical directionality and correlation were analyzed in three scenarios that correspond to three wind speed conditions. The noise field was dominated by distant shipping noise sources when the wind speed was less than 3 m/s, and then the spatial vertical directionality and vertical correlation of the total noise field were nearly consistent with those of distant shipping noise field. The total noise field was completely dominated by near field wind generated noise sources when the wind speed was greater than 12 m/s at 150 Hz, and then the spatial vertical correlation coefficient and directionality pattern of the total noise field was approximately consistent with that of the wind-driven noise field. The spatial characteristics of the total noise field for wind speeds between 3 m/s and 12 m/s were the weighted results of wind-driven and distant shipping noise fields. Furthermore, the spatial characteristics of low-frequency ambient noise field were compared with the classical Cron/Sherman deep water noise field coherence function. Simulation results with the described modeling method showed good agreement with the experimental measurement results based on the vertical line

  18. Spatial Vertical Directionality and Correlation of Low-Frequency Ambient Noise in Deep Ocean Direct-Arrival Zones

    Science.gov (United States)

    Yang, Qiulong; Yang, Kunde; Cao, Ran; Duan, Shunli

    2018-01-01

    Wind-driven and distant shipping noise sources contribute to the total noise field in the deep ocean direct-arrival zones. Wind-driven and distant shipping noise sources may significantly and simultaneously affect the spatial characteristics of the total noise field to some extent. In this work, a ray approach and parabolic equation solution method were jointly utilized to model the low-frequency ambient noise field in a range-dependent deep ocean environment by considering their calculation accuracy and efficiency in near-field wind-driven and far-field distant shipping noise fields. The reanalysis databases of National Center of Environment Prediction (NCEP) and Volunteer Observation System (VOS) were used to model the ambient noise source intensity and distribution. Spatial vertical directionality and correlation were analyzed in three scenarios that correspond to three wind speed conditions. The noise field was dominated by distant shipping noise sources when the wind speed was less than 3 m/s, and then the spatial vertical directionality and vertical correlation of the total noise field were nearly consistent with those of distant shipping noise field. The total noise field was completely dominated by near field wind generated noise sources when the wind speed was greater than 12 m/s at 150 Hz, and then the spatial vertical correlation coefficient and directionality pattern of the total noise field was approximately consistent with that of the wind-driven noise field. The spatial characteristics of the total noise field for wind speeds between 3 m/s and 12 m/s were the weighted results of wind-driven and distant shipping noise fields. Furthermore, the spatial characteristics of low-frequency ambient noise field were compared with the classical Cron/Sherman deep water noise field coherence function. Simulation results with the described modeling method showed good agreement with the experimental measurement results based on the vertical line array deployed near

  19. γ-γ directional angular correlations measurements for transitions in 140 Ce

    International Nuclear Information System (INIS)

    Zamboni, C.B.; Lapolli, A.L.; Silva Figueira, M.C. da; Yoneama, M.L.; Dias, J.F.; Medeiros, J.A.G. de.

    1990-01-01

    The directional correlations of coincident gamma transitions have been measured in 140 Ce following the β - decay of 140 La, with T 1/2 = 40,3 hs, using a spectrometer consisting of two Ge detectors. The measurements were carried out for 8 gamma cascades and the multipole mixing ratios, δ, for the majority gamma transitions were extracted from the present results. (author)

  20. Degree-degree correlations in directed networks with heavy-tailed degrees

    NARCIS (Netherlands)

    van der Hoorn, W.L.F.; Litvak, Nelli

    2013-01-01

    In network theory, Pearson's correlation coefficients are most commonly used to measure the degree assortativity of a network. We investigate the behavior of these coefficients in the setting of directed networks with heavy-tailed degree sequences. We prove that for graphs where the in- and

  1. Mapping soil deformation around plant roots using in vivo 4D X-ray Computed Tomography and Digital Volume Correlation.

    Science.gov (United States)

    Keyes, S D; Gillard, F; Soper, N; Mavrogordato, M N; Sinclair, I; Roose, T

    2016-06-14

    The mechanical impedance of soils inhibits the growth of plant roots, often being the most significant physical limitation to root system development. Non-invasive imaging techniques have recently been used to investigate the development of root system architecture over time, but the relationship with soil deformation is usually neglected. Correlative mapping approaches parameterised using 2D and 3D image data have recently gained prominence for quantifying physical deformation in composite materials including fibre-reinforced polymers and trabecular bone. Digital Image Correlation (DIC) and Digital Volume Correlation (DVC) are computational techniques which use the inherent material texture of surfaces and volumes, captured using imaging techniques, to map full-field deformation components in samples during physical loading. Here we develop an experimental assay and methodology for four-dimensional, in vivo X-ray Computed Tomography (XCT) and apply a Digital Volume Correlation (DVC) approach to the data to quantify deformation. The method is validated for a field-derived soil under conditions of uniaxial compression, and a calibration study is used to quantify thresholds of displacement and strain measurement. The validated and calibrated approach is then demonstrated for an in vivo test case in which an extending maize root in field-derived soil was imaged hourly using XCT over a growth period of 19h. This allowed full-field soil deformation data and 3D root tip dynamics to be quantified in parallel for the first time. This fusion of methods paves the way for comparative studies of contrasting soils and plant genotypes, improving our understanding of the fundamental mechanical processes which influence root system development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. In vivo 1D and 2D correlation MR spectroscopy of the soleus muscle at 7T

    Science.gov (United States)

    Ramadan, Saadallah; Ratai, Eva-Maria; Wald, Lawrence L.; Mountford, Carolyn E.

    2010-05-01

    AimThis study aims to (1) undertake and analyse 1D and 2D MR correlation spectroscopy from human soleus muscle in vivo at 7T, and (2) determine T1 and T2 relaxation time constants at 7T field strength due to their importance in sequence design and spectral quantitation. MethodSix healthy, male volunteers were consented and scanned on a 7T whole-body scanner (Siemens AG, Erlangen, Germany). Experiments were undertaken using a 28 cm diameter detunable birdcage coil for signal excitation and an 8.5 cm diameter surface coil for signal reception. The relaxation time constants, T1 and T2 were recorded using a STEAM sequence, using the 'progressive saturation' method for the T1 and multiple echo times for T2. The 2D L-Correlated SpectroscopY (L-COSY) method was employed with 64 increments (0.4 ms increment size) and eight averages per scan, with a total time of 17 min. ResultsT1 and T2 values for the metabolites of interest were determined. The L-COSY spectra obtained from the soleus muscle provided information on lipid content and chemical structure not available, in vivo, at lower field strengths. All molecular fragments within multiple lipid compartments were chemically shifted by 0.20-0.26 ppm at this field strength. 1D and 2D L-COSY spectra were assigned and proton connectivities were confirmed with the 2D method. ConclusionIn vivo 1D and 2D spectroscopic examination of muscle can be successfully recorded at 7T and is now available to assess lipid alterations as well as other metabolites present with disease. T1 and T2 values were also determined in soleus muscle of male healthy volunteers.

  3. Correlating In Vitro Splice Switching Activity With Systemic In Vivo Delivery Using Novel ZEN-modified Oligonucleotides

    Directory of Open Access Journals (Sweden)

    Suzan M Hammond

    2014-01-01

    Full Text Available Splice switching oligonucleotides (SSOs induce alternative splicing of pre-mRNA and typically employ chemical modifications to increase nuclease resistance and binding affinity to target pre-mRNA. Here we describe a new SSO non-base modifier (a naphthyl-azo group, “ZEN™” to direct exon exclusion in mutant dystrophin pre-mRNA to generate functional dystrophin protein. The ZEN modifier is placed near the ends of a 2′-O-methyl (2′OMe oligonucleotide, increasing melting temperature and potency over unmodified 2′OMe oligonucleotides. In cultured H2K cells, a ZEN-modified 2′OMe phosphorothioate (PS oligonucleotide delivered by lipid transfection greatly enhanced dystrophin exon skipping over the same 2′OMePS SSO lacking ZEN. However, when tested using free gymnotic uptake in vitro and following systemic delivery in vivo in dystrophin deficient mdx mice, the same ZEN-modified SSO failed to enhance potency. Importantly, we show for the first time that in vivo activity of anionic SSOs is modelled in vitro only when using gymnotic delivery. ZEN is thus a novel modifier that enhances activity of SSOs in vitro but will require improved delivery methods before its in vivo clinical potential can be realized.

  4. In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Hadrup, Niels; Boberg, Julie

    2013-01-01

    Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3.All five single pesticides and the two mixtures were investigated...... for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity.The two......, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable...

  5. Correlations of Mean Process Parameters for Agricultural Products Drying in Thin Bed in Solar Direct Dryers

    Directory of Open Access Journals (Sweden)

    MSc. Ciro César Bergues-Ricardo

    2015-11-01

    Full Text Available A group of correlations is given between mean parameters of drying process drying velocity, energy losses, useful energy, and thermal efficiency. Those are suitable for conditions of thin bed drying, in direct solar dryers, and may help for developing of an integral approach of solar drying in those conditions. Correlations are reliable for drying processes of diverse crop products specified, suchas roots, seeds, vegetables, fruits, wood, etc, with natural or forced convection. Correlations were validated in Cuba for usual ranges of efficiency and products in solar dryers of cover, cabinet and house types, in tropical conditions. These correlations are useful for design and exploitation ofdryers and for theoretical and practical comprehension of solar drying like a system.

  6. The in Vivo Toxicity of Hydroxyurea Depends on Its Direct Target Catalase*

    OpenAIRE

    Juul, Trine; Malolepszy, Anna; Dybk?r, Karen; Kidmose, Rune; Rasmussen, Jan Trige; Andersen, Gregers Rom; Johnsen, Hans Erik; J?rgensen, Jan-Elo; Andersen, Stig Uggerh?j

    2010-01-01

    Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified ...

  7. In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents

    Energy Technology Data Exchange (ETDEWEB)

    Tedeschi, Enrico; Canna, Antonietta; Cocozza, Sirio; Russo, Carmela; Angelini, Valentina; Brunetti, Arturo [University ' ' Federico II' ' , Neuroradiology, Department of Advanced Biomedical Sciences, Naples (Italy); Palma, Giuseppe; Quarantelli, Mario [National Research Council, Institute of Biostructure and Bioimaging, Naples (Italy); Borrelli, Pasquale; Salvatore, Marco [IRCCS SDN, Naples (Italy); Lanzillo, Roberta; Postiglione, Emanuela; Morra, Vincenzo Brescia [University ' ' Federico II' ' , Department of Neurosciences, Reproductive and Odontostomatological Sciences, Naples (Italy)

    2016-12-15

    To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA). In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis. The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA. In RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given. (orig.)

  8. Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats with a portacaval shunt

    NARCIS (Netherlands)

    van der Graaff, M; Vermeulen, N P; Joeres, R P; Breimer, D D

    1984-01-01

    To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate 'high-clearance' compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control

  9. Molecular dynamics simulations of Gay-Berne nematic liquid crystal: Elastic properties from direct correlation functions

    International Nuclear Information System (INIS)

    Stelzer, J.; Trebin, H.R.; Longa, L.

    1994-08-01

    We report NVT and NPT molecular dynamics simulations of a Gay-Berne nematic liquid crystal using generalization of recently proposed algorithm by Toxvaerd [Phys. Rev. E47, 343, 1993]. On the basis of these simulations the Oseen-Zoher-Frank elastic constants K 11 , K 22 and K 33 as well as the surface constants K 13 and K 24 have been calculated within the framework of the direct correlation function approach of Lipkin et al. [J. Chem. Phys. 82, 472 (1985)]. The angular coefficients of the direct pair correlation function, which enter the final formulas, have been determined from the computer simulation data for the pair correlation function of the nematic by combining the Ornstein-Zernike relation and the Wienier-Hopf factorization scheme. The unoriented nematic approximation has been assumed when constructing the reference, isotropic state of Lipkin et al. By an extensive study of the model over a wide range of temperatures, densities and pressures a very detailed information has been provided about elastic behaviour of the Gay-Berne nematic. Interestingly, it is found that the results for the surface elastic constants are qualitatively different than those obtained with the help of analytical approximations for the isotropic, direct pair correlation function. For example, the values of the surface elastic constants are negative and an order of magnitude smaller than the bulk elasticity. (author). 30 refs, 9 figs

  10. Search for small-scale angular correlations of neutrino arrival directions in IceCube

    Energy Technology Data Exchange (ETDEWEB)

    Schimp, Michael; Glagla, Martin; Haack, Christian; Leuermann, Martin; Raedel, Leif; Reimann, Rene; Schoenen, Sebastian; Wiebusch, Christopher [III. Physikalisches Institut, RWTH Aachen University, 52056 Aachen (Germany); Collaboration: IceCube-Collaboration

    2015-07-01

    Recently, the IceCube Neutrino Observatory discovered a diffuse flux of extra-terrestrial high-energy neutrinos. The identification of their astrophysical sources is one of the goals of current investigations. This analysis is based on the expansion of muon neutrino arrival directions in spherical harmonics, which is sensitive to angular correlations. A large number of point sources distributed over the sky would leave an imprint on the spectrum of observed expansion coefficients, even if the sources are too weak to be detected individually. We present the analysis method and discuss possible astrophysical interpretations for the observation or non-observation of such a correlation.

  11. Tumor Oxygen Dynamics: Correlation of In Vivo MRI with Histological Findings

    Directory of Open Access Journals (Sweden)

    Dawen Zhao

    2003-07-01

    Full Text Available Tumor oxygenation has long been recognized as a significant factor influencing cancer therapy. We recently established a novel magnetic resonance in vivo approach to measuring regional tumor oxygen tension, FREDOM (Fluorocarbon Relaxometry Using Echo Planar Imaging for Dynamic Oxygen Mapping, using hexafluorobenzene (HFB as the reporter molecule. We have now investigated oxygen dynamics in the two Dunning prostate R3327 rat tumor sublines, AT1 and H. FREDOM revealed considerable intratumoral heterogeneity in the distribution of pO2 values in both sublines. The anaplastic fastergrowing AT1 tumors were more hypoxic compared with the size-matched, well-differentiated, and slower-growing H tumors. Respiratory challenge with oxygen produced significant increases in mean and median pO2 in all the H tumors (P3 cm3. Immunohistochemical studies using the hypoxia marker, pimonidazole, and the vascular endothelial cell marker, CD31, confirmed that the H tumors had more extensive vasculature and less hypoxia than the AT1 tumors. These results further validate the utilization of FREDOM to monitor tumor oxygenation and concur with the hypothesis that the level of hypoxia is related to tumor growth rate and poor vascularity.

  12. Cortical microinfarcts detected in vivo on 3 Tesla MRI: clinical and radiological correlates.

    Science.gov (United States)

    van Dalen, Jan Willem; Scuric, Eva E M; van Veluw, Susanne J; Caan, Matthan W A; Nederveen, Aart J; Biessels, Geert Jan; van Gool, Willem A; Richard, Edo

    2015-01-01

    Cortical microinfarcts (CMIs) are a common postmortem finding associated with vascular risk factors, cognitive decline, and dementia. Recently, CMIs identified in vivo on 7 Tesla MRI also proved retraceable on 3 Tesla MRI. We evaluated CMIs on 3 Tesla MRI in a population-based cohort of 194 nondemented older people (72-80 years) with systolic hypertension. Using a case-control design, participants with and without CMIs were compared on age, sex, cardiovascular risk factors, and white matter hyperintensity volume. We identified 23 CMIs in 12 participants (6%). CMIs were associated with older age, higher diastolic blood pressure, and a history of recent stroke. There was a trend for a higher white matter hyperintensity volume in participants with CMIs. We found an association of CMIs with clinical parameters, including age and cardiovascular risk factors. Although the prevalence of CMIs is relatively low, our results suggest that the study of CMIs in larger clinical studies is possible using 3 Tesla MRI. This opens the possibility of large-scale prospective investigation of the clinical relevance of CMIs in older people. © 2014 American Heart Association, Inc.

  13. Two-dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo.

    Science.gov (United States)

    Singhal, Aparna; Nagarajan, Rajakumar; Hinkin, Charles H; Kumar, Rajesh; Sayre, James; Elderkin-Thompson, Virginia; Huda, Amir; Gupta, Rakesh K; Han, Steven-Huy; Thomas, M Albert

    2010-07-01

    To evaluate regional cerebral metabolic and structural changes in patients with minimal hepatic encephalopathy (MHE) using two-dimensional (2D) MR spectroscopy (MRS) and T( (1) )-weighted MRI, to correlate the observed MR changes with neuropsychological (NP) test scores, and to compare the diagnostic accuracy of MRI, 2D MRS, and NP tests in discriminating between patients and healthy subjects. Thirty-three MHE patients and 30 healthy controls were investigated. The 2D localized correlated spectroscopy (L-COSY) was performed in the frontal and occipital brain on a 1.5 Tesla (T) MR scanner. The NP test battery included 15 tests, grouped into 6 cognitive domains. Globus pallidus signal intensities were calculated from T(1)-weighted images. The 2D MRS showed significant differences in ratios of the following metabolite(s) peaks with respect to creatine (Cr): decreased myo-inositol (mI), choline (Ch), mICh, and increased (glutamate plus glutamine) (Glx) in patients compared with healthy subjects in both occipital and frontal lobes. Frontal lobe taurine also showed a decline in patients. The NP test results revealed declines in cognitive speed, motor function, executive function, and global cognitive status. Significant correlations were found between the altered metabolites and NP tests. Alteration in the mICh/Cr ratio was noted as a powerful discriminant between healthy subjects and the patients. The study demonstrates that relative metabolite levels determined by 2D MRS, in particular mICh/Cr, provide the best diagnostic prediction for MHE. The results suggest that depletions of myo-inositol, choline and taurine with respect to creatine correlate with measures of neuropsychological impairment. (c) 2010 Wiley-Liss, Inc.

  14. Histological correlation of 7 T multi-parametric MRI performed in ex-vivo Achilles tendon

    Energy Technology Data Exchange (ETDEWEB)

    Juras, Vladimir [Center of Excellence for High Field MR, Department of Radiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090, Vienna (Austria); Institute of Measurement Science, Department of Imaging Methods, Dubravska cesta 9, 84104, Bratislava (Slovakia); Apprich, Sebastian; Pressl, Christina; Zbyn, Stefan [Center of Excellence for High Field MR, Department of Radiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090, Vienna (Austria); Szomolanyi, Pavol [Center of Excellence for High Field MR, Department of Radiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090, Vienna (Austria); Institute of Measurement Science, Department of Imaging Methods, Dubravska cesta 9, 84104, Bratislava (Slovakia); Domayer, Stephan; Hofstaetter, Jochen G. [Department of Orthopedic Surgery, Vienna General Hospital, Medical University of Vienna, A-1090 Vienna (Austria); Trattnig, Siegfried, E-mail: siegfried.trattnig@meduniwien.ac.at [Center of Excellence for High Field MR, Department of Radiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090, Vienna (Austria)

    2013-05-15

    Introduction: The goal of this in vitro validation study was to investigate the feasibility of biochemical MRI techniques, such as sodium imaging, T{sub 2} mapping, fast imaging with steady state precession (FISP), and reversed FISP (PSIF), as potential markers for collagen, glycosaminoglycan and water content in the Achilles tendon. Materials and methods: Five fresh cadaver ankles acquired from a local anatomy department were used in the study. To acquire a sodium signal from the Achilles tendon, a 3D-gradient-echo sequence, optimized for sodium imaging, was used with TE = 7.71 ms and TR = 17 ms. The T{sub 2} relaxation times were obtained using a multi-echo, spin-echo technique with a repetition time (TR) of 1200 ms and six echo times. A 3D, partially balanced, steady-state gradient echo pulse sequence was used to acquire FISP and PSIF images, with TR/TE = 6.96/2.46 ms. MRI parameters were correlated with each other, as well as with histologically assessed glycosaminoglycan and water content in cadaver Achilles tendons. Results: The highest relevant Pearson correlation coefficient was found between sodium SNR and glycosaminoglycan content (r = 0.71, p = 0.007). Relatively high correlation was found between the PSIF signal and T{sub 2} values (r = 0.51, p = 0.036), and between the FISP signal and T{sub 2} values (r = 0.56, p = 0.047). Other correlations were found to be below the moderate level. Conclusion: This study demonstrated the feasibility of progressive biochemical MRI methods for the imaging of the AT. A GAG-specific, contrast-free method (sodium imaging), as well as collagen- and water-sensitive methods (T{sub 2} mapping, FISP, PSIF), may be used in fast-relaxing tissues, such as tendons, in reasonable scan times.

  15. Histological correlation of 7 T multi-parametric MRI performed in ex-vivo Achilles tendon

    International Nuclear Information System (INIS)

    Juras, Vladimir; Apprich, Sebastian; Pressl, Christina; Zbyn, Stefan; Szomolanyi, Pavol; Domayer, Stephan; Hofstaetter, Jochen G.; Trattnig, Siegfried

    2013-01-01

    Introduction: The goal of this in vitro validation study was to investigate the feasibility of biochemical MRI techniques, such as sodium imaging, T 2 mapping, fast imaging with steady state precession (FISP), and reversed FISP (PSIF), as potential markers for collagen, glycosaminoglycan and water content in the Achilles tendon. Materials and methods: Five fresh cadaver ankles acquired from a local anatomy department were used in the study. To acquire a sodium signal from the Achilles tendon, a 3D-gradient-echo sequence, optimized for sodium imaging, was used with TE = 7.71 ms and TR = 17 ms. The T 2 relaxation times were obtained using a multi-echo, spin-echo technique with a repetition time (TR) of 1200 ms and six echo times. A 3D, partially balanced, steady-state gradient echo pulse sequence was used to acquire FISP and PSIF images, with TR/TE = 6.96/2.46 ms. MRI parameters were correlated with each other, as well as with histologically assessed glycosaminoglycan and water content in cadaver Achilles tendons. Results: The highest relevant Pearson correlation coefficient was found between sodium SNR and glycosaminoglycan content (r = 0.71, p = 0.007). Relatively high correlation was found between the PSIF signal and T 2 values (r = 0.51, p = 0.036), and between the FISP signal and T 2 values (r = 0.56, p = 0.047). Other correlations were found to be below the moderate level. Conclusion: This study demonstrated the feasibility of progressive biochemical MRI methods for the imaging of the AT. A GAG-specific, contrast-free method (sodium imaging), as well as collagen- and water-sensitive methods (T 2 mapping, FISP, PSIF), may be used in fast-relaxing tissues, such as tendons, in reasonable scan times

  16. Correlation of regional disease and in vivo PO2 in rat mammary adenocarcinoma.

    OpenAIRE

    Cole, M. A.; Crawford, D. W.; Warner, N. E.; Puffer, H. W.

    1983-01-01

    A knowledge of the distribution of oxygen tension (PO2) and vascularization in neoplasia has been fundamental to understanding relationships between tumor growth, hypoxia, and therapy. We have combined recessed oxygen microcathode and freeze-substitution techniques to correlate in situ PO2 profiles and morphologic features in 7,12-dimethylbenz(a)anthracene (DMBA) tumors in rats. Overlying connective tissue of transplanted tumor was exposed by a 1-2 mm incision and a cross-stitch pattern demar...

  17. Correlation between magnetocapacitance effect and polarization flop direction in a slanted magnetic field in multiferroic helimagnets

    International Nuclear Information System (INIS)

    Abe, Nobuyuki; Sagayama, Hajime; Arima, Taka-hisa; Taniguchi, Kouji

    2011-01-01

    The relationship between the magnetocapacitance effect and rotation direction of electric polarization (P) in a canted magnetic field has been investigated for multiferroic RMnO 3 (R = Tb 1-x Dy x and Eu 0.6 Y 0.4 ). We observed a clear correlation between the enhancement of the magnetocapacitance effect and the rotation direction of P in a P-flop transition. These results indicate that the mobility and the stability of the 90 deg. domain wall in a P-flop transition are dominated by its thickness.

  18. Cross-correlation analysis of pulse wave propagation in arteries: in vitro validation and in vivo feasibility.

    Science.gov (United States)

    Nauleau, Pierre; Apostolakis, Iason; McGarry, Matthew; Konofagou, Elisa

    2018-05-29

    The stiffness of the arteries is known to be an indicator of the progression of various cardiovascular diseases. Clinically, the pulse wave velocity (PWV) is used as a surrogate for arterial stiffness. Pulse wave imaging (PWI) is a non-invasive, ultrasound-based imaging technique capable of mapping the motion of the vessel walls, allowing the local assessment of arterial properties. Conventionally, a distinctive feature of the displacement wave (e.g. the 50% upstroke) is tracked across the map to estimate the PWV. However, the presence of reflections, such as those generated at the carotid bifurcation, can bias the PWV estimation. In this paper, we propose a two-step cross-correlation based method to characterize arteries using the information available in the PWI spatio-temporal map. First, the area under the cross-correlation curve is proposed as an index for locating the regions of different properties. Second, a local peak of the cross-correlation function is tracked to obtain a less biased estimate of the PWV. Three series of experiments were conducted in phantoms to evaluate the capabilities of the proposed method compared with the conventional method. In the ideal case of a homogeneous phantom, the two methods performed similarly and correctly estimated the PWV. In the presence of reflections, the proposed method provided a more accurate estimate than conventional processing: e.g. for the soft phantom, biases of  -0.27 and -0.71 m · s -1 were observed. In a third series of experiments, the correlation-based method was able to locate two regions of different properties with an error smaller than 1 mm. It also provided more accurate PWV estimates than conventional processing (biases:  -0.12 versus -0.26 m · s -1 ). Finally, the in vivo feasibility of the proposed method was demonstrated in eleven healthy subjects. The results indicate that the correlation-based method might be less precise in vivo but more accurate than the conventional method.

  19. A study of the dynamics of PTEN proteins in living cells using in vivo fluorescence correlation spectroscopy

    Science.gov (United States)

    Du, Zhixue; Dong, Chaoqing; Ren, Jicun

    2017-06-01

    PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most important tumor-suppressor proteins, which plays a key role in negative regulation of the PI3K/AKT pathway, and governs many cellular processes including growth, proliferation, survival and migration. The dynamics of PTEN proteins in single living cells is as yet unclear owing to a shortage of suitable in vivo approaches. Here, we report a single-molecule method for in vivo study of the dynamics of PTEN proteins in living cells using fluorescence correlation spectroscopy (FCS). First, we established a monoclonal H1299 stable cell line expressing enhanced green fluorescent protein (EGFP) and PTEN (EGFP-PTEN) fusion proteins; we then developed an in vivo FCS method to study the dynamics of EGFP-PTEN both in the nucleus and the cytoplasm. We investigated the diffusion behaviors of EGFP and EGFP-PTEN in solution, nucleus and cytosol, and observed that the motion of PTEN in living cells was restricted compared with EGFP. Finally, we investigated the protein dynamics in living cells under oxidative stress stimulation and a cellular ATP depletion treatment. Under oxidative stress stimulation, the EGFP-PTEN concentration increased in the nucleus, but slightly decreased in the cytoplasm. The diffusion coefficient and alpha value of EGFP-PTEN reduced significantly both in the nucleus and cytoplasm; the significantly decreased alpha parameter indicates a more restricted Brownian diffusion behavior. Under the cellular ATP depletion treatment, the concentration of EGFP-PTEN remained unchanged in the nucleus and decreased significantly in cytosol. The diffusion coefficient of EGFP-PTEN decreased significantly in cytosol, but showed no significant change in the nucleus; the alpha value decreased significantly in both the nucleus and cytoplasm. These results suggest that the concentration and mobility of PTEN in the nucleus and cytoplasm can be regulated by stimulation methods. Our approach provides a unique

  20. Fluorescence correlation spectroscopy and fluorescence cross-correlation spectroscopy reveal the cytoplasmic origination of loaded nuclear RISC in vivo in human cells.

    Science.gov (United States)

    Ohrt, Thomas; Mütze, Jörg; Staroske, Wolfgang; Weinmann, Lasse; Höck, Julia; Crell, Karin; Meister, Gunter; Schwille, Petra

    2008-11-01

    Studies of RNA interference (RNAi) provide evidence that in addition to the well-characterized cytoplasmic mechanisms, nuclear mechanisms also exist. The mechanism by which the nuclear RNA-induced silencing complex (RISC) is formed in mammalian cells, as well as the relationship between the RNA silencing pathways in nuclear and cytoplasmic compartments is still unknown. Here we show by applying fluorescence correlation and cross-correlation spectroscopy (FCS/FCCS) in vivo that two distinct RISC exist: a large approximately 3 MDa complex in the cytoplasm and a 20-fold smaller complex of approximately 158 kDa in the nucleus. We further show that nuclear RISC, consisting only of Ago2 and a short RNA, is loaded in the cytoplasm and imported into the nucleus. The loaded RISC accumulates in the nucleus depending on the presence of a target, based on an miRNA-like interaction with impaired cleavage of the cognate RNA. Together, these results suggest a new RISC shuttling mechanism between nucleus and cytoplasm ensuring concomitant gene regulation by small RNAs in both compartments.

  1. Direct evaluation of radiation damage in human hematopoietic progenitor cells in vivo

    International Nuclear Information System (INIS)

    Kyoizumi, Seishi; McCune, J.M.; Namikawa, Reiko

    1994-01-01

    We have developed techniques by which normal functional elements of human bone marrow can be implanted into immunodeficient C.B-17 scid/scid (SCID) mice. Afterward, long-term multilineage human hematopoiesis is sustained in vivo. We evaluated the effect of irradiation on the function of human bone marrow with this in vivo model. After whole-body X irradiation of the engrafted animals, it was determined that the D 0 value of human committed progenitor cells within the human marrow was 1.00 ± 0.09 (SEM) Gy for granulocyte-macrophage colony-forming units (CFU-GM) and 0.74 ± 0.12 Gy for erythroidburst-forming units (BFU-E). The effects of irradiation on the hematopoietic elements were reduced when the radioprotective agent WR-2721 was administered prior to irradiation. After low-dose irradiation, recovery of human granulocyte colony-stimulating factor (G-CSF). This small animal model may prove amenable for the analysis of the risk of the exposure of humans to irradiation as well as for the development of new modalities for the prevention and treatment of radiation-induced hematopoietic damage. 41 refs., 5 figs., 1 tab

  2. In vivo stability and inertness of various direct labelled and chelate-tagged protein

    International Nuclear Information System (INIS)

    Janoki, A.; Korosi, L.; Klivenyi, G.; Spett, B.

    1987-01-01

    There were looking for methods giving precise information about composition and activity distribution of protein components, both in the initial samples and serum samples after intravenous administration. It was tested the applicability of electroimmunoassay, polyacrilamide gel electrophoresis and high performance liquid chromatography for the assessment of in vivo stability and labelled proteins. The model compound was human serum albumin (HSA) labelled with 99m Tc and 125 I, respectively. Bifunctional chelate labelling was done with desferrioxamine, in this case protein was labelled with 67 Ga. Biodistribution of the labelled compounds and their elimination from the blood were studied in rabbits. Experience with various labelling proteins, especially with Tc-Sn-HSA system indicate that in vivo stability of this compounds are generally low. Following intravenous injection of proteins labelled with metal isotopes, due to dilution and to the presence of considerable amount of compatitive protein in the serum, part of the label is being detached from the carrier protein. Distribution of the detached metal is different from the original distribution of the protein. This problem arises also with radiopharmaceuticals based on monoclonal antibodies. (M.E.L.) [es

  3. Direct noninvasive observation of near infrared photobleaching of autofluorescence in human volar side fingertips in vivo

    Science.gov (United States)

    Deng, Bin; Wright, Colin; Lewis-Clark, Eric; Shaheen, G.; Geier, Roman; Chaiken, J.

    2010-02-01

    Human transdermal in vivo spectroscopic applications for tissue analysis involving near infrared (NIR) light often must contend with broadband NIR fluorescence that, depending on what kind of spectroscopy is being employed, can degrade signal to noise ratios and dynamic range. Such NIR fluorescence, i.e. "autofluorescence" is well known to originate in blood tissues and various other endogenous materials associated with the static tissues. Results of recent experiments on human volar side fingertips in vivo are beginning to provide a relative ordering of the contributions from various sources. Preliminary results involving the variation in the bleaching effect across different individuals suggest that for 830 nm excitation well over half of the total fluorescence comes from the static tissues and remainder originates with the blood tissues, i.e. the plasma and the hematocrit. Of the NIR fluorescence associated with the static tissue, over half originates with products of well-known post-enzymatic glycation reactions, i.e. Maillard chemistry, in the skin involving glucose and other carbohydrates and skin proteins like collagen and cytosol proteins.

  4. In vivo time-gated diffuse correlation spectroscopy at quasi-null source-detector separation.

    Science.gov (United States)

    Pagliazzi, M; Sekar, S Konugolu Venkata; Di Sieno, L; Colombo, L; Durduran, T; Contini, D; Torricelli, A; Pifferi, A; Mora, A Dalla

    2018-06-01

    We demonstrate time domain diffuse correlation spectroscopy at quasi-null source-detector separation by using a fast time-gated single-photon avalanche diode without the need of time-tagging electronics. This approach allows for increased photon collection, simplified real-time instrumentation, and reduced probe dimensions. Depth discriminating, quasi-null distance measurement of blood flow in a human subject is presented. We envision the miniaturization and integration of matrices of optical sensors of increased spatial resolution and the enhancement of the contrast of local blood flow changes.

  5. Total and Direct Correlation Function Integrals from Molecular Simulation of Binary Systems

    DEFF Research Database (Denmark)

    Wedberg, Nils Hejle Rasmus Ingemar; O’Connell, John P.; Peters, Günther H.J.

    2011-01-01

    The possibility for obtaining derivative properties for mixtures from integrals of spatial total and direct correlation functions obtained from molecular dynamics simulations is explored. Theoretically well-supported methods are examined to extend simulation radial distribution functions to long...... are consistent with an excess Helmholtz energy model fitted to available simulations. In addition, simulations of water/methanol and water/t-butanol mixtures have been carried out. The method yields results for partial molar volumes, activity coefficient derivatives, and individual correlation function integrals...... in reasonable agreement with smoothed experimental data. The proposed method for obtaining correlation function integrals is shown to perform at least as well as or better than two previously published approaches....

  6. Reversed stereo depth and motion direction with anti-correlated stimuli.

    Science.gov (United States)

    Read, J C; Eagle, R A

    2000-01-01

    We used anti-correlated stimuli to compare the correspondence problem in stereo and motion. Subjects performed a two-interval forced-choice disparity/motion direction discrimination task for different displacements. For anti-correlated 1d band-pass noise, we found weak reversed depth and motion. With 2d anti-correlated stimuli, stereo performance was impaired, but the perception of reversed motion was enhanced. We can explain the main features of our data in terms of channels tuned to different spatial frequencies and orientation. We suggest that a key difference between the solution of the correspondence problem by the motion and stereo systems concerns the integration of information at different orientations.

  7. Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium.

    Science.gov (United States)

    Borkar, Nrupa; Xia, Dengning; Holm, René; Gan, Yong; Müllertz, Anette; Yang, Mingshi; Mu, Huiling

    2014-01-23

    Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs are not fully understood. This study aimed at investigating the effect of particle size of LMP on drug release in vitro as well as absorption in vivo in order to get a better understanding on the effect of degradation of lipid particles on drug solubilisation and absorption. Fenofibrate, a model poorly water-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (pmicroparticles>control. In summary, the present study demonstrated the particle size dependence of bioavailability of fenofibrate loaded LMP in rat model which correlates well with the in vitro drug release performed in the biorelevant medium. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Prediction of direct and indirect genetic gains and genotypic correlations in rubber tree progenies

    Directory of Open Access Journals (Sweden)

    Cecília Khusala Verardi

    2011-09-01

    Full Text Available The objective of this work was to estimate the genetic parameters, genotypic and phenotypic correlations, and direct and indirect genetic gains among and within rubber tree (Hevea brasiliensis progenies. The experiment was set up at the Municipality of Jaú, SP, Brazil. A randomized complete block design was used, with 22 treatments (progenies, 6 replicates, and 10 plants per plot at a spacing of 3x3 m. Three‑year‑old progenies were assessed for girth, rubber yield, and bark thickness by direct and indirect gains and genotypic correlations. The number of latex vessel rings showed the best correlations, correlating positively and significantly with girth and bark thickness. Selection gains among progenies were greater than within progeny for all the variables analyzed. Total gains obtained were high, especially for girth increase and rubber yield, which were 93.38 and 105.95%, respectively. Young progeny selection can maximize the expected genetic gains, reducing the rubber tree selection cycle.

  9. Fluorescence lifetime measurement with confocal endomicroscopy for direct analysis of tissue biochemistry in vivo

    Directory of Open Access Journals (Sweden)

    Youngjae Won

    2016-08-01

    Full Text Available Confocal endomicroscopy is a powerful tool for in vivo real-time imaging at cellular resolution inside a living body without tissue resection. Microscopic fluorescence lifetime measurement can provide information about localized biochemical conditions such as pH and the concentrations of oxygen and calcium. We hypothesized that combining these techniques could assist accurate cancer discrimination by providing both biochemical and morphological information. We designed a dual-mode experimental setup for confocal endomicroscopic imaging and fluorescence lifetime measurement and applied it to a mouse xenograft model of activated human pancreatic cancer generated by subcutaneous injection of AsPC-1 tumor cells. Using this method with pH-sensitive sodium fluorescein injection, we demonstrated discrimination between normal and cancerous tissues in a living mouse. With further development, this method may be useful for clinical cancer detection.

  10. Tumor p-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Erica Lynn Bradshaw-Pierce

    2013-03-01

    Full Text Available P-glycoprotein (P-gp, a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309, a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1 (P-gp expression was evaluated by microarray for these cell lines. P-gp expression was determined by western blot and activity determined by rhodamine efflux assay. Knock down of P-gp and pharmacologic inhibition of P-gp to restore PF-309 activity was performed in vitro. PF-309 activity was evaluated in vivo in cell line xenograft models and in primary patient derived tumor xenografts (PDTX. Mice were treated with 25 mg/kg PF-309 orally, twice daily. On the last day of treatment, tumor and plasma were collected for PF-309 analysis. Here we show that ABCB1 gene expression correlates with resistance to PF-309 treatment in vitro and the expression and activity of P-gp was verified in a panel of resistant cells. Furthermore, inhibition of P-gp increased the sensitivity of resistant cells, resulting in a 4-100 fold decrease in the IC50s. Eleven cell line xenografts and 12 PDTX models were treated with PF-309. From the cell line xenografts, we found a significant correlation between ABCB1 gene expression profiles and tumor response. We evaluated tumor and plasma concentrations for 8 tumor models (3 cell line xenografts and 5 PDTX models and a significant correlation was found between tumor concentration and response. Additionally, we show that tumor concentration is approximately 4-fold lower in tumors that express P-gp, verified by western blot. Our in vitro and in vivo data strongly suggests that PF-309 efficacy is influenced by the expression of tumor P-gp.

  11. Tityus serrulatus Scorpion Venom: In Vitro Tests and Their Correlation with In Vivo Lethal Dose Assay

    Directory of Open Access Journals (Sweden)

    Daniela Cajado-Carvalho

    2017-11-01

    Full Text Available Scorpion stings are the main cause of human envenomation in Brazil and, for the treatment of victims, the World Health Organization (WHO recommends the use of antivenoms. The first step to achieve effective antivenom is to use a good quality venom pool and to evaluate it, with LD50 determination as the most accepted procedure. It is, however, time-consuming and requires advanced technical training. Further, there are significant ethical concerns regarding the number of animals required for testing. Hence, we investigated the correspondence between LD50 results, in vitro assays, and a strong correlation with proteolytic activity levels was observed, showing, remarkably, that proteases are potential toxicity markers for Tityus serrulatus venom. The comparison of reversed-phase chromatographic profiles also has a potential application in venoms’ quality control, as there were fewer neurotoxins detected in the venom with high LD50 value. These results were confirmed by mass spectrometry analysis. Therefore, these methods could precede the LD50 assay to evaluate the venom excellence by discriminating—and discarding—poor-quality batches, and, consequently, with a positive impact on the number of animals used. Notably, proposed assays are fast and inexpensive, being technically and economically feasible in Tityus serrulatus venom quality control to produce effective antivenoms.

  12. Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations

    Science.gov (United States)

    von Moltke, Lisa L; Greenblatt, David J; Granda, Brian W; Duan, Su Xiang; Grassi, Jeffrey M; Venkatakrishnan, Karthik; Harmatz, Jerold S; Shader, Richard I

    1999-01-01

    Aims To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. Methods Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. Results The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50) of 0.61 μm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by ≈40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels. Conclusions The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition. PMID:10383565

  13. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

    Science.gov (United States)

    Lee, Brendan; Yu, Hong; Jahoor, Farook; O'Brien, William; Beaudet, Arthur L.; Reeds, Peter

    2000-01-01

    Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [18O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [15N]urea and [15N]glutamine during i.v. co-infusions of [5-(amide)15N]glutamine and [18O]urea. The ratio of the isotopic enrichments of 15N-urea/15N-glutamine distinguished normal control subjects (ratio = 0.42 ± 0.06) from urea cycle patients with late (0.17 ± 0.03) and neonatal (0.003 ± 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0.22 ± 0.03), argininosuccinate lyase deficiency (0.35 ± 0.11), and partial ornithine transcarbamylase deficiency (0.26 ± 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The 15N-urea/15N-glutamine ratio

  14. Direct Generation and Detection of Quantum Correlated Photons with 3.2 um Wavelength Spacing.

    Science.gov (United States)

    Sua, Yong Meng; Fan, Heng; Shahverdi, Amin; Chen, Jia-Yang; Huang, Yu-Ping

    2017-12-13

    Quantum correlated, highly non-degenerate photons can be used to synthesize disparate quantum nodes and link quantum processing over incompatible wavelengths, thereby constructing heterogeneous quantum systems for otherwise unattainable superior performance. Existing techniques for correlated photons have been concentrated in the visible and near-IR domains, with the photon pairs residing within one micron. Here, we demonstrate direct generation and detection of high-purity photon pairs at room temperature with 3.2 um wavelength spacing, one at 780 nm to match the rubidium D2 line, and the other at 3950 nm that falls in a transparent, low-scattering optical window for free space applications. The pairs are created via spontaneous parametric downconversion in a lithium niobate waveguide with specially designed geometry and periodic poling. The 780 nm photons are measured with a silicon avalanche photodiode, and the 3950 nm photons are measured with an upconversion photon detector using a similar waveguide, which attains 34% internal conversion efficiency. Quantum correlation measurement yields a high coincidence-to-accidental ratio of 54, which indicates the strong correlation with the extremely non-degenerate photon pairs. Our system bridges existing quantum technology to the challenging mid-IR regime, where unprecedented applications are expected in quantum metrology and sensing, quantum communications, medical diagnostics, and so on.

  15. Correlation researches of the outgoing directions 'shake-off' electron and positron at β+ - decay

    International Nuclear Information System (INIS)

    Mitrokhovich, N.F.; Kupryashkin, V.T.; Sidorenko, L.P.

    2012-01-01

    The correlation properties electron 'shake-off' at β + -decay is studied. The measurements were fulfilled in compare with such properties 'shake-off' electron at β - -decay for explanation mechanism, accountable for correlation motion 'shake-off' electron and main particle (electron at β'--decay and positron at β + -decay). 152 Eu decay was used for it. The measurements were performed on the installation of coincidences of γ-quanta with electrons and low energy electrons, including of e 0 -electrons of the secondary electron emission (γγee 0 -coincidences). The registration of electrons 'shake-off' implemented on e 0 -electrons, created by them. On obtained data, the space correlation of electron 'shake-off' with positron at β + -decay in direction forward is much less that those correlating s hake-off - electron at β - -decay. 'Shake-off'-electrons at β + -decay are predominantly moving in large solid angles relate positron. The mechanism, accountable for it, is proposed

  16. Magnetic resonance imaging of articular cartilage: ex vivo study on normal cartilage correlated with magnetic resonance microscopy

    International Nuclear Information System (INIS)

    Cova, M.; Frezza, F.; Pozzi-Mucelli, R.S.; Dalla-Palma, L.; Toffanin, R.; Pozzi-Mucelli, M.; Mlynarik, V.; Vittur, F.

    1998-01-01

    The aims of this study were (a) to compare the MR appearance of normal articular cartilage in ex vivo MR imaging (MRI) and MR microscopy (MRM) images of disarticulated human femoral heads, (b) to evaluate by MRM the topographic variations in articular cartilage of disarticulated human femoral heads, and subsequently, (c) to compare MRM images with histology. Ten disarticulated femoral heads were examined. Magnetic resonance images were obtained using spin-echo (SE) and gradient-echo (GE) sequences. Microimages were acquired on cartilage-bone cylindrical plugs excised from four regions (superior, inferior, anterior, posterior) of one femoral head, using a modified SE sequence. Both MRI and MRM images were obtained before and after a 90 rotation of the specimen, around the axis perpendicular to the examined cartilage surface. Finally, MRM images were correlated with histology. A trilaminar appearance of articular cartilage was observed with MRI and with a greater detail with MRM. A good correlation between MRI and MRM features was demonstrated. Both MRI and MRM showed a loss of the trilaminar cartilage appearance after specimen rotation, with greater evidence on MRM images. Cartilage excised from the four regions of the femoral head showed a different thickness, being thickest in the samples excised from the superior site. The MRM technique confirms the trilaminar MRI appearance of human articular cartilage, showing good correlation with histology. The loss of the trilaminar appearance of articular cartilage induced by specimen rotation suggests that this feature is partially related to the collagen-fiber orientation within the different layers. The MRM technique also shows topographic variations in thickness of human articular cartilage. (orig.)

  17. Impact of data base structure in a successful in vitro-in vivo correlation for pharmaceutical products.

    Science.gov (United States)

    Roudier, B; Davit, B; Schütz, H; Cardot, J-M

    2015-01-01

    The in vitro-in vivo correlation (IVIVC) (Food and Drug Administration 1997) aims to predict performances in vivo of a pharmaceutical formulation based on its in vitro characteristics. It is a complex process that (i) incorporates in a gradual and incremental way a large amount of information and (ii) requires information from different properties (formulation, analytical, clinical) and associated dedicated treatments (statistics, modeling, simulation). These results in many studies that are initiated and integrated into the specifications (quality target product profile, QTPP). This latter defines the appropriate experimental designs (quality by design, QbD) (Food and Drug Administration 2011, 2012) whose main objectives are determination (i) of key factors of development and manufacturing (critical process parameters, CPPs) and (ii) of critical points of physicochemical nature relating to active ingredients (API) and critical quality attribute (CQA) which may have implications in terms of efficiency, safety, and inoffensiveness for the patient, due to their non-inclusion. These processes generate a very large amount of data that is necessary to structure. In this context, the storage of information in a database (DB) and the management of this database (database management system, DBMS) become an important issue for the management of projects and IVIVC and more generally for development of new pharmaceutical forms. This article describes the implementation of a prototype object-oriented database (OODB) considered as a tool, which is helpful for decision taking, responding in a structured and consistent way to the issues of project management of IVIVC (including bioequivalence and bioavailability) (Food and Drug Administration 2003) necessary for the implementation of QTPP.

  18. Impact of bioavailability on the correlation between in vitro cytotoxic and in vivo acute fish toxic concentrations of chemicals

    International Nuclear Information System (INIS)

    Guelden, Michael; Seibert, Hasso

    2005-01-01

    concentrations instead of the nominal cytotoxic concentrations were used as measure of cytotoxic potency. The few remaining prominent differences between cytotoxic and acute toxic concentrations can be explained by a more specific mechanism of acute toxic action than basal cytotoxicity. It is concluded that the frequently observed low sensitivity of in vitro cytotoxicity test systems, compared to fish acute toxicity assays, at least in part, can be explained by differences in the availability of chemicals in vitro and in vivo. Moreover, neglecting these differences systematically causes a bias of the correlation between in vivo and in vitro toxic potencies of chemicals. Taking them into account, however, increases the predictivity of the in vitro assays

  19. In vivo elimination of parental clones in general and site-directed mutagenesis.

    Science.gov (United States)

    Holland, Erika G; Acca, Felicity E; Belanger, Kristina M; Bylo, Mary E; Kay, Brian K; Weiner, Michael P; Kiss, Margaret M

    2015-02-01

    The Eco29k I restriction endonuclease is a Sac II isoschizomer that recognizes the sequence 5'-CCGCGG-3' and is encoded, along with the Eco29k I methylase, in the Escherichia coli strain 29k. We have expressed the Eco29k I restriction-methylation system (RM2) in E. coli strain TG1 to produce the strain AXE688. We have developed a directed molecular evolution (DME) mutagenesis method that uses Eco29k I to restrict incoming parental DNA in transformed cells. Using our DME method, we have demonstrated that our AXE688 strain results in mutated directed molecular evolution libraries with diversity greater than 10(7) from a single transformation and with greater than 90% recombinant clones. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies.

    Science.gov (United States)

    Le Plénier, Servane; Goron, Arthur; Sotiropoulos, Athanassia; Archambault, Eliane; Guihenneuc, Chantal; Walrand, Stéphane; Salles, Jérome; Jourdan, Marion; Neveux, Nathalie; Cynober, Luc; Moinard, Christophe

    2017-01-01

    Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated (P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control. Copyright © 2017 the American Physiological Society.

  1. Jovian electron bursts: Correlation with the interplanetary field direction and hydromagnetic waves

    International Nuclear Information System (INIS)

    Smith, E.J.; Tsurutani, B.T.; Chenette, D.L.; Conlon, T.F.; Simpson, J.A.

    1976-01-01

    The bursts of relativistic electrons detected on Pioneer 10 upstream from Jupiter and within 400r/subj/ of the planet have been found to be correlated with the interplanetary magnetic field. In the three examples upon which this study is based, during the month prior to the Pioneer 10 encounter, electrons with energies between 3 and 6 MeV escaping from Jupiter's magnetosphere were observed only when the interplanetary magnetic field was along the Jupiter-spacecraft line. In addition, large-amplitude interplanetary waves with characteristic periods of 10 min were observed and found to be well correlated with intervals during which the field was along the Jupiter-spacecraft line. Abrupt changes in the field away from the preferred direction caused equally abrupt terminations of the waves with an accompanying reduction in the electron flux. These results are consistent with propagation of the electrons from Jupiter to Pioneer along, rather than across, the magnetic field lines. The direction of the interplanetary magnetic field is apparently not affected by the electron bursts or by other particles from Jupiter. The average Parker spiral direction is clear with no enhancement in the Jupiter-spacecraft direction. Two alternative possibilities are considered for the origin of the waves. If they were generated near Jupiter, they would have to propagate to the spacecraft in the whistler mode. The expected attenuation of these waves over distances of several hundred r/subj/ an their long travel times make this explanation unattractive. Alternatively, hydromagnetic wave generation by Jovian charged particles, presumably the relativistic electrons themselves, as they travel upstream, appears to be an attractive explanation

  2. Targeted in vitro and in vivo gene transfer into T Lymphocytes: potential of direct inhibition of allo-immune activation

    Directory of Open Access Journals (Sweden)

    Mehra Mandeep R

    2006-11-01

    Full Text Available Abstract Background Successful inhibition of alloimmune activation in organ transplantation remains one of the key events in achieving a long-term graft survival. Since T lymphocytes are largely responsible for alloimmune activation, targeted gene transfer of gene of cyclin kinase inhibitor p21 into T cells might inhibit their aberrant proliferation. A number of strategies using either adenoviral or lentiviral vectors linked to mono or bispecific antibodies directed against T cell surface markers/cytokines did not yield the desired results. Therefore, this study was designed to test if a CD3promoter-p21 chimeric construct would in vitro and in vivo transfer p21 gene to T lymphocytes and result in inhibition of proliferation. CD3 promoter-p21 chimeric constructs were prepared with p21 in the sense and antisense orientation. For in vitro studies EL4-IL-2 thyoma cells were used and for in vivo studies CD3p21 sense and antisense plasmid DNA was injected intramuscularly in mice. Lymphocyte proliferation was quantified by 3H-thymidine uptake assay; IL-2 mRNA expression was studied by RT-PCR and using Real Time PCR assay, we monitored the CD3, p21, TNF-α and IFN-γ mRNA expression. Results Transfection of CD3p21 sense and antisense in mouse thyoma cell line (EL4-IL-2 resulted in modulation of mitogen-induced proliferation. The intramuscular injection of CD3p21 sense and antisense plasmid DNA into mice also modulated lymphocyte proliferation and mRNA expression of pro-inflammatory cytokines. Conclusion These results demonstrate a novel strategy of in vitro and in vivo transfer of p21 gene to T cells using CD3-promoter to achieve targeted inhibition of lymphocyte proliferation and immune activation.

  3. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    Science.gov (United States)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  4. Gamma--gamma directional correlations and coincidence studies in /sup 154/Gd

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, J B; Gupta, S L; Hamilton, J H; Ramayya, A V [Vanderbilt Univ., Nashville, Tenn. (USA). Dept. of Physics; Delhi Univ. (India). Ramjas Coll.)

    1977-06-01

    The intensities, placements and E2/M1 mixing ratios of transitions in the decay of /sup 154/Eu have been carefully studied to provide accurate data for microscopic calculations. Coincidence relationships in thhe decay of /sup 154/Eu have been studied extensively with a multiparameter ..gamma..-..gamma.. coincidence system with two large volume Ge(Li) detectors. Spectra in coincidence with twenty energy gates were analyzed. Twenty-nine new coincidence relationships were established and confirmed most, but not all, of several levels previously assigned by energy fits only. From an analysis of coincidence spectra and singles spectra with a 18% efficiency Ge(Li) detector new information on the gamma-ray intensities were obtained. Precise values of the E2/M1 mixing ratios of transitions from the gamma- and beta-vibrational bands to the g.s. band have been determined from ..gamma..-..gamma.. directional correlation measurements with a NaI(Tl)-Ge(Li) detector coincidence system. Mixing ratios were obtained for a number of other transitions including those from KPI = 0/sup -/ and 2+ bands from direct and skipped cascade correlations.

  5. Gamma-gamma directional correlations and coincidence studies in 154Gd

    International Nuclear Information System (INIS)

    Gupta, J.B.; Gupta, S.L.; Hamilton, J.H.; Ramayya, A.V.; Delhi Univ.

    1977-01-01

    The intensities, placements and E2/M1 mixing ratios of transitions in the decay of 154 Eu have been carefully studied to provide accurate data for microscopic calculations. Coincidence relationships in thhe decay of 154 Eu have been studied extensively with a multiparameter γ-γ coincidence system with two large volume Ge(Li) detectors. Spectra in coincidence with twenty energy gates were analyzed. Twenty-nine new coincidence relationships were established and confirmed most, but not all, of several levels previously assigned by energy fits only. From an analysis of coincidence spectra and singles spectra with a 18% efficiency Ge(Li) detector new information on the gamma-ray intensities were obtained. Precise values of the E2/M1 mixing ratios of transitions from the gamma- and beta-vibrational bands to the g.s. band have been determined from γ-γ directional correlation measurements with a NaI(Tl)-Ge(Li) detector coincidence system. Mixing ratios were obtained for a number of other transitions including those from KPI = 0 - and 2+ bands from direct and skipped cascade correlations. (orig.) [de

  6. Control of directed cell migration in vivo by membrane-to-cortex attachment.

    Directory of Open Access Journals (Sweden)

    Alba Diz-Muñoz

    2010-11-01

    Full Text Available Cell shape and motility are primarily controlled by cellular mechanics. The attachment of the plasma membrane to the underlying actomyosin cortex has been proposed to be important for cellular processes involving membrane deformation. However, little is known about the actual function of membrane-to-cortex attachment (MCA in cell protrusion formation and migration, in particular in the context of the developing embryo. Here, we use a multidisciplinary approach to study MCA in zebrafish mesoderm and endoderm (mesendoderm germ layer progenitor cells, which migrate using a combination of different protrusion types, namely, lamellipodia, filopodia, and blebs, during zebrafish gastrulation. By interfering with the activity of molecules linking the cortex to the membrane and measuring resulting changes in MCA by atomic force microscopy, we show that reducing MCA in mesendoderm progenitors increases the proportion of cellular blebs and reduces the directionality of cell migration. We propose that MCA is a key parameter controlling the relative proportions of different cell protrusion types in mesendoderm progenitors, and thus is key in controlling directed migration during gastrulation.

  7. In Vivo CT Direct Volume Rendering: A Three-Dimensional Anatomical Description of the Heart

    International Nuclear Information System (INIS)

    Cutroneo, Giuseppina; Bruschetta, Daniele; Trimarchi, Fabio; Cacciola, Alberto; Cinquegrani, Maria; Duca, Antonio; Rizzo, Giuseppina; Alati, Emanuela; Gaeta, Michele; Milardi, Demetrio

    2016-01-01

    Since cardiac anatomy continues to play an important role in the practice of medicine and in the development of medical devices, the study of the heart in three dimensions is particularly useful to understand its real structure, function and proper location in the body. This study demonstrates a fine use of direct volume rendering, processing the data set images obtained by Computed Tomography (CT) of the heart of 5 subjects with age range between 18 and 42 years (2 male, 3 female), with no history of any overt cardiac disease. The cardiac structure in CT images was first extracted from the thorax by marking manually the regions of interest on the computer, and then it was stacked to create new volumetric data. The use of a specific algorithm allowed us to observe with a good perception of depth the heart and the skeleton of the thorax at the same time. Besides, in all examined subjects, it was possible to depict its structure and its position within the body and to study the integrity of papillary muscles, the fibrous tissue of cardiac valve and chordae tendineae and the course of coronary arteries. Our results demonstrated that one of the greatest advantages of algorithmic modifications of direct volume rendering parameters is that this method provides much necessary information in a single radiologic study. It implies a better accuracy in the study of the heart, being complementary to other diagnostic methods and facilitating the therapeutic plans

  8. Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo.

    Science.gov (United States)

    Chhatbar, Pratik Y; Kautz, Steven A; Takacs, Istvan; Rowland, Nathan C; Revuelta, Gonzalo J; George, Mark S; Bikson, Marom; Feng, Wuwei

    2018-03-13

    Transcranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted. We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo. Patients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages. Voltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages. Our findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology.

    Directory of Open Access Journals (Sweden)

    Courtney M Tate

    Full Text Available Bone morphogenetic proteins (BMPs, members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.

  10. A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology.

    Science.gov (United States)

    Tate, Courtney M; Mc Entire, Jacquelyn; Pallini, Roberto; Vakana, Eliza; Wyss, Lisa; Blosser, Wayne; Ricci-Vitiani, Lucia; D'Alessandris, Quintino Giorgio; Morgante, Liliana; Giannetti, Stefano; Larocca, Luigi Maria; Todaro, Matilde; Benfante, Antonina; Colorito, Maria Luisa; Stassi, Giorgio; De Maria, Ruggero; Rowlinson, Scott; Stancato, Louis

    2015-01-01

    Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.

  11. The diffusion dynamics of PEGylated liposomes in the intact vitreous of the ex vivo porcine eye: A fluorescence correlation spectroscopy and biodistribution study

    DEFF Research Database (Denmark)

    Eriksen, Anne Zebitz; Brewer, Jonathan; Andresen, Thomas Lars

    2017-01-01

    correlation spectroscopy (FCS) to determine liposome diffusion coefficients in the intact vitreous (DVit) of ex vivo porcine eyes using a modified Miyake-Apple technique to minimize the disruption of the vitreous fine structure. We chose to investigate whether the zeta potential of polyethylene glycol...

  12. Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis.

    Science.gov (United States)

    Walsh, T J; Gonzalez, C E; Piscitelli, S; Bacher, J D; Peter, J; Torres, R; Shetti, D; Katsov, V; Kligys, K; Lyman, C A

    2000-06-01

    Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC. MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, /=64 microgram/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P OPEC due to C. albicans.

  13. Directly patching high-level exchange-correlation potential based on fully determined optimized effective potentials

    Science.gov (United States)

    Huang, Chen; Chi, Yu-Chieh

    2017-12-01

    The key element in Kohn-Sham (KS) density functional theory is the exchange-correlation (XC) potential. We recently proposed the exchange-correlation potential patching (XCPP) method with the aim of directly constructing high-level XC potential in a large system by patching the locally computed, high-level XC potentials throughout the system. In this work, we investigate the patching of the exact exchange (EXX) and the random phase approximation (RPA) correlation potentials. A major challenge of XCPP is that a cluster's XC potential, obtained by solving the optimized effective potential equation, is only determined up to an unknown constant. Without fully determining the clusters' XC potentials, the patched system's XC potential is "uneven" in the real space and may cause non-physical results. Here, we developed a simple method to determine this unknown constant. The performance of XCPP-RPA is investigated on three one-dimensional systems: H20, H10Li8, and the stretching of the H19-H bond. We investigated two definitions of EXX: (i) the definition based on the adiabatic connection and fluctuation dissipation theorem (ACFDT) and (ii) the Hartree-Fock (HF) definition. With ACFDT-type EXX, effective error cancellations were observed between the patched EXX and the patched RPA correlation potentials. Such error cancellations were absent for the HF-type EXX, which was attributed to the fact that for systems with fractional occupation numbers, the integral of the HF-type EXX hole is not -1. The KS spectra and band gaps from XCPP agree reasonably well with the benchmarks as we make the clusters large.

  14. Measurement of the beta-gamma directional correlation of the transition 46Sc→46Ti

    International Nuclear Information System (INIS)

    Krexner, G.

    1978-01-01

    Measuring the forward - backward asymmetry of the direction of gamma quanta with respect to the direction of a preceding beta particle emission is one of the methods which have been developed over the past twenty years to investigate parity admixtures in nuclear states. Both theoretical calculations and experiments using this method yield very small values for the considered effect. Moreover the accuracy is limited for statistical reasons. Hence there exists a fundamental interest in proving the experimental arrangement to be free of systematic errors. The subject of this work is an experiment checking a six - detector apparatus which has been used to investigate the beta - gamma directional correlation in the decay 203 Hg→ 203 Tl. For the control measurement the transition 46 Sc→ 46 Ti was chosen. The asymmetry coefficient should yield zero and thus furnish evidence of the absence of systematic errors. The necessary 46 Sc source had to meet very restricting requirements. The feasibility of various methods for producing radioactive samples was reviewed; finally a specially designed high vacuum evaporation plant was constructed. The concept of this device and the preparation of the source are dealt with in detail. A preliminary result of the control experiment is given. However, at present a definite interpretation of the obtained values is not possible. (author)

  15. Direct Current Combined With Bipolar Radiofrequency Ablation: An Ex Vivo Feasibility Study

    International Nuclear Information System (INIS)

    Tanaka, Toshihiro; Penzkofer, Tobias; Isfort, Peter; Bruners, Philipp; Disselhorst-Klug, Catherine; Junker, Elmar; Kichikawa, Kimihiko; Schmitz-Rode, Thomas; Mahnken, Andreas H.

    2011-01-01

    The combination of radiofrequency ablation (RFA) with direct current (DC) is a promising strategy to improve the efficiency of RFA. However, DC-enhanced monopolar RFA is limited by electrolytic injury at the positive-electrode site. The aim of this study was to investigate the feasibility of the DC-enhanced bipolar RFA. To obviate the need for the subcutaneous positive electrode, the DC circuit was combined with a commercially available bipolar RFA system, in which both poles of the DC circuit are connected to a single RF probe. DC was applied for 15 min and followed by RFA in bovine livers using the following various DC currents: (1) no DC (control), (2) 3V continued until the end of RFA, (3) 5V continued until the end of RFA, (4) 10V continued until the end of RFA, (5) 5V continued in the circuit with reversed pole, (6) 3V stopped after initiation of RFA, and (7) 5V stopped. Coagulation volume, temperatures at a distance of 5, 10, and 15 mm from the RF probe, mean amperage, ablation duration, applied energy, minimum impedance, and degree of tissue charring were assessed and compared (analysis of variance, Student–Newman–Keuls test). All combined DC and RFA groups did increase coagulation volume. The 10V continued group showed significantly lower applied energy, shortest ablation duration, highest minimum impedance, and highest degree of charring with the lowest coagulation volume (p < 0.05). DC-enhanced bipolar RFA with both poles of the DC circuit on a single probe appears to be ineffective.

  16. Correlated responses in tissue weights measured in vivo by computer tomography in Dorset Down sheep selected for lean tissue growth

    International Nuclear Information System (INIS)

    Nsoso, S.J.; Young, M.J.; Beatson, P.R.

    2003-01-01

    The aim of this study was to estimate correlated responses in lean, fat and bone weights in vivo in Dorset Down sheep selected for lean tissue growth. Over the period 1986-1992 inclusive, the lean tissue growth line had been selected using two economic indices for an increased aggregate breeding value incorporating predicted lean and fat weights with positive and negative economic weightings, respectively. The control line was selected for no change in lean tissue growth each year. Animals were born and run on pasture all year round. X-ray computer tomography was used to estimate the weights of lean, fat and bone in vivo in the 1994-born sheep, aged 265-274 days and selected randomly into 12 rams and 12 ewes from the selected line and 10 rams and 9 ewes from the control line. The lean tissue growth line had significantly greater responses in lean weight (+0.65 + 0.10 kg) and lean percentage (+1.19 + 0.17%) and significantly lesser fat weight (-0.36 + 0.08 kg) and fat percentage (-1.88 + 0.20%) compared to the control line. There was a significant increase in bone weight (+0.27 + 0.03 kg) and bone percentage (+0.69 + 0.09%) in the lean tissue growth line compared to the control line. Responses differed significantly between sexes of the lean tissue growth line, rams having a greater response in weight of lean (+1.22 + 0.20 vs. +0.08 + 0.22 kg) and bone (+0.45 + 0.06 vs. +0.09 + 0.07 kg), and a lesser response in weight of fat (-0.03 + 0.15 vs. -0.70 + 0.16 kg) than the ewes. Selection led to significant changes in lean (increase) and fat weights (decrease), and bone weight increased. Although responses in the lean tissue growth line differed significantly between sexes, there were confounding factors due to differences in management and lack of comparison at equal stage of development. Therefore, to assess real genetic differences further studies should be conducted taking these factors into consideration

  17. Quantitative Correlation of in Vivo Properties with in Vitro Assay Results: The in Vitro Binding of a Biotin–DNA Analogue Modifier with Streptavidin Predicts the in Vivo Avidin-Induced Clearability of the Analogue-Modified Antibody

    Science.gov (United States)

    Dou, Shuping; Virostko, John; Greiner, Dale L.; Powers, Alvin C.; Liu, Guozheng

    2016-01-01

    Quantitative prediction of in vivo behavior using an in vitro assay would dramatically accelerate pharmaceutical development. However, studies quantitatively correlating in vivo properties with in vitro assay results are rare because of the difficulty in quantitatively understanding the in vivo behavior of an agent. We now demonstrate such a correlation as a case study based on our quantitative understanding of the in vivo chemistry. In an ongoing pretargeting project, we designed a trifunctional antibody (Ab) that concomitantly carried a biotin and a DNA analogue (hereafter termed MORF). The biotin and the MORF were fused into one structure prior to conjugation to the Ab for the concomitant attachment. Because it was known that avidin-bound Ab molecules leave the circulation rapidly, this design would theoretically allow complete clearance by avidin. The clearability of the trifunctional Ab was determined by calculating the blood MORF concentration ratio of avidin-treated Ab to non-avidin-treated Ab using mice injected with these compounds. In theory, any compromised clearability should be due to the presence of impurities. In vitro, we measured the biotinylated percentage of the Ab-reacting (MORF-biotin)⊃-NH2 modifier, by addition of streptavidin to the radiolabeled (MORF-biotin)⊃-NH2 samples and subsequent high-performance liquid chromatography (HPLC) analysis. On the basis of our previous quantitative understanding, we predicted that the clearability of the Ab would be equal to the biotinylation percentage measured via HPLC. We validated this prediction within a 3% difference. In addition to the high avidin-induced clearability of the trifunctional Ab (up to ~95%) achieved by the design, we were able to predict the required quality of the (MORF-biotin)⊃-NH2 modifier for any given in vivo clearability. This approach may greatly reduce the steps and time currently required in pharmaceutical development in the process of synthesis, chemical analysis, in

  18. Liquid direct correlation function, singlet densities and the theory of freezing

    International Nuclear Information System (INIS)

    March, N.H.; Tosi, M.P.

    1981-04-01

    We have examined the solutions for the singlet density rho(r) in the hierarchical equation connecting rho(r) with the liquid direct correlation function c(r). In addition to the homogeneous solution rho(r)=rhosub(liquid), we exhibit a periodic solution which can co-exist with the liquid solution. If the defining equation for this is linearized, we recover the bifurcation condition of Lovett and Buff. We stress the difference between the two treatments as that between first and second-order transitions. It turns out that the treatment presented here leads to the same periodic density as that derived, using the hypernetted chain approximation, by Ramakrishnan and Yussouff in their theory of freezing. Invoking that approximation is shown thereby to be inessential. (author)

  19. Epithelial and stromal metabolite changes in the transition from cervical intraepithelial neoplasia to cervical cancer: an in vivo 1H magnetic resonance spectroscopic imaging study with ex vivo correlation

    International Nuclear Information System (INIS)

    Silva, Sonali S. de; Payne, Geoffrey S.; Morgan, Veronica A.; Ind, Thomas E.J.; Shepherd, John H.; Barton, Desmond P.J.; Souza, Nandita M. de

    2009-01-01

    To investigate epithelial and stromal metabolite changes in cervical intraepithelial neoplasia (CIN) and cervical cancer in vivo and correlate findings with MR spectroscopy of tissue samples. Forty-seven women (19 with CIN, 28 with cervical cancer) underwent endovaginal MR at 1.5 T with T2-W and localised 2D MR spectroscopic imaging (PRESS, TR=1,500 ms, TE=135 ms). tCho, 2 ppm and -CH 2 lipid peaks were measured in epithelial (>50% epithelium, no tumour), stromal (>50% stroma, no tumour) and tumour (>30% tumour) voxels. Unsuppressed water signal from the same voxel provided a concentration reference. 1 H HR-MAS MR spectra were acquired from tissue in 37 patients (11.74 T, pulse-acquire and cpmg sequences, with water pre-saturation). Analysable data from 17 CIN and 25 cancer patients showed significant increases in tCho (p=0.03) and 2 ppm (p=0.007) in tumour compared with epithelial voxels from CIN patients, but not with epithelial voxels from cancer patients. No significant differences were seen in stroma from cancer compared with CIN patients. Differences in -CH 2 lipids were not significant between groups. There was no significant correlation between in vivo and ex vivo tCho or -CH 2 lipids. Estimated in vivo concentrations of tCho and 2 ppm resonances increase in tumour and adjacent epithelium in progression from CIN to cervical cancer. (orig.)

  20. On the Direct Correlation between Gamma-Rays and PeV Neutrinos from Blazars

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Shan; Pohl, Martin; Winter, Walter, E-mail: shan.gao@desy.de [Deutsches Elektronen-Synchrotron (DESY), Platanenallee 6, D-15738 Zeuthen (Germany)

    2017-07-10

    We study the frequently used assumption in multi-messenger astrophysics that the gamma-ray and neutrino fluxes are directly connected because they are assumed to be produced by the same photohadronic production chain. An interesting candidate source for this test is the flat-spectrum radio quasar PKS B1424-418, which recently called attention to a potential correlation between an IceCube PeV neutrino event and its burst phase. We simulate both the multi-waveband photon and the neutrino emission from this source using a self-consistent radiation model. We demonstrate that a simple hadronic model cannot adequately describe the spectral energy distribution for this source, but a lepto-hadronic model with a subdominant hadronic component can reproduce the multi-waveband photon spectrum observed during various activity phases of the blazar. As a conclusion, up to about 0.3 neutrino events may coincide with the burst, which implies that the leptonic contribution dominates in the relevant energy band. We also demonstrate that the time-wise correlation between the neutrino event and burst phase is weak.

  1. Directed partial correlation: inferring large-scale gene regulatory network through induced topology disruptions.

    Directory of Open Access Journals (Sweden)

    Yinyin Yuan

    Full Text Available Inferring regulatory relationships among many genes based on their temporal variation in transcript abundance has been a popular research topic. Due to the nature of microarray experiments, classical tools for time series analysis lose power since the number of variables far exceeds the number of the samples. In this paper, we describe some of the existing multivariate inference techniques that are applicable to hundreds of variables and show the potential challenges for small-sample, large-scale data. We propose a directed partial correlation (DPC method as an efficient and effective solution to regulatory network inference using these data. Specifically for genomic data, the proposed method is designed to deal with large-scale datasets. It combines the efficiency of partial correlation for setting up network topology by testing conditional independence, and the concept of Granger causality to assess topology change with induced interruptions. The idea is that when a transcription factor is induced artificially within a gene network, the disruption of the network by the induction signifies a genes role in transcriptional regulation. The benchmarking results using GeneNetWeaver, the simulator for the DREAM challenges, provide strong evidence of the outstanding performance of the proposed DPC method. When applied to real biological data, the inferred starch metabolism network in Arabidopsis reveals many biologically meaningful network modules worthy of further investigation. These results collectively suggest DPC is a versatile tool for genomics research. The R package DPC is available for download (http://code.google.com/p/dpcnet/.

  2. Direct radioimmunoassay (RIA) of salivary testosterone: correlation with free and total serium testosterone

    International Nuclear Information System (INIS)

    Vittek, J.; L'Hommedieu, D.G.; Gordon, G.G.; Rappaport, S.C.; Southren, A.L.

    1985-01-01

    Simple and sensitive direct RIA for determination of salivary testosterone was developed by using RSL NOSOLVEX TM (125 1) kit produced by Radioassay System Laboratories (Carcon, California). In addition, a relationship between salivary and serum free and total testosterone concentrations was studied in randomly selected 45 healthy subjects, 5 females on oral contraceptive pills and 28 hypertensive patients on various treatment regimens. The lowest weight of testosterone detectable by the modified method was equivalent to 1 pg/ml of saliva, taking into account analytical variability. Intra- and interassay coefficients of variation were 5.09 +/- 2.7% and 8.2 +/- 5.9% respectively. Statistically significant correlations were found between salivary and serum free testosterone (r = 0.97) and salivary and serum total testosterone concentrations (r = 0.70 - 0.87). The exception to this was a group of hypertensive females in which no correlation (r = 0.14) between salivary and total serum testosterone was found. It is also of interest that, while salivary testosterone was significantly increased in subjects taking oral contraceptives and most of the hypertensive patients, the total serum testosterone concentration was in normal range. These findings suggest that the determination of salivary testosterone is a reliable method to detect changes in the concentration of available biologically active hormone in the circulation. 21 references, 4 figures, 1 table

  3. Approximating the Shifted Hartree-Exchange-Correlation Potential in Direct Energy Kohn-Sham Theory.

    Science.gov (United States)

    Sharpe, Daniel J; Levy, Mel; Tozer, David J

    2018-02-13

    Levy and Zahariev [Phys. Rev. Lett. 113 113002 (2014)] have proposed a new approach for performing density functional theory calculations, termed direct energy Kohn-Sham (DEKS) theory. In this approach, the electronic energy equals the sum of orbital energies, obtained from Kohn-Sham-like orbital equations involving a shifted Hartree-exchange-correlation potential, which must be approximated. In the present study, density scaling homogeneity considerations are used to facilitate DEKS calculations on a series of atoms and molecules, leading to three nonlocal approximations to the shifted potential. The first two rely on preliminary Kohn-Sham calculations using a standard generalized gradient approximation (GGA) exchange-correlation functional and the results illustrate the benefit of describing the dominant Hartree component of the shift exactly. A uniform electron gas analysis is used to eliminate the need for these preliminary Kohn-Sham calculations, leading to a potential with an unconventional form that yields encouraging results, providing strong motivation for further research in DEKS theory.

  4. Three-dimensional histological imaging of primate brain and correlation with in vivo medical device images Imagerie histologique tri-dimensionnelle du cerveau de primate et corrélation avec l'imagerie médicale in vivo

    Directory of Open Access Journals (Sweden)

    Julien Dauguet

    2011-02-01

    Full Text Available The 3D reconstruction of series of histological slices is an imaging technique that appeared about 25 years ago but that is only starting now to become recognized as an imaging modality per se. Thanks to this technique, it becomes possible to restore the spatial consistency of the brain and to match accurately histological slices with an in vivo medical device image such as an MRI or a PET scan. This is of high interest since it allows direct comparison between the histology, often considered as the gold standard in terms of information, and the same medical devices used in clinical routine to image human patients. Thanks to the similarity of their brain with humans and the disease models widely developed for them, non-human primates are privileged species to benefit from this possibility of 3D analysis and in vivo - post mortem correlation. We present in this article a state of the art review of the main techniques proposed to achieve this original imaging technique, followed by a set of some particularly promising neuroimaging applications.La reconstruction 3D de séries de coupes histologiques est une technique d'imagerie qui est apparue il y a 25 ans environ mais qui commence seulement à être reconnue comme une modalité d'imagerie à part entière. Grâce à cette technique, la cohérence 3D du cerveau est rétablie et il devient notamment possible de mettre en correspondance précisément des coupes histologiques avec un examen issu d'un imageur médical comme une IRM ou une TEP. C'est d'un intérêt majeur car cela permet une comparaison directe entre l'histologie, souvent considérée comme la référence étalon en termes d'information fournie, et les mêmes imageurs médicaux que ceux utilisés en routine clinique pour suivre les patients humains. Grâce à leur similarité avec les humains et aux nombreux modèles animaux de maladies développés pour eux, les primates non-humains sont une espèce privilégiée pour bénéficier de

  5. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15

    Science.gov (United States)

    Xu, Yang; Zhang, Ming; Ramos, Carlos A.; Durett, April; Liu, Enli; Dakhova, Olga; Liu, Hao; Creighton, Chad J.; Gee, Adrian P.; Heslop, Helen E.; Rooney, Cliona M.; Savoldo, Barbara

    2014-01-01

    Adoptive transfer of T lymphocytes expressing a CD19-specific chimeric antigen receptor (CAR.CD19) induces complete tumor regression in patients with lymphoid malignancies. Although in vivo persistence of CAR-T cells correlates with clinical responses, it remains unknown whether specific cell subsets within the CAR–T-cell product correlate with their subsequent in vivo expansion and persistence. We analyzed 14 patients with B-cell malignancies infused with autologous CAR.CD19-redirected T cells expanded ex vivo using IL-2, and found that their in vivo expansion only correlated with the frequency within the infused product of a CD8+CD45RA+CCR7+ subset, whose phenotype is closest to “T-memory stem cells.” Preclinical models showed that increasing the frequency of CD8+CD45RA+CCR7+ CAR-T cells in the infused line by culturing the cells with IL-7 and IL-15 produced greater antitumor activity of CAR-T cells mediated by increased resistance to cell death, following repetitive encounters with the antigen, while preserving their migration to secondary lymphoid organs. This trial was registered at www.clinicaltrials.gov as #NCT00586391 and #NCT00709033. PMID:24782509

  6. 3D contrast-enhanced MR portography and direct X-ray portography: a correlation study

    International Nuclear Information System (INIS)

    Lin Jiang; Zhou Kangrong; Chen Zuang; Wang Jianhua; Yan Ziping; Wang Yixiang, J.

    2003-01-01

    Our objective was to compare 3D contrast-enhanced MR portography (3D CE MRP) on a 1.5-T MR imager with direct X-ray portography. Twenty-six consecutive patients underwent 3D CE MRP with in-plane resolution of 1.4 or 1.8 mm, and direct X-ray portography. The findings of these two methods were evaluated and compared. The main portal vein (PV), right PV with its anterior and posterior segmental branches, and left PV including its sagittal segment were shown clearly without diagnostic problem in all cases on MRP. The main PV appearance was accordant with MRP and X-ray. For intrahepatic PVs, the results agreed in 21 patients but disagreed in 5 patients. In 1 patient with a huge tumor in right liver, the right posterior PV was classified as occluded at MRP, but diffusely narrowed at X-ray. The findings of left intrahepatic PV were discordant in 3 patients with hepatocelluar carcinoma in the left lobe. The MRP demonstrated complete occlusion of the left PVs, whereas X-ray showed proximal narrowing and distal occlusion. In another patient with hepatocelluar carcinoma, a small non-occlusive thrombus involving the sagittal segment of the left PV was seen on MRP but not on X-ray. With demonstration of varices and portosystemic shunts, MRP showed results similar to those of X-ray, except one recanalized para-umbilical vein was excluded from the field of view at MRP due to the patient's limited ability of breathholding. The 3D CE MRP correlated well with direct X-ray portography in most cases, it was limited in distinguishing narrowing of an intrahepatic PV from occlusion, but it showed advantage in demonstrating small thrombus within PV. (orig.)

  7. Preliminary observations on the correlation of proliferative phenomena with in vivo /sup 31/P NMR spectroscopy after tumor chemotherapy

    International Nuclear Information System (INIS)

    Schiffer, L.M.; Braunschweiger, P.G.; Glickson, J.D.; Evanochko, W.T.; Ng, T.C.

    1985-01-01

    In order to translate the concepts that have been developed in animal systems to human treatment programs, there is an urgent need for noninvasive techniques to study tumor cell biology. The characteristics of the ideal technique for the noninvasive monitoring of cell proliferation are truly imposing. The method should not require repeated biopsies; it should be amenable to repeated studies at frequent intervals without patient discomfort; it should monitor the proliferative response to the treatment modality; and it should not, in itself, perturb the tumor. Ideally, one would also like to be able to evaluate normal cell proliferation as well. It appears now that a new technique, /sup 31/P nuclear magnetic resonance (/sup 31/PNMR), may fulfill these rather rigid requirements. However, many studies in animal systems are necessary before it can be applied to the study of human tumors. The theory and mechanics of /sup 31/P NMR have been well described. Recently, its use as a noninvasive technique to study in vivo metabolic processes has become important. The authors presented a series of reports on the use of /sup 31/P NMR for the evaluation of tumor metabolism in animal systems under a variety of conditions. Studies of subcutaneously transplanted mouse tumors and human xenografts detected significant changes in nucleotide triphosphate (NTP), phosphocreatine, and inorganic phosphorus (Pi) as a result of tumor growth and perturbation with chemotherapeutic drugs, radiation, and hyperthermia. Their collabortive studies were designed to evaluate the changing effects of a noncurative single dose of cyclophosphamide on the /sup 31/P NMR resonances from the RIF-1 tumor, and to compare them with the proliferative changes that occur with time after drug administration. They were carried out in the hope of finding a noninvasive correlate with tumor cell proliferation

  8. An automated process for building reliable and optimal in vitro/in vivo correlation models based on Monte Carlo simulations.

    Science.gov (United States)

    Sutton, Steven C; Hu, Mingxiu

    2006-05-05

    Many mathematical models have been proposed for establishing an in vitro/in vivo correlation (IVIVC). The traditional IVIVC model building process consists of 5 steps: deconvolution, model fitting, convolution, prediction error evaluation, and cross-validation. This is a time-consuming process and typically a few models at most are tested for any given data set. The objectives of this work were to (1) propose a statistical tool to screen models for further development of an IVIVC, (2) evaluate the performance of each model under different circumstances, and (3) investigate the effectiveness of common statistical model selection criteria for choosing IVIVC models. A computer program was developed to explore which model(s) would be most likely to work well with a random variation from the original formulation. The process used Monte Carlo simulation techniques to build IVIVC models. Data-based model selection criteria (Akaike Information Criteria [AIC], R2) and the probability of passing the Food and Drug Administration "prediction error" requirement was calculated. To illustrate this approach, several real data sets representing a broad range of release profiles are used to illustrate the process and to demonstrate the advantages of this automated process over the traditional approach. The Hixson-Crowell and Weibull models were often preferred over the linear. When evaluating whether a Level A IVIVC model was possible, the model selection criteria AIC generally selected the best model. We believe that the approach we proposed may be a rapid tool to determine which IVIVC model (if any) is the most applicable.

  9. Novel Antiseptic Urinary Catheters for Prevention of Urinary Tract Infections: Correlation of In Vivo and In Vitro Test Results▿

    Science.gov (United States)

    Hachem, Ray; Reitzel, Ruth; Borne, Agatha; Jiang, Ying; Tinkey, Peggy; Uthamanthil, Rajesh; Chandra, Jyotsna; Ghannoum, Mahmoud; Raad, Issam

    2009-01-01

    Urinary catheters are widely used for hospitalized patients and are often associated with high rates of urinary tract infection. We evaluated in vitro the antiadherence activity of a novel antiseptic Gendine-coated urinary catheter against several multidrug-resistant bacteria. Gendine-coated urinary catheters were compared to silver hydrogel-coated Foley catheters and uncoated catheters. Bacterial biofilm formation was assessed by quantitative culture and scanning electron microscopy. These data were further correlated to an in vivo rabbit model. We challenged 31 rabbits daily for 4 days by inoculating the urethral meatus with 1.0 × 109 CFU streptomycin-resistant Escherichia coli per day. In vitro, Gendine-coated urinary catheters reduced the CFU of all organisms tested for biofilm adherence compared with uncoated and silver hydrogel-coated catheters (P < 0.004). Scanning electron microscopy analysis showed that a thick biofilm overlaid the control catheter and the silver hydrogel-coated catheters but not the Gendine-coated urinary catheter. Similar results were found with the rabbit model. Bacteriuria was present in 60% of rabbits with uncoated catheters and 71% of those with silver hydrogel-coated catheters (P < 0.01) but not in those with Gendine-coated urinary catheters. No rabbits with Gendine-coated urinary catheters had invasive bladder infections. Histopathologic assessment revealed no differences in toxicity or staining. Gendine-coated urinary catheters were more efficacious in preventing catheter-associated colonization and urinary tract infections than were silver hydrogel-coated Foley catheters and uncoated catheters. PMID:19805562

  10. MicroRNA-494 inhibits cell proliferation and invasion of chondrosarcoma cells in vivo and in vitro by directly targeting SOX9.

    Science.gov (United States)

    Li, Jingyuan; Wang, Lijuan; Liu, Zongzhi; Zu, Chao; Xing, Fanfan; Yang, Pei; Yang, Yongkang; Dang, Xiaoqian; Wang, Kunzheng

    2015-09-22

    Accumulating evidence indicates that dysregulation of miRNAs could contribute to tumor growth and metastasis of chondrosarcoma by infuencing cell proliferation and invasion. In the current study, we are interested to examine the role of miRNAs in the carcinogenesis and progression of chondrosarcoma. Here, using comparative miRNA profiling of tissues and cells of chondrosarcoma and cartilage, we identified miR-494 as a commonly downregulated miRNA in the tissues of patients with chondrosarcoma and chondrosarcoma cancer cell line, and upregulation of miR-494 could inhibit proliferation and invasion of chondrosarcoma cancer cells in vivo and in vitro. Moreover, our data demonstrated that SOX9, the essential regulator of the process of cartilage differentiation, was the direct target and functional mediator of miR-494 in chondrosarcoma cells. And downregulation of SOX9 could also inhibit migration and invasion of chondrosarcoma cells. In the last, we identified low expression of miR-494 was significantly correlated with poor overall survival and prognosis of chondrosarcoma patients. Thus, miR-494 may be a new common therapeutic target and prognosis biomarker for chondrosarcoma.

  11. Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo.

    Science.gov (United States)

    Sowa, Yoshihiro; Kishida, Tsunao; Tomita, Koichi; Yamamoto, Kenta; Numajiri, Toshiaki; Mazda, Osam

    2017-04-01

    Schwann cells (SCs) play pivotal roles in the maintenance and regeneration of the peripheral nervous system. Although transplantation of SCs enhances repair of experimentally damaged peripheral and central nerve tissues, it is difficult to prepare a sufficient number of functional SCs for transplantation therapy without causing adverse events for the donor. Here, we generated functional SCs by somatic cell reprogramming procedures and demonstrated their capability to promote peripheral nerve regeneration. Normal human fibroblasts were phenotypically converted into SCs by transducing SOX10 and Krox20 genes followed by culturing for 10 days resulting in approximately 43% directly converted Schwann cells (dSCs). The dSCs expressed SC-specific proteins, secreted neurotrophic factors, and induced neuronal cells to extend neurites. The dSCs also displayed myelin-forming capability both in vitro and in vivo. Moreover, transplantation of the dSCs into the transected sciatic nerve in mice resulted in significantly accelerated regeneration of the nerve and in improved motor function at a level comparable to that with transplantation of the SCs obtained from a peripheral nerve. The dSCs induced by our procedure may be applicable for novel regeneration therapy for not only peripheral nerve injury but also for central nerve damage and for neurodegenerative disorders related to SC dysfunction. Stem Cells Translational Medicine 2017;6:1207-1216. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  12. Quantitative in vivo fluorescence cross-correlation analyses highlight the importance of competitive effects in the regulation of protein-protein interactions.

    Science.gov (United States)

    Sadaie, Wakako; Harada, Yoshie; Matsuda, Michiyuki; Aoki, Kazuhiro

    2014-09-01

    Computer-assisted simulation is a promising approach for clarifying complicated signaling networks. However, this approach is currently limited by a deficiency of kinetic parameters determined in living cells. To overcome this problem, we applied fluorescence cross-correlation spectrometry (FCCS) to measure dissociation constant (Kd) values of signaling molecule complexes in living cells (in vivo Kd). Among the pairs of fluorescent molecules tested, that of monomerized enhanced green fluorescent protein (mEGFP) and HaloTag-tetramethylrhodamine was most suitable for the measurement of in vivo Kd by FCCS. Using this pair, we determined 22 in vivo Kd values of signaling molecule complexes comprising the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. With these parameters, we developed a kinetic simulation model of the EGFR-Ras-ERK MAP kinase pathway and uncovered a potential role played by stoichiometry in Shc binding to EGFR during the peak activations of Ras, MEK, and ERK. Intriguingly, most of the in vivo Kd values determined in this study were higher than the in vitro Kd values reported previously, suggesting the significance of competitive bindings inside cells. These in vivo Kd values will provide a sound basis for the quantitative understanding of signal transduction. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  13. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Daldrup-Link, Heike E.; Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J.; Rudelius, Martina; Piontek, Guido; Schlegel, Juergen; Piert, Morand; Uherek, Christoph; Wels, Winfried

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P 6 NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10 6 parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast

  14. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Daldrup-Link, Heike E. [UCSF Medical Center, Department of Radiology, San Francisco, CA (United States); Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J. [Technical University Munich, Department of Radiology, Munich (Germany); Rudelius, Martina; Piontek, Guido; Schlegel, Juergen [Technical University Munich, Institute of Pathology, Division of Neuropathology, Munich (Germany); Piert, Morand [Technical University Munich, Department of Nuclear Medicine, Munich (Germany); Uherek, Christoph; Wels, Winfried [University of Frankfurt, Georg Speyer House, Frankfurt (Germany)

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P<0.05). After intravenous injection of 5 x 10{sup 6} NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10{sup 6} parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently

  15. Polymer density functional theory approach based on scaling second-order direct correlation function.

    Science.gov (United States)

    Zhou, Shiqi

    2006-06-01

    A second-order direct correlation function (DCF) from solving the polymer-RISM integral equation is scaled up or down by an equation of state for bulk polymer, the resultant scaling second-order DCF is in better agreement with corresponding simulation results than the un-scaling second-order DCF. When the scaling second-order DCF is imported into a recently proposed LTDFA-based polymer DFT approach, an originally associated adjustable but mathematically meaningless parameter now becomes mathematically meaningful, i.e., the numerical value lies now between 0 and 1. When the adjustable parameter-free version of the LTDFA is used instead of the LTDFA, i.e., the adjustable parameter is fixed at 0.5, the resultant parameter-free version of the scaling LTDFA-based polymer DFT is also in good agreement with the corresponding simulation data for density profiles. The parameter-free version of the scaling LTDFA-based polymer DFT is employed to investigate the density profiles of a freely jointed tangent hard sphere chain near a variable sized central hard sphere, again the predictions reproduce accurately the simulational results. Importance of the present adjustable parameter-free version lies in its combination with a recently proposed universal theoretical way, in the resultant formalism, the contact theorem is still met by the adjustable parameter associated with the theoretical way.

  16. Foreign Direct Investment and Energy Supply in the Middle East and North Africa: A Correlational Study

    Science.gov (United States)

    Elghali, Siddig

    Middle East and North Africa countries have been criticized for failing to utilize foreign direct investment energy resources efficiently. The changing of energy resources environment of the past decades with its growing emphasis on the importance of imminent energy supply challenges require strategists to consider different types of energy resources investment to improve energy supply. One type of energy investment will show effectiveness and efficiency in utilizing foreign direct investment in exposing RE, fossil fuels, natural gas, and reducing CO2 emissions. The purpose of this quantitative correlational study was to utilize foreign direct investment to predict total primary energy supply in the Middle East and North Africa region between 1971 and 2013. The study was conducted using a sample size of 43 years of energy supply resources and foreign direct investment from 1971 to 2013, which includes all of the years for which FDI is available. RE potential may equip Middle East and North Africa countries with sustainable and clean electricity for centuries to come, as non-renewable energy resources may not meet the demands globally and domestically or environmentally. As demands for fossil fuels grow, carbon emissions will increase. RE may be a better option of CO 2 emissions sequestration and will increase electricity to rural areas without government subsidies and complex decision-making policies. RE infrastructure will reduce water desalinization costs, cooling systems, and be useful in heating. Establishing concentrated solar power may be useful for the region cooperation, negotiations, and integration to share this energy. The alternative sought to fossil fuels was nuclear power. However, nuclear power depends on depleting, non-renewable uranium resources. The cost of uranium will increase if widely used and the presence of a nuclear plant in an unstable region is unsafe. Thus, renewable energy as a long-term option is efficient. A nonlinear regression

  17. What is the correlation of in vivo wear and damage patterns with in vitro TDR motion response?

    Science.gov (United States)

    Kurtz, Steven M.; Patwardhan, Avinash; MacDonald, Daniel; Ciccarelli, Lauren; van Ooij, André; Lorenz, Mark; Zindrick, Michael; O’Leary, Patrick; Isaza, Jorge; Ross, Raymond

    2008-01-01

    Background Context Total disc replacements (TDRs) have been used to reduce pain and preserve motion. However, the comparison of polyethylene wear following long-term implantation to those tested using an in vitro model had not yet been investigated. Purpose The purpose of this study was to correlate wear and damage patterns in retrieved TDRs with motion patterns observed in a clinically validated in vitro lumbar spine model. We also sought to determine whether one-sided wear and motion patterns were associated with greater in vivo wear. Study Design This two-part study combined the evaluation of retrieved total disc replacements with a biomechanical study using human lumbar spines. Patient Sample 38 CHARITÉ lumbar artificial discs were retrieved from 32 patients (24 female, 75%) after 7.3 years average implantation (range: 1.8 to 16.1y). The components were implanted at L2/L3 (n=1), L3/L4 (n=2), L4/L5 (n=20), and L5/S1 (n=15). All the implants were removed due to intractable back pain and/or facet degeneration. In addition, they were removed due to subsidence (n=10), anterior migration (n=3), core dislocation (n=2), lateral subluxation (n=1), endplate loosening (n = 2), and osteolysis (n=1). In parallel, 7 new implants were evaluated at L4-L5 and 13 implants at L5-S1 in an in vitro lumbar spine model. Outcome Measures Retrieval analysis included evaluation of clinical data, dimensional measurements and assessment of the extent and severity of PE surface damage mechanisms. In vitro testing involved the observation of motion patterns during physiological loading. Methods For the retrievals, each side of the PE core was independently analyzed at the rim and dome for the presence of machining marks, wear, and fracture. 35 cores were further analyzed using MicroCT to determine whether the wear was one-sided, or symmetrically distributed. For the in vitro study the new implants were tested under physiologic loads (flexion-extension with a compressive follower preload

  18. Neural Correlates of Direct Access Trading in a Real Stock Market: An fMRI Investigation.

    Science.gov (United States)

    Raggetti, GianMario; Ceravolo, Maria G; Fattobene, Lucrezia; Di Dio, Cinzia

    2017-01-01

    Background: While financial decision making has been barely explored, no study has previously investigated the neural correlates of individual decisions made by professional traders involved in real stock market negotiations, using their own financial resources. Aim: We sought to detect how different brain areas are modulated by factors like age, expertise, psychological profile (speculative risk seeking or aversion) and, eventually, size and type (Buy/Sell) of stock negotiations, made through Direct Access Trading (DAT) platforms. Subjects and methods: Twenty male traders underwent fMRI while negotiating in the Italian stock market using their own preferred trading platform. Results: At least 20 decision events were collected during each fMRI session. Risk averse traders performed a lower number of financial transactions with respect to risk seekers, with a lower average economic value, but with a higher rate of filled proposals. Activations were observed in cortical and subcortical areas traditionally involved in decision processes, including the ventrolateral and dorsolateral prefrontal cortex (vlPFC, dlPFC), the posterior parietal cortex (PPC), the nucleus accumbens (NAcc), and dorsal striatum. Regression analysis indicated an important role of age in modulating activation of left NAcc, while traders' expertise was negatively related to activation of vlPFC. High value transactions were associated with a stronger activation of the right PPC when subjects' buy rather than sell. The success of the trading activity, based on a large number of filled transactions, was related with higher activation of vlPFC and dlPFC. Independent of chronological and professional age, traders differed in their attitude to DAT, with distinct brain activity profiles being detectable during fMRI sessions. Those subjects who described themselves as very self-confident, showed a lower or absent activation of both the caudate nucleus and the dlPFC, while more reflexive traders showed

  19. Neural Correlates of Direct Access Trading in a Real Stock Market: An fMRI Investigation

    Directory of Open Access Journals (Sweden)

    GianMario Raggetti

    2017-09-01

    Full Text Available Background: While financial decision making has been barely explored, no study has previously investigated the neural correlates of individual decisions made by professional traders involved in real stock market negotiations, using their own financial resources.Aim: We sought to detect how different brain areas are modulated by factors like age, expertise, psychological profile (speculative risk seeking or aversion and, eventually, size and type (Buy/Sell of stock negotiations, made through Direct Access Trading (DAT platforms.Subjects and methods: Twenty male traders underwent fMRI while negotiating in the Italian stock market using their own preferred trading platform.Results: At least 20 decision events were collected during each fMRI session. Risk averse traders performed a lower number of financial transactions with respect to risk seekers, with a lower average economic value, but with a higher rate of filled proposals. Activations were observed in cortical and subcortical areas traditionally involved in decision processes, including the ventrolateral and dorsolateral prefrontal cortex (vlPFC, dlPFC, the posterior parietal cortex (PPC, the nucleus accumbens (NAcc, and dorsal striatum. Regression analysis indicated an important role of age in modulating activation of left NAcc, while traders' expertise was negatively related to activation of vlPFC. High value transactions were associated with a stronger activation of the right PPC when subjects' buy rather than sell. The success of the trading activity, based on a large number of filled transactions, was related with higher activation of vlPFC and dlPFC. Independent of chronological and professional age, traders differed in their attitude to DAT, with distinct brain activity profiles being detectable during fMRI sessions. Those subjects who described themselves as very self-confident, showed a lower or absent activation of both the caudate nucleus and the dlPFC, while more reflexive traders

  20. In vivo comparison of Kodak E-speed film and direct digital imaging system for assessment of interproximal bone loss

    Directory of Open Access Journals (Sweden)

    Mellekatte C Neetha

    2014-01-01

    Full Text Available Aims: To evaluate the diagnostic accuracy of direct digital radiography as compared to a conventional radiographic film for the assessment of interproximal bone loss with intrasurgical measurements as the gold standard. Materials and Methods: A total of 100 patients, with untreated moderate-to-advanced periodontal disease, were included in the study. The presurgical radiographs were made using a Kodak E-speed film and a Dexis digital sensor simultaneously, for sites with interproximal bone loss. At the time of surgery, the distance from the cementoenamel junction to the bone defect (CEJ-BD was measured for 331 interproximal defects. The radiographs were randomized and then linear measurements were taken for the same sites in both conventional and digital radiographs. Stastistical Analysis: Comparison between the conventional, digital, and intrasurgical measurements was done statistically using the Student′s t-test. The agreement and correlation among the methods was assessed using the weighted Kappa measure of agreement and Pearson′s correlation, respectively. Results: The results showed that the conventional (5.15 ± 2.19 mm and digital analyzing techniques (5.13 ± 2.19 mm underestimated the interproximal bone loss, as compared to the intrasurgical measurements (6.07 ± 2.05 mm (p < 0.001. The difference between conventional and digital radiographic methods was found to be statistically insignificant (p = 0.92. Conclusion: Under normal clinical use, the alveolar bone levels revealed on intraoral direct digital radiographs and Kodak E speed film were almost same. Therefore, the digital radiographic system can be routinely used in clinical practice as an alternative to conventional film.

  1. Directional dependence of depth of correlation due to in-plane fluid shear in microscopic particle image velocimetry

    International Nuclear Information System (INIS)

    Olsen, Michael G

    2009-01-01

    An analytical model for the microscopic particle image velocimetry (microPIV) correlation signal peak in a purely shearing flow was derived for the case of in-plane shearing (out-of-plane shearing was not considered). This model was then used to derive equations for the measured velocity weighting functions for the two velocity components, and the weighting functions were in turn used to define the depths of correlation associated with the two measured velocity components. The depth of correlation for the velocity component perpendicular to the shear was found to be unaffected by the shear rate. However, the depth of correlation for the velocity component in the direction of the shear was found to be highly dependent on the shear rate, with the depth of correlation increasing as the shear rate increased. Thus, in a flow with shear, there is not a single value for the depth of correlation within an interrogation region. Instead, the depth of correlation exhibits directional dependence, with a different depth of correlation for each of the two measured velocity components. The increase in the depth of correlation due to the shear rate is greater for large numerical aperture objectives than for small numerical aperture objectives. This increase in the depth of correlation in a shearing flow can be quite large, with increases in the depth of correlation exceeding 100% being very possible for high numerical aperture objectives. The effects of out-of-plane shear are beyond the capabilities of this analysis, although the possible consequences of out-of-plane shear are discussed

  2. Correlation between the results of in vitro and in vivo chromosomal damage tests in consideration of exposure levels of test chemicals.

    Science.gov (United States)

    Yamamura, Eiji; Aruga, Chinami; Muto, Shigeharu; Baba, Nobuyuki; Uno, Yoshifumi

    2018-01-01

    We examined the correlation between the results of in vitro and in vivo chromosomal damage tests by using in-house data of 18 pharmaceutical candidates that showed positive results in the in vitro chromosomal aberration or micronucleus test using CHL/IU cells, and quantitatively analyzed them especially in regard to exposure levels of the compounds. Eight compounds showed that the exposure levels [maximum plasma concentration (C max ) and AUC 0-24h ] were comparable with or higher than the in vitro exposure levels [the lowest effective (positive) concentration (LEC) and AUC vitro  = LEC (μg/mL) × treatment time (h)]. Among them, 3 compounds were positive in the in vivo rodent micronucleus assays using bone marrow cells. For 2 compounds, cytotoxicity might produce false-positive results in the in vitro tests. One compound showed in vitro positive results only in the condition with S9 mix which indicated sufficient concentration of unidentified active metabolite(s) might not reach the bone marrow to induce micronuclei. These facts suggested that the in vivo exposure levels being equal to or higher than the in vitro exposure levels might be an important factor to detect in vivo chromosomal damage induced by test chemicals.

  3. Resveratrol-Loaded Lipid Nanocarriers: Correlation between In Vitro Occlusion Factor and In Vivo Skin Hydrating Effect

    Directory of Open Access Journals (Sweden)

    Lucia Montenegro

    2017-12-01

    Full Text Available Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions (NEs, solid lipid nanoparticles (SLNs and nanostructured lipid carriers (NLCs. These lipid nanocarriers were loaded with trans-resveratrol (RSV and incorporated in gel vehicles. In vitro occlusion factor was in the order SLNs > NLCs > NEs. Gels containing unloaded or RSV loaded lipid nanocarriers were applied on the back of a hand of 12 healthy volunteers twice a day for one week, recording skin hydration changes using the instrument Soft Plus. An increase of skin hydration was observed for all lipid nanocarriers (SLNs > NLCs > NEs. RSV loading into these nanocarriers did not affect in vitro and in vivo lipid nanocarriers effects. A linear relationship (r2 = 0.969 was observed between occlusion factor and in vivo increase of skin hydration. Therefore, the results of this study showed the feasibility of using the occlusion factor to predict in vivo skin hydration resulting from topical application of different lipid nanocarriers loading an active ingredient with no inherent hydrating activity.

  4. Identify super quality markers from prototype-based pharmacokinetic markers of Tangzhiqing tablet (TZQ) based on in vitro dissolution/ permeation and in vivo absorption correlations.

    Science.gov (United States)

    Li, Ziqiang; Liu, Jia; Li, Yazhuo; Du, Xi; Li, Yanfen; Wang, Ruihua; Lv, Chunxiao; He, Xin; Wang, Baohe; Huang, Yuhong; Zhang, Deqin

    2018-06-01

    A quality marker (Q-marker) is defined as an inherent chemical compound that is used for the quality control of a drug. Its biological activities are closely related to safety and therapeutic effects. Generally, a multiple-component herbal medicine may have many Q-markers. We therefore proposed a concept of "super Q-marker" satisfying both the criterion of Q-markers and PK-markers to be used in more effective quality control of herbal medicine. The first aim was to find suitable prototype-based PK-markers from Tangzhiqing tablets (TZQ), a Chinese patent medicine. Then super Q-markers were expected to be identified from the prototype-based PK-markers based on an in vitro-in vivo correlation study. Potentially eligible prototype-based PK-markers were identified in a single- and multiple-dose pharmacokinetic study on TZQ in 30 healthy volunteers. The in vitro dissolution and permeation profiles of the prototype-based PK-markers of TZQ were evaluated by the physiologically-based drug dissolution/absorption simulating system (DDASS). An in vitro-in vivo correlation analysis was conducted between the dissolution/permeation behaviors in DDASS and the actual absorption profiles in human to test the transferability and traceability of the promising super Q-markers for TZQ. In human, plasma paeoniflorin and nuciferine as prototype-based PK-markers exhibited the appropriate pharmacokinetic properties, including dose-dependent systemic exposure (AUC, C max ) and a proper elimination half-life (1∼3h). In DDASS, it was predicted that paeoniflorin and nuciferine are highly permeable but the absorption rates are primarily limited by the dissolution rates. Moreover, the established in vitro-in vivo correlations of paeoniflorin and nuciferine were in support of the super Q-markers features. Paeoniflorin and nuciferine are identified as the super Q-markers from the prototype-based PK-markers of TZQ based on findings from a combination of in vitro, in vivo, and in vitro-in vivo

  5. Generation of Novel Single-Chain Antibodies by Phage-Display Technology to Direct Imaging Agents Highly Selective to Pancreatic β- or α-Cells In Vivo

    Science.gov (United States)

    Ueberberg, Sandra; Meier, Juris J.; Waengler, Carmen; Schechinger, Wolfgang; Dietrich, Johannes W.; Tannapfel, Andrea; Schmitz, Inge; Schirrmacher, Ralf; Köller, Manfred; Klein, Harald H.; Schneider, Stephan

    2009-01-01

    OBJECTIVE Noninvasive determination of pancreatic β-cell mass in vivo has been hampered by the lack of suitable β-cell–specific imaging agents. This report outlines an approach for the development of novel ligands homing selectively to islet cells in vivo. RESEARCH DESIGN AND METHODS To generate agents specifically binding to pancreatic islets, a phage library was screened for single-chain antibodies (SCAs) on rat islets using two different approaches. 1) The library was injected into rats in vivo, and islets were isolated after a circulation time of 5 min. 2) Pancreatic islets were directly isolated, and the library was panned in the islets in vitro. Subsequently, the identified SCAs were extensively characterized in vitro and in vivo. RESULTS We report the generation of SCAs that bind highly selective to either β- or α-cells. These SCAs are internalized by target cells, disappear rapidly from the vasculature, and exert no toxicity in vivo. Specific binding to β- or α-cells was detected in cell lines in vitro, in rats in vivo, and in human tissue in situ. Electron microscopy demonstrated binding of SCAs to the endoplasmatic reticulum and the secretory granules. Finally, in a biodistribution study the labeling intensity derived from [125I]-labeled SCAs after intravenous administration in rats strongly predicted the β-cell mass and was inversely related to the glucose excursions during an intraperitoneal glucose tolerance test. CONCLUSIONS Our data provide strong evidence that the presented SCAs are highly specific for pancreatic β-cells and enable imaging and quantification in vivo. PMID:19592622

  6. Direct formulation to Cholesky decomposition of a general nonsingular correlation matrix.

    Science.gov (United States)

    Madar, Vered

    2015-08-01

    We present two novel and explicit parametrizations of Cholesky factor of a nonsingular correlation matrix. One that uses semi-partial correlation coefficients, and a second that utilizes differences between the successive ratios of two determinants. To each, we offer a useful application.

  7. Simulation of a directed random-walk model: the effect of pseudo-random-number correlations

    OpenAIRE

    Shchur, L. N.; Heringa, J. R.; Blöte, H. W. J.

    1996-01-01

    We investigate the mechanism that leads to systematic deviations in cluster Monte Carlo simulations when correlated pseudo-random numbers are used. We present a simple model, which enables an analysis of the effects due to correlations in several types of pseudo-random-number sequences. This model provides qualitative understanding of the bias mechanism in a class of cluster Monte Carlo algorithms.

  8. Charge correlation measurements of double-sided direct-coupled silicon mirostrip detectors

    International Nuclear Information System (INIS)

    Wood, M.L.; Kuehler, J.F.; Kalbfleisch, G.R.; Kaplan, D.H.; Skubic, P.; Lucas, A.D.; Wilburn, C.D.

    1991-01-01

    Charge correlation measurements of several Micron 38 mm by 58 mm by 300 micron thick double-sided DC-coupled microstripe detectors have been made. They have been bench tested with a Sr-90 source, with the detectors operated at -22C. The correlation of the charges collected from both the diode ('holes') and the ohmic ('electrons') stripes are equal within a signal to noise resolution of 20:1 (i.e., 1,200 electrons noise) using common-mode subtracted double-correlated sampling with the Berkeley SVXD readout chip

  9. Correlations between the in vitro and in vivo bioactivity of the Ti/HA composites fabricated by a powder metallurgy method.

    Science.gov (United States)

    Ning, Congqin; Zhou, Yu

    2008-11-01

    Ti/HA composites were successfully prepared by a powder metallurgy method and the effect of phase composition on the in vitro and in vivo bioactivity of the Ti/HA composites was investigated in the present study. The correlations between the in vitro and in vivo biological behaviors were highlighted. The results showed that the in vitro and in vivo bioactivity of the Ti/HA composites was dependent on their phase composition. The in vitro bioactivity of the Ti/HA composites was evaluated in simulated body fluid with ion concentrations similar to those of human plasma. After immersion in the simulated body fluid for a certain time, apatite precipitations formed on the surface of the composites with an initial titanium content of 50 and 70 wt.%, and no apatite was found on the surface of the composite with 30% titanium. Ti(2)O was responsible for the apatite formation on the surfaces of the composites. For in vivo analysis, Ti/HA cylinders were implanted in the metaphases of the rabbit femur. At the early stage of implantation, the new bone formed on the surface of the composite with 30% titanium was much less than that on the surfaces of the composites with 50% and 70% titanium. All the Ti/HA composites formed a chemical bone-bonding interface with the host bone by 6 months after implantation. The Ti/HA composites formed the bone-bonding interface with the surrounding bone through an apatite layer. The results in the present study suggested that the in vivo results agreed well with the in vitro results.

  10. MRI morphologic alterations after liver SBRT. Direct dose correlation with intermodal matching

    Energy Technology Data Exchange (ETDEWEB)

    Boda-Heggemann, Judit; Jahnke, Anika; Jahnke, Lennart; Vogel, Lena; Simeonova-Chergou, Anna O.; Herskind, Carsten; Wenz, Frederik; Lohr, Frank [University of Heidelberg, Department of Radiation Oncology, University Medical Center Mannheim, Mannheim (Germany); Attenberger, Ulrike; Budjan, Johannes [University of Heidelberg, Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim (Germany)

    2016-09-15

    CT morphologic and histopathologic alterations have been reported after SBRT. We analyzed the correlation of MRI morphologic alterations with radiation doses to assess the potential for MRI-based dose-effect correlation in healthy liver tissue. MRI data of 24 patients with liver metastases 7±3 weeks after image-guided SBRT in deep-inspiration breath-hold were retrospectively analyzed. MRI images were intermodally matched to the planning CT and corresponding dose distribution. Absolute doses were converted to EQD{sub 2,α/β=x} with α/β values of 2, 3 for healthy liver tissue, 8 Gy for modelled predamaged liver tissue and 10 Gy for tumor tissue. A central nonenhancing area was observed within the isodose lines of nominally 48.2 ± 15.2 Gy, EQD{sub 2Gy/α/β=10} 92.5 ± 27.7 Gy. Contrast-enhancement around the central nonenhancing area was observed within the isodose lines of nominally 46.9 ± 15.3 Gy, EQD{sub 2Gy/α/β=10} 90.5 ± 28.3 Gy. Outside the high-dose volume, in the beam path, characteristic sharply defined, nonblurred MRI morphologic alterations were observed that corresponded with the following isodose lines: T1-intensity changes occurred at isodose lines of nominally 21.9 ± 6.7 Gy (EQD{sub 2,α/β=2} 42.5 ± 8.7 Gy, EQD{sub 2,α/β=3} 38.5 ± 7.6 Gy, EQD{sub 2,α/β=8} 30.2 ±6.3 Gy). T2-hyper/hypointensity was observed within isodose lines of nominally 22.4 ± 6.6 Gy (EQD{sub 2,α/β=2} 42.7 ± 8.1 Gy, EQD{sub 2,α/β=3} 38.7 ± 7 Gy; EQD{sub 2,α/β=8} 30.5 ± 5.9 Gy). Using deformable matching, direct spatial/dosimetric correlation of SBRT-induced changes in liver tissue was possible. In the PTV high-dose region, a central nonenhancing area and peripheral contrast medium accumulation was observed. Beam path doses of 38-42 Gy (EQD{sub 2,α/β=2-3}) induce characteristic MRI morphologic alterations. (orig.) [German] CT-morphologische Veraenderungen nach SBRT sind beschrieben und korrelieren mit histopathologischen Veraenderungen. Ziel war es, MRT

  11. In vitro–in vivo correlations for endocrine activity of a mixture of 5 currently used pesticides

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Hadrup, Niels; Boberg, Julie

    2013-01-01

    , indicating increased aromatase activity. The pesticide-mixtures were also investigated in vivo in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. All 5 pesticides could be detected in the amniotic fluid, demonstrating exposure of the fetuses. Decreased estradiol...... with steroidogenesis, and it is suggested that one underlying mechanism for these pesticides is disturbance of steroidogenic enzymes....

  12. A Correlational Study of Self-Directed Learning Readiness and Learning Activity Preference for Continuing Medical Education among Family Physicians

    Science.gov (United States)

    Barrett, Theresa J.

    2014-01-01

    This quantitative, nonexperimental, correlational study sought to determine whether a relationship exists between family physicians' levels of self-directed learning readiness (SDLR) and their preferences for continuing medical education (CME) activities. The study also sought to determine whether years in clinical practice or size of clinical…

  13. Gamma-gamma directional correlations for levels excited up to 2.5 MeV of 214Po

    International Nuclear Information System (INIS)

    Morales, A.; Nunez-Lagos, R.; Morales, J.; Plo, M.

    1984-01-01

    The spin of twenty two excited states (up to an energy of 2.5 MeV) of 214 Po have been measured by using gamma-gamma directional correlation techniques, twelve of them for the first time. The multipole mixing ratios of the corresponding electromagnetic transition from these levels to the first excited level have also been determined. (author)

  14. Bayesian estimation of direct and correlated responses to selection on linear or ratio expressions of feed efficiency in pigs

    DEFF Research Database (Denmark)

    Shirali, Mahmoud; Varley, Patrick Francis; Jensen, Just

    2018-01-01

    meat percentage (LMP) along with the derived traits of RFI and FCR; and (3) deriving Bayesian estimates of direct and correlated responses to selection on RFI, FCR, ADG, ADFI, and LMP. Response to selection was defined as the difference in additive genetic mean of the selected top individuals, expected......, respectively. Selection against RFIG showed a direct response of − 0.16 kg/d and correlated responses of − 0.16 kg/kg for FCR and − 0.15 kg/d for ADFI, with no effect on other production traits. Selection against FCR resulted in a direct response of − 0.17 kg/kg and correlated responses of − 0.14 kg/d for RFIG......, − 0.18 kg/d for ADFI, and 0.98% for LMP. Conclusions: The Bayesian methodology developed here enables prediction of breeding values for FCR and RFI from a single multi-variate model. In addition, we derived posterior distributions of direct and correlated responses to selection. Genetic parameter...

  15. Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig.

    Science.gov (United States)

    Janson, Juliette; Eketjäll, Susanna; Tunblad, Karin; Jeppsson, Fredrik; Von Berg, Stefan; Niva, Camilla; Radesäter, Ann-Cathrin; Fälting, Johanna; Visser, Sandra A G

    2014-03-01

    The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid β (Aβ) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel β-secretase (BACE1) inhibitors. BACE1-mediated inhibition of Aβ was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aβ production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach. Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aβ40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells. The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.

  16. Evaluation of the Correlation Coefficient of Polyethylene Glycol Treated and Direct Prolactin Results and Comparability with Different Assay System Results.

    Science.gov (United States)

    Pal, Shyamali

    2017-12-01

    The presence of Macro prolactin is a significant cause of elevated prolactin resulting in misdiagnosis in all automated systems. Poly ethylene glycol (PEG) pretreatment is the preventive process but such process includes the probability of loss of a fraction of bioactive prolactin. Surprisingly, PEG treated EQAS & IQAS samples in Cobas e 411 are found out to be correlating with direct results of at least 3 immunoassay systems and treated and untreated Cobas e 411 results are comparable by a correlation coefficient. Comparison of EQAS, IQAS and patient samples were done to find out the trueness of such correlation factor. Study with patient's results have established the correlation coefficient is valid for very small concentration of prolactin also. EQAS, IQAS and 150 patient samples were treated with PEG and prolactin results of treated and untreated samples obtained from Roche Cobas e 411. 25 patient's results (treated) were compared with direct results in Advia Centaur, Architect I & Access2 systems. Correlation coefficient was obtained from trend line of the treated and untreated results. Two tailed p-value obtained from regression coefficient(r) and sample size. The correlation coefficient is in the range (0.761-0.771). Reverse correlation range is (1.289-1.301). r value of two sets of calculated results were 0.995. Two tailed p- value is zero approving dismissal of null hypothesis. The z-score of EQAS does not always assure authenticity of resultsPEG precipitation is correlated by the factor 0.761 even in very small concentrationsAbbreviationsGFCgel filtration chromatographyPEGpolyethylene glycolEQASexternal quality assurance systemM-PRLmacro prolactinPRLprolactinECLIAelectro-chemiluminescence immunoassayCLIAclinical laboratory improvement amendmentsIQASinternal quality assurance systemrregression coefficient.

  17. The generation of random directed networks with prescribed 1-node and 2-node degree correlations

    Energy Technology Data Exchange (ETDEWEB)

    Zamora-Lopez, Gorka; Kurths, Juergen [Institute of Physics, University of Potsdam, PO Box 601553, 14415 Potsdam (Germany); Zhou Changsong [Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong (China); Zlatic, Vinko [Rudjer Boskovic Institute, PO Box 180, HR-10002 Zagreb (Croatia)

    2008-06-06

    The generation of random networks is a very common problem in complex network research. In this paper, we have studied the correlation nature of several real networks and found that, typically, a large number of links are deterministic, i.e. they cannot be randomized. This finding permits fast generation of ensembles of maximally random networks with prescribed 1-node and 2-node degree correlations. When the introduction of self-loops or multiple-links are not desired, random network generation methods typically reach blocked states. Here, a mechanism is proposed, the 'force-and-drop' method, to overcome such states. Our algorithm can be easily simplified for undirected graphs and reduced to account for any subclass of 2-node degree correlations.

  18. The generation of random directed networks with prescribed 1-node and 2-node degree correlations

    International Nuclear Information System (INIS)

    Zamora-Lopez, Gorka; Kurths, Juergen; Zhou Changsong; Zlatic, Vinko

    2008-01-01

    The generation of random networks is a very common problem in complex network research. In this paper, we have studied the correlation nature of several real networks and found that, typically, a large number of links are deterministic, i.e. they cannot be randomized. This finding permits fast generation of ensembles of maximally random networks with prescribed 1-node and 2-node degree correlations. When the introduction of self-loops or multiple-links are not desired, random network generation methods typically reach blocked states. Here, a mechanism is proposed, the 'force-and-drop' method, to overcome such states. Our algorithm can be easily simplified for undirected graphs and reduced to account for any subclass of 2-node degree correlations

  19. Foreign Direct Investments and Tax Correlation: Some of EU Countries and Turkey

    Directory of Open Access Journals (Sweden)

    Ali YAVUZ

    2010-06-01

    Full Text Available In the globalizing world; individuals, markets and capital are more mobile than the past for that reason countries are in cutthroat competition for attract the direct and indirect investments. Especially, developing countries overview their own tax policy and perform incentive measures including tax incentives to attract the direct investments which have a positive effect of production and employment level. In this process, some countries achieve their goals and some are not. The purpose of this study evaluate the difference of tax policies in Turkey which in EU candidacy process and some old central, east Europe countries which are in EU and the main rival of Turkey to attracting direct investments. In this evaluation process, changing income tax, corporate tax, value added tax and performance of attracking the direct investments which was performed in selected countries, were evaluated by comparative

  20. Foreign Direct Investments and Tax Correlation: Some of EU Countries and Turkey

    OpenAIRE

    Ali YAVUZ; Serdar ÇİÇEK

    2010-01-01

    In the globalizing world; individuals, markets and capital are more mobile than the past for that reason countries are in cutthroat competition for attract the direct and indirect investments. Especially, developing countries overview their own tax policy and perform incentive measures including tax incentives to attract the direct investments which have a positive effect of production and employment level. In this process, some countries achieve their goals and some are not. The purpose of t...

  1. Co-localized or randomly distributed? Pair cross correlation of in vivo grown subgingival biofilm bacteria quantified by digital image analysis.

    Directory of Open Access Journals (Sweden)

    Claudia Schillinger

    Full Text Available The polymicrobial nature of periodontal diseases is reflected by the diversity of phylotypes detected in subgingival plaque and the finding that consortia of suspected pathogens rather than single species are associated with disease development. A number of these microorganisms have been demonstrated in vitro to interact and enhance biofilm integration, survival or even pathogenic features. To examine the in vivo relevance of these proposed interactions, we extended the spatial arrangement analysis tool of the software daime (digital image analysis in microbial ecology. This modification enabled the quantitative analysis of microbial co-localization in images of subgingival biofilm species, where the biomass was confined to fractions of the whole-image area, a situation common for medical samples. Selected representatives of the disease-associated red and orange complexes that were previously suggested to interact with each other in vitro (Tannerella forsythia with Fusobacterium nucleatum and Porphyromonas gingivalis with Prevotella intermedia were chosen for analysis and labeled with specific fluorescent probes via fluorescence in situ hybridization. Pair cross-correlation analysis of in vivo grown biofilms revealed tight clustering of F. nucleatum/periodonticum and T. forsythia at short distances (up to 6 µm with a pronounced peak at 1.5 µm. While these results confirmed previous in vitro observations for F. nucleatum and T. forsythia, random spatial distribution was detected between P. gingivalis and P. intermedia in the in vivo samples. In conclusion, we successfully employed spatial arrangement analysis on the single cell level in clinically relevant medical samples and demonstrated the utility of this approach for the in vivo validation of in vitro observations by analyzing statistically relevant numbers of different patients. More importantly, the culture-independent nature of this approach enables similar quantitative analyses for "as

  2. Visualizing the Acute Effects of Vascular-Targeted Therapy In Vivo Using Intravital Microscopy and Magnetic Resonance Imaging: Correlation with Endothelial Apoptosis, Cytokine Induction, and Treatment Outcome

    Directory of Open Access Journals (Sweden)

    Mukund Seshadri

    2007-02-01

    Full Text Available The acute effects of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA were investigated in vivo using intravital microscopy (IVM and magnetic resonance imaging (MRI. Changes in vascular permeability and blood flow of syngeneic CT-26 murine colon adenocarcinomas were assessed at 4 and 24 hours after DMXAA treatment (30 mg/kg, i.p. and correlated with induction of tumor necrosis factor-α (TNF-α, endothelial damage [CD31/terminal deoxynucleotidyl transferase (TdT], and treatment outcome. Intravital imaging revealed a marked increase in vascular permeability 4 hours after treatment, consistent with increases in intratumoral mRNA and protein levels of TNF-α. Parallel contrast-enhanced MRI studies showed a ~ 4-fold increase in longitudinal relaxation rates (ΔR1, indicative of increased contrast agent accumulation within the tumor. Dualimmunostained tumor sections (CD31/TdT revealed evidence of endothelial apoptosis at this time point. Twenty-four hours after treatment, extensive hemorrhage and complete disruption of vascular architecture were observed with IVM, along with a significant reduction in ΔR1 and virtual absence of CD31 immunostaining. DMXAA-induced tumor vascular damage resulted in significant long-term (60-day cures compared to untreated controls. Multimodality imaging approaches are useful in visualizing the effects of antivascular therapy in vivo. Such approaches allow cross validation and correlation of findings with underlying molecular changes contributing to treatment outcome.

  3. Direct and correlated responses to selection for total weight of lamb ...

    African Journals Online (AJOL)

    The estimated selection responses indicate that direct selection for TWW would be the most suitable selection criterion for improving reproductive performance in flocks with a high reproduction rate where an increase in the number of lambs would be undesirable. (South African Journal of Animal Science, 2001, 31(2): ...

  4. Vector velocity estimation using directional beam forming and cross-correlation

    DEFF Research Database (Denmark)

    2000-01-01

    The two-dimensional velocity vector using a pulsed ultrasound field can be determined with the invention. The method uses a focused ultrasound field along the velocity direction for probing the moving medium under investigation. Several pulses are emitted and the focused received fields along...

  5. Direct and correlated responses to selection for total weight of lamb ...

    African Journals Online (AJOL)

    Unknown

    productivity and that each of these components can be used as a selection criterion, as each has a direct impact on total ewe ... of lamb weaned per ewe joined is more efficient than selection for number of lambs born, number of lambs weaned or weaning ... The estimated grazing capacity is 5.5 ha per small stock unit.

  6. Dynamic Aftershock Triggering Correlated with Cyclic Loading in the Slip Direction

    Science.gov (United States)

    Hardebeck, J.

    2014-12-01

    Dynamic stress changes have been shown to contribute to aftershock triggering, but the physical triggering mechanisms are not fully understood. Some proposed mechanisms are based on dynamic stress loading of the target fault in a direction that encourages earthquake slip (e.g. dynamic Coulomb stress triggering), while other mechanisms are based on fault weakening due to shaking. If dynamic stress loading in the fault slip direction plays a role in aftershock triggering, we would expect to see a relationship between the dynamic stress orientations and the aftershock focal mechanisms. Alternatively, if dynamic stress change triggering functions only through a fault weakening mechanism that is independent of the slip direction of the target fault, no such relationship is expected. I study aftershock sequences of 4 M≥6.7 mainshocks in southern California, and find a small but significant relationship between modeled dynamic stress direction and aftershock focal mechanisms. The mainshock dynamic stress changes have two observed impacts: changing the focal mechanisms in a given location to favor those aligned with the dynamic stress change, and changing the spatial distribution of seismicity to favor locations where the dynamic stress change aligns with the background stress. The aftershock focal mechanisms are significantly more aligned with the dynamic stress changes than the preshock mechanisms for only the first 0.5-1 year following most mainshocks, although for at least 10 years following Hector Mine. Dynamic stress effects on focal mechanisms are best observed at long periods (30-60 sec). Dynamic stress effects are only observed when using metrics based on repeated stress cycling in the same direction, for example considering the dominant stress orientation over the full time series, and not for the peak dynamic stress. These results imply that dynamic aftershock triggering operates at least in part through cyclic loading in the direction of fault slip, although

  7. Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium

    DEFF Research Database (Denmark)

    Borkar, Nrupa Nitin; Xia, Dengning; Holm, René

    2014-01-01

    Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs......-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.......e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (p

  8. Direct and efficient transfection of mouse neural stem cells and mature neurons by in vivo mRNA electroporation.

    Science.gov (United States)

    Bugeon, Stéphane; de Chevigny, Antoine; Boutin, Camille; Coré, Nathalie; Wild, Stefan; Bosio, Andreas; Cremer, Harold; Beclin, Christophe

    2017-11-01

    In vivo brain electroporation of DNA expression vectors is a widely used method for lineage and gene function studies in the developing and postnatal brain. However, transfection efficiency of DNA is limited and adult brain tissue is refractory to electroporation. Here, we present a systematic study of mRNA as a vector for acute genetic manipulation in the developing and adult brain. We demonstrate that mRNA electroporation is far more efficient than DNA electroporation, and leads to faster and more homogeneous protein expression in vivo Importantly, mRNA electroporation allows the manipulation of neural stem cells and postmitotic neurons in the adult brain using minimally invasive procedures. Finally, we show that this approach can be efficiently used for functional studies, as exemplified by transient overexpression of the neurogenic factor Myt1l and by stably inactivating Dicer nuclease in vivo in adult born olfactory bulb interneurons and in fully integrated cortical projection neurons. © 2017. Published by The Company of Biologists Ltd.

  9. Endocytosis via galactose receptors in vivo. Ligand size directs uptake by hepatocytes and/or liver macrophages

    International Nuclear Information System (INIS)

    Schlepper-Schaefer, J.; Huelsmann, D.; Djovkar, A.; Meyer, H.E.; Herbertz, L.; Kolb, H.; Kolb-Bachofen, V.

    1986-01-01

    The intrahepatic binding and uptake of variously sized ligands with terminal galactosyl residues is rat liver was followed. The ligands were administered to prefixed livers in binding studies and in vivo and in situ (serum-free perfused livers) in uptake studies. Gold sols with different particle diameters were prepared: 5 nm (Au 5 ), 17 nm (Au 17 ), 50 nm (Au 50 ) and coated with galactose exposing glycoproteins (asialofetuin (ASF) or lactosylated BSA (LacBSA)). Electron microscopy of mildly prefixed livers perfused with LacBSA-Au 5 in serum-free medium showed ligand binding to liver macrophages, hepatocytes and endothelial cells. Ligands bound to prefixed cell surfaces reflect the initial distribution of receptor activity: pre-aggregated clusters of ligands are found on liver macrophages, single particles statistically distributed on hepatocytes and pre-aggregated clusters of particles restricted to coated pits on endothelial cells. Ligand binding is prevented in the presence of 80 mM N-acetylgalactosamine (GalNAc), while N-acetylglucosamine (GlcNAc) is without effect. Electron microscopy of livers after ligand injection into the tail vein shows that in vivo uptake of electron-dense galactose particles by liver cells is size-dependent. In vivo uptake by liver macrophages is mediated by galactose-specific recognition as shown by inhibition with GalNAc

  10. The Correlation between Managers’ Delegation of Authority with the Manner of Employee Direction in Hospitals of Qom Province

    OpenAIRE

    Maleki M.R; Nasiri Pour A.A; Amini F; Parham M

    2011-01-01

    Background and Objectives: The destructive effect of centralized management can be found throughout each organization, which is a barrier for delegation of authority and productivity leading to administrative violence increase and compression and frigidity of affairs. With attention to the importance of delegation of authority this research aimed at determining the correlation between the manager's delegation of authority with the manner of employee direction in Qom hospitals, designed for co...

  11. Direct correlation of observed phonon anomalies and maxima in the generalized susceptibilities of transition metal carbides

    International Nuclear Information System (INIS)

    Gupta, M.J.; Freeman, A.B.

    1976-01-01

    The generalized susceptibility, chi(q), of both NbC and TaC determined from APW energy band calculations show large maxima to occur at precisely those q/sub max/ values at which soft phonon modes were observed by Smith. Maxima in chi(q) are predicted for other directions. The locus of these q/sub max/ values can be represented by a warped cube of dimension approximately 1.2(2π/a) in momentum space--in striking agreement with the soft mode surface proposed phenomenologically by Weber. In sharp contrast, the chi(q) calculated for both ZrC and HfC--for which no phonon anomalies have been observed--fall off in all symmetry directions away from the zone center. The phonon anomalies in the transition metal carbides are thus interpreted as due to an ''overscreening'' effect resulting from an anomalous increase of the response function of the conduction electrons

  12. Reliability of fetal cardiac volumetry using spatiotemporal image correlation: assessment of in-vivo and in-vitro measurements

    NARCIS (Netherlands)

    Uittenbogaard, L.B.; Haak, M.C.; Tromp, C.H.N.; Terwee, C.B.; van Vugt, J.M.G.

    2010-01-01

    Objective To assess the reliability of measurement of fetal cardiac ventricular volume, stroke volume, and ejection fraction with four-dimensional ultrasound using spatiotemporal image correlation (STIC). Methods Volume datasets were collected from two sources: 24 from fetuses over a range of

  13. Activity-dependent increases in local oxygen consumption correlate with postsynaptic currents in the mouse cerebellum in vivo

    DEFF Research Database (Denmark)

    Mathiesen, Claus; Caesar, Kirsten; Thomsen, Kirsten Engelund

    2011-01-01

    Evoked neural activity correlates strongly with rises in cerebral metabolic rate of oxygen (CMRO(2)) and cerebral blood flow (CBF). Activity-dependent rises in CMRO(2) fluctuate with ATP turnover due to ion pumping. In vitro studies suggest that increases in cytosolic Ca(2+) stimulate oxidative m...

  14. Activity-dependent increases in local oxygen consumption correlate with post-synaptic currents in the mouse cerebellum in vivo

    DEFF Research Database (Denmark)

    Mathiesen, Claus; Caesar, Kirsten; Thomsen, Kirsten Joan

    2011-01-01

    Evoked neural activity correlates strongly with rises in cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow. Activity-dependent rises in CMRO2 fluctuate with ATP turnover due to ion pumping. In vitro studies suggest that increases in cytosolic Ca2+ stimulate oxidative metabolism vi...

  15. Hepatocarcinogenesis tumor grading correlated with in vivo image-guided 1H-NMR spectroscopy in a rat model

    International Nuclear Information System (INIS)

    Towner, Rheal A.; Foley, Lesley M.; Painter, Dorothy M.

    2005-01-01

    Hepatocellular carcinoma (HCC) is a common malignancy worldwide, the occurrence of which is unevenly distributed. Most hepatocellular carcinoma cases present late and have a poor prognosis; therefore, early diagnosis is essential to prolong survival. Differential diagnosis with magnetic resonance imaging (MRI) is difficult. We studied the feasibility of using magnetic resonance spectroscopy (MRS) at 7.0 T for the diagnosis and grading of liver tumors. An animal model of hepatocarcinogenesis was used, which allowed tumor progression from precancerous lesions to hepatocellular carcinomas. This study was focused primarily on the grading of the tumors and its correlation with the ratio between the MRS peaks arising from MRS-detected lipid hydrogens (0.9, 1.3 and 5.3 ppm) and compared to the γ-methylene hydrogens of glutamate (Glu) and glutamine (Gln) which was used as an internal reference (2.4 ppm). The lipid methylene hydrogen (1.3 ppm) to (Glu + Gln) ratio was found to correlate with the formation of differentiated small foci and (precancerous) hepatic nodules, whereas the unsaturated olefinic lipid hydrogen (5.3 ppm) to (Glu + Gln) ratio was able to correlate with the formation of late stage tumors such as adenomas and hepatocellular carcinomas. The results of our study suggest that MRS-detected alterations in lipid metabolism can be correlated with the grading of liver tumor tissue at different stages during the carcinogenesis process

  16. Mechanical torque measurement in the proximal femur correlates to failure load and bone mineral density ex vivo

    Directory of Open Access Journals (Sweden)

    Stefan Grote

    2013-06-01

    Full Text Available Knowledge of local bone quality is essential for surgeons to determine operation techniques. A device for intraoperative measurement of local bone quality has been developed by the AO-Research Foundation (DensiProbe®. We used this device to experimentally measure peak breakaway torque of trabecular bone in the proximal femur and correlated this with local bone mineral density (BMD and failure load. Bone mineral density of 160 cadaver femurs was measured by ex situ dual-energy X-ray absorptiometry. The failure load of all femurs was analyzed by side-impact analysis. Femur fractures were fixed and mechanical peak torque was measured with the DensiProbe® device. Correlation was calculated whereas correlation coefficient and significance was calculated by Fisher’s Z-transformation. Moreover, linear regression analysis was carried out. The unpaired Student’s t-test was used to assess the significance of differences. The Ward triangle region had the lowest BMD with 0.511 g/cm2 (±0.17 g/cm2, followed by the upper neck region with 0.546 g/cm2 (±0.16 g/cm2, trochanteric region with 0.685 g/cm2 (±0.19 g/cm2 and the femoral neck with 0.813 g/cm2 (±0.2 g/cm2. Peak torque of DensiProbe® in the femoral head was 3.48 Nm (±2.34 Nm. Load to failure was 4050.2 N (±1586.7 N. The highest correlation of peak torque measured by Densi Probe® and load to failure was found in the femoral neck (r=0.64, P<0.001. The overall correlation of mechanical peak torque with T-score was r=0.60 (P<0.001. A correlation was found between mechanical peak torque, load to failure of bone and BMD in vitro. Trabecular strength of bone and bone mineral density are different aspects of bone strength, but a correlation was found between them. Mechanical peak torque as measured may contribute additional information about bone strength, especially in the perioperative testing.

  17. The Correlation between Managers’ Delegation of Authority with the Manner of Employee Direction in Hospitals of Qom Province

    Directory of Open Access Journals (Sweden)

    Maleki M.R

    2011-08-01

    Full Text Available Background and Objectives: The destructive effect of centralized management can be found throughout each organization, which is a barrier for delegation of authority and productivity leading to administrative violence increase and compression and frigidity of affairs. With attention to the importance of delegation of authority this research aimed at determining the correlation between the manager's delegation of authority with the manner of employee direction in Qom hospitals, designed for contributing to improvement of managers’ performance in hospitals.Methods: This correlational and cross-sectional research, was carried out on all the employees under the control of managers and chiefs of Qom province hospitals (N=2167. Sampling was done by cluster sampling method through the use of Cokran sampling based on Morgan and kerjsi chart. 998 samples with the confidence level of %95 and permitted errors of 0.05 were randomly selected. Data were collected via questionnaires which were answered by self-report method. The data were then analyzed by the Pearson correlation coefficient, variance's test F analyses, multiple variant regression and T-test.Results: The mean score of the manager's non-delegation of authority was (32.4. Among the indicators of the direction, there was a significant relationship between the motivation (mean= 61.44 and organizational communication (49.39, also there was a significant relationship between the managers’ delegation of authority and the manner of their employees direction (non-delegation of authority R=-0.13. Conclusion: Due to the meaningful and direct relationship between most of direction variables with the managers’ delegation of authority, increasing the delegation of authority and deconcentration can lead to an increase in employee motivation and (vertical and formal communication and improved performance of affairs.

  18. Two-baryon systems from HAL QCD method and the mirage in the temporal correlation of the direct method

    Science.gov (United States)

    Iritani, Takumi

    2018-03-01

    Both direct and HAL QCD methods are currently used to study the hadron interactions in lattice QCD. In the direct method, the eigen-energy of two-particle is measured from the temporal correlation. Due to the contamination of excited states, however, the direct method suffers from the fake eigen-energy problem, which we call the "mirage problem," while the HAL QCD method can extract information from all elastic states by using the spatial correlation. In this work, we further investigate systematic uncertainties of the HAL QCD method such as the quark source operator dependence, the convergence of the derivative expansion of the non-local interaction kernel, and the single baryon saturation, which are found to be well controlled. We also confirm the consistency between the HAL QCD method and the Lüscher's finite volume formula. Based on the HAL QCD potential, we quantitatively confirm that the mirage plateau in the direct method is indeed caused by the contamination of excited states.

  19. Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood

    DEFF Research Database (Denmark)

    Herndon, Thomas M; Chen, Shih-Ann; Saba, Nakhle S

    2017-01-01

    of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs. Using a deuterium oxide ((2)H) in vivo labeling...... method in which patients consumed deuterated (heavy) water ((2)H2O), we determined CLL cell kinetics in concurrently obtained samples from LN, PB and BM. The LN was identified as the anatomical site harboring the largest fraction of newly born cells, compared to PB and BM. In fact, the calculated birth...

  20. Nuclear-data evaluation based on direct and indirect measurements with general correlations

    International Nuclear Information System (INIS)

    Muir, D.W.

    1988-01-01

    Optimum procedures for the statistical improvement, or updating, of an existing nuclear-data evaluation are reviewed and redeveloped from first principles, consistently employing a minimum-variance viewpoint. A set of equations is derived which provides improved values of the data and their covariances, taking into account information from supplementary measurements and allowing for general correlations among all measurements. The minimum-variance solutions thus obtained, which we call the method of 'partitioned least squares,' are found to be equivalent to a method suggested by Yu. V. Linnik and applied by a number of authors to the analysis of fission-reactor integral experiments; however, up to now, the partitioned-least-squares formulae have not found widespread use in the field of basic data evaluation. This approach is shown to give the same results as the more commonly applied Normal equations, but with reduced matrix inversion requirements. Examples are provided to indicate potential areas of application. (author)

  1. Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation.

    Science.gov (United States)

    McDonald, Tom O; Giardiello, Marco; Martin, Philip; Siccardi, Marco; Liptrott, Neill J; Smith, Darren; Roberts, Phill; Curley, Paul; Schipani, Alessandro; Khoo, Saye H; Long, James; Foster, Alison J; Rannard, Steven P; Owen, Andrew

    2014-03-01

    Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion-templated freeze-drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non-nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z-average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four-fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Fast evaluation of 69 basal cell carcinomas with ex vivo fluorescence confocal microscopy: criteria description, histopathological correlation, and interobserver agreement.

    Science.gov (United States)

    Bennàssar, Antoni; Carrera, Cristina; Puig, Susana; Vilalta, Antoni; Malvehy, Josep

    2013-07-01

    Fluorescence confocal microscopy (FCM) represents a first step toward a rapid "bedside pathology" in the Mohs surgery setting and in other fields of general pathology. To describe and validate FCM criteria for the main basal cell carcinoma (BCC) subtypes and to demonstrate the overall agreement with classic pathologic analysis of hematoxylin-eosin-stained samples. DESIGN A total of 69 BCCs from 66 patients were prospectively imaged using ex vivo FCM. Confocal mosaics were evaluated in real time and compared with classic pathologic analysis. Department of Dermatology, Hospital Clínic of Barcelona, Barcelona, Spain, between November 2010 and July 2011. Patients with BCC attending the Mohs Surgery Unit. Presence or absence of BCC and histological subtype (superficial, nodular, and infiltrating) in the confocal mosaics. Eight criteria for BCC were described, evaluated, and validated. Although there were minor differences among BCC subtypes, the most BCC-defining criteria were peripheral palisading, clefting, nuclear pleomorphism, and presence of stroma. These criteria were validated with independent observers (κ values >0.7 [corrected] for most criteria). We herein propose, describe, and validate FCM criteria for BCC diagnosis. Fluorescence confocal microscopy is an attractive alternative to histopathologic analysis of frozen sections during Mohs surgery because large areas of freshly excised tissue can be assessed in real time without the need for tissue processing while minimizing labor and costs.

  3. Blood pressure directly correlates with blood viscosity in diabetes type 1 children but not in normals.

    Science.gov (United States)

    Vázquez, Beatriz Y Salazar; Vázquez, Miguel A Salazar; Jáquez, Manuel Guajardo; Huemoeller, Antonio H Bracho; Intaglietta, Marcos; Cabrales, Pedro

    2010-01-01

    To determine the relationship between mean arterial blood pressure (MAP) and blood viscosity in diabetic type 1 children and healthy controls to investigate whether MAP is independent of blood viscosity in healthy children, and vice versa. Children with diabetes type 1 treated by insulin injection were studied. Controls were healthy children of both sexes. MAP was calculated from systolic and diastolic pressure measurements. Blood viscosity was determined indirectly by measuring blood hemoglobin (Hb) content. The relationship between Hb, hematocrit (Hct) and blood viscosity was determined in a subgroup of controls and diabetics selected at random. 21 (10.6+/-2.5 years) type 1 diabetic children treated with insulin and 25 healthy controls age 9.6+/-1.7 years were studied. Hb was 13.8+/-0.8 g/dl in normal children vs. 14.3+/-0.9 g/dl in the diabetic group (p<0.05). MAP was 71.4+/-8.2 in the normal vs. 82.9+/-7.2 mmHg in the diabetic group (p<0.001). Glucose was 89.3+/-10.6 vs. 202.4+/-87.4 mg/dl respectively. Diabetics had a positive MAP/Hb correlation (p=0.007), while normals showed a non significant (p=0.2) negative correlation. The blood viscosity/Hb relationship was studied in a subgroup of 8 healthy controls and 8 diabetic type 1 children. There was no significant difference in Hb and Hct between groups. Diabetics showed a trend of increasing blood viscosity (+7%, p=0.15). Normal children compensate for the increase in vascular resistance due to increased blood viscosity (increased Hb and Hct) while diabetic children do not, probably due to endothelial dysfunction.

  4. Correlates between kinematics and baropodometric measurements for an integrated in-vivo assessment of the segmental foot function in gait.

    Science.gov (United States)

    Giacomozzi, Claudia; Leardini, Alberto; Caravaggi, Paolo

    2014-08-22

    Baropodometry and multi-segmental foot kinematics are frequently employed to obtain insight into the mechanics of the foot-ground interaction in both basic research and clinical settings. However, nothing hitherto has been reported on the full integration of kinematics with baropodometric parameters, and only a few studies have addressed the association between intersegmental kinematics and plantar loading within specific foot regions. The aim of this study was to understanding the relationships between foot joint mobility and plantar loading by focusing on the correlation between these two measures. An integrated pressure-force-kinematics system was used to measure plantar pressure and rotations between foot segments during the stance phase of walking in 10 healthy subjects. An anatomically-based mask was applied to each footprint to obtain six regions according to the position of the markers; hence each kinematic segment was paired with a corresponding area of the plantar surface. Relationships between segmental motion and relevant baropodometric data were explored by means of correlation analysis. Negative, weak-to-moderate correlations (R(2)plantar pressure in almost all regions. The study helps improve our understanding of the relationship between joint mobility and plantar loading in the healthy foot and represents a critical preliminary analysis before addressing possible clinical applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Directional Atherectomy in Iliac Stent Failure: Clinical Technique and Histopathologic Correlation

    International Nuclear Information System (INIS)

    Ettles, Duncan F.; MacDonald, Alastair W.; Burgess, Paul A.; Nicholson, Anthony A.; Dyet, John F.

    1998-01-01

    Purpose: To assess the feasibility and efficacy of directional atherectomy in the treatment of iliac stent stenosis or occlusion and to evaluate the histologic composition of excised atherectomy specimens. Methods: Directional atherectomy of six occluded and 10 severely stenosed iliac stents was undertaken in 12 patients at a mean interval of 28 months (range 3-69 months) after stent insertion for occlusive aortoiliac disease. In cases of stent occlusion, atherectomy was preceded by low-dose thrombolysis. In all patients stent clearance with return of femoral pulses was achieved within 24 hr and there were no significant complications. All excised specimens were sent for histologic examination. Results: Eleven patients (92%) remain symptom free with unlimited walking distance at a mean follow-up interval of 11.5 months (range 3-31 months) after treatment. Histologic examination revealed typical myointimal hyperplasia at three excision sites, intimal fibrosis at three sites, atheroma at four sites and organized thrombus at six sites. Conclusion: Atherectomy offers an effective treatment in iliac stent occlusion and restenosis with no significant adverse effects. Debulking of these lesions seems to offer a more logical approach than simple balloon angioplasty. Clinical and duplex follow-up confirms satisfactory outcome within the first year but longer-term results are not yet known. The histologic data obtained demonstrate that stent restenosis and occlusion are likely to be multifactorial, and challenge the assumption that myointimal hyperplasia is the sole cause of iliac stent occlusion

  6. Direct correlation of observed phonon anomalies and maxima in the generalized susceptibilities of transition metal carbides

    International Nuclear Information System (INIS)

    Gupta, M.; Freeman, A.J.

    1976-01-01

    The generalized susceptibility, chi(q vector), of both NbC and TaC determined from APW energy band calculations show large maxima to occur at precisely those q vector/sub max/ values at which soft phonon modes were observed by Smith. Maxima in chi (q vector) are predicted for other directions. The locus of these q vector/sub max/ values can be represented by a warped cube of dimension approximately 1.2 (2π/a) in momentum space, in striking agreement with the soft mode surface proposed phenomenologically by Weber. In sharp contrast, the chi(q vector) calculated for both ZrC and HfC (for which no phonon anomalies have been observed) fall off in all symmetry directions away from the zone center. The phonon anomalies in the transition metal carbides are interpreted as due to an ''overscreening'' effect resulting from an anomalous increase of the response function of the conduction electrons. 8 figures, 41 references

  7. Direct fitness correlates and thermal consequences of facultative aggregation in a desert lizard.

    Directory of Open Access Journals (Sweden)

    Alison R Davis Rabosky

    Full Text Available Social aggregation is a common behavioral phenomenon thought to evolve through adaptive benefits to group living. Comparing fitness differences between aggregated and solitary individuals in nature--necessary to infer an evolutionary benefit to living in groups--has proven difficult because communally-living species tend to be obligately social and behaviorally complex. However, these differences and the mechanisms driving them are critical to understanding how solitary individuals transition to group living, as well as how and why nascent social systems change over time. Here we demonstrate that facultative aggregation in a reptile (the Desert Night Lizard, Xantusia vigilis confers direct reproductive success and survival advantages and that thermal benefits of winter huddling disproportionately benefit small juveniles, which can favor delayed dispersal of offspring and the formation of kin groups. Using climate projection models, however, we estimate that future aggregation in night lizards could decline more than 50% due to warmer temperatures. Our results support the theory that transitions to group living arise from direct benefits to social individuals and offer a clear mechanism for the origin of kin groups through juvenile philopatry. The temperature dependence of aggregation in this and other taxa suggests that environmental variation may be a powerful but underappreciated force in the rapid transition between social and solitary behavior.

  8. In-vivo Imaging of Magnetic Fields Induced by Transcranial Direct Current Stimulation (tDCS) in Human Brain using MRI

    Science.gov (United States)

    Jog, Mayank V.; Smith, Robert X.; Jann, Kay; Dunn, Walter; Lafon, Belen; Truong, Dennis; Wu, Allan; Parra, Lucas; Bikson, Marom; Wang, Danny J. J.

    2016-10-01

    Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that applies mA currents at the scalp to modulate cortical excitability. Here, we present a novel magnetic resonance imaging (MRI) technique, which detects magnetic fields induced by tDCS currents. This technique is based on Ampere’s law and exploits the linear relationship between direct current and induced magnetic fields. Following validation on a phantom with a known path of electric current and induced magnetic field, the proposed MRI technique was applied to a human limb (to demonstrate in-vivo feasibility using simple biological tissue) and human heads (to demonstrate feasibility in standard tDCS applications). The results show that the proposed technique detects tDCS induced magnetic fields as small as a nanotesla at millimeter spatial resolution. Through measurements of magnetic fields linearly proportional to the applied tDCS current, our approach opens a new avenue for direct in-vivo visualization of tDCS target engagement.

  9. siRNA associated with immunonanoparticles directed against cd99 antigen improves gene expression inhibition in vivo in Ewing's sarcoma.

    Science.gov (United States)

    Ramon, A L; Bertrand, J R; de Martimprey, H; Bernard, G; Ponchel, G; Malvy, C; Vauthier, C

    2013-07-01

    Ewing's sarcoma is a rare, mostly pediatric bone cancer that presents a chromosome abnormality called EWS/Fli-1, responsible for the development of the tumor. In vivo, tumor growth can be inhibited specifically by delivering small interfering RNA (siRNA) associated with nanoparticles. The aim of the work was to design targeted nanoparticles against the cell membrane glycoprotein cd99, which is overexpressed in Ewing's sarcoma cells to improve siRNA delivery to tumor cells. Biotinylated poly(isobutylcyanoacrylate) nanoparticles were conceived as a platform to design targeted nanoparticles with biotinylated ligands and using the biotin-streptavidin coupling method. The targeted nanoparticles were validated in vivo for the targeted delivery of siRNA after systemic administration to mice bearing a tumor model of the Ewing's sarcoma. The expression of the gene responsible of Ewing's sarcoma was inhibited at 78% ± 6% by associating the siRNA with the cd99-targeted nanoparticles compared with an inhibition of only 41% ± 9% achieved with the nontargeted nanoparticles. Copyright © 2013 John Wiley & Sons, Ltd.

  10. The pan-Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo

    DEFF Research Database (Denmark)

    Hansen, Henrik H; Weikop, Pia; Mikkelsen, Maria D

    2017-01-01

    Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener ...... by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo....

  11. Correlation of In Vivo and In Vitro Methods in Measuring Choroidal Vascularization Volumes Using a Subretinal Injection Induced Choroidal Neovascularization Model

    Directory of Open Access Journals (Sweden)

    Chuang Nie

    2015-01-01

    Full Text Available Background: In vivo quantification of choroidal neovascularization (CNV based on noninvasive optical coherence tomography (OCT examination and in vitro choroidal flatmount immunohistochemistry stained of CNV currently were used to evaluate the process and severity of age-related macular degeneration (AMD both in human and animal studies. This study aimed to investigate the correlation between these two methods in murine CNV models induced by subretinal injection. Methods: CNV was developed in 20 C57BL6/j mice by subretinal injection of adeno-associated viral delivery of a short hairpin RNA targeting sFLT-1 (AAV.shRNA.sFLT-1, as reported previously. After 4 weeks, CNV was imaged by OCT and fluorescence angiography. The scaling factors for each dimension, x, y, and z (μm/pixel were recorded, and the corneal curvature standard was adjusted from human (7.7 to mice (1.4. The volume of each OCT image stack was calculated and then normalized by multiplying the number of voxels by the scaling factors for each dimension in Seg3D software (University of Utah Scientific Computing and Imaging Institute, available at http://www.sci.utah.edu/cibc-software/seg3d.html. Eighteen mice were prepared for choroidal flatmounts and stained by CD31. The CNV volumes were calculated using scanning laser confocal microscopy after immunohistochemistry staining. Two mice were stained by Hematoxylin and Eosin for observing the CNV morphology. Results: The CNV volume calculated using OCT was, on average, 2.6 times larger than the volume calculated using the laser confocal microscopy. The correlation statistical analysis showed OCT measuring of CNV correlated significantly with the in vitro method (R 2 =0.448, P = 0.001, n = 18. The correlation coefficient for CNV quantification using OCT and confocal microscopy was 0.693 (n = 18, P = 0.001. Conclusions: There is a fair linear correlation on CNV volumes between in vivo and in vitro methods in CNV models induced by subretinal

  12. Correlation between direction and severity of temporomandibular joint disc displacement and reduction ability during mouth opening.

    Science.gov (United States)

    Litko, M; Berger, M; Szkutnik, J; Różyło-Kalinowska, I

    2017-12-01

    The most common temporomandibular joint (TMJ) internal derangement is an abnormal relationship of the disc with respect to the mandibular condyle, articular eminence and glenoid fossa-disc displacement. The aim of our study was to analyse the correlation between partial/complete disc displacement in the intercuspal position (IP) and its reduction in the open-mouth position (OMP) in both oblique sagittal and coronal planes on magnetic resonance imaging (MRI) in patients with temporomandibular disorders. Multisection MRI analysis of 382 TMJs was conducted in 191 patients with disc displacement according to the RDC/TMD criteria (148 women, 43 men; aged 14-60 years). The disc position was evaluated on all oblique sagittal and coronal images in the IP and the OMP. Univariate logistic regression analysis showed that the severity of disc displacement in the sagittal plane is a statistically significant predictor of reduction ability during mouth opening (B = 3.118; P displacement in both planes is also a significant predictor of disc reduction in OMP (B = 2.200; P displacement in IP, in both sagittal and coronal planes. Multisection analysis of all MR images allows distinguishing the correct disc position from disc displacement and can improve the ability to distinguish between various stages of TMJ internal derangement. © 2017 John Wiley & Sons Ltd.

  13. UNMASKING MASKED HYPERTENSION: PREVALENCE, CLINICAL IMPLICATIONS, DIAGNOSIS, CORRELATES, AND FUTURE DIRECTIONS

    Science.gov (United States)

    Peacock, James; Diaz, Keith M.; Viera, Anthony J.; Schwartz, Joseph E.; Shimbo, Daichi

    2014-01-01

    ‘Masked hypertension’ is defined as having non-elevated clinic blood pressure (BP) with elevated out-of-clinic average BP, typically determined by ambulatory BP monitoring. Approximately 15–30% of adults with non-elevated clinic BP have masked hypertension. Masked hypertension is associated with increased risks of cardiovascular morbidity and mortality compared to sustained normotension (non-elevated clinic and ambulatory BP), which is similar to or approaching the risk associated with sustained hypertension (elevated clinic and ambulatory BP). The confluence of increased cardiovascular risk and a failure to be diagnosed by the conventional approach of clinic BP measurement makes masked hypertension a significant public health concern. However, many important questions remain. First, the definition of masked hypertension varies across studies. Further, the best approach in the clinical setting to exclude masked hypertension also remains unknown. It is unclear whether home BP monitoring is an adequate substitute for ambulatory BP monitoring in identifying masked hypertension. Few studies have examined the mechanistic pathways that may explain masked hypertension. Finally, scarce data are available on the best approach to treating individuals with masked hypertension. Herein, we review the current literature on masked hypertension including definition, prevalence, clinical implications, special patient populations, correlates, issues related to diagnosis, treatment, and areas for future research. PMID:24573133

  14. Direct correlation between potentiometric and impedance biosensing of antibody-antigen interactions using an integrated system

    Science.gov (United States)

    Tsai, Meng-Yen; Creedon, Niamh; Brightbill, Eleanor; Pavlidis, Spyridon; Brown, Billyde; Gray, Darren W.; Shields, Niall; Sayers, Ríona; Mooney, Mark H.; O'Riordan, Alan; Vogel, Eric M.

    2017-08-01

    A fully integrated system that combines extended gate field-effect transistor (EGFET)-based potentiometric biosensors and electrochemical impedance spectroscopy (EIS)-based biosensors has been demonstrated. This integrated configuration enables the sequential measurement of the same immunological binding event on the same sensing surface and consequently sheds light on the fundamental origins of sensing signals produced by FET and EIS biosensors, as well as the correlation between the two. Detection of both the bovine serum albumin (BSA)/anti-BSA model system in buffer solution and bovine parainfluenza antibodies in complex blood plasma samples was demonstrated using the integrated biosensors. Comparison of the EGFET and EIS sensor responses reveals similar dynamic ranges, while equivalent circuit modeling of the EIS response shows that the commonly reported total impedance change (ΔZtotal) is dominated by the change in charge transfer resistance (Rct) rather than surface capacitance (Csurface). Using electrochemical kinetics and the Butler-Volmer equation, we unveil that the surface potential and charge transfer resistance, measured by potentiometric and impedance biosensors, respectively, are, in fact, intrinsically linked. This observation suggests that there is no significant gain in using the FET/EIS integrated system and leads to the demonstration that low-cost EGFET biosensors are sufficient as a detection tool to resolve the charge information of biomolecules for practical sensing applications.

  15. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer

    OpenAIRE

    Bradshaw-Pierce, Erica Lynn; Pitts, Todd M.; Tan, Aik-Choon; McPhillips, Kelly; West, Mark; Gustafson, Daniel L.; Halsey, Charles; Nguyen, Leslie; Lee, Nathan V.; Kan, Julie L. C.; Murray, Brion William; Eckhardt, S. Gail

    2013-01-01

    P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1...

  16. Tumor p-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer.

    OpenAIRE

    Erica Lynn Bradshaw-Pierce; Erica Lynn Bradshaw-Pierce; Todd M Pitts; Aik-Choon eTan; Kelly eMcPhillips; Mark eWest; Daniel L Gustafson; Charles eHalsey; Leslie eNguyen; Nathan V Lee; Julie LC Kan; Brion William Murray; S. Gail eEckhardt

    2013-01-01

    P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB...

  17. Development and validation of an in vitro–in vivo correlation (IVIVC model for propranolol hydrochloride extended-release matrix formulations

    Directory of Open Access Journals (Sweden)

    Chinhwa Cheng

    2014-06-01

    Full Text Available The objective of this study was to develop an in vitro–in vivo correlation (IVIVC model for hydrophilic matrix extended-release (ER propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid.

  18. Airway reactivity in chronic obstructive pulmonary disease. Failure of in vivo methacholine responsiveness to correlate with cholinergic, adrenergic, or nonadrenergic responses in vitro.

    Science.gov (United States)

    Taylor, S M; Paré, P D; Armour, C L; Hogg, J C; Schellenberg, R R

    1985-07-01

    This study aimed to determine whether in vivo airways hyperreactivity was manifested by either enhanced bronchial smooth muscle responses to contractile stimuli or by deficient responses to relaxant stimuli in vitro. Quantitative responses to nebulized methacholine were obtained in 12 human subjects prior to pulmonary resection. The provocative concentration of methacholine producing a 20% reduction in FEV1 (PC20) was calculated, and these values were compared with in vitro responses of bronchial smooth muscle strips from the surgical specimens. Both contractile cholinergic responses and relaxant nonadrenergic noncholinergic dose-response data were obtained for the in vitro bronchial specimens by electrical field stimulation. In addition, cumulative dose responses were obtained to exogenously added methacholine, the beta-adrenergic agonist salbutamol, and the adenylate cyclase activator forskolin. Despite a wide range of PC20 values, the in vivo airway responsiveness did not correlate with any of the in vitro responses examined, suggesting that airway reactivity is not due solely to the responsiveness of smooth muscle to contractile agonists nor to a localized deficiency in the nonadrenergic inhibitory system, beta-adrenergic inhibition, or abnormal cyclic-AMP-mediated pathways of relaxation.

  19. Neural correlates of mirth and laughter: a direct electrical cortical stimulation study.

    Science.gov (United States)

    Yamao, Yukihiro; Matsumoto, Riki; Kunieda, Takeharu; Shibata, Sumiya; Shimotake, Akihiro; Kikuchi, Takayuki; Satow, Takeshi; Mikuni, Nobuhiro; Fukuyama, Hidenao; Ikeda, Akio; Miyamoto, Susumu

    2015-05-01

    Laughter consists of both motor and emotional aspects. The emotional component, known as mirth, is usually associated with the motor component, namely, bilateral facial movements. Previous electrical cortical stimulation (ES) studies revealed that mirth was associated with the basal temporal cortex, inferior frontal cortex, and medial frontal cortex. Functional neuroimaging implicated a role for the left inferior frontal and bilateral temporal cortices in humor processing. However, the neural origins and pathways linking mirth with facial movements are still unclear. We hereby report two cases with temporal lobe epilepsy undergoing subdural electrode implantation in whom ES of the left basal temporal cortex elicited both mirth and laughter-related facial muscle movements. In one case with normal hippocampus, high-frequency ES consistently caused contralateral facial movement, followed by bilateral facial movements with mirth. In contrast, in another case with hippocampal sclerosis (HS), ES elicited only mirth at low intensity and short duration, and eventually laughter at higher intensity and longer duration. In both cases, the basal temporal language area (BTLA) was located within or adjacent to the cortex where ES produced mirth. In conclusion, the present direct ES study demonstrated that 1) mirth had a close relationship with language function, 2) intact mesial temporal structures were actively engaged in the beginning of facial movements associated with mirth, and 3) these emotion-related facial movements had contralateral dominance. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Quality control of technetium-99m DTPA: correlation of analytic tests with in vivo protein binding in man

    International Nuclear Information System (INIS)

    Russell, C.D.; Rowell, K.; Scott, J.W.

    1986-01-01

    When [/sup 99m/Tc]DTPA is administered, a small fraction of the activity (presumably an impurity) is bound to plasma proteins. This causes an error in the calculation of glomerular filtration rate from plasma clearance. This paper presents two methods of laboratory quality control for measuring the fraction that binds to plasma proteins. One method involves in vitro binding to human serum albumin followed by gel filtration. The other method involves descending paper chromatography on wet pre-equilibrated anion exchange paper. In a series of 80 patients, correlation was demonstrated between laboratory characteristics and actual clinical performance of the [/sup 99m/Tc]DTPA preparation. Both laboratory methods appear suitable for routine quality control

  1. Evaluation of Cholinesterase Activities During in Vivo Intoxication Using an Electrochemical Sensor Strip – Correlation With Intoxication Symptoms

    Directory of Open Access Journals (Sweden)

    Jana Zdarova-Karasova

    2009-05-01

    Full Text Available Cholinesterase activity in blood of laboratory rats was monitored. Rats were intoxicated with paraoxon at dosis of 0 – 65 – 125 – 170 – 250 – 500 nmol. The 250 nmol dose was found to be the LD50. An electrochemical sensor was found useful to provide information about cholinesterase activity. The decrease of cholinesterase activity was correlated to intoxication symptoms and mortality level. It was found that the symptoms of intoxication are not observed while at least 50% of cholinesterase activity in blood remains. The minimal cholinesterase activity essential to survival is around 10%, when compared with the initial state. No changes in levels of low moleculary weight antioxidants were observed.

  2. An in vivo analysis of facial muscle change treated with botulinum toxin type A using digital image speckle correlation

    Science.gov (United States)

    Xu, Yan; Palmaccio, Samantha Palmaccio; Bui, Duc; Dagum, Alexander; Rafailovich, Miriam

    Been famous for clinical use from early 1980s, the neuromuscular blocking agent Botulinum toxin type A (BTX-A), has been used to reduce wrinkles for a long time. Only little research has been done to quantify the change of muscle contraction before and after injection and most research paper depend on subjective evaluation from both patients and surgeons. In our research, Digital Image Speckle Correlation (DISC) was employed to study the mechanical properties of skin, contraction mode of muscles (injected) and reaction of neighbor muscle group (un-injected).At the same time, displacement patterns (vector maps)generated by DISC can predict injection locus for surgeons who normally handle it depending only on visual observation.

  3. Individual differences in learning correlate with modulation of brain activity induced by transcranial direct current stimulation

    Science.gov (United States)

    Falcone, Brian; Wada, Atsushi; Parasuraman, Raja

    2018-01-01

    Transcranial direct current stimulation (tDCS) has been shown to enhance cognitive performance on a variety of tasks. It is hypothesized that tDCS enhances performance by affecting task related cortical excitability changes in networks underlying or connected to the site of stimulation facilitating long term potentiation. However, many recent studies have called into question the reliability and efficacy of tDCS to induce modulatory changes in brain activity. In this study, our goal is to investigate the individual differences in tDCS induced modulatory effects on brain activity related to the degree of enhancement in performance, providing insight into this lack of reliability. In accomplishing this goal, we used functional magnetic resonance imaging (fMRI) concurrently with tDCS stimulation (1 mA, 30 minutes duration) using a visual search task simulating real world conditions. The experiment consisted of three fMRI sessions: pre-training (no performance feedback), training (performance feedback which included response accuracy and target location and either real tDCS or sham stimulation given), and post-training (no performance feedback). The right posterior parietal cortex was selected as the site of anodal tDCS based on its known role in visual search and spatial attention processing. Our results identified a region in the right precentral gyrus, known to be involved with visual spatial attention and orienting, that showed tDCS induced task related changes in cortical excitability that were associated with individual differences in improved performance. This same region showed greater activity during the training session for target feedback of incorrect (target-error feedback) over correct trials for the tDCS stim over sham group indicating greater attention to target features during training feedback when trials were incorrect. These results give important insight into the nature of neural excitability induced by tDCS as it relates to variability in

  4. Selection of suitable prodrug candidates for in vivo studies via in vitro studies; the correlation of prodrug stability in between cell culture homogenates and human tissue homogenates.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2012-01-01

    To determine the correlations/discrepancies of drug stabilities between in the homogenates of human culture cells and of human tissues. Amino acid/dipeptide monoester prodrugs of floxuridine were chosen as the model drugs. The stabilities (half-lives) of floxuridine prodrugs in human tissues (pancreas, liver, and small intestine) homogenates were obtained and compared with ones in cell culture homogenates (AcPC-1, Capan-2, and Caco-2 cells) as well as human liver microsomes. The correlations of prodrug stability in human small bowel tissue homogenate vs. Caco-2 cell homogenate, human liver tissue homogenate vs. human liver microsomes, and human pancreatic tissue homogenate vs. pancreatic cell, AsPC-1 and Capan-2, homogenates were examined. The stabilities of floxuridine prodrugs in human small bowel homogenate exhibited the great correlation to ones in Caco-2 cell homogenate (slope = 1.0-1.3, r2 = 0.79-0.98). The stability of those prodrugs in human pancreas tissue homogenate also exhibited the good correlations to ones in AsPC-1 and Capan-2 cells homogenates (slope = 0.5-0.8, r2 = 0.58-0.79). However, the correlations of prodrug stabilities between in human liver tissue homogenates and in human liver microsomes were weaker than others (slope = 1.3-1.9, r2 = 0.07-0.24). The correlations of drug stabilities in cultured cell homogenates and in human tissue homogenates were compared. Those results exhibited wide range of correlations between in cell homogenate and in human tissue homogenate (r2 = 0.07 - 0.98). Those in vitro studies in cell homogenates would be good tools to predict drug stabilities in vivo and to select drug candidates for further developments. In the series of experiments, 5'-O-D-valyl-floxuridine and 5'-O-L-phenylalanyl-L-tyrosyl-floxuridine would be selected as candidates of oral drug targeting delivery for cancer chemotherapy due to their relatively good stabilities compared to other tested prodrugs.

  5. The Correlation between Managers’ Delegation of Authority with the Manner of Employee Direction in Hospitals of Qom Province

    Directory of Open Access Journals (Sweden)

    M.R Maleki

    2012-05-01

    Full Text Available

    Background and Objectives: The destructive effect of centralized management can be found throughout each organization, which is a barrier for delegation of authority and productivity leading to administrative violence increase and compression and frigidity of affairs. With attention to the importance of delegation of authority this research aimed at determining the correlation between the manager's delegation of authority with the manner of employee direction in Qom hospitals, designed for contributing to improvement of managers’ performance in hospitals.

     

    Methods: This correlational and cross-sectional research, was carried out on all the employees under the control of managers and chiefs of Qom province hospitals (N=2167. Sampling was done by cluster sampling method through the use of Cokran sampling based on Morgan and kerjsi chart. 998 samples with the confidence level of 95% and permitted errors of 0.05 were randomly selected. Data were collected via questionnaires which were answered by self-report method. The data were then analyzed by the Pearson correlation coefficient, variance's test F analyses, multiple variant regression and T-test.

     

    Results: The mean score of the manager's non-delegation of authority was (32.4. Among the indicators of the direction, there was a significant relationship between the motivation (mean= 61.44 and organizational communication (49.39, also there was a significant relationship between the managers’ delegation of authority and the manner of their employees direction (non-delegation of authority R=-0.13.

     

    Conclusion: Due to the meaningful and direct relationship between most of direction variables with the managers’ delegation of authority, increasing the delegation of authority and deconcentration can lead to an increase

  6. Correlation between Initial BIC and the Insertion Torque/Depth Integral Recorded with an Instantaneous Torque-Measuring Implant Motor: An in vivo Study.

    Science.gov (United States)

    Capparé, Paolo; Vinci, Raffaele; Di Stefano, Danilo Alessio; Traini, Tonino; Pantaleo, Giuseppe; Gherlone, Enrico Felice; Gastaldi, Giorgio

    2015-10-01

    Quantitative intraoperative evaluation of bone quality at implant placement site and postinsertion implant primary stability assessment are two key parameters to perform implant-supported rehabilitation properly. A novel micromotor has been recently introduced allowing to measure bone density at implant placement site and to record implant insertion-related parameters, such as the instantaneous, average and peak insertion torque values, and the insertion torque/depth integral. The aim of this study was to investigate in vivo if any correlation existed between initial bone-to-implant contact (BIC) and bone density and integral values recorded with the instrument. Twenty-five patients seeking for implant-supported rehabilitation of edentulous areas were consecutively treated. Before implant placement, bone density at the insertion site was measured. For each patient, an undersized 3.3 × 8-mm implant was placed, recording the insertion torque/depth integral values. After 15 minutes, the undersized implant was retrieved with a 0.5 mm-thick layer of bone surrounding it. Standard implants were consequently placed. Retrieved implants were analyzed for initial BIC quantification after fixation, dehydration, acrylic resin embedment, sections cutting and grinding, and toluidine-blue and acid fuchsine staining. Correlation between initial BIC values, bone density at the insertion site, and the torque/depth integral values was investigated by linear regression analysis. A significant linear correlation was found to exist between initial BIC and (a) bone density at the insertion site (R = 0.96, explained variance R(2)  = 0.92) and (b) torque/depth integral at placement (R = 0.81, explained variance R(2)  = 0.66). The system provided quantitative, reliable data correlating significantly with immediate postinsertion initial BIC, and could therefore represent a valuable tool both for clinical research and for the oral implantologist in his/her daily clinical

  7. Wetting and adhesion evaluation of cosmetic ingredients and products: correlation of in vitro-in vivo contact angle measurements.

    Science.gov (United States)

    Capra, P; Musitelli, G; Perugini, P

    2017-08-01

    The aim of this work was to use the contact angle measurement in order to predict the behaviour of ingredients and finished cosmetic products on skin to improve skin feel and product texture. Different classes of cosmetic ingredients and formulations were evaluated. The contact angle measurements were carried out by the sessile drop method using an apparatus, designed and set up in laboratory. Glass, Teflon and human skin were the reference substrates. In a preliminary phase, TEWL parameter, sebum content and hydration of human skin were measured to set up method. Data demonstrated that glass substrate may be used as replacement of the skin:critical surface tension of skin and glass were about of 27 and 31 dyne cm -1 , respectively. Non-ionic surfactant with increasing HLB was evaluated: a correlation between contact angle measured and HLB was not observed because of different and complex molecular structure. In detail, ethylhexyl hydroxystearate (θ glass = 17.1°) showed lower contact angle value with respect to Polysorbate 20 (θ glass = 28.1°). Sodium laureth sulphate and stearalkonium chloride were also evaluated: anionic molecule showed more affinity for glass with respect to Teflon (θ glass = 21.7° and θ Teflon = 52.3°). Lipids and silicones showed different affinity for substrate according to hydrophilic groups and hydrocarbon chain: contact angles of silicones remained unchanged independently from substrate. Finished cosmetic products (O/W, W/O emulsions, cleansing oil, dry skin oil) showed different profiles according to surfactant and its affinity for continuous phase of the formulation. Comparing the values of the contact angle on skin of non-ionic surfactants, as ethylhexyl hydroxystearate and Polysorbate 20, they showed values lower (near to zero) than ones of sodium laureth sulphate and Stearalkonium Chloride (21.7° and 66.8°, respectively). Finally, finished cosmetic products tested on human skin showed different profile: corresponded contact

  8. Wind direction correlated measurements of radon and radon progeny in atmosphere: a method for radon source identification

    International Nuclear Information System (INIS)

    Akber, R.A.; Pfitzner, J.; Johnston, A.

    1994-01-01

    This paper describes the basic principles and methodology of a wind direction correlated measurement technique which is used to distinguish the mine-related and background components of radon and radon progeny concentrations in the vicinity of the ERA Ranger Uranium Mine. Simultaneous measurements of atmospheric radon and radon progeny concentrations and wind speed and direction were conducted using automatic sampling stations. The data were recorded as a time series of half hourly averages and grouped into sixteen 22.5 degrees wind sectors. The sampling interval and the wind sector width were chosen considering wind direction variability (σ θ ) over the sampling time interval. The data were then analysed for radon and radon progeny concentrations in each wind sector. Information about the wind frequency wind speed seasonal and diurnal variations in wind direction and radon concentrations was required for proper data analysis and interpretation of results. A comparison with model-based estimates for an identical time period shows agreement within about a factor of two between the two methods. 15 refs., 1 tab., 5 figs

  9. Applications of the direct photon absorption technique for measuring bone mineral content in vivo. Determination of body composition in vivo. Annual progress report, 15 July 1971--15 July 1972

    International Nuclear Information System (INIS)

    Cameron, J.R.

    1972-01-01

    The bone mineral content, BMC, determined by monoenergetic photon absorption technique, of 29 different locations on the long bones and vertebral columns of 24 skeletons was measured. Compressive tests were made on bone from these locations in which the maximum load and maximum stress were measured. Also the ultimate strain, modulus of elasticity and energy absorbed to failure were determined for compact bone from the femoral diaphysis and cancellous bone from the eighth through eleventh thoracic vertebrae. Correlations and predictive relationships between these parameters were examined to investigate the applicability of using the BMC at sites normally measured in vivo, i.e. radius and ulna in estimating the BMC and/or strength of the spine or femoral neck. It was found that the BMC at sites on the same bone were highly correlated and the BMC at sites on different bones were also highly interrelated. The BMC at various sites on the long bones could be estimated to between 10 and 15 per cent from the BMC of sites on the radius or ulna. (U.S.)

  10. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

    International Nuclear Information System (INIS)

    Beyer, G.J.; Soloviev, D.; Buchegger, F.; Miederer, M.; Vranjes-Duric, S.; Comor, J.J.; Kuenzi, G.; Hartley, O.; Senekowitsch-Schmidtke, R.

    2004-01-01

    This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10 6 Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 μg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with 149 Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach. (orig.)

  11. In vivo correlation between c-Fos expression and corticotroph stimulation by adrenocorticotrophic hormone secretagogues in rat anterior pituitary gland.

    Science.gov (United States)

    Takigami, Shu; Fujiwara, Ken; Kikuchi, Motoshi; Yashiro, Takashi

    2008-03-01

    In the anterior pituitary gland, c-Fos expression is evoked by various stimuli. However, whether c-Fos expression is directly related to the stimulation of anterior pituitary cells by hypothalamic secretagogues is unclear. To confirm whether the reception of hormone-releasing stimuli evokes c-Fos expression in anterior pituitary cells, we have examined c-Fos expression of anterior pituitary glands in rats administered with synthetic corticotrophin-releasing hormone (CRH) intravenously or subjected to restraint stress. Single intravenous administration of CRH increases the number of c-Fos-expressing cells, and this number does not change even if the dose is increased. Double-immunostaining has revealed that most of the c-Fos-expressing cells contain adrenocorticotrophic hormone (ACTH); corticotrophs that do not express c-Fos in response to CRH have also been found. However, restraint stress evokes c-Fos expression in most of the corticotrophs and in a partial population of lactotrophs. These results suggest that c-Fos expression increases in corticotrophs stimulated by ACTH secretagogues, including CRH. Furthermore, we have found restricted numbers of corticotrophs expressing c-Fos in response to CRH. Although the mechanism underlying the different responses to CRH is not apparent, c-Fos is probably a useful immunohistochemical marker for corticotrophs stimulated by ACTH secretagogues.

  12. Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

    Energy Technology Data Exchange (ETDEWEB)

    Jardanhazy, Anett [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary); Molnar, Mark [Department of Psychophysiology, Institute for Psychology of the Hungarian Academy of Sciences, P.O. Box 398, Budapest H-1394 (Hungary)], E-mail: molnar@cogpsyphy.hu; Jardanhazy, Tamas [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary)], E-mail: jt@nepsy.szote.u-szeged.hu

    2009-04-15

    The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

  13. Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

    International Nuclear Information System (INIS)

    Jardanhazy, Anett; Molnar, Mark; Jardanhazy, Tamas

    2009-01-01

    The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

  14. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    Science.gov (United States)

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

  15. The diagnostic value of direct CT arthrography using MDCT in the evaluation of acetabular labral tear: with arthroscopic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Yong-Chan; Kim, Jae Yoon [Chung-Ang University College of Medicine, Department of Orthopaedic Surgery, Seoul (Korea, Republic of); Choi, Jung-Ah; Lee, Guen Young; Kang, Heung Sik [Seoul National University Bundang Hospital, Departments of Radiology, Seoul National University College of Medicine, 166 Gumi-ro, Bundang-gu, Seongnam (Korea, Republic of); Lee, Young-Kyun; Koo, Kyung-Hoi [Seoul National University Bundang Hospital, Orthopaedic Surgery, Seoul National University College of Medicine, Seongnam (Korea, Republic of)

    2013-05-15

    The purpose of this study was first, to determine the sensitivity, specificity, and accuracy of MDCT arthrography (CTA) for the diagnosis of acetabular labral tear and sulcus; second, to correlate tear types using the Lage classification system on CTA compared with the arthroscopic classification; and third, to correlate CTA localization with arthroscopic localization. Direct CTA was performed using 16- or 64-slice MDCT in 126 hips (124 patients) who had chronic groin pain and positive impingement test. Images were reviewed and evaluated by two experienced musculoskeletal radiologists preoperatively. CTA findings were compared with arthroscopic findings in 58 hips (56 patients) under consensus by two orthopedic surgeons. Forty-one of the 58 hips were diagnosed as labral tears on CT arthrography. Forty-three of the 58 hips were shown to have a labral tear on arthroscopy. Sensitivity, specificity, and accuracy for detecting labral tear and sulcus by CTA were 90.7%, 86.7%, and 89.7%, and 93.8%, 97.6% and 96.6% respectively for observer 1, and 90.7% and 80.0%, 87.9% and 87.5%, 95.2%, and 93.1 % respectively for observer 2. Thirty-five out of 41 hips (85%) that were diagnosed with labral tear on CTA correlated substantially with arthroscopic Lage classification (kappa coefficient = 0.65). CTA and arthroscopic findings showed similar distribution patterns of the tears with most lesions located in antero- and postero-superior areas (p = 0.013). Direct CT arthrography using MDCT may be a useful diagnostic technique in the detection of acetabular labral tear. (orig.)

  16. Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity

    Directory of Open Access Journals (Sweden)

    Campana Dario

    2010-10-01

    Full Text Available Abstract Background The possibility that autologous NK cells could serve as an effective treatment modality for solid tumors has long been considered. However, implementation is hampered by (i the small number of NK cells in peripheral blood, (ii the difficulties associated with large-scale production of GMP compliant cytolytic NK cells, (iii the need to activate the NK cells in order to induce NK cell mediated killing and (iv the constraints imposed by autologous inhibitory receptor-ligand interactions. To address these issues, we determined (i if large numbers of NK cells could be expanded from PBMC and GMP compliant cell fractions derived by elutriation, (ii their ability to kill allogeneic and autologous tumor targets by direct cytotoxitiy and by antibody-mediated cellular cytotoxicity and (iii defined NK cell specific receptor-ligand interactions that mediate tumor target cell killing. Methods Human NK cells were expanded during 14 days. Expansion efficiency, NK receptor repertoire before and after expansion, expression of NK specific ligands, cytolytic activity against allogeneic and autologous tumor targets, with and without the addition of chimeric EGFR monoclonal antibody, were investigated. Results Cell expansion shifted the NK cell receptor repertoire towards activation and resulted in cytotoxicity against various allogeneic tumor cell lines and autologous gastric cancer cells, while sparing normal PBMC. Blocking studies confirmed that autologous cytotoxicity is established through multiple activating receptor-ligand interactions. Importantly, expanded NK cells also mediated ADCC in an autologous and allogeneic setting by antibodies that are currently being used to treat patients with select solid tumors. Conclusion These data demonstrate that large numbers of cytolytic NK cells can be generated from PBMC and lymphocyte-enriched fractions obtained by GMP compliant counter current elutriation from PBMC, establishing the preclinical

  17. Direct evidence of iNOS-mediated in vivo free radical production and protein oxidation in acetone-induced ketosis

    Science.gov (United States)

    Stadler, Krisztian; Bonini, Marcelo G.; Dallas, Shannon; Duma, Danielle; Mason, Ronald P.; Kadiiska, Maria B.

    2008-01-01

    Diabetic patients frequently encounter ketosis that is characterized by the breakdown of lipids with the consequent accumulation of ketone bodies. Several studies have demonstrated that reactive species are likely to induce tissue damage in diabetes, but the role of the ketone bodies in the process has not been fully investigated. In this study, electron paramagnetic resonance (EPR) spectroscopy combined with novel spin-trapping and immunological techniques has been used to investigate in vivo free radical formation in a murine model of acetone-induced ketosis. A six-line EPR spectrum consistent with the α-(4-pyridyl-1-oxide)-N-t-butylnitrone radical adduct of a carbon-centered lipid-derived radical was detected in the liver extracts. To investigate the possible enzymatic source of these radicals, inducible nitric oxide synthase (iNOS) and NADPH oxidase knockout mice were used. Free radical production was unchanged in the NADPH oxidase knockout but much decreased in the iNOS knockout mice, suggesting a role for iNOS in free radical production. Longer-term exposure to acetone revealed iNOS overexpression in the liver together with protein radical formation, which was detected by confocal microscopy and a novel immunospin-trapping method. Immunohistochemical analysis revealed enhanced lipid peroxidation and protein oxidation as a consequence of persistent free radical generation after 21 days of acetone treatment in control and NADPH oxidase knockout but not in iNOS knockout mice. Taken together, our data demonstrate that acetone administration, a model of ketosis, can lead to protein oxidation and lipid peroxidation through a free radical-dependent mechanism driven mainly by iNOS overexpression. PMID:18559982

  18. Histochemical detection of the in vivo produced cellular aldehydes by means of direct Schiff's reaction in CCl/sub 4/ intoxicated rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Taper, H.S.; Somer, M.P.; Lans, M.; Gerlache, J. de; Roberfroid, M.

    1988-04-01

    A histochemical technique for detection of the in vivo induced cellular aldehydes based on the direct Schiff's reaction is reported in this paper. CCl/sub 4/-intoxicated rat liver was used as an experimental model. Fresh and non-pretreated rat liver cryostat sections fixed in 10% formol calcium solution and washed in distilled water were exposed to Schiff's reagent. The sections were then immersed in two baths of sodium bisulphite solution, then in water, dehydrated in ethanol, cleared in xylene and mounted in a synthetic anhydrous mounting medium. As Schiff positive areas presented well circumscribed foci which increased with time following intoxication, semiquantitative planimetric measurements were feasible. The direct Schiff's reaction detects cellular aldehydes in a sensitive, rapid histologically and topographically estimable way. The appearance of these aldehydes precedes distinctly morphological alterations detectable by other histochemical of histological techniques. No positive results were obtained in control, non-intocicated rat livers. Inhibitons of this direct Schiff's was obtained in positive control rat liver sections preincubated in solutions of aldehyde blockers. Histochemical detection of aldehydes may give useful information on different aspects of tissue and organ intoxication such as their topography, appearance, evolution, extension, consequences and effects of treatment. The direct Schiff's reaction can be considered as a valuable tool in fundamental and applied reasearch dealing with various toxicological, environmental, pathological, cancer-related and therapeutic problems.

  19. Correlation between in vivo and in vitro pulmonary responses to jet propulsion fuel-8 using precision-cut lung slices and a dynamic organ culture system.

    Science.gov (United States)

    Hays, Allison M; Lantz, R Clark; Witten, Mark L

    2003-01-01

    In tissue slice models, interactions between the heterogeneous cell types comprising the lung parenchyma are maintained thus providing a controlled system for the study of pulmonary toxicology in vitro. However, validation of the model in vitro system must be affirmed. Previous reports, in in vivo systems, have demonstrated that Clara cells and alveolar type II cells are the targets following inhalation of JP-8 jet fuel. We have utilized the lung slice model to determine if cellular targets are similar following in vitro exposure to JP-8. Agar-filled adult rat lung explants were cored and precision cut, using the Brende/Vitron tissue slicer. Slices were cultured on titanium screens located as half-cylinders in cylindrical Teflon cradles that were loaded into standard scintillation vials and incubated at 37 degrees C. Slices were exposed to JP-8 jet fuel (0.5 mg/ml, 1.0 mg/ml, and 1.5 mg/ml in medium) for up to 24 hours. We determined ATP content using a luciferin-luciferase bioluminescent assay. No significant difference was found between the JP-8 jet fuel doses or time points, when compared to controls. Results were correlated with structural alterations following aerosol inhalation of JP-8. As a general observation, ultrastructural evaluation of alveolar type cells revealed an apparent increase in the number and size of surfactant secreting lamellar bodies that was JP-8 jet fuel-dose dependent. These results are similar to those observed following aerosol inhalation exposure. Thus, the lung tissue slice model appears to mimic in vivo effects of JP-8 and therefore is a useful model system for studying the mechanisms of lunginjury following JP-8 exposure.

  20. Direct restoration modalities of fractured central maxillary incisors: A multi-levels validated finite elements analysis with in vivo strain measurements.

    Science.gov (United States)

    Davide, Apicella; Raffaella, Aversa; Marco, Tatullo; Michele, Simeone; Syed, Jamaluddin; Massimo, Marrelli; Marco, Ferrari; Antonio, Apicella

    2015-12-01

    To quantify the influence of fracture geometry and restorative materials rigidity on the stress intensity and distribution of restored fractured central maxillary incisors (CMI) with particular investigation of the adhesive interfaces. Ancillary objectives are to present an innovative technology to measure the in vivo strain state of sound maxillary incisors and to present the collected data. A validation experimental biomechanics approach has been associated to finite element analysis. FEA models consisted of CMI, periodontal ligament and the corresponding alveolar bone process. Three models were created representing different orientation of the fracture planes. Three different angulations of the fracture plane in buccal-palatal direction were modeled: the fracture plane perpendicular to the long axis in the buccal-palatal direction (0°); the fracture plane inclined bucco-palatally in apical-coronal direction (-30°); the fracture plane inclined palatal-buccally in apical-coronal direction (+30°). First set of computing runs was performed for in vivo FE-model validation purposes. In the second part, a 50N force was applied on the buccal aspect of the CMI models. Ten patients were selected and subjected to the strain measurement of CMI under controlled loading conditions. The main differences were noticed in the middle and incisal thirds of incisors crowns, due to the presence of the incisal portion restoration. The stress intensity in -30° models is increased in the enamel structure close to the restoration, due to a thinning of the remaining natural tissues. The rigidity of the restoring material slightly reduces such phenomenon. -30° model exhibits the higher interfacial stress in the adhesive layer with respect to +30° and 0° models. The lower stress intensity was noticed in the 0° models, restoration material rigidity did not influenced the interfacial stress state in 0° models. On the contrary, material rigidity influenced the interfacial stress state

  1. Direct profiling of phytochemicals in tulip tissues and in vivo monitoring of the change of carbohydrate content in tulip bulbs by probe electrospray ionization mass spectrometry.

    Science.gov (United States)

    Yu, Zhan; Chen, Lee Chuin; Suzuki, Hiroaki; Ariyada, Osamu; Erra-Balsells, Rosa; Nonami, Hiroshi; Hiraoka, Kenzo

    2009-12-01

    Probe electrospray ionization (PESI) is a recently developed ESI-based ionization technique which generates electrospray from the tip of a solid needle. In this study, we have applied PESI interfaced with a time of flight mass spectrometer (TOF-MS) for direct profiling of phytochemicals in a section of a tulip bulb in different regions, including basal plate, outer and inner rims of scale, flower bud and foliage leaves. Different parts of tulip petals and leaves have also been investigated. Carbohydrates, amino acids and other phytochemicals were detected. A series of in vivo PESI-MS experiments were carried out on the second outermost scales of four living tulip bulbs to monitoring the change of carbohydrate content during the first week of initial growth. The breakdown of carbohydrates was observed which was in accordance with previous reports achieved by other techniques. This study has indicated that PESI-MS can be used for rapid and direct analysis of phytochemicals in living biological systems with advantages of low sample consumption and little sample preparation. Therefore, PESI-MS can be a new choice for direct analysis/profiling of bioactive compounds or monitoring metabolic changes in living biological systems.

  2. Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation.

    Science.gov (United States)

    Maetani, Micah; Zoller, Jochen; Melillo, Bruno; Verho, Oscar; Kato, Nobutaka; Pu, Jun; Comer, Eamon; Schreiber, Stuart L

    2017-08-16

    The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC 50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp 3 )-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

  3. Direct assessment of lipoprotein outflow from in vivo-labeled arterial tissue as determined in an in vitro perfusion system.

    Science.gov (United States)

    Björnheden, T; Bondjers, G; Wiklund, O

    1998-12-01

    The rate of cholesterol deposition during the atherosclerotic process is determined by the balance between the inflow and outflow of plasma lipoproteins in the arterial wall. Whereas the rate of inflow may be measured directly, the rate of outflow has most often been calculated indirectly from lipoprotein uptake by using the 2-compartment model. One objection against such calculations is that lipoprotein binding is not being considered. In the present study 2 different protocols were used to obtain a direct measure of the outflow of lipoproteins from atherosclerotic rabbit aortas. Thus, 3 rabbits with experimental atherosclerosis were given 125I-LDL intravenously and 3 were given [14C]cholesterol perorally. Twenty-four hours later the aortas were removed and the outflow of label was monitored during in vitro perfusion. Despite the different protocols, our results were consistent and indicated that fractional loss relative to whole tissue was approximately 0.01 pool/h, which is 1 order of magnitude lower than current estimates based on the 2-compartment model (0.04 to 0.4 pool/h). Furthermore, whereas as much as 2/3 to 3/4 of the tracer that had entered the arterial wall was effectively trapped, the remainder equilibrated at a faster rate (0.06 pool/h). In conclusion, it seems that tissue binding constitutes a prominent and possibly underrated mechanism of lipoprotein deposition, at least in the atherosclerotic rabbit aorta. Furthermore, this means that current estimates of lipoprotein exchange parameters based on the 2-compartment model (eg, fractional loss) may rest on invalid assumptions and should be regarded with caution.

  4. [Relation between frequency modulation direction selectivity and forward masking of inferior collicular neurons: a study on in vivo intracellular recording in mice].

    Science.gov (United States)

    Fu, Zi-Ying; Zeng, Hong; Tang, Jia; Li, Jie; Li, Juan; Chen, Qi-Cai

    2013-06-25

    It has been reported that the frequency modulation (FM) or FM direction sensitivity and forward masking of central auditory neurons are related with the neural inhibition, but there are some arguments, because no direct evidence of inhibitory synaptic input was obtained in previous studies using extracellular recording. In the present study, we studied the relation between FM direction sensitivity and forward masking of the inferior collicular (IC) neurons using in vivo intracellular recordings in 20 Mus musculus Km mice. Thirty seven with complete data among 93 neurons were analyzed and discussed. There was an inhibitory area which consisted of inhibitory postsynaptic potentials (IPSP) at high frequency side of frequency tuning of up-sweep FM (FMU) sensitive neurons (n = 12) and at low frequency side of frequency tuning of down-sweep FM (FMD) selective neurons (n = 8), while there was no any inhibitory area at both sides of frequency tuning of non-FM sweep direction (FMN) sensitive neurons (n = 17). Therefore, these results show that the inhibitory area at low or high frequency side of frequency tuning is one of the mechanisms for forming FM sweep direction sensitivity of IC neurons. By comparison of forward masking produced by FMU and FMD sound stimuli in FMU, FMD and FMN neurons, the selective FM sounds could produce stronger forward masking than the non-selective in FMU and FMD neurons, while there was no forward masking difference between FMU and FMD stimuli in the FMN neurons. We suggest that the post-action potential IPSP is a potential mechanism for producing stronger forward masking in FMU and FMD neurons.

  5. Quantity of residual thrombus after successful catheter-directed thrombolysis for iliofemoral deep venous thrombosis correlates with recurrence.

    Science.gov (United States)

    Aziz, F; Comerota, A J

    2012-08-01

    Iliofemoral deep venous thrombosis (IFDVT) is an independent risk factor for recurrent DVT. It has been observed that recurrent DVT correlates with residual thrombus. This study evaluates whether risk of recurrence is related to the amount of residual thrombus following catheter-directed thrombolysis (CDT) for IFDVT. Patients who underwent CDT for IFDVT had their degree of lysis quantified by a reader blind to the patients' long-term clinical outcome. Patients were classified into two groups, ≥50% and thrombus. Recurrence was defined as a symptomatic presentation with image verification of new or additional thrombus. A total of 75 patients underwent CDT for IFDVT. Median follow-up was 35.9 months. Sixty-eight patients (91%) had no evidence of recurrence and seven (9%) developed recurrence. Of the patients who had ≥50% (mean 80%) residual thrombus, 50% (4/8) experienced recurrence, but in those with thrombus, only 5% (3/67) had recurrent DVT (P = 0.0014). The burden of residual thrombus at completion of CDT correlates with the risk of DVT recurrence. Patients having CDT for IFDVT had a lower risk of recurrence than expected. Successful clearing of acute clot in IFDVT patients significantly reduces the recurrence risk compared to patients with a large residual thrombus burden. Copyright © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  6. AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo

    Directory of Open Access Journals (Sweden)

    Ky V. Hoang

    2017-09-01

    Full Text Available Francisella tularensis (F. tularensis is the causative agent of tularemia and is classified as a Tier 1 select agent. No licensed vaccine is currently available in the United States and treatment of tularemia is confined to few antibiotics. In this study, we demonstrate that AR-13, a derivative of the cyclooxygenase-2 inhibitor celecoxib, exhibits direct in vitro bactericidal killing activity against Francisella including a type A strain of F. tularensis (SchuS4 and the live vaccine strain (LVS, as well as toward the intracellular proliferation of LVS in macrophages, without causing significant host cell toxicity. Identification of an AR-13-resistant isolate indicates that this compound has an intracellular target(s and that efflux pumps can mediate AR-13 resistance. In the mouse model of tularemia, AR-13 treatment protected 50% of the mice from lethal LVS infection and prolonged survival time from a lethal dose of F. tularensis SchuS4. Combination of AR-13 with a sub-optimal dose of gentamicin protected 60% of F. tularensis SchuS4-infected mice from death. Taken together, these data support the translational potential of AR-13 as a lead compound for the further development of new anti-Francisella agents.

  7. Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

    Science.gov (United States)

    Simon, Alice; Amaro, Maria Inês; Healy, Anne Marie; Cabral, Lucio Mendes; de Sousa, Valeria Pereira

    2016-10-15

    In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Direct ex vivo detection of HLA-DR3-restricted cytomegalovirus- and Mycobacterium tuberculosis-specific CD4+ T cells.

    Science.gov (United States)

    Bronke, Corine; Palmer, Nanette M; Westerlaken, Geertje H A; Toebes, Mireille; van Schijndel, Gijs M W; Purwaha, Veenu; van Meijgaarden, Krista E; Schumacher, Ton N M; van Baarle, Debbie; Tesselaar, Kiki; Geluk, Annemieke

    2005-09-01

    In order to detect epitope-specific CD4+ T cells in mycobacterial or viral infections in the context of human class II major histocompatibility complex protein human leukocyte antigen (HLA)-DR3, two HLA-DR3 tetrameric molecules were successfully produced. One contained an immunodominant HLA-DR3-restricted T-cell epitope derived from the 65-kDa heat-shock protein of Mycobacterium tuberculosis, peptide 1-13. For the other tetramer, we used an HLA-DR3-restricted T-cell epitope derived from cytomegalovirus (CMV) pp65 lower matrix protein, peptide 510-522, which induced high levels of interferon (IFN)-gamma-producing CD4+ T cells in three of four HLA-DR3-positive CMV-seropositive individuals up to 0.84% of CD4+ T cells by intracellular cytokine staining. In peripheral blood mononuclear cells from M. tuberculosis-exposed, Mycobacterium bovis bacille Calmette-Guérin (BCG)-vaccinated, or CMV-seropositive individuals, we were able to directly detect with both tetramers epitope-specific T cells up to 0.62% and 0.45% of the CD4+ T-cell population reactive to M. tuberculosis and CMV, respectively. After a 6-day culture with peptide p510-522, the frequency of CMV-specific tetramer-binding T cells was expanded up to 9.90% tetramer+ CFSElow (5,6-carboxyfluorescein diacetate succinimidyl ester) cells within the CD4+ T-cell population, further confirming the specificity of the tetrameric molecules. Thus, HLA-DR3/peptide tetrameric molecules can be used to investigate HLA-DR3-restricted antigen-specific CD4+ T cells in clinical disease or after vaccination.

  9. Direct in vivo characterization of delta 5 desaturase activity in humans by deuterium labeling: Effect of insulin

    International Nuclear Information System (INIS)

    el Boustani, S.; Causse, J.E.; Descomps, B.; Monnier, L.; Mendy, F.; Crastes de Paulet, A.

    1989-01-01

    The conversion of dihomogamma linolenic acid (DHLA) into arachidonic acid (AA) was compared in normal subjects and diabetic patients before and after treatment with insulin. The kinetics of the incorporation of deuterium-labeled DHLA and its conversion product, deuterium-labeled AA, was determined in plasma triglycerides, plasma phospholipids, and platelet lipids of subjects after ingestion of 2 g of the labeled precursor. Analysis was performed by gas liquid chromatography-mass spectrometry using multiple ion detection. In normal subjects, the deuterium-labeled DHLA concentration rose to 24 to 69 mg/L in plasma triglycerides four to nine hours after ingestion and to 20 to 34 mg/L in plasma phospholipids about four hours later. Deuterium-labeled AA appeared at 12 hours, rose to 2.4 to 3.8 mg/L between 48 and 72 hours in plasma phospholipids, but remained at the limit of detection in plasma triglycerides and was undetectable in platelet lipids. In diabetic patients both before and after insulin treatment, the deuterium-labeled DHLA concentration in plasma triglycerides and in plasma phospholipids followed the same pattern as in normal subjects. However, the deuterium-labeled arachidonic acid concentration was below 1 mg/L in plasma phospholipids before insulin. After insulin treatment the patients recovered normal DHLA metabolism because deuterium-labeled AA rose in phospholipids to a mean value of 3.5 mg/L, which is in the same range as that observed in normal subjects (3.2 mg/L). The present data provide direct evidence for the conversion of DHLA into AA in humans. The effect of insulin and the data from the literature of animal studies suggest insulin dependence of delta 5 desaturase in humans

  10. A novel co-processed directly compressible release-retarding polymer: In vitro, solid state and in vivo evaluation

    Directory of Open Access Journals (Sweden)

    Prashant Kumar Choudhari

    2018-06-01

    Full Text Available Directly compressible (DC co-processed excipient capable of providing nearly zero order release with improved functionality was developed without any chemical modification by employed various techniques such as physical mixing, high shear mixer granulation and spray drying. Co-processed excipient was developed by using release retarding polymer Eudragit RSPO, separately, in combination with different concentration of hydroxyl propyl methyl cellulose 100 cps (Methocel K100 LV, HPMC, ethyl cellulose (Ethocel N50, EC and hydroxyl propyl cellulose (Klucel EF, HPC. All co-processed excipients were evaluated for their flow properties in terms of angle of repose, bulk density, tapped density, compressibility index and Hausner's ratio. Out of eighteen combinations, the nine co-processed excipients exhibited promising flow properties were found suitable for direct compression and formulated as tablets. Metoprolol succinate, a BCS Class I drug, was selected as a model drug and the formulation was developed employing direct compression approach. The developed tablets were evaluated for physical parameters like uniformity of weight, thickness, hardness, friability and assay. In vitro dissolution study confirms that formulation prepared using co-processed excipient showed sustained drug release. The optimized tablet formulation was characterized by DSC, FTIR and PXRD which confirms the absence of any chemical change during co-processing. The optimized formulation was kept for stability study for six months as per ICH guidelines and found to be stable. In vivo pharmacokinetic study of optimized formulation in rats showed similar pharmacokinetic behaviour as was observed with the marketed brand. Study revealed that co-processed excipient has advantage over polymers with single property and can be utilised for sustained release formulation. Keywords: Co-processed excipient, Metoprolol succinate, Extended-release, Direct compression, Zero-order release

  11. Do the results of respirable dust samples obtained from direct-on-filter X-ray diffraction, direct-on-filter infrared and indirect infrared (KBr pellet) methods correlate?

    CSIR Research Space (South Africa)

    Pretorius, C

    2010-11-01

    Full Text Available The objective of this study was to determine whether a correlation exists between the quartz results obtained from direct-on-filter X-ray Diffraction analysis, direct-on-filter Fourier-Transform Infrared analysis and indirect analysis (Potassium...

  12. Stable T-bet+GATA-3+ Th1/Th2 Hybrid Cells Arise In Vivo, Can Develop Directly from Naive Precursors, and Limit Immunopathologic Inflammation

    Science.gov (United States)

    Peine, Michael; Fröhlich, Anja; Hegazy, Ahmed N.; Kühl, Anja A.; Grevelding, Christoph G.; Höfer, Thomas; Hartmann, Susanne; Löhning, Max

    2013-01-01

    Differentiated T helper (Th) cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN)-γ and interleukin (IL)-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet+GATA-3+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation. PMID:23976880

  13. Stable T-bet(+GATA-3(+ Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation.

    Directory of Open Access Journals (Sweden)

    Michael Peine

    Full Text Available Differentiated T helper (Th cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN-γ and interleukin (IL-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet(+GATA-3(+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation.

  14. Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity Both In Vitro and In Vivo.

    Science.gov (United States)

    Zeng, Xingruo; Xu, Zhou; Gu, Jiayan; Huang, Haishan; Gao, Guangxun; Zhang, Xiaoru; Li, Jingxia; Jin, Honglei; Jiang, Guosong; Sun, Hong; Huang, Chuanshu

    2016-03-01

    Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell-cycle G0-G1 arrest as well as downregulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In the current study, the potential ISO inhibition of bladder tumor formation has been explored in a xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anticancer activities have been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by directly targeting Sp1 mRNA 3'-untranslated region (UTR). Similar to ISO treatment, ectopic expression of miR-137 alone led to G0-G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by overexpression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced inhibition of Sp1/Cyclin D1 expression, induction of G0-G1 cell growth arrest, and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3'-UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0-G1 growth arrest, and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anticancer activity of ISO in the therapy of human bladder cancer. ©2016 American Association for Cancer Research.

  15. Increasing Public Awareness of Direct-to-Consumer Genetic Tests: Health Care Access, Internet Use, and Population Density Correlates

    International Nuclear Information System (INIS)

    Rutten, L. J. F.; Gollust, S. E.; Naveed, S.; Moser, R. P.

    2012-01-01

    Uncertainty around the value of and appropriate regulatory models for direct-to-consumer (DTC) genetic testing underscores the importance of tracking public awareness of these services. We analyzed nationally representative, cross-sectional data from the Health Information National Trends Survey in 2008 (n=7, 674) and 2011 (n=3, 959) to assess population-level changes in awareness of DTC genetic testing in the U.S. and to explore socio demographic, health care, Internet use, and population density correlates. Overall, awareness increased significantly from 29% in 2008 to 37% in 2011. The observed increase in awareness from 2008 to 2011 remained significant (OR=1.39) even when adjusted for socio demographic variables, health care access, Internet use, and population density. Independent of survey year, the odds of awareness of DTC genetic tests were significantly higher for those aged 50-64 (OR=1.64), and 65-74 (O R=1.60); college graduates (OR=2.02 ); those with a regular source of health care (OR=1.27); those with a prior cancer diagnosis (OR=1.24); those who use the Internet (OR=1.27); and those living in urban areas ( OR=1.25). Surveillance of awareness-along with empirical data on use of and response to genetic risk information-can inform public health and policy efforts to maximize benefits and minimize risks of DTC genetic testing.

  16. Increasing Public Awareness of Direct-to-Consumer Genetic Tests: Health Care Access, Internet Use, and Population Density Correlates

    Directory of Open Access Journals (Sweden)

    Lila J. Finney Rutten

    2012-01-01

    Full Text Available Uncertainty around the value of and appropriate regulatory models for direct-to-consumer (DTC genetic testing underscores the importance of tracking public awareness of these services. We analyzed nationally representative, cross-sectional data from the Health Information National Trends Survey in 2008 (n=7,674 and 2011 (n=3,959 to assess population-level changes in awareness of DTC genetic testing in the U.S. and to explore sociodemographic, health care, Internet use, and population density correlates. Overall, awareness increased significantly from 29% in 2008 to 37% in 2011. The observed increase in awareness from 2008 to 2011 remained significant (OR=1.39 even when adjusted for sociodemographic variables, health care access, Internet use, and population density. Independent of survey year, the odds of awareness of DTC genetic tests were significantly higher for those aged 50–64 (OR=1.64, and 65–74 (OR=1.60; college graduates (OR=2.02; those with a regular source of health care (OR=1.27; those with a prior cancer diagnosis (OR=1.24; those who use the Internet (OR=1.27; and those living in urban areas (OR=1.25. Surveillance of awareness—along with empirical data on use of and response to genetic risk information—can inform public health and policy efforts to maximize benefits and minimize risks of DTC genetic testing.

  17. Increasing Public Awareness of Direct-to-Consumer Genetic Tests: Health Care Access, Internet Use, and Population Density Correlates.

    Science.gov (United States)

    Finney Rutten, Lila J; Gollust, Sarah E; Naveed, Sana; Moser, Richard P

    2012-01-01

    Uncertainty around the value of and appropriate regulatory models for direct-to-consumer (DTC) genetic testing underscores the importance of tracking public awareness of these services. We analyzed nationally representative, cross-sectional data from the Health Information National Trends Survey in 2008 (n = 7, 674) and 2011 (n = 3, 959) to assess population-level changes in awareness of DTC genetic testing in the U.S. and to explore sociodemographic, health care, Internet use, and population density correlates. Overall, awareness increased significantly from 29% in 2008 to 37% in 2011. The observed increase in awareness from 2008 to 2011 remained significant (OR = 1.39) even when adjusted for sociodemographic variables, health care access, Internet use, and population density. Independent of survey year, the odds of awareness of DTC genetic tests were significantly higher for those aged 50-64 (OR = 1.64), and 65-74 (OR = 1.60); college graduates (OR = 2.02); those with a regular source of health care (OR = 1.27); those with a prior cancer diagnosis (OR = 1.24); those who use the Internet (OR = 1.27); and those living in urban areas (OR = 1.25). Surveillance of awareness-along with empirical data on use of and response to genetic risk information-can inform public health and policy efforts to maximize benefits and minimize risks of DTC genetic testing.

  18. In-vivo identification of direct electron transfer from Shewanella oneidensis MR-1 to electrodes via outer-membrane OmcA-MtrCAB protein complexes

    Energy Technology Data Exchange (ETDEWEB)

    Okamoto, Akihiro [Department of Applied Chemistry, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan); Nakamura, Ryuhei, E-mail: nakamura@light.t.u-tokyo.ac.jp [Department of Applied Chemistry, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan); Hashimoto, Kazuhito, E-mail: hashimoto@light.t.u-tokyo.ac.jp [Department of Applied Chemistry, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan); ERATO/JST, HASHIMOTO Light Energy Conversion Project (Japan)

    2011-06-30

    Graphical abstract: . Display Omitted Highlights: > Monolayer biofilm of Shewanella cells was prepared on an ITO electrode. > Extracellular electron transfer (EET) process was examined with series of mutants. > Direct ET was confirmed with outer-membrane-bound OmcA-MtrCAB complex. > The EET process was not prominently influenced by capsular polysaccharide. - Abstract: The direct electron-transfer (DET) property of Shewanella bacteria has not been resolved in detail due to the complexity of in vivo electrochemistry in whole-cell systems. Here, we report the in vivo assignment of the redox signal indicative of the DET property in biofilms of Shewanella oneidensis MR-1 by cyclic voltammetry (CV) with a series of mutants and a chemical marking technique. The CV measurements of monolayer biofilms formed by deletion mutants of c-type cytochromes ({Delta}mtrA, {Delta}mtrB, {Delta}mtrC/{Delta}omcA, and {Delta}cymA), and pilin ({Delta}pilD), capsular polysaccharide ({Delta}SO3177) and menaquinone ({Delta}menD) biosynthetic proteins demonstrated that the electrochemical redox signal with a midpoint potential at 50 mV (vs. SHE) was due to an outer-membrane-bound OmcA-MtrCAB protein complex of decaheme cytochromes, and did not involve either inner-membrane-bound CymA protein or secreted menaquinone. Using the specific binding affinity of nitric monoxide for the heme groups of c-type cytochromes, we further confirmed this conclusion. The heterogeneous standard rate constant for the DET process was estimated to be 300 {+-} 10 s{sup -1}, which was two orders of magnitude higher than that previously reported for the electron shuttling process via riboflavin. Experiments using a mutant unable to produce capsular polysaccharide ({Delta}SO3177) revealed that the DET property of the OmcA-MtrCAB complex was not influenced by insulating and hydrophilic extracellular polysaccharide. Accordingly, under physiological conditions, S. oneidensis MR-1 utilizes a high density of outer

  19. Nucleosomes correlate with in vivo progression pattern of de novo methylation of p16 CpG islands in human gastric carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Zhe-Ming Lu

    Full Text Available BACKGROUND: The exact relationship between nucleosome positioning and methylation of CpG islands in human pathogenesis is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we characterized the nucleosome position within the p16 CpG island and established a seeding methylation-specific PCR (sMSP assay based on bisulfite modification to enrich the p16 alleles containing methylated-CpG at the methylation "seeding" sites within its intron-1 in gastric carcinogenesis. The sMSP-positive rate in primary gastric carcinoma (GC samples (36/40 was significantly higher than that observed in gastritis (19/45 or normal samples (7/13 (P<0.01. Extensive clone sequencing of these sMSP products showed that the density of methylated-CpGs in p16 CpG islands increased gradually along with the severity of pathological changes in gastric tissues. In gastritis lesions the methylation was frequently observed in the region corresponding to the exon-1 coding-nucleosome and the 5'UTR-nucleosome; the methylation was further extended to the region corresponding to the promoter-nucleosome in GC samples. Only few methylated-CpG sites were randomly detected within p16 CpG islands in normal tissues. The significantly inversed relationship between the p16 exon-1 methylation and its transcription was observed in GC samples. An exact p16 promoter-specific 83 bp-MSP assay confirms the result of sMSP (33/55 vs. 1/6, P<0.01. In addition, p16 methylation in chronic gastritis lesions significantly correlated with H. pylori infection; however, such correlation was not observed in GC specimens. CONCLUSIONS/SIGNIFICANCE: It was determined that de novo methylation was initiated in the coding region of p16 exon-1 in gastritis, then progressed to its 5'UTR, and ultimately to the proximal promoter in GCs. Nucleosomes may function as the basic extension/progression unit of de novo methylation of p16 CpG islands in vivo.

  20. Mouse Mammary Tumor Virus Promoter-Containing Retroviral Promoter Conversion Vectors for Gene-Directed Enzyme Prodrug Therapy are Functional in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Reinhard Klein

    2008-01-01

    Full Text Available Gene directed-enzyme prodrug therapy (GDEPT is an approach for sensitization of tumor cells to an enzymatically activated, otherwise nontoxic, prodrug. Cytochrome P450 2B1 (CYP2B1 metabolizes the prodrugs cyclophosphamide (CPA and ifosfamide (IFA to produce the cytotoxic substances phosphoramide mustard and isophosphoramide mustard as well as the byproduct acrolein. We have constructed a retroviral promoter conversion (ProCon vector for breast cancer GDEPT. The vector allows expression of CYP2B1 from the mouse mammary tumor virus (MMTV promoter known to be active in the mammary glands of transgenic animals. It is anticipated to be used for the generation of encapsulated viral vector producing cells which, when placed inside or close to a tumor, will act as suppliers of the therapeutic CYP2B1 protein as well as of the therapeutic vector itself. The generated vector was effectively packaged by virus producing cells and allowed the production of high levels of enzymatically active CYP2B1 in infected cells which sensitized them to killing upon treatment with both IFA and CPA. Determination of the respective IC50 values demonstrated that the effective IFA dose was reduced by sixteen folds. Infection efficiencies in vivo were determined using a reporter gene-bearing vector in a mammary cancer cell-derived xenograft tumor mouse model.

  1. Direct evaluation of thyroid 127I and iodine overload: in vivo study by X-ray fluorescence and in vitro by SIMS microscopy

    International Nuclear Information System (INIS)

    Briancon, C.; Jeusset, J.; Halpern, S.; Fragu, P.

    1992-01-01

    This review describes the two methods which allow direct estimation of stable iodine ( 127 I) within thyroid gland either in vivo by X-ray fluorescence or in vitro by secondary ion mass spectrometry (SIMS) microscopy on tissue section. Although the measurement of thyroid iodine content (TIC) by X-ray fluorescence has little relevance for routine explorations of thyroid function, this is a valuable method for understanding complex pathophysiological conditions such as the thyroid adaptation to iodine overload. On the other hand, SIMS microscopy which is able to characterize the functional activity of thyroid tissue by measuring 127 I concentration within the thyroid follicles, can be used to determine the extent to which exogeneous iodine affects the regulation of iodine within the thyroid follicles. Both methods were used to evaluate the quantitative changes in thyroid 127 I induced by amiodarone iodine overload. TIC measurements shows that hyperthyroidism occured only in patients who increased their iodine stores, while the patients who developed hypothyroidism has low iodine stores. The SIMS microscopy data obtained in mice demonstrated that the thyroid response to amiodarone is related to dietary iodine intake leading to an increase in local iodine concentration in iodine deficient mice and to a decrease in iodine supplemented mice. This response is specific and different from that induced by an iodine overload. These results could explain that hyperthyroidism with high thyroid iodine content occured in areas with low thyroid iodine content in areas with a supplemented iodine diet

  2. Site-targeted non-viral gene delivery by direct DNA injection into the pancreatic parenchyma and subsequent in vivo electroporation in mice.

    Science.gov (United States)

    Sato, Masahiro; Inada, Emi; Saitoh, Issei; Ohtsuka, Masato; Nakamura, Shingo; Sakurai, Takayuki; Watanabe, Satoshi

    2013-11-01

    The pancreas is considered an important gene therapy target because the organ is the site of several high burden diseases, including diabetes mellitus, cystic fibrosis, and pancreatic cancer. We aimed to develop an efficient in vivo gene delivery system using non-viral DNA. Direct intra-parenchymal injection of a solution containing circular plasmid pmaxGFP DNA was performed on adult anesthetized ICR female mice. The injection site was sandwiched with a pair of tweezer-type electrode disks, and electroporated using a square-pulse generator. Green fluorescent protein (GFP) expression within the injected pancreatic portion was observed one day after gene delivery. GFP expression reduced to baseline within a week of transfection. Application of voltages over 40 V resulted in tissue damage during electroporation. We demonstrate that electroporation is effective for safe and efficient transfection of pancreatic cells. This novel gene delivery method to the pancreatic parenchyma may find application in gene therapy strategies for pancreatic diseases and in investigation of specific gene function in situ. © 2013 The Authors. Biotechnology Journal published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptions are made.

  3. Rosa26-GFP direct repeat (RaDR-GFP mice reveal tissue- and age-dependence of homologous recombination in mammals in vivo.

    Directory of Open Access Journals (Sweden)

    Michelle R Sukup-Jackson

    2014-06-01

    Full Text Available Homologous recombination (HR is critical for the repair of double strand breaks and broken replication forks. Although HR is mostly error free, inherent or environmental conditions that either suppress or induce HR cause genomic instability. Despite its importance in carcinogenesis, due to limitations in our ability to detect HR in vivo, little is known about HR in mammalian tissues. Here, we describe a mouse model in which a direct repeat HR substrate is targeted to the ubiquitously expressed Rosa26 locus. In the Rosa26 Direct Repeat-GFP (RaDR-GFP mice, HR between two truncated EGFP expression cassettes can yield a fluorescent signal. In-house image analysis software provides a rapid method for quantifying recombination events within intact tissues, and the frequency of recombinant cells can be evaluated by flow cytometry. A comparison among 11 tissues shows that the frequency of recombinant cells varies by more than two orders of magnitude among tissues, wherein HR in the brain is the lowest. Additionally, de novo recombination events accumulate with age in the colon, showing that this mouse model can be used to study the impact of chronic exposures on genomic stability. Exposure to N-methyl-N-nitrosourea, an alkylating agent similar to the cancer chemotherapeutic temozolomide, shows that the colon, liver and pancreas are susceptible to DNA damage-induced HR. Finally, histological analysis of the underlying cell types reveals that pancreatic acinar cells and liver hepatocytes undergo HR and also that HR can be specifically detected in colonic somatic stem cells. Taken together, the RaDR-GFP mouse model provides new understanding of how tissue and age impact susceptibility to HR, and enables future studies of genetic, environmental and physiological factors that modulate HR in mammals.

  4. Direct Vpr-Vpr Interaction in Cells monitored by two Photon Fluorescence Correlation Spectroscopy and Fluorescence Lifetime Imaging

    Directory of Open Access Journals (Sweden)

    Mély Yves

    2008-09-01

    Full Text Available Abstract Background The human immunodeficiency virus type 1 (HIV-1 encodes several regulatory proteins, notably Vpr which influences the survival of the infected cells by causing a G2/M arrest and apoptosis. Such an important role of Vpr in HIV-1 disease progression has fuelled a large number of studies, from its 3D structure to the characterization of specific cellular partners. However, no direct imaging and quantification of Vpr-Vpr interaction in living cells has yet been reported. To address this issue, eGFP- and mCherry proteins were tagged by Vpr, expressed in HeLa cells and their interaction was studied by two photon fluorescence lifetime imaging microscopy and fluorescence correlation spectroscopy. Results Results show that Vpr forms homo-oligomers at or close to the nuclear envelope. Moreover, Vpr dimers and trimers were found in the cytoplasm and in the nucleus. Point mutations in the three α helices of Vpr drastically impaired Vpr oligomerization and localization at the nuclear envelope while point mutations outside the helical regions had no effect. Theoretical structures of Vpr mutants reveal that mutations within the α-helices could perturb the leucine zipper like motifs. The ΔQ44 mutation has the most drastic effect since it likely disrupts the second helix. Finally, all Vpr point mutants caused cell apoptosis suggesting that Vpr-mediated apoptosis functions independently from Vpr oligomerization. Conclusion We report that Vpr oligomerization in HeLa cells relies on the hydrophobic core formed by the three α helices. This oligomerization is required for Vpr localization at the nuclear envelope but not for Vpr-mediated apoptosis.

  5. A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway.

    Science.gov (United States)

    Cheraghchi-Bashi, Azadeh; Parker, Christine A; Curry, Ed; Salazar, Jean-Frederic; Gungor, Hatice; Saleem, Azeem; Cunnea, Paula; Rama, Nona; Salinas, Cristian; Mills, Gordon B; Morris, Shannon R; Kumar, Rakesh; Gabra, Hani; Stronach, Euan A

    2015-12-08

    Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.

  6. Direct tumor in vivo dosimetry in highly-conformal radiotherapy: A feasibility study of implantable MOSFETs for hypofractionated extracranial treatments using the Cyberknife system

    International Nuclear Information System (INIS)

    Scalchi, Paolo; Righetto, Roberto; Cavedon, Carlo; Francescon, Paolo; Colombo, Federico

    2010-01-01

    Purpose: In highly-conformal radiotherapy, due to the complexity of both beam configurations and dose distributions, traditional in vivo dosimetry is unpractical or even impossible. The ideal dosimeter would be implanted inside the planning treatment volume so that it can directly measure the total delivered dose during each fraction with no additional uncertainty due to calculation models. The aim of this work is to verify if implantable metal oxide semiconductors field effect transistors (MOSFETs) can achieve a sufficient degree of dosimetric accuracy when used inside extracranial targets undergoing radiotherapy treatments using the Cyberknife system. Methods: Based on the preliminary findings of this study, new prototypes for high dose fractionations were developed to reduce the time dependence for long treatment delivery times. These dosimeters were recently cleared and are marketed as DVS-HFT. Multiple measurements were performed using both Virtual Water and water phantoms to characterize implantable MOSFETs under the Cyberknife beams, and included the reference-dosimetry consistency, the dependence of the response on the collimator size, on the daily delivered dose, and the time irradiation modality. Finally a Cyberknife prostate treatment simulation using a body phantom was conducted, and both MOSFET and ionization readings were compared to Monte Carlo calculations. The feasibility analysis was conducted based on the ratios of the absorbed dose divided by the dose reading, named as ''further calibration factor'' (FCF). Results: The average FCFs resulted to be 0.98 for the collimator dependence test, and about 1.00 for the reference-dosimetry test, the dose-dependence test, and the time-dependence test. The average FCF of the prostate treatment simulation test was 0.99. Conclusions: The obtained results are well within DVS specifications, that is, the factory calibration is still valid for such kind of treatments using the Cyberknife system, with no need of

  7. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Directory of Open Access Journals (Sweden)

    Nibedita Chattopadhyay

    Full Text Available In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  8. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Science.gov (United States)

    Chattopadhyay, Nibedita; Berger, Allison J; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  9. A note on the correlation between circular and linear variables with an application to wind direction and air temperature data in a Mediterranean climate

    Science.gov (United States)

    Lototzis, M.; Papadopoulos, G. K.; Droulia, F.; Tseliou, A.; Tsiros, I. X.

    2018-04-01

    There are several cases where a circular variable is associated with a linear one. A typical example is wind direction that is often associated with linear quantities such as air temperature and air humidity. The analysis of a statistical relationship of this kind can be tested by the use of parametric and non-parametric methods, each of which has its own advantages and drawbacks. This work deals with correlation analysis using both the parametric and the non-parametric procedure on a small set of meteorological data of air temperature and wind direction during a summer period in a Mediterranean climate. Correlations were examined between hourly, daily and maximum-prevailing values, under typical and non-typical meteorological conditions. Both tests indicated a strong correlation between mean hourly wind directions and mean hourly air temperature, whereas mean daily wind direction and mean daily air temperature do not seem to be correlated. In some cases, however, the two procedures were found to give quite dissimilar levels of significance on the rejection or not of the null hypothesis of no correlation. The simple statistical analysis presented in this study, appropriately extended in large sets of meteorological data, may be a useful tool for estimating effects of wind on local climate studies.

  10. Direct Effect of Remifentanil and Glycine Contained in Ultiva® on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses.

    Directory of Open Access Journals (Sweden)

    Makoto Sumie

    Full Text Available Ultiva® is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva® is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva® provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva® contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva® potentially complicates its effects. We examined how Ultiva® directly affects nociceptive transmission in the spinal cord.We made patch-clamp recordings from substantia gelatinosa (SG neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva® onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli.Bath application of Ultiva® hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs evoked by the stimuli was suppressed by Ultiva®. Miniature EPSCs (mEPSCs were depressed in frequency but not amplitude. Ultiva®-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva®-induced currents demonstrated a specific equilibrium potential similar to glycine.We found that intrathecal administration of Ultiva® to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva®-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous

  11. Tissue-specific direct microtransfer of nanomaterials into Drosophila embryos as a versatile in vivo test bed for nanomaterial toxicity assessment

    Directory of Open Access Journals (Sweden)

    Vega-Alvarez S

    2014-04-01

    Full Text Available Sasha Vega-Alvarez,1 Adriana Herrera,2 Carlos Rinaldi,2–4 Franklin A Carrero-Martínez1,5 1Department of Biology, 2Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico; 3J Crayton Pruitt Family Department of Biomedical Engineering, 4Department of Chemical Engineering, University of Florida, Gainesville, FL, USA; 5Department of Anatomy and Neuroscience, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico Abstract: Nanomaterials are the subject of intense research, focused on their synthesis, modification, and biomedical applications. Increased nanomaterial production and their wide range of applications imply a higher risk of human and environmental exposure. Unfortunately, neither environmental effects nor toxicity of nanomaterials to organisms are fully understood. Cost-effective, rapid toxicity assays requiring minimal amounts of materials are needed to establish both their biomedical potential and environmental safety standards. Drosophila exemplifies an efficient and cost-effective model organism with a vast repertoire of in vivo tools and techniques, all with high-throughput scalability and screening feasibility throughout its life cycle. Here we report tissue specific nanomaterial assessment through direct microtransfer into target tissues. We tested several nanomaterials with potential biomedical applications such as single-wall carbon nanotubes, multiwall carbon nanotubes, silver, gold, titanium dioxide, and iron oxide nanoparticles. Assessment of nanomaterial toxicity was conducted by evaluating progression through developmental morphological milestones in Drosophila. This cost-effective assessment method is amenable to high-throughput screening. Keywords: nanotoxicity, Drosophila, microtransfer, nanoparticle, iron oxide, silver, gold, titanium dioxide, carbon nanotube

  12. Bimodal electric tissue ablation (BETA) - in-vivo evaluation of the effect of applying direct current before and during radiofrequency ablation of porcine liver

    International Nuclear Information System (INIS)

    Cockburn, J.F.; Maddern, G.J.; Wemyss-Holden, S.A.

    2007-01-01

    Aim: To examine the effect of applying increasing amounts of direct current (DC) before and during alternating current radiofrequency ablation of porcine liver. Materials and methods: Using a Radiotherapeutics RF3000 generator, a 9 V AC/DC transformer and a 16 G plain aluminium tube as an electrode, a control group of 24 porcine hepatic radiofrequency ablation zones was compared with 24 zones created using a bimodal electric tissue ablation (BETA) technique in three pigs. All ablations were terminated when tissue impedance rose to greater than 999 Ω or radiofrequency energy input fell below 5 W on three successive measurements taken at 1 min intervals. BETA ablations were performed in two phases: an initial phase of variable duration DC followed by a second phase during which standard radiofrequency ablation was applied simultaneously with DC. During this second phase, radiofrequency power input was regulated by the feedback circuitry of the RF3000 generator according to changes in tissue impedance. The diameters (mm) of each ablation zone were measured by two observers in two planes perpendicular to the plane of needle insertion. The mean short axis diameter of each ablation zone was subjected to statistical analysis. Results: With increased duration of prior application of DC, there was a progressive increase in the diameter of the ablation zone (p < 0.001). This effect increased sharply up to 300 s of pre-treatment after which a further increase in diameter occurred, but at a much lesser rate. A maximum ablation zone diameter of 32 mm was produced (control diameters 10-13 mm). Conclusion: Applying a 9 V DC to porcine liver in vivo, and continuing this DC application during subsequent radiofrequency ablation, results in larger ablation zone diameters compared with radiofrequency ablation alone

  13. Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation.

    Science.gov (United States)

    Vogus, Douglas R; Pusuluri, Anusha; Chen, Renwei; Mitragotri, Samir

    2018-01-01

    Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA-MB-231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA-MB-231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo. Differences in drug exposure and cellular behavior in vivo compared to in vitro are likely responsible. This study emphasizes the importance in understanding how schedule impacts drug synergy and the need to develop more advanced strategies to translate synergy to the clinic.

  14. Theory for site-site pair distribution functions of molecular fluids. II. Approximations for the Percus--Yevick site-site direct correlation functions

    International Nuclear Information System (INIS)

    Johnson, E.

    1977-01-01

    A theory for site-site pair distribution functions of molecular fluids is derived from the Ornstein-Zernike equation. Atom-atom pair distribution functions of this theory which were obtained by using different approximations for the Percus-Yevick site-site direct correlation functions are compared

  15. Quantum correlation and entanglement between an ionizing system and a neighboring atom interacting directly and via a quantized field

    Czech Academy of Sciences Publication Activity Database

    Peřinová, V.; Lukš, A.; Křepelka, J.; Peřina ml., Jan

    2014-01-01

    Roč. 90, č. 3 (2014), "033428-1"-"033428-10" ISSN 1050-2947 Institutional support: RVO:68378271 Keywords : quantum correlation * ionizing system Subject RIV: BH - Optics , Masers, Lasers Impact factor: 2.808, year: 2014

  16. Broadening of coreceptor usage by human immunodeficiency virus type 2 does not correlate with increased pathogenicity in an in vivo model.

    NARCIS (Netherlands)

    M.E. van der Ende (Marchina); C. Guillon (Christophe); P.H.M. Boers (Patrick); R.A. Gruters (Rob); P. Racz; K. Tenner-Racz; A.D.M.E. Osterhaus (Albert); M. Schutten (Martin)

    2000-01-01

    textabstractThe pathogenic properties of four primary human immunodeficiency virus type 2 (HIV-2) isolates and two primary HIV-2 biological clones were studied in an in vivo human-to-mouse chimeric model. The cell-associated viral load and the ability to reduce the severity of the induced

  17. Digital Radiography for Determination of Primary Tooth Length: In Vivo and Ex Vivo Studies

    Directory of Open Access Journals (Sweden)

    Maria D. Basso

    2015-01-01

    Full Text Available Background. Methods for determining the root canal length of the primary tooth should yield accurate and reproducible results. In vitro studies show some limitations, which do not allow their findings to be directly transferred to a clinical situation. Aim. To compare the accuracy of radiographic tooth length obtained from in vivo digital radiograph with that obtained from ex vivo digital radiograph. Method. Direct digital radiographs of 20 upper primary incisors were performed in teeth (2/3 radicular resorption that were radiographed by an intraoral sensor, according to the long-cone technique. Teeth were extracted, measured, and mounted in a resin block, and then radiographic template was used to standardise the sensor-target distance (30 cm. The apparent tooth length (APTL was obtained from the computer screen by means of an electronic ruler accompanying the digital radiography software (CDR 2.0, whereas the actual tooth length (ACTL was obtained by means of a digital calliper following extraction. Data were compared to the ACTL by variance analysis and Pearson’s correlation test. Results. The values for APTL obtained from in vivo radiography were slightly underestimated, whereas those values obtained from ex vivo were slightly overestimated. No significance was observed (P≤0.48 between APTL and ACTL. Conclusion. The length of primary teeth estimated by in vivo and ex vivo comparisons using digital radiography was found to be similar to the actual tooth length.

  18. Evolution of floral display in Eichhornia paniculata (Pontederiaceae): direct and correlated responses to selection on flower size and number.

    Science.gov (United States)

    Worley, A C; Barrett, S C

    2000-10-01

    Trade-offs between flower size and number seem likely to influence the evolution of floral display and are an important assumption of several theoretical models. We assessed floral trade-offs by imposing two generations of selection on flower size and number in a greenhouse population of bee-pollinated Eichhornia paniculata. We established a control line and two replicate selection lines of 100 plants each for large flowers (S+), small flowers (S-), and many flowers per inflorescence (N+). We compared realized heritabilities and genetic correlations with estimates based on restricted-maximum-likelihood (REML) analysis of pedigrees. Responses to selection confirmed REML heritability estimates (flower size, h2 = 0.48; daily flower number, h2 = 0.10; total flower number, h2 = 0.23). Differences in nectar, pollen, and ovule production between S+ and S- lines supported an overall divergence in investment per flower. Both realized and REML estimates of the genetic correlation between daily and total flower number were r = 1.0. However, correlated responses to selection were inconsistent in their support of a trade-off. In both S- lines, correlated increases in flower number indicated a genetic correlation of r = -0.6 between flower size and number. In contrast, correlated responses in N+ and S+ lines were not significant, although flower size decreased in one N+ line. In addition, REML estimates of genetic correlations between flower size and number were positive, and did not differ from zero when variation in leaf area and age at first flowering were taken into account. These results likely reflect the combined effects of variation in genes controlling the resources available for flowering and genes with opposing effects on flower size and number. Our results suggest that the short-term evolution of floral display is not necessarily constrained by trade-offs between flower size and number, as is often assumed.

  19. Can We Retrieve the Information Which Was Intentionally Forgotten? Electrophysiological Correlates of Strategic Retrieval in Directed Forgetting

    Directory of Open Access Journals (Sweden)

    Xinrui Mao

    2017-08-01

    Full Text Available Retrieval inhibition hypothesis of directed forgetting effects assumed TBF (to-be-forgotten items were not retrieved intentionally, while selective rehearsal hypothesis assumed the memory representation of retrieved TBF (to-be-forgotten items was weaker than TBR (to-be-remembered items. Previous studies indicated that directed forgetting effects of item-cueing method resulted from selective rehearsal at encoding, but the mechanism of retrieval inhibition that affected directed forgetting of TBF (to-be-forgotten items was not clear. Strategic retrieval is a control process allowing the selective retrieval of target information, which includes retrieval orientation and strategic recollection. Retrieval orientation via the comparison of tasks refers to the specific form of processing resulted by retrieval efforts. Strategic recollection is the type of strategies to recollect studied items for the retrieval success of targets. Using a “directed forgetting” paradigm combined with a memory exclusion task, our investigation of strategic retrieval in directed forgetting assisted to explore how retrieval inhibition played a role on directed forgetting effects. When TBF items were targeted, retrieval orientation showed more positive ERPs to new items, indicating that TBF items demanded more retrieval efforts. The results of strategic recollection indicated that: (a when TBR items were retrieval targets, late parietal old/new effects were only evoked by TBR items but not TBF items, indicating the retrieval inhibition of TBF items; (b when TBF items were retrieval targets, the late parietal old/new effect were evoked by both TBR items and TBF items, indicating that strategic retrieval could overcome retrieval inhibition of TBF items. These findings suggested the modulation of strategic retrieval on retrieval inhibition of directed forgetting, supporting that directed forgetting effects were not only caused by selective rehearsal, but also retrieval

  20. Intraclass Correlation Coefficients in Hierarchical Design Studies with Discrete Response Variables: A Note on a Direct Interval Estimation Procedure

    Science.gov (United States)

    Raykov, Tenko; Marcoulides, George A.

    2015-01-01

    A latent variable modeling procedure that can be used to evaluate intraclass correlation coefficients in two-level settings with discrete response variables is discussed. The approach is readily applied when the purpose is to furnish confidence intervals at prespecified confidence levels for these coefficients in setups with binary or ordinal…

  1. CORRELATIONS OF THE ARRIVAL DIRECTIONS OF ULTRA-HIGH ENERGY COSMIC RAYS WITH EXTRAGALACTIC OBJECTS AS OBSERVED BY THE TELESCOPE ARRAY EXPERIMENT

    Energy Technology Data Exchange (ETDEWEB)

    Abu-Zayyad, T.; Allen, M.; Anderson, R.; Barcikowski, E.; Belz, J. W.; Bergman, D. R.; Blake, S. A.; Cady, R.; Hanlon, W. [High Energy Astrophysics Institute and Department of Physics and Astronomy, University of Utah, Salt Lake City, UT (United States); Aida, R. [Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu, Yamanashi (Japan); Azuma, R.; Fukuda, T. [Graduate School of Science and Engineering, Tokyo Institute of Technology, Meguro, Tokyo (Japan); Cheon, B. G.; Cho, E. J. [Department of Physics and The Research Institute of Natural Science, Hanyang University, Seongdong-gu, Seoul (Korea, Republic of); Chiba, J. [Department of Physics, Tokyo University of Science, Noda, Chiba (Japan); Chikawa, M. [Department of Physics, Kinki University, Higashi Osaka, Osaka (Japan); Cho, W. R. [Department of Physics, Yonsei University, Seodaemun-gu, Seoul (Korea, Republic of); Fujii, H. [Institute of Particle and Nuclear Studies, KEK, Tsukuba, Ibaraki (Japan); Fujii, T. [Graduate School of Science, Osaka City University, Osaka (Japan); Fukushima, M. [Institute for Cosmic Ray Research, University of Tokyo, Kashiwa, Chiba (Japan); and others

    2013-11-10

    We search for correlations between the positions of extragalactic objects and the arrival directions of ultra-high energy cosmic rays (UHECRs) with primary energy E ≥ 40 EeV as observed by the surface detector array of the Telescope Array (TA) experiment during the first 40 months of operation. We examine several public astronomical object catalogs, including the Veron-Cetty and Veron catalog of active galactic nuclei. We count the number of TA events correlated with objects in each catalog as a function of three parameters: the maximum angular separation between a TA event and an object, the minimum energy of the events, and the maximum redshift of the objects. We determine the combination of these parameters that maximizes the correlations, and we calculate the probability of having the same levels of correlations from an isotropic distribution of UHECR arrival directions. No statistically significant correlations are found when penalties for scanning over the above parameters and for searching in several catalogs are taken into account.

  2. Dissociating the Electrophysiological correlates between Item Retrieval and Associative Retrieval in Associative Recognition: From the Perspective of Directed Forgetting

    Directory of Open Access Journals (Sweden)

    Yujuan Wang

    2016-11-01

    Full Text Available Although many behavioral studies have reported associative memory was different from item memory, evidence coming from ERP researches has been in debate. In addition, directed forgetting effect for items has been fully discussed, but whether association between items can be directed-forgotten was unclear. The directed forgetting effect was important for disassociating the item retrieval and associative retrieval because of the one-to-one mapping relationship both between item retrieval and familiarity and between associative retrieval and recollection Thus, the aim of this study was to investigate the dissociation between item retrieval and associative retrieval and test directed forgetting effect for associative information. Associative recognition paradigm combined with directed forgetting paradigm by ERP recording was employed. Old/rearranged effect in to-be-remembered condition, which was associated with associative memory, was significant at 500-800 ms (LPC but not at 300-500 ms interval (FN400, indicating that item information was retrieved prior to associative information. The ERP wave calculated by subtracting the to-be-forgotten old pairs with old response from those with rearranged response, which reflected associative retrieval in the to-be-forgotten condition, was negative from 500 to 800 ms (reversal old/new effect, indicating that association between items can be directed-forgotten. Similar evidence was obtained by contrasting rearranged responses aimed to the to-be-forgotten old pairs with those aimed to the to-be-remembered rearranged pairs, which actually represented the complete failure of associative retrieval. Therefore, item retrieval and associative retrieval were indexed by FN400 and LPC respectively, with associative retrieval more inhibited than item retrieval.

  3. The Correlation between Managers’ Delegation of Authority with the Manner of Employee Direction in Hospitals of Qom Province

    OpenAIRE

    M.R Maleki

    2012-01-01

    Background and Objectives: The destructive effect of centralized management can be found throughout each organization, which is a barrier for delegation of authority and productivity leading to administrative violence increase and compression and frigidity of affairs. With attention to the importance of delegation of authority this research aimed at determining the correlation between the manager's delegation of authority with the man...

  4. Spectral shapes and a beta-gamma directional correlation in the beta decay of 172Tm (Jpi = 2-)

    DEFF Research Database (Denmark)

    Gregers Hansen, P.; Loft Nielsen, H.; Wilsky, K.

    1966-01-01

    The isotope 172Tm populates the 0+, 2+ and 4+ states of the 172Yb ground-state rotational band directly in beta decay. The shapes and intensities of the three beta groups have been measured by means of a six-gap magnetic spectrometer operated in coincidence with a Nal(Tl) crystal. The experimenta...

  5. Neurophysiological correlates of emotional directed-forgetting in persons with Schizophrenia: An event-related brain potential study.

    Science.gov (United States)

    Patrick, Regan E; Kiang, Michael; Christensen, Bruce K

    2015-12-01

    Recent research has shown that patients with schizophrenia (SCZ) exhibit reduced directed forgetting (DF) for negative words, suggesting impaired ability to instantiate goal-directed inhibition in order to suppress a competing, emotion-driven responses (i.e., emotional memory enhancement). However, disrupted inhibition is not the only possible mechanism by which patients could manifest reduced emotional DF. Therefore, the primary objective of the current study was to use event-related brain potential (ERP) recordings to investigate alternative hypotheses. ERPs were recorded while patients and controls completed an item-method DF paradigm using negative and neutral words. The N2 indexed goal-directed inhibition of to-be-forgotten items. The late positive potential (LPP) indexed emotional memory enhancement for negative study items. The P300 indexed selective rehearsal of to-be-remembered items. The SCZ group exhibited a reduced DF effect overall, but this was not modulated by emotion. N2 amplitude at anterior sites was larger for forget versus remember cues in the control group only, but this effect was not modulated by emotion. LPP amplitude was greater for negative versus neutral words in both groups, independent of region. P300 amplitude at posterior sites was greater for remember versus forget cues in the control group only. These data suggest that reduced DF in SCZ may be due, in part, to both diminished goal-directed inhibition of to-be-forgotten items and reduced selective rehearsal of to-be-remembered items. However, these data do not support the hypothesis that goal-directed, inhibitory processes are disrupted by competing, emotion-driven processes in SCZ. Patients' ERP data also suggested that they did not exhibit disproportionately heightened encoding of emotional stimuli, nor did they have deficient selective rehearsal of to-be-remembered emotional items. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Direct determination of two-pion correlations for $\\overline{p}p \\to 2\\pi^{+}2\\pi^{-}$ annihilation at rest

    CERN Document Server

    Angelopoulos, Angelos; Aslanides, Elie; Backenstoss, Gerhard; Bargassa, P; Behnke, O; Benelli, A; Bertin, V; Blanc, F; Bloch, P; Carlson, P J; Carroll, M; Carvalho, J; Cawley, E; Charalambous, S; Chardin, G; Chertok, M B; Cody, A; Danielsson, M; Dejardin, M; Derré, J; Ealet, A; Eleftheriadis, C; Evangelou, I; Faravel, L; Ferreira-Marques, R; Fetscher, W; Fidecaro, Maria; Filipcic, A; Francis, D; Fry, J; Gabathuler, Erwin; Gamet, R; Garreta, D; Gerber, H J; Go, A; Haselden, A; Hayman, P J; Henry-Coüannier, F; Hollander, R W; Hubert, E; Jon-And, K; Kettle, P R; Kokkas, P; Kreuger, R; Le Gac, R; Leimgruber, F; Liolios, A; Machado, E; Mandic, I; Manthos, N; Marel, Gérard; Mikuz, M; Miller, J; Montanet, François; Müller, A; Nakada, Tatsuya; Pagels, B; Papadopoulos, I M; Pavlopoulos, P; Pinto da Cunha, J; Policarpo, Armando; Polivka, G; Rickenbach, R; Roberts, B L; Ruf, T; Sakelliou, L; Sanders, P; Schäfer, M; Schaller, L A; Schietinger, T; Schopper, A; Soares, A; Tauscher, Ludwig; Thibault, C; Touchard, F; Touramanis, C; Triantis, F A; Van Beveren, E; van Eijk, C W E; Vlachos, S; Weber, P; Wigger, O; Wolter, M; Yéche, C; Zavrtanik, D; Zimmerman, D; Locher, M P; Markushin, V E

    1998-01-01

    We study $\\pi\\pi$ correlations in the exclusive reaction $\\ppb \\to 2\\pi^+2\\pi^-$ at rest measured by the CPLEAR experiment. Avoiding the introduction of an arbitrary reference sample, we analyse differential distributions for equal charge pion pairs removing the phase-space factor event by event. A peak at small relative momenta is most pronounced for large total momentum of the pair. The physical implications of bosonic symmetrization for the properties of the pion source, in particular its radius, are briefly discussed. The two extremes considered are the chaotic Hanbury-Brown--Twiss mechanism and the coherent Skyrmion model.

  7. Direct relationship between cell density and FDG uptake in asymptomatic aortic aneurysm close to surgical threshold: an in vivo and in vitro study

    Energy Technology Data Exchange (ETDEWEB)

    Marini, Cecilia [CNR Institute of Bioimaging and Molecular Physiology, Milan, Genoa Section, Genoa (Italy); Oftalmologia e Genetica dell' Universita di Genova, Dipartimento di Neuroscienze, Genoa (Italy); Morbelli, Silvia; Armonino, Riccardo; Riondato, Mattia; Massollo, Michela; Augeri, Carla; Fiz, Francesco; Sambuceti, Gianmario [University of Genoa, Department Internal Medicine, Chair of Nuclear Medicine, Genoa (Italy); Spinella, Giovanni; Pane, Bianca; Palmieri, Daniela; Palombo, Domenico [San Martino University Hospital, University of Genoa, Division of Vascular and Endovascular Surgery, Genoa (Italy); Sarocchi, Francesca; Abete, Luca; Fulcheri, Ezio [University of Genoa, Department of Surgical and Diagnostic Sciences, Pathology, Genoa (Italy); Ghigliotti, Giorgio [University of Genoa, Department of Internal Medicine, Chair of Cardiology, Genoa (Italy); Cittadini, Giuseppe [Hospital San Martino, Department of Radiology, Genoa (Italy)

    2012-01-15

    Conflicting results have been reported about the clinical value of fluorodeoxyglucose (FDG) imaging in predicting the risk of rupture of abdominal aortic aneurysm (AAA). The present study tests the hypothesis that FDG uptake is low in asymptomatic noninflammatory AAA due to the low cell density in aneurysmal walls. Positron emission tomography (PET)/CT imaging was performed in 12 consecutive candidates for AAA surgical repair and in 12 age- and sex-matched controls. At intervention, aneurysmal walls were cut into three sequential blocks. Block A was frozen to cut three 5-{mu}m slices for incubation with 2-3 MBq of FDG for 5 min. Block C was first incubated with the same tracer solution for the same time and subsequently frozen to cut three 5-{mu}m slices. Autoradiographic images were coregistered with immunohistochemical pictures of cell density, type and DNA synthesis as assessed on block B. No visible uptake in abdominal aorta occurred in any patient or control subject. Immunohistochemistry documented a severe loss of wall structure, with low numbers of cells. Tracer retention directly correlated with overall cell density and with prevalence of cells synthesizing DNA. The metabolic nature of FDG uptake was confirmed by the selective effect of preliminary freezing that decreased tracer content by 90% in regions with high cell density and only by 34% in cold acellular areas. The loss of tissue structure and the marked decrease in cell density account for the low prevalence of positive findings at FDG PET imaging, at least in asymptomatic patients bearing AAAs whose diameter is close to surgical indication. (orig.)

  8. Correlation between mixed-function oxidase enzyme induction and aflatoxin B1-induced unscheduled DNA synthesis in the chick embryo, in vivo

    International Nuclear Information System (INIS)

    Hamilton, J.W.; Bloom, S.E.

    1984-01-01

    The unscheduled DNA synthesis (UDS) technique has been adapted for use in the chick embryo, in vivo, to determine the relationship between induction of the mixed-function oxidase (MFO) enzyme system and genetic damage from an indirect-acting mutagen-carcinogen. Embryos were injected at 6 days of incubation (DI) with either phenobarbital (PB), a specific inducer of P-450-associated enzyme activities, or 3,4,3',4'-tetrachlorobiphenyl (TCB), a specific inducer of P 1 -450-associated enzyme activities. Aflatoxin B 1 (AFB1) was injected 24 hr later (7 DI), followed by a 5-hr continuous 3 H-thymidine exposure. The livers were removed, prepared for autoradiography, and hepatocytes were scored for an increase in grains/nucleus, indicative of UDS. Aflatoxin B 1 caused a dose-related increase in UDS in all control and induction groups. Phenobarbital-induced embryos had an increased UDS response while TCB-induced embryos had a decreased UDS response, relative to noninduced embryos, for each dosage of AFB1. This suggests that the genotoxicity of an indirect-acting mutagen-carcinogen can be either increased or decreased, in vivo, depending on the inducer used. The chick embryo provides an excellent system for studying the effect of MFO induction on the genotoxicity of promutagen-carcinogens in a developing system

  9. Investigating the neural correlates of voice versus speech-sound directed information in pre-school children.

    Directory of Open Access Journals (Sweden)

    Nora Maria Raschle

    Full Text Available Studies in sleeping newborns and infants propose that the superior temporal sulcus is involved in speech processing soon after birth. Speech processing also implicitly requires the analysis of the human voice, which conveys both linguistic and extra-linguistic information. However, due to technical and practical challenges when neuroimaging young children, evidence of neural correlates of speech and/or voice processing in toddlers and young children remains scarce. In the current study, we used functional magnetic resonance imaging (fMRI in 20 typically developing preschool children (average age  = 5.8 y; range 5.2-6.8 y to investigate brain activation during judgments about vocal identity versus the initial speech sound of spoken object words. FMRI results reveal common brain regions responsible for voice-specific and speech-sound specific processing of spoken object words including bilateral primary and secondary language areas of the brain. Contrasting voice-specific with speech-sound specific processing predominantly activates the anterior part of the right-hemispheric superior temporal sulcus. Furthermore, the right STS is functionally correlated with left-hemispheric temporal and right-hemispheric prefrontal regions. This finding underlines the importance of the right superior temporal sulcus as a temporal voice area and indicates that this brain region is specialized, and functions similarly to adults by the age of five. We thus extend previous knowledge of voice-specific regions and their functional connections to the young brain which may further our understanding of the neuronal mechanism of speech-specific processing in children with developmental disorders, such as autism or specific language impairments.

  10. Efficient in vivo gene transfer to xenotransplanted human skin by lentivirus-mediated, but not by AAV-directed, gene delivery

    DEFF Research Database (Denmark)

    Jakobsen, Maria Vad; Askou, Anne Louise; Dokkedahl, Karin Stenderup

    skin graft, and firefly luciferase expression was observed primarily in neighboring tissue beneath or surrounding the graft. In contrast, gene delivery by intradermally injected lentiviral vectors was efficient and led to extensive and persistent firefly luciferase expression within the human skin...... graft only. The study demonstrates limited capacity of single-stranded AAV vectors of six commonly used serotypes for gene delivery to human skin in vivo....

  11. Direct Filling Golds: An In-Vitro Study of Microleakage as a Function of Condensation Force: An In-Vivo Study of Marginal Quality

    Science.gov (United States)

    1979-01-01

    three teeth in vivo in dogs . All three showed penetration surrounding the restorations. No mention was made as to whether a cavity varnish was...gingival reactions to gold foil restorations. J Periodontal 46:614, 1975. 12. Christensen, C.J.: -iologic implications of dental restorations. J -m Acad...1ack, C.17.: An investignr-ian of the physical characters of thle huna. tee--: in relation to their diseases and to practical dental o-ierations

  12. Detection of Galactomannan Antigenemia in Patients Receiving Piperacillin-Tazobactam and Correlations between In Vitro, In Vivo, and Clinical Properties of the Drug-Antigen Interaction

    Science.gov (United States)

    Walsh, Thomas J.; Shoham, Shmuel; Petraitiene, Ruta; Sein, Tin; Schaufele, Robert; Kelaher, Amy; Murray, Heidi; Mya-San, Christine; Bacher, John; Petraitis, Vidmantas

    2004-01-01

    Recent case reports describe patients receiving piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 ± 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 ± 0.08) and compared to healthy blood bank donors (0.14 ± 0.06) (P 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only piperacillin-tazobactam contains

  13. Direct correlation of charge transfer absorption with molecular donor:acceptor interfacial area via photothermal deflection spectroscopy

    KAUST Repository

    Domingo, Ester

    2015-04-09

    We show that the Charge Transfer (CT) absorption signal in bulk-heterojunction (BHJ) solar cell blends, measured by photothermal deflection spectroscopy (PDS), is directly proportional to the density of molecular donor/acceptor interfaces. Since the optical transitions from ground state to the interfacial CT state are weakly allowed at photon energies below the optical gap of both donor and acceptor, we can exploit the use of this sensitive linear absorption spectroscopy for such quantification. Moreover, we determine the absolute molar extinction coefficient of the CT transition for an archetypical polymer-fullerene interface. The latter is ~100 times lower than the extinction coefficient of the donor chromophore involved, allowing us to experimentally estimate the transition dipole moment (0.3 D) and the electronic coupling between ground state and CT state to be on the order of 30 meV.

  14. Effectiveness of ancestral irradiation on the direct and correlated responses to selection for body weight in rats

    International Nuclear Information System (INIS)

    Gianola, D.

    1975-01-01

    The effects of ancestral irradiation of rat spermatogonia (a cumulative total of 4050 r of x-rays) were studied in a highly inbred line of rats to explore the feasibility of using irradiation to enhance the effectiveness of selection. Six generations after irradiation was terminated, a selection experiment for body weight at six weeks of age was started in both ancestrally irradiated and non-irradiated populations. There were two non-contemporaneous replicates in each of the populations. Within each of the ancestral treatment-replicate combinations one line was selected for high, one for low body weight at six weeks of age, and a third line was maintained by random selection. In each line, avoidance of mating of animals with grandparents in common was attempted. Data on the first ten progeny generations of selection were included in this study. Five types of covariances among relatives were used to estimate causal components of variance for five different genetic models within the ''non-irradiated'' and ''irradiated'' randomly selected models. The parameters in the genetic models were estimated by generalized least-squares. This analysis suggested that a genetic model including direct genetic and maternal genetic effects was adequate to describe the body weights at 3, 6 and 10 weeks of age and the weight gains between these ages. Ancestral irradiation seemed to have enhanced the maternal genetic variance and the covariance between the direct genetic and the maternal genetic effects. On the basis of the above analysis, it was deduced that mass selection should have been more effective in the descendants of irradiated males than in those of the non-irradiated males as a consequence of greater phenotypic variability in their progeny and an enhancement in the regression of the genetic value on the selection criterion

  15. RADIO MONITORING OF THE PERIODICALLY VARIABLE IR SOURCE LRLL 54361: NO DIRECT CORRELATION BETWEEN THE RADIO AND IR EMISSIONS

    Energy Technology Data Exchange (ETDEWEB)

    Forbrich, Jan, E-mail: jan.forbrich@univie.ac.at [University of Vienna, Department of Astrophysics, Türkenschanzstraße 17, A-1180 Vienna (Austria); Rodríguez, Luis F.; Palau, Aina; Zapata, Luis A. [Instituto de Radioastronomía y Astrofísica, UNAM, Apdo. Postal 3-72 (Xangari), 58089 Morelia, Michoacán (Mexico); Muzerolle, James [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Gutermuth, Robert A. [Department of Astronomy, University of Massachusetts, Amherst, MA 01003 (United States)

    2015-11-20

    LRLL 54361 is an infrared source located in the star-forming region IC 348 SW. Remarkably, its infrared luminosity increases by a factor of 10 over roughly one week every 25.34 days. To understand the origin of these remarkable periodic variations, we obtained sensitive 3.3 cm JVLA radio continuum observations of LRLL 54361 and its surroundings in six different epochs: three of them during the IR-on state and three during the IR-off state. The radio source associated with LRLL 54361 remained steady and did not show a correlation with the IR variations. We suggest that the IR is tracing the results of fast (with a timescale of days) pulsed accretion from an unseen binary companion, while the radio traces an ionized outflow with an extent of ∼100 AU that smooths out the variability over a period of the order of a year. The average flux density measured in these 2014 observations, 27 ± 5 μJy, is about a factor of two less than that measured about 1.5 years before, 53 ± 11 μJy, suggesting that variability in the radio is present, but over larger timescales than in the IR. We discuss other sources in the field, in particular two infrared/X-ray stars that show rapidly varying gyrosynchrotron emission.

  16. Direct observation of cation distributions of ideal inverse spinel CoFe2O4 nanofibres and correlated magnetic properties

    KAUST Repository

    Zeng, Xue

    2017-04-25

    Low-dimensional spinel ferrites have recently attracted increasing attention because their tunable magnetic properties make them attractive candidates as spin-filtering tunnel barriers in spintronic devices and as magnetic components in artificial multiferroic heterostructures. Although we know that the distribution of cations (Fe3+ and Co2+) in a spinel structure governs its magnetic properties, their distribution in the so-called ideal inverse spinel structure of a ferrite, CoFe2O4, has not yet been imaged with sub-ångstrom resolution. In this work, we fill this gap in evidence by reporting a direct observation of the distribution of cations in an ideal inverse spinel structure of CoFe2O4 nanofibres using aberration-corrected transmission electron microscopy (TEM). The ordering of Co2+ and Fe3+ at the octahedral sites imaged along either [001], [011] or [-112] orientation was identified as 1 : 1, in accordance with the ideal inverse spinel structure. The saturation magnetisation calculated based on the crystal structure as determined from the TEM image is in good agreement with that measured experimentally on the spinel CoFe2O4 nanofibres, further confirming results from TEM.

  17. Useful oriented immobilization of antibodies on chimeric magnetic particles: direct correlation of biomacromolecule orientation with biological activity by AFM studies.

    Science.gov (United States)

    Marciello, Marzia; Filice, Marco; Olea, David; Velez, Marisela; Guisan, José M; Mateo, Cesar

    2014-12-16

    The preparation and performance of a suitable chimeric biosensor based on antibodies (Abs) immobilized on lipase-coated magnetic particles by means of a standing orienting strategy are presented. This novel system is based on hydrophobic magnetic particles coated with modified lipase molecules able to orient and further immobilize different Abs in a covalent way without any previous site-selective chemical modification of biomacromolecules. Different key parameters attending the process were studied and optimized. The optimal preparation was performed using a controlled loading (1 nmol Ab g(-1) chimeric support) at pH 9 and a short reaction time to recover a biological activity of about 80%. AFM microscopy was used to study and confirm the Abs-oriented immobilization on lipase-coated magnetic particles and the final achievement of a highly active and recyclable chimeric immune sensor. This direct technique was demonstrated to be a powerful alternative to the indirect immunoactivity assay methods for the study of biomacromolecule-oriented immobilizations.

  18. Comparison of Simplexa universal direct PCR with cytotoxicity assay for diagnosis of Clostridium difficile infection: performance, cost, and correlation with disease.

    Science.gov (United States)

    Landry, Marie L; Ferguson, David; Topal, Jeffrey

    2014-01-01

    Simplexa Clostridium difficile universal direct PCR, a real-time PCR assay for the detection of the C. difficile toxin B (tcdB) gene using the 3M integrated cycler, was compared with a two-step algorithm which includes the C. Diff Chek-60 glutamate dehydrogenase (GDH) antigen assay followed by cytotoxin neutralization. Three hundred forty-two liquid or semisolid stools submitted for diagnostic C. difficile testing, 171 GDH antigen positive and 171 GDH antigen negative, were selected for the study. All samples were tested by the C. Diff Chek-60 GDH antigen assay, cytotoxin neutralization, and Simplexa direct PCR. Of 171 GDH-positive samples, 4 were excluded (from patients on therapy or from whom duplicate samples were obtained) and 88 were determined to be true positives for toxigenic C. difficile. Of the 88, 67 (76.1%) were positive by the two-step method and 86 (97.7%) were positive by PCR. Seventy-nine were positive by the GDH antigen assay only. Of 171 GDH antigen-negative samples, none were positive by PCR. One antigen-negative sample positive by the cytotoxin assay only was deemed a false positive based on chart review. Simplexa C. difficile universal direct PCR was significantly more sensitive for detecting toxigenic C. difficile bacteria than cytotoxin neutralization (P = 0.0002). However, most PCR-positive/cytotoxin-negative patients did not have clear C. difficile disease. The estimated cost avoidance provided by a more rapid molecular diagnosis was outweighed by the cost of isolating and treating PCR-positive/cytotoxin-negative patients. The costs, clinical consequences, and impact on nosocomial transmission of treating and/or isolating patients positive for toxigenic C. difficile by PCR but negative for in vivo toxin production merit further study.

  19. Plant traits correlated with generation time directly affect inbreeding depression and mating system and indirectly genetic structure

    Directory of Open Access Journals (Sweden)

    Hardy Olivier J

    2009-07-01

    differences in stature, as proposed earlier, but rather to differences in generation time. Conclusion Plant traits correlated with generation time affect both inbreeding depression and mating system. These in turn modify genetic drift and gene flow and ultimately genetic structure.

  20. Comparison and combination of "direct" and fragment based local correlation methods: Cluster in molecules and domain based local pair natural orbital perturbation and coupled cluster theories

    Science.gov (United States)

    Guo, Yang; Becker, Ute; Neese, Frank

    2018-03-01

    Local correlation theories have been developed in two main flavors: (1) "direct" local correlation methods apply local approximation to the canonical equations and (2) fragment based methods reconstruct the correlation energy from a series of smaller calculations on subsystems. The present work serves two purposes. First, we investigate the relative efficiencies of the two approaches using the domain-based local pair natural orbital (DLPNO) approach as the "direct" method and the cluster in molecule (CIM) approach as the fragment based approach. Both approaches are applied in conjunction with second-order many-body perturbation theory (MP2) as well as coupled-cluster theory with single-, double- and perturbative triple excitations [CCSD(T)]. Second, we have investigated the possible merits of combining the two approaches by performing CIM calculations with DLPNO methods serving as the method of choice for performing the subsystem calculations. Our cluster-in-molecule approach is closely related to but slightly deviates from approaches in the literature since we have avoided real space cutoffs. Moreover, the neglected distant pair correlations in the previous CIM approach are considered approximately. Six very large molecules (503-2380 atoms) were studied. At both MP2 and CCSD(T) levels of theory, the CIM and DLPNO methods show similar efficiency. However, DLPNO methods are more accurate for 3-dimensional systems. While we have found only little incentive for the combination of CIM with DLPNO-MP2, the situation is different for CIM-DLPNO-CCSD(T). This combination is attractive because (1) the better parallelization opportunities offered by CIM; (2) the methodology is less memory intensive than the genuine DLPNO-CCSD(T) method and, hence, allows for large calculations on more modest hardware; and (3) the methodology is applicable and efficient in the frequently met cases, where the largest subsystem calculation is too large for the canonical CCSD(T) method.

  1. Correlation between visual and radiographic examinations of non-cavitated occlusal caries lesions: an in vivo study Correlação entre os exames visual e radiográfico de lesões de cárie oclusal não cavitadas: estudo in vivo

    Directory of Open Access Journals (Sweden)

    Victor Ferrás Wolwacz

    2004-06-01

    Full Text Available The aim of this study was to conduct an in vivo investigation of the correlation between the visual and radiographic scoring systems by Ekstrand et al.7 (1997 for the diagnosis of occlusal caries lesions. The study sample comprised 147 occlusal sites from 23 patients. Two trained and experienced examiners performed the clinical visual examinations. A third examiner, which was also trained, experienced and blind to the results of the visual clinical examination, performed the analysis of the bitewing radiographs. The correlation between visual and radiographic scores was assessed by Goodman & Kruskal's gamma correlation coefficient. Results showed a strong correlation between the scores for occlusal caries found in the visual and radiographic diagnosis systems used in this study.O presente estudo verificou in vivo a correlação existente entre os sistemas de escore visual e radiográfico de Ekstrand et al.7 (1997 para diagnóstico de lesões de cárie oclusal. A amostra do estudo foi constituída de 147 sítios oclusais obtidos a partir de 23 pacientes. Os exames clínicos visuais foram realizados por dois examinadores treinados e calibrados. A análise das radiografias interproximais foi realizada por um terceiro examinador também treinado e calibrado, que desconhecia os resultados do exame clínico visual. A correlação entre os escores visual e radiográfico foi avaliada por meio do coeficiente de correlação gamma de Goodman & Kruskal. Os resultados revelaram uma forte correlação existente entre os escores dos sistemas de diagnóstico visual e radiográfico de cárie oclusal adotados no presente estudo.

  2. Direct correlations of structural and optical properties of three-dimensional GaN/InGaN core/shell micro-light emitting diodes

    Science.gov (United States)

    Sadat Mohajerani, Matin; Müller, Marcus; Hartmann, Jana; Zhou, Hao; Wehmann, Hergo-H.; Veit, Peter; Bertram, Frank; Christen, Jürgen; Waag, Andreas

    2016-05-01

    Three-dimensional (3D) InGaN/GaN quantum-well (QW) core-shell light emitting diodes (LEDs) are a promising candidate for the future solid state lighting. In this contribution, we study direct correlations of structural and optical properties of the core-shell LEDs using highly spatially-resolved cathodoluminescence spectroscopy (CL) in combination with scanning electron microscopy (SEM) and scanning transmission electron microscopy (STEM). Temperature-dependent resonant photoluminescence (PL) spectroscopy has been performed to understand recombination mechanisms and to estimate the internal quantum efficiency (IQE).

  3. Investigation of parity admixtures in nuclear states by measuring the β-γ directional correlation of the 203Hg → 203Tl decay

    International Nuclear Information System (INIS)

    Dydak, F.

    1972-01-01

    As a consequence of a weak nucleon-nucleon interaction parity admixtures in nuclear states give rise to a small forward-backward asymmetry of γ-quanta with respect to the direction of β-particle emission. A highly accurate arrangement using four β- and two γ-detectors has been developed to determine the odd Legendre term A cos(theta) in the β-γ directional correlation of the cascade decay 203 Hg→ 203 Tl as well as a control value which should be zero. The electronic equipment is a specially designed nanosecond system. The sources were prepared by means of a mass separator. Possible systematic distortions of the experimental data were carefully examined. A generalized least squares fit method symmetric in all variables was deduced for a correct data evaluation. The measurements yielded the coefficient A 1 = -(2,7+-0,7).10 -4 and the control value +(0,7+-0,8).10 -4 . (author)

  4. In vivo estradiol-dependent dephosphorylation of the repressor MDBP-2-H1 correlates with the loss of in vitro preferential binding to methylated DNA.

    Science.gov (United States)

    Bruhat, A; Jost, J P

    1995-01-01

    We have previously shown that estradiol treatment of roosters resulted in a rapid loss of binding activity of the repressor MDBP-2-H1 (a member of the histone H1 family) to methylated DNA that was not due to a decrease in MDBP-2-H1 concentration. Here we demonstrate that MDBP-2-H1 from rooster liver nuclear extracts is a phosphoprotein. Phosphoamino acid analysis reveals that the phosphorylation occurs exclusively on serine residues. Two-dimensional gel electrophoresis and tryptic phosphopeptide analysis show that MDBP-2-H1 is phosphorylated at several sites. Treatment of roosters with estradiol triggers a dephosphorylation of at least two sites in the protein. Phosphatase treatment of purified rooster MDBP-2-H1 combined with gel mobility shift assay indicates that phosphorylation of MDBP-2-H1 is essential for the binding to methylated DNA and that the dephosphorylation can occur on the protein bound to methylated DNA causing its release from DNA. Thus, these results suggest that in vivo modification of the phosphorylation status of MDBP-2-H1 caused by estradiol treatment may be a key step for the down regulation of its binding to methylated DNA. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7731964

  5. Correlation of Streptococcus mutans and Streptococcus sanguinis colonization and ex vivo hydrogen peroxide production in carious lesion-free and high caries adults.

    Science.gov (United States)

    Giacaman, Rodrigo A; Torres, Sebastián; Gómez, Yenifer; Muñoz-Sandoval, Cecilia; Kreth, Jens

    2015-01-01

    This study was conducted to estimate oral colonization by Streptococcus mutans and Streptococcus sanguinis in adults with high and without any caries experience. Furthermore, differences in the amount of hydrogen peroxide (H2O2) produced by S. sanguinis isolated from both groups were assessed. Forty adults were divided into: (i) carious lesion-free, without any carious lesion, assessed by the International Caries Detection and Assessment System (ICDAS), or restoration, (CF) and (ii) high caries experience (HC). Saliva samples were collected and seeded on respective agar-plates for enumeration of total streptococci, S. mutans and S. sanguinis (CFU/mL) and compared between groups. Additionally, S. sanguinis colonies obtained from both groups were inoculated on Prussian blue agar for H2O2 detection. Production of H2O2 was quantified and compared between the two groups. S. sanguinis counts were significantly higher in CF than HC individuals (pmutans showed significantly higher levels in HC than CF subjects (pmutans in saliva of adults without caries experience. In those people, S. sanguinis produces more H2O2ex vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Correlating Anatomy and Function with Gene Expression in Individual Neurons by Combining in Vivo Labeling, Patch Clamp, and Single Cell RNA-seq

    Directory of Open Access Journals (Sweden)

    Carsten K. Pfeffer

    2017-11-01

    Full Text Available The classification of neurons into distinct types is an ongoing effort aimed at revealing and understanding the diversity of the components of the nervous system. Recently available methods allow us to determine the gene expression pattern of individual neurons in the mammalian cerebral cortex to generate powerful categorization schemes. For a thorough understanding of neuronal diversity such genetic categorization schemes need to be combined with traditional classification parameters like position, axonal projection or response properties to sensory stimulation. Here we describe a method to link the gene expression of individual neurons with their position, axonal projection, or sensory response properties. Neurons are labeled in vivo based on their anatomical or functional properties and, using patch clamp pipettes, their RNA individually harvested in vitro for RNAseq. We validate the methodology using multiple established molecularly and anatomically distinct cell populations and explore molecular differences between uncharacterized neurons in mouse visual cortex. Gene expression patterns between L5 neurons projecting to frontal or contralateral cortex are distinct while L2 neurons differing in position, projection, or function are molecularly similar. With this method we can determine the genetic expression pattern of functionally and anatomically identified individual neurons.

  7. Correlation of iron deposition and change of gliocyte metabolism in the basal ganglia region evaluated using magnetic resonance imaging techniques: an in vivo study

    OpenAIRE

    Liu, Haodi; Wang, Xiaoming

    2016-01-01

    Introduction We assessed the correlation between iron deposition and the change of gliocyte metabolism in healthy subjects? basal ganglia region, by using 3D-enhanced susceptibility weighted angiography (ESWAN) and proton magnetic resonance spectroscopy (1H-MRS). Material and methods Seventy-seven healthy volunteers (39 female and 38 male subjects; age range: 24?82 years old) were enrolled in the experiment including ESWAN and proton MRS sequences, consent for which was provided by themselves...

  8. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells.

    Science.gov (United States)

    Rodman, C; Almeida-Porada, G; George, S K; Moon, J; Soker, S; Pardee, T; Beaty, M; Guida, P; Sajuthi, S P; Langefeld, C D; Walker, S J; Wilson, P F; Porada, C D

    2017-06-01

    Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone. Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.

  9. A novel dendritic cell-based direct ex vivo assay for detection and enumeration of circulating antigen-specific human T cells.

    Science.gov (United States)

    Carrio, Roberto; Zhang, Ge; Drake, Donald R; Schanen, Brian C

    2018-05-07

    Although a variety of assays have been used to examine T cell responses in vitro, standardized ex vivo detection of antigen-specific CD4 + T cells from human circulatory PBMCs remains constrained by low-dimensional characterization outputs and the need for polyclonal, mitogen-induced expansion methods to generate detectable response signals. To overcome these limitations, we developed a novel methodology utilizing antigen-pulsed autologous human dendritic target cells in a rapid and sensitive assay to accurately enumerate antigen-specific CD4 + T cell precursor frequency by multiparametric flow cytometry. With this approach, we demonstrate the ability to reproducibly quantitate poly-functional T cell responses following both primary and recall antigenic stimulation. Furthermore, this approach enables more comprehensive phenotypic profiling of circulating antigen-specific CD4 + T cells, providing valuable insights into the pre-existing polarization of antigen-specific T cells in humans. Combined, this approach permits sensitive and detailed ex vivo detection of antigen-specific CD4 + T cells delivering an important tool for advancing vaccine, immune-oncology and other therapeutic studies.

  10. Neuromodulatory adaptive combination of correlation-based learning in cerebellum and reward-based learning in basal ganglia for goal-directed behavior control.

    Science.gov (United States)

    Dasgupta, Sakyasingha; Wörgötter, Florentin; Manoonpong, Poramate

    2014-01-01

    Goal-directed decision making in biological systems is broadly based on associations between conditional and unconditional stimuli. This can be further classified as classical conditioning (correlation-based learning) and operant conditioning (reward-based learning). A number of computational and experimental studies have well established the role of the basal ganglia in reward-based learning, where as the cerebellum plays an important role in developing specific conditioned responses. Although viewed as distinct learning systems, recent animal experiments point toward their complementary role in behavioral learning, and also show the existence of substantial two-way communication between these two brain structures. Based on this notion of co-operative learning, in this paper we hypothesize that the basal ganglia and cerebellar learning systems work in parallel and interact with each other. We envision that such an interaction is influenced by reward modulated heterosynaptic plasticity (RMHP) rule at the thalamus, guiding the overall goal directed behavior. Using a recurrent neural network actor-critic model of the basal ganglia and a feed-forward correlation-based learning model of the cerebellum, we demonstrate that the RMHP rule can effectively balance the outcomes of the two learning systems. This is tested using simulated environments of increasing complexity with a four-wheeled robot in a foraging task in both static and dynamic configurations. Although modeled with a simplified level of biological abstraction, we clearly demonstrate that such a RMHP induced combinatorial learning mechanism, leads to stabler and faster learning of goal-directed behaviors, in comparison to the individual systems. Thus, in this paper we provide a computational model for adaptive combination of the basal ganglia and cerebellum learning systems by way of neuromodulated plasticity for goal-directed decision making in biological and bio-mimetic organisms.

  11. Separating Direct and Indirect Turbofan Engine Combustion Noise While Estimating Post-Combustion (Post-Flame) Residence Time Using the Correlation Function

    Science.gov (United States)

    Miles, Jeffrey Hilton

    2011-01-01

    A previous investigation on the presence of direct and indirect combustion noise for a full-scale turbofan engine using a far-field microphone at 130 is extended by also examining signals obtained at two additional downstream directions using far-field microphones at 110 deg and 160 deg. A generalized cross-correlation function technique is used to study the change in propagation time to the far field of the combined direct and indirect combustion noise signal as a sequence of low-pass filters are applied. The filtering procedure used produces no phase distortion. As the low-pass filter frequency is decreased, the travel time increases because the relative amount of direct combustion noise is reduced. The indirect combustion noise signal travels more slowly because in the combustor entropy fluctuations move with the flow velocity, which is slow compared to the local speed of sound. The indirect combustion noise signal travels at acoustic velocities after reaching the turbine and being converted into an acoustic signal. The direct combustion noise is always propagating at acoustic velocities. The results show that the estimated indirect combustion noise time delay values (post-combustion residence times) measured at each angle are fairly consistent with one another for a relevant range of operating conditions and demonstrate source separation of a mixture of direct and indirect combustion noise. The results may lead to a better idea about the acoustics in the combustor and may help develop and validate improved reduced-order physics-based methods for predicting turbofan engine core noise.

  12. The Role of Endogenous D2 Receptor Levels in Morphine Addiction: A Correlative Study of Morphine Place Conditioning and In Vivo [3H]-Raclopride Binding

    Energy Technology Data Exchange (ETDEWEB)

    Khan, N.; Gatley, S.

    2004-01-01

    Dopamine is a neurotransmitter that has a wide array of effects on an individual’s mental state. It is vital in the regulation of motor skills and in generating the effects of substance abuse. This study examined the dopamine D2 receptors found in the striatum of the brain. The impetus for investigating this receptor lies in the perception that it plays an influential role in drug addiction. It has been conjectured on the basis of human PET studies that possession of low levels of D2 receptors will heighten an individual’s susceptibility to drug addiction. However, an alternative explanation of low D2 receptor levels in drug dependent individuals is that these levels are a consequence of drug abuse. To understand this phenomenon, the present study employed the paradigm of conditioned place preference (CPP). In CPP, individuals of an out-bred mouse strain are observed to spend time in environments where they had previously been exposed to a drug that is abused by humans. The drug chosen for our studies was morphine because it has been previously shown to generate a robust place preference in mice and is a prototypic abused drug in humans. D2 receptor levels were quantified using an in vivo binding study involving [3H]raclopride, a radioactive compound that binds to D2 receptors. The results showed a significant place preference for morphine following the conditioning procedure. Additionally, data from the binding analysis agreed with previous studies that the striatum contains high levels of D2 receptors. However, there was no consistent relationship between the extent of morphine CPP and D2 receptor levels as revealed by [3H]-RAC binding. This finding does not support the hypothesis that low levels of D2 receptors predispose a mouse to easy morphine conditioning. Further experiments are required to determine the ability to generalize our findings to other species and other drugs of abuse.

  13. In vivo evaluation of biosensors volumetric bio-distribution for measurement of metabolic activity by X-ray correlation, fluorescence, Cerenkov image and radioisotope

    International Nuclear Information System (INIS)

    Ramirez N, G. J.

    2016-01-01

    The aim of this study was to characterize the in vivo volumetric distribution of three folate based biosensors by different imaging modalities (X-ray, fluorescence, Cerenkov luminescence and radioisotopic imaging) through the development of a tri dimensional (3D) image reconstruction algorithm. The preclinical and multimodal Xtreme imaging system, with a Multimodal Animal Rotation System (Mars), was used to acquire bidimensional (2D) images, which were processed to obtain the 3D reconstruction. Images of mice at different times (biosensor distribution) were simultaneously obtained from the four imaging modalities. The filtered backprojection and inverse Radon transformation were used as main image-processing techniques. In the first instance, the algorithm developed in Mat lab was able to reconstruct in the 3D form the skeleton of the mice under study. Subsequently, the algorithm was able to get the volumetric profiles of "9"9"mTc-Folate-Bombesin (radioisotopic image), "1"7"7Lu-Folate-Bombesin (Cerenkov image), and FolateRSense 680 (fluorescence image) in the tumors and kidneys of the mice. No significant differences were detected between the volumetric quantifications using the standard measurement techniques and the quantifications obtained with the proposal made in this study, nor between the volumetric uptakes in the structures of interest. With the structures reconstructed in the 3D form, the fusion of anatomical (as the skeleton) and functional structures derived from the images of the biosensors uptake was achieved The imaging 3D reconstruction algorithm can be easily extrapolated to different 2D acquisition-type images. This characteristic flexibility of the algorithm developed in this study is an advantage in comparison to similar reconstruction methods. (Author)

  14. Bi-exponential T2 analysis of healthy and diseased Achilles tendons: an in vivo preliminary magnetic resonance study and correlation with clinical score.

    Science.gov (United States)

    Juras, Vladimir; Apprich, Sebastian; Szomolanyi, Pavol; Bieri, Oliver; Deligianni, Xeni; Trattnig, Siegfried

    2013-10-01

    To compare mono- and bi-exponential T2 analysis in healthy and degenerated Achilles tendons using a recently introduced magnetic resonance variable-echo-time sequence (vTE) for T2 mapping. Ten volunteers and ten patients were included in the study. A variable-echo-time sequence was used with 20 echo times. Images were post-processed with both techniques, mono- and bi-exponential [T2 m, short T2 component (T2 s) and long T2 component (T2 l)]. The number of mono- and bi-exponentially decaying pixels in each region of interest was expressed as a ratio (B/M). Patients were clinically assessed with the Achilles Tendon Rupture Score (ATRS), and these values were correlated with the T2 values. The means for both T2 m and T2 s were statistically significantly different between patients and volunteers; however, for T2 s, the P value was lower. In patients, the Pearson correlation coefficient between ATRS and T2 s was -0.816 (P = 0.007). The proposed variable-echo-time sequence can be successfully used as an alternative method to UTE sequences with some added benefits, such as a short imaging time along with relatively high resolution and minimised blurring artefacts, and minimised susceptibility artefacts and chemical shift artefacts. Bi-exponential T2 calculation is superior to mono-exponential in terms of statistical significance for the diagnosis of Achilles tendinopathy. • Magnetic resonance imaging offers new insight into healthy and diseased Achilles tendons • Bi-exponential T2 calculation in Achilles tendons is more beneficial than mono-exponential • A short T2 component correlates strongly with clinical score • Variable echo time sequences successfully used instead of ultrashort echo time sequences.

  15. Two-Particle Correlations with Neutral Pion and Direct Photon Triggers in pp and Pb+Pb Collisions with ALICE at the LHC

    CERN Document Server

    Zhu, Xiangrong; Constantinos, Loizides; Zhongbao, Yin; Loizides, Constantinos; Zhongbao, Yin

    Two-particle correlations is considered as a powerful probe for understanding the properties of the strongly interacting hot and dense medium. In such an analysis, a particle is chosen from higher $p_{\\rm T}$ region and called the trigger particle, which is presumably from jet fragmentations. The so called associated particles from lower $p_{\\rm T}$ region are always from the other fragmentation of the jet, or another production, such as collective flow. At RHIC and LHC, the measurements of the azimuthal angle distribution from two-particle correlations in A+A collisions show a strong suppression even disappeared at the high $p_{\\rm T}$ and enhancement with double-peak at the low $p_{\\rm T}$ on the away side, and ``ridge'' structure in pseudo-rapidity direction at the low $p_{\\rm T}$ on the near side compared to pp collisions. All the measurements can be explained as the effects of the hot and dense medium, and imply the Quark-Gluon Plasma is indeed formed in the heavy-ion collisions. When the direct ph...

  16. SOCS3 Expression Correlates with Severity of Inflammation, Expression of Proinflammatory Cytokines, and Activation of STAT3 and p38 MAPK in LPS-Induced Inflammation In Vivo

    Directory of Open Access Journals (Sweden)

    João Antônio Chaves de Souza

    2013-01-01

    Full Text Available SOCS3 is an inducible endogenous negative regulator of JAK/STAT pathway, which is relevant in inflammatory conditions. We used a model of LPS-induced periodontal disease in rats to correlate SOCS3 expression with the inflammatory status. In vitro we used a murine macrophage cell line to assess the physical interaction between SOCS3 and STAT3 by coimmunoprecipitation. 30 ug of LPS from Escherichia coli were injected in the gingival tissues on the palatal aspect of first molars of the animals 3x/week for up to 4 weeks. Control animals were injected with the vehicle (PBS. The rats were sacrificed at 7, 15, and 30 days. Inflammation and gene expression were assessed by stereometric analysis, immunohistochemistry, RT-qPCR, and western blot. LPS injections increased inflammation, paralleled by an upregulation of SOCS3, of the proinflammatory cytokines IL-1β, IL-6, and TNF-α and increased phosphorylation of STAT3 and p38 MAPK. SOCS3 expression accompanied the severity of inflammation and the expression of proinflammatory cytokines, as well as the activation status of STAT3 and p38 MAPK. LPS stimulation in a macrophage cell line in vitro induced transient STAT3 activation, which was inversely correlated with a dynamic physical interaction with SOCS3, suggesting that this may be a mechanism for SOCS3 regulatory function.

  17. In silico and in vivo analysis of Toxoplasma gondii epitopes by correlating survival data with peptide-MHC-I binding affinities.

    Science.gov (United States)

    Huang, Si-Yang; Jensen, Maria Risager; Rosenberg, Carina Agerbo; Zhu, Xing-Quan; Petersen, Eskild; Vorup-Jensen, Thomas

    2016-07-01

    Protein antigens comprising peptide motifs with high binding affinity to major histocompatibility complex class I (MHC-I) molecules are expected to induce a stronger cytotoxic T-lymphocyte response and thus provide better protection against infection with microorganisms where cytotoxic T-cells are the main effector arm of the immune system. Data on cyst formation and survival were extracted from past studies on the DNA immunization of mice with plasmids coding for Toxoplasma gondii antigens. From in silico analyses of the vaccine antigens, the correlation was tested between the predicted affinity for MHC-I molecules of the vaccine peptides and the survival of immunized mice after challenge with T. gondii. ELISPOT analysis was used for the experimental testing of peptide immunogenicity. Predictions for the Db MHC-I molecule produced a strong, negative correlation between survival and the dissociation constant of vaccine-derived peptides. The in silico analyses of nine T. gondii antigens identified peptides with a predicted dissociation constant in the interval from 10nM to 40μM. ELISPOT assays with splenocytes from T. gondii-infected mice further supported the importance of the peptide affinity for MHC-I. In silico analysis clearly helped the search for protective vaccine antigens. The ELISPOT analysis confirmed that the predicted T-cell epitopes were immunogenic by their ability to release interferon gamma in spleen cells. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Gaora Peadar Ó

    2010-10-01

    Full Text Available Abstract Background Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of

  19. Understanding the relative contributions of direct environmental effects and passive genotype-environment correlations in the association between familial risk factors and child disruptive behavior disorders.

    Science.gov (United States)

    Bornovalova, M A; Cummings, J R; Hunt, E; Blazei, R; Malone, S; Iacono, W G

    2014-03-01

    Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect (a) the direct effects of familial environment and (b) a passive gene-environment correlation (r(GE)), wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive r(GE) by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict and divorce; offspring DBDs included attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD). Mixed-level regressions estimated the main effects of familial environment, adoption status and the familial environment by adoption status interaction term, which tested for the presence of passive r(GE). There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive r(GE). Many familial risk factors affected children equally across genetically related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive r(GE), where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children.

  20. Estimation of femoral bone density from trabecular direct wave and cortical guided wave ultrasound velocities measured at the proximal femur in vivo

    DEFF Research Database (Denmark)

    Barkmann, Reinhard; Dencks, Stefanie; Bremer, Alexander

    2008-01-01

    but not soft tissue SOS. Coefficient of determination, percentage residual error (RMSE) and level of significance (p) were R(2)=0.51, RMSE=12.6%, p2)=0.53, RMSE=12.3%, p... the correlation to R(2)=0.69, RMSE=10.4%, p

  1. Direct in vitro and in vivo comparison of {sup 161}Tb and {sup 177}Lu using a tumour-targeting folate conjugate

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Cristina; Reber, Josefine; Haller, Stephanie [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Dorrer, Holger; Tuerler, Andreas [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); University of Bern, Laboratory of Radiochemistry and Environmental Chemistry, Department of Chemistry and Biochemistry, Bern (Switzerland); Bernhardt, Peter [The Sahlgrenska Academy, University of Gothenburg, Department of Radiation Physics, Gothenburg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Medical Bioengeneering, Gothenburg (Sweden); Zhernosekov, Konstantin [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

    2014-03-15

    The radiolanthanide {sup 161}Tb (T{sub 1/2} = 6.90 days, Eβ{sup -}{sub av} = 154 keV) was recently proposed as a potential alternative to {sup 177}Lu (T{sub 1/2} = 6.71 days, Eβ{sup -}{sub av} = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare {sup 161}Tb and {sup 177}Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). {sup 161}Tb-cm09 and {sup 177}Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo {sup 161}Tb-cm09 and {sup 177}Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using {sup 99m}Tc-dimercaptosuccinic acid (DMSA). To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for {sup 161}Tb-cm09 (IC{sub 50} ∝0.014 MBq/ml and ∝2.53 MBq/ml) compared to {sup 177}Lu-cm09 (IC{sub 50} ∝0.063 MBq/ml and ∝4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies {sup 161}Tb-cm09 reduced tumour growth more efficiently than {sup 177}Lu-cm09. These findings were in line with the higher absorbed tumour dose for {sup 161}Tb-cm09 (3.3 Gy/MBq) compared to {sup 177}Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Compared to {sup 177}Lu-cm09 we demonstrated equal imaging

  2. Precursors (pre-CFCmulti) of multilineage hemopoietic colony-forming cells quantitated in vitro. Uniqueness of IL-1 requirement, partial separation from pluripotential colony-forming cells, and correlation with long term reconstituting cells in vivo

    International Nuclear Information System (INIS)

    Iscove, N.N.; Yan, X.Q.

    1990-01-01

    Pluripotential colony-forming cells (CFCmulti) from mouse marrow can expand significantly in number during 4 days of suspension culture with IL-1 and IL-3. In this study, the cells (pre-CFCmulti) which originate this response are characterized in terms of their frequency, progeny number, factor requirements, buoyant density, and extent of restoration following marrow transplantation. Parallel measurements of both CFCmulti and cells providing long term marrow reconstitution in vivo allowed direct comparisons to be made with pre-CFCmulti. The proliferative response of pre-CFCmulti was found to depend uniquely on the combination of IL-1 and IL-3, and neither of these regulators was replaceable by any of IL-4, IL-6, IL-7, GM-CSF, G-CSF, M-CSF or LIF. After separation on density gradients, pre-CFCmulti were recovered in fractions of lower density than most of the CFCmulti, but in the same fractions that contained most of the in vivo reconstituting cells. After irradiation and marrow transplantation, marrow CFCmulti were restored to near normal levels, while both pre-CFCmulti as well as reconstituting stem cells remained profoundly depressed. These results show pre-CFCmulti to be distinct from most CFCmulti and to represent the closest approach to quantitative detection of reconstituting stem cells so far achieved in vitro

  3. Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo.

    Science.gov (United States)

    Song, Yanjing; Tong, Chuan; Wang, Yao; Gao, Yunhe; Dai, Hanren; Guo, Yelei; Zhao, Xudong; Wang, Yi; Wang, Zizheng; Han, Weidong; Chen, Lin

    2017-03-10

    Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.

  4. Superadditive correlation

    International Nuclear Information System (INIS)

    Giraud, B.G.; Heumann, J.M.; Lapedes, A.S.

    1999-01-01

    The fact that correlation does not imply causation is well known. Correlation between variables at two sites does not imply that the two sites directly interact, because, e.g., correlation between distant sites may be induced by chaining of correlation between a set of intervening, directly interacting sites. Such 'noncausal correlation' is well understood in statistical physics: an example is long-range order in spin systems, where spins which have only short-range direct interactions, e.g., the Ising model, display correlation at a distance. It is less well recognized that such long-range 'noncausal' correlations can in fact be stronger than the magnitude of any causal correlation induced by direct interactions. We call this phenomenon superadditive correlation (SAC). We demonstrate this counterintuitive phenomenon by explicit examples in (i) a model spin system and (ii) a model continuous variable system, where both models are such that two variables have multiple intervening pathways of indirect interaction. We apply the technique known as decimation to explain SAC as an additive, constructive interference phenomenon between the multiple pathways of indirect interaction. We also explain the effect using a definition of the collective mode describing the intervening spin variables. Finally, we show that the SAC effect is mirrored in information theory, and is true for mutual information measures in addition to correlation measures. Generic complex systems typically exhibit multiple pathways of indirect interaction, making SAC a potentially widespread phenomenon. This affects, e.g., attempts to deduce interactions by examination of correlations, as well as, e.g., hierarchical approximation methods for multivariate probability distributions, which introduce parameters based on successive orders of correlation. copyright 1999 The American Physical Society

  5. Multicontrast-weighted magnetic resonance imaging of atherosclerotic plaques at 3.0 and 1.5 Tesla: ex-vivo comparison with histopathologic correlation

    International Nuclear Information System (INIS)

    Koops, Andreas; Ittrich, Harald; Priest, Andrew; Stork, Alexander; Adam, Gerhard; Weber, Christoph; Petri, Susan; Lockemann, Ute

    2007-01-01

    The purpose was to analyze magnetic resonance (MR) plaque imaging at 3.0 Tesla and 1.5 Tesla in correlation with histopathology. MR imaging (MRI) of the abdominal aorta and femoral artery was performed on seven corpses using T1-weighted, T2-weighted, and PD-weighted sequences at 3.0 and 1.5 Tesla. Cross-sectional images at the branching of the inferior mesenteric artery and the profunda femoris were rated with respect to image quality. Corresponding cross sections of the imaged vessels were obtained at autopsy. The atherosclerotic plaques in the histological slides and MR images were classified according to the American Heart Association (AHA) and analyzed for differences. MRI at 3.0 Tesla offered superior depiction of arterial wall composition in all contrast weightings, rated best for T2-weighted images. Comparing for field strength, the highest differences were observed in T1-weighted and T2-weighted techniques (both P≤0.001), with still significant differences in PD-weighted sequence (P≤0.005). The majority of plaques were histologically classified as calcified plaques. In up to 21% of the cases, MRI at both field strengths detected signal loss characteristic of calcification although calcified plaque was absent in histology. MRI at 3.0 Tesla offers superior plaque imaging quality compared with 1.5 Tesla, but further work is necessary to determine whether this translates in superior diagnostic accuracy. (orig.)

  6. Evaluation of Elastin/Collagen Content in Human Dermis in-Vivo by Multiphoton Tomography—Variation with Depth and Correlation with Aging

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Pittet

    2014-08-01

    Full Text Available The aim of this study was to evaluate the influence of the depth of the dermis on the measured collagen and elastin levels and to establish the correlation between the amount of these two extracellular matrix (ECM components and age. Multiphoton Microscopy (MPM that measures the autofluorescence (AF and second harmonic generation (SHG was used to quantify the levels of elastin and collagen and to determine the SAAID (SHG-to-AF Aging Index of Dermis at two different skin depths. A 50 MHz ultrasound scanner was used for the calculation of the Sub Epidermal Non Echogenic Band (SENEB. The measurements of the skin mechanical properties were done with a cutometer. All measurements were performed on two groups of 30 healthy female volunteers. The MPM showed a decrease of the quantity of collagen and elastin as a function of depth of the dermis as well as age. The SAAID was lower for the older skin in the deeper dermis. Ultrasound imaging revealed a significant decrease of SENEB as a function of aging. The mechanical properties confirmed a loss of cutaneous elasticity and firmness. Although multiphoton microscopy is a powerful technique to study the characteristics of the dermis and its age-related damage, the location of the measurements (depth remains very important for the validation of these variations. These variations do not seem to be homogeneous according to the part of the dermis that is studied.

  7. Mitigation of direct neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein kinase in vitro and in vivo

    NARCIS (Netherlands)

    Lirk, Philipp; Haller, Ingrid; Myers, Robert R.; Klimaschewski, Lars; Kau, Yi-Chuan; Hung, Yu-Chun; Gerner, Peter

    2006-01-01

    Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell

  8. Neuromodulatory Adaptive Combination of Correlation-based Learning in Cerebellum and Reward-based Learning in Basal Ganglia for Goal-directed Behavior Control

    DEFF Research Database (Denmark)

    Dasgupta, Sakyasingha; Wörgötter, Florentin; Manoonpong, Poramate

    2014-01-01

    Goal-directed decision making in biological systems is broadly based on associations between conditional and unconditional stimuli. This can be further classified as classical conditioning (correlation-based learning) and operant conditioning (reward-based learning). A number of computational...... and experimental studies have well established the role of the basal ganglia in reward-based learning, where as the cerebellum plays an important role in developing specific conditioned responses. Although viewed as distinct learning systems, recent animal experiments point toward their complementary role...... in behavioral learning, and also show the existence of substantial two-way communication between these two brain structures. Based on this notion of co-operative learning, in this paper we hypothesize that the basal ganglia and cerebellar learning systems work in parallel and interact with each other. We...

  9. Characterization of the plasminogen activator of herpesvirus-transformed cells and examination of its correlation with the tumorigenic and metastatic ability of in vivo-derived sublines

    International Nuclear Information System (INIS)

    Marks, G.J.

    1986-01-01

    Herpes simplex virus type 2-transformed hamster embryo fibroblasts (333-8-9 cells) produce increased amounts of plasminogen activator (PA) compared with normal hamster cells. The 333-8-9 PA activity was quantitated in comparison to a PA standard, urokinase (UK). Using a direct PA assay in which 125 I-labeled plasminogen is cleaved, a linear dose-response was seen over a 1000-fold range in UK concentration when plotted on a semi-logarithmic scale. Extracellular PA activity secreted by the HSV-2-transformed cell line, 333-8-9, followed a similar dose-response slop. The optimum pH and osmolarity for detection of the 333-8-9 extracellular PA activity were pH 8.9 and approximately 150 mOsmol, respectively. Secretion of PA by the 333-8-9 cells did not vary significantly on a per cell basis over cell densities ranging from 0.1 to 8.0 x 10 7 cells/T-75 cm 2 flask. This assay was accurate, reproducible, and demonstrated that the 333-8-9 cells produced at least a 20-fold greater amount of PA activity than their normal cell counterparts. Based on the molecular weight (50-58 Kd) of the secreted 333-8-9 cell PA and lack of fibrin stimulation of the PA activity, it is concluded to be a urokinase-type PA

  10. Dynamics of spectral bio-indicators and their correlations with light use efficiency using directional observations at a Douglas-fir forest

    Science.gov (United States)

    Cheng, Yen-Ben; Middleton, Elizabeth M.; Hilker, Thomas; Coops, Nicholas C.; Black, T. Andrew; Krishnan, Praveena

    2009-09-01

    The carbon science community must rely on satellite remote sensing to obtain global estimates of photosynthetic activity, typically expressed as net primary production (NPP), gross primary production (GPP) or light use efficiency (LUE). The photochemical reflectance index (PRI), calculated as a normalized difference reflectance index using a physiologically active green band (~531 nm) and another physiologically insensitive green reference band (~570 nm), denoted as PRI(570), has been confirmed in many studies as being strongly related to LUE. Here, we examined the potential of utilizing PRI(570) observations under different illumination conditions for canopy LUE estimation of a forest. In order to evaluate this, directional hyperspectral reflectance measurements were collected continuously throughout the daytime periods using an automated spectroradiometer in conjunction with tower-based eddy covariance fluxes and environmental measurements at a coastal conifer forest in British Columbia, Canada throughout the 2006 growing season. A parameter calculated as the PRI(570) difference (dPRI(570)) between shaded versus sunlit canopy foliage sectors showed a strong correlation to tower-based LUE. The seasonal pattern for this correlation produced a dramatic change from high negative (r ~ -0.80) values in the springtime and early fall to high positive values (r ~ 0.80) during the summer months, which could represent the seasonality of physiological characteristics and environmental factors. Although the PRI(570) successfully tracked canopy LUE, one or both of its green bands (~531 and 570 nm) used to calculate the PRI are unavailable on most existing and planned near-term satellites. Therefore, we examined the potential to use 24 other spectral indexes for LUE monitoring that might be correlated to PRI, and thereby a substitute for it. We also continued our previous investigations into the influence of illumination conditions on the observed PRI(570) and other indexes

  11. Dynamics of spectral bio-indicators and their correlations with light use efficiency using directional observations at a Douglas-fir forest

    International Nuclear Information System (INIS)

    Cheng, Yen-Ben; Middleton, Elizabeth M; Hilker, Thomas; Coops, Nicholas C; Black, T Andrew; Krishnan, Praveena

    2009-01-01

    The carbon science community must rely on satellite remote sensing to obtain global estimates of photosynthetic activity, typically expressed as net primary production (NPP), gross primary production (GPP) or light use efficiency (LUE). The photochemical reflectance index (PRI), calculated as a normalized difference reflectance index using a physiologically active green band (∼531 nm) and another physiologically insensitive green reference band (∼570 nm), denoted as PRI(570), has been confirmed in many studies as being strongly related to LUE. Here, we examined the potential of utilizing PRI(570) observations under different illumination conditions for canopy LUE estimation of a forest. In order to evaluate this, directional hyperspectral reflectance measurements were collected continuously throughout the daytime periods using an automated spectroradiometer in conjunction with tower-based eddy covariance fluxes and environmental measurements at a coastal conifer forest in British Columbia, Canada throughout the 2006 growing season. A parameter calculated as the PRI(570) difference (dPRI(570)) between shaded versus sunlit canopy foliage sectors showed a strong correlation to tower-based LUE. The seasonal pattern for this correlation produced a dramatic change from high negative (r ∼ −0.80) values in the springtime and early fall to high positive values (r ∼ 0.80) during the summer months, which could represent the seasonality of physiological characteristics and environmental factors. Although the PRI(570) successfully tracked canopy LUE, one or both of its green bands (∼531 and 570 nm) used to calculate the PRI are unavailable on most existing and planned near-term satellites. Therefore, we examined the potential to use 24 other spectral indexes for LUE monitoring that might be correlated to PRI, and thereby a substitute for it. We also continued our previous investigations into the influence of illumination conditions on the observed PRI(570) and other

  12. Occlusal force is correlated with cognitive function directly as well as indirectly via food intake in community-dwelling older Japanese: From the SONIC study.

    Science.gov (United States)

    Ikebe, Kazunori; Gondo, Yasuyuki; Kamide, Kei; Masui, Yukie; Ishizaki, Taturo; Arai, Yasumichi; Inagaki, Hiroki; Nakagawa, Takeshi; Kabayama, Mai; Ryuno, Hirochika; Okubo, Hitomi; Takeshita, Hajime; Inomata, Chisato; Kurushima, Yuko; Mihara, Yusuke; Hatta, Kohdai; Fukutake, Motoyoshi; Enoki, Kaori; Ogawa, Taiji; Matsuda, Ken-Ichi; Sugimoto, Ken; Oguro, Ryosuke; Takami, Yoichi; Itoh, Norihisa; Takeya, Yasushi; Yamamoto, Koichi; Rakugi, Hiromi; Murakami, Shinya; Kitamura, Masahiro; Maeda, Yoshinobu

    2018-01-01

    Growing evidence suggests that oral health may be an important factor associated with cognitive function in aged populations. However, many previous studies on this topic used insensitive oral indicators or did not include certain essential covariates. Thus, we examined the association between occlusal force and cognitive function in a large sample of older adults, controlling for dietary intake, vascular risk factors, inflammatory biomarkers, depression, and genetic factors. In this cross-sectional study of older community-dwelling Japanese adults, we examined data collected from 994 persons aged 70 years and 968 persons aged 80 years. Cognitive function was measured using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral status and function were evaluated according to the number of remaining teeth, periodontal pocket depth, and maximal occlusal force. Associations between MoCA-J scores and occlusal force were investigated via bivariate and multivariate analyses. Education level, financial status, depression score, and intake of green and yellow vegetables, as well as number of teeth and occlusal force, were significantly correlated with MoCA-J scores in both age groups. Among individuals aged 80 years, CRP and periodontal status were weakly but significantly associated with MoCA-J score. After controlling for all significant variables via bivariate analyses, the correlation between maximal occlusal force and cognitive function persisted. A path analysis confirmed the hypothesis that cognitive function is associated with occlusal force directly as well as indirectly via food intake. After controlling for possible factors, maximal occlusal force was positively associated with cognitive function directly as well as indirectly through dietary intake.

  13. Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.

    Science.gov (United States)

    Maussang, David; Mujić-Delić, Azra; Descamps, Francis J; Stortelers, Catelijne; Vanlandschoot, Peter; Stigter-van Walsum, Marijke; Vischer, Henry F; van Roy, Maarten; Vosjan, Maria; Gonzalez-Pajuelo, Maria; van Dongen, Guus A M S; Merchiers, Pascal; van Rompaey, Philippe; Smit, Martine J

    2013-10-11

    The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the "Nanobody platform" to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced β-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.

  14. Defining human mesenchymal stem cell efficacy in vivo

    Directory of Open Access Journals (Sweden)

    Lennon Donald P

    2010-10-01

    Full Text Available Abstract Allogeneic human mesenchymal stem cells (hMSCs can suppress graft versus host disease (GvHD and have profound anti-inflammatory and regenerative capacity in stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of disease. There is significant clinical hMSC variability in efficacy and the ultimate response in vivo. The challenge in hMSC based therapy is defining the efficacy of hMSC in vivo. Models which may provide insight into hMSC bioactivity in vivo would provide a means to distinguish hMSCs for clinical utility. hMSC function has been described as both regenerative and trophic through the production of bioactive factors. The regenerative component involves the multi-potentiality of hMSC progenitor differentiation. The secreted factors generated by the hMSCs are milieu and injury specific providing unique niches for responses in vivo. These bioactive factors are anti-scarring, angiogenic, anti-apoptotic as well as regenerative. Further, from an immunological standpoint, hMSC's can avoid host immune response, providing xenographic applications. To study the in vivo immuno-regulatory effectiveness of hMSCs, we used the ovalbumin challenge model of acute asthma. This is a quick 3 week in vivo pulmonary inflammation model with readily accessible ways of measuring effectiveness of hMSCs. Our data show that there is a direct correlation between the traditional ceramic cube score to hMSCs attenuation of cellular recruitment due to ovalbumin challenge. The results from these studies verify the in vivo immuno-modulator effectiveness of hMSCs and support the potential use of the ovalbumin model as an in vivo model of hMSC potency and efficacy. Our data also support future directions toward exploring hMSCs as an alternative therapeutic for the treatment of airway inflammation associated with asthma.

  15. In search of genetic constraints limiting the evolution of egg size: direct and correlated responses to artificial selection on a prenatal maternal effector.

    Science.gov (United States)

    Pick, J L; Hutter, P; Tschirren, B

    2016-06-01

    Maternal effects are an important force in nature, but the evolutionary dynamics of the traits that cause them are not well understood. Egg size is known to be a key mediator of prenatal maternal effects with an established genetic basis. In contrast to theoretical expectations for fitness-related traits, there is a large amount of additive genetic variation in egg size observed in natural populations. One possible mechanism for the maintenance of this variation is through genetic constraints caused by a shared genetic basis among traits. Here we created replicated, divergent selection lines for maternal egg investment in Japanese quail (Coturnix japonica) to quantify the role of genetic constraints in the evolution of egg size. We found that egg size responds rapidly to selection, accompanied by a strong response in all egg components. Initially, we observed a correlated response in body size, but this response declined over time, showing that egg size and body size can evolve independently. Furthermore, no correlated response in fecundity (measured as the proportion of days on which a female laid an egg) was observed. However, the response to selection was asymmetrical, with egg size plateauing after one generation of selection in the high but not the low investment lines. We attribute this pattern to the presence of genetic asymmetries, caused by directional dominance or unequal allele frequencies. Such asymmetries may contribute to the evolutionary stasis in egg size observed in natural populations, despite a positive association between egg size and fitness.

  16. Directly measuring spinal cord blood flow and spinal cord perfusion pressure via the collateral network: correlations with changes in systemic blood pressure.

    Science.gov (United States)

    Kise, Yuya; Kuniyoshi, Yukio; Inafuku, Hitoshi; Nagano, Takaaki; Hirayasu, Tsuneo; Yamashiro, Satoshi

    2015-01-01

    During thoracoabdominal surgery in which segmental arteries are sacrificed over a large area, blood supply routes from collateral networks have received attention as a means of avoiding spinal cord injury. The aim of this study was to investigate spinal cord blood supply through a collateral network by directly measuring spinal cord blood flow and spinal cord perfusion pressure experimentally. In beagle dogs (n = 8), the thoracoabdominal aorta and segmental arteries L1-L7 were exposed, and a temporary bypass was created for distal perfusion. Next, a laser blood flow meter was placed on the spinal dura mater in the L5 region to measure the spinal cord blood flow. The following were measured simultaneously when the direct blood supply from segmental arteries L2-L7 to the spinal cord was stopped: mean systemic blood pressure, spinal cord perfusion pressure (blood pressure within the aortic clamp site), and spinal cord blood flow supplied via the collateral network. These variables were then investigated for evidence of correlations. Positive correlations were observed between mean systemic blood pressure and spinal cord blood flow during interruption of segmental artery flow both with (r = 0.844, P flow with and without distal perfusion (r = 0.803, P network from outside the interrupted segmental arteries, and high systemic blood pressure (∼1.33-fold higher) was needed to obtain the preclamping spinal cord blood flow, whereas 1.68-fold higher systemic blood pressure was needed when distal perfusion was halted. Spinal cord blood flow is positively correlated with mean systemic blood pressure and spinal cord perfusion pressure under spinal cord ischemia caused by clamping a wide range of segmental arteries. In open and endovascular thoracic and thoracoabdominal surgery, elevating mean systemic blood pressure is a simple and effective means of increasing spinal cord blood flow, and measuring spinal cord perfusion pressure seems to be useful for monitoring

  17. Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

    Directory of Open Access Journals (Sweden)

    Maria A de Souza Silva

    2016-04-01

    drugs. Conclusions: The results (a demonstrate a direct central action of intranasally applied dopamine on the dopamine transporter in the dorsal striatum, indicating enhanced DA availability and (b provide first evidence of a Pavlovian conditioned DA response at the DA transporter. The latter results have relevance to understanding neurochemical mechanisms the underlie placebo action in the treatment of

  18. Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

    Science.gov (United States)

    de Souza Silva, Maria A; Mattern, Claudia; Decheva, Cvetana; Huston, Joseph P; Sadile, Adolfo G; Beu, Markus; Müller, H-W; Nikolaus, Susanne

    2016-01-01

    Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor. Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand. (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs. (a) demonstrate a direct central action of intranasally

  19. Langerhans cell-like dendritic cells stimulated with an adjuvant direct the development of Th1 and Th2 cells in vivo.

    Science.gov (United States)

    Matsui, K; Mori, A; Ikeda, R

    2015-10-01

    It is well known that Langerhans cells (LCs) work as the primary orchestrators in the polarization of immune responses towards a T helper type 1 (Th1) or Th2 milieu. In this study, we attempted to generate LCs from murine bone marrow cells and elicit a Th1- or Th2-prone immune response through the LCs after stimulation with Th1 or Th2 adjuvant. LCs were generated from murine bone marrow cells using granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and transforming growth factor (TGF)-β, and were obtained as I-A(d) positive cells. Mice were primed with Th1/Th2 adjuvant- and ovalbumin (OVA)-pulsed LCs and then given a booster injection of OVA 2 days later via the hind footpad. Five days after the OVA injection, the cytokine response in the draining popliteal lymph nodes was investigated by reverse transcription-polymerase chain reaction (RT-PCR) flow cytometry and enzyme-linked immunosorbent assay (ELISA). The generated LCs expressed typical LC surface markers, E-cadherin and Langerin, and were classified accordingly as LC-like dendritic cells (LDCs). Administration of Th1 adjuvant, cytosine-phosphate-guanosine (CpG)-DNA- and OVA-pulsed LDCs into the hind footpads of mice induced a Th1-prone immune response, as represented by up-regulation of IFN-γ production and down-regulation of IL-4 production in the lymph node cells. Conversely, Th2 adjuvant, histamine-pulsed LDCs induced a Th2-prone immune response, as represented by up-regulation of IL-4 production and down-regulation of IFN-γ production. These results suggest that LDCs may be used as a substitute for LCs and have the ability to induce the development of Th1 and Th2 cells in vivo. Our experimental system would therefore be useful for screening of inhibitors of Th1/Th2 differentiation in order to control allergic disease. © 2015 British Society for Immunology.

  20. Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo.

    Science.gov (United States)

    Tower, R J; Campbell, G M; Müller, M; Glüer, C C; Tiwari, S

    2015-05-01

    The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in

  1. Profiling the HER3/PI3K Pathway in Breast Tumors Using Proximity-Directed Assays Identifies Correlations between Protein Complexes and Phosphoproteins

    Science.gov (United States)

    Mukherjee, Ali; Badal, Youssouf; Nguyen, Xuan-Thao; Miller, Johanna; Chenna, Ahmed; Tahir, Hasan; Newton, Alicia; Parry, Gordon; Williams, Stephen

    2011-01-01

    Background The identification of patients for targeted antineoplastic therapies requires accurate measurement of therapeutic targets and associated signaling complexes. HER3 signaling through heterodimerization is an important growth-promoting mechanism in several tumor types and may be a principal resistance mechanism by which EGFR and HER2 expressing tumors elude targeted therapies. Current methods that can study these interactions are inadequate for formalin-fixed, paraffin-embedded (FFPE) tumor samples. Methodology and Principal Findings Herein, we describe a panel of proximity-directed assays capable of measuring protein-interactions and phosphorylation in FFPE samples in the HER3/PI3K/Akt pathway and examine the capability of these assays to inform on the functional state of the pathway. We used FFPE breast cancer cell line and tumor models for this study. In breast cancer cell lines we observe both ligand-dependent and independent activation of the pathway and strong correlations between measured activation of key analytes. When selected cell lines are treated with HER2 inhibitors, we not only observe the expected molecular effects based on mechanism of action knowledge, but also novel effects of HER2 inhibition on key targets in the HER receptor pathway. Significantly, in a xenograft model of delayed tumor fixation, HER3 phosphorylation is unstable, while alternate measures of pathway activation, such as formation of the HER3PI3K complex is preserved. Measurements in breast tumor samples showed correlations between HER3 phosphorylation and receptor interactions, obviating the need to use phosphorylation as a surrogate for HER3 activation. Significance This assay system is capable of quantitatively measuring therapeutically relevant responses and enables molecular profiling of receptor networks in both preclinical and tumor models. PMID:21297994

  2. Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls.

    Science.gov (United States)

    Kesisoglou, Filippos; Hermans, Andre; Neu, Colleen; Yee, Ka Lai; Palcza, John; Miller, Jessica

    2015-09-01

    Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its application to establishing dissolution specifications and in-process controls. Four different 40 mg batches were manufactured at different tablet hardnesses to produce distinct dissolution profiles. These batches were evaluated in a relative bioavailability clinical study in healthy volunteers. Although no differences were observed for the total exposure (AUC) of the different batches, a clear relationship between dissolution and Cmax was observed. A validated Multiple Level C IVIVC against Cmax was developed for the 10, 15, 20, 30, and 45 min dissolution time points and the tablet disintegration time. The relationship established between tablet tensile strength and dissolution was subsequently used to inform suitable tablet hardness ranges within acceptable Cmax limits. This is the first published report for a validated Multiple Level C IVIVC for an IR solid dispersion formulation demonstrating how this approach can facilitate Quality by Design in formulation development and help toward clinically relevant specifications and in-process controls. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  3. 3D Ultrashort TE MRI for Evaluation of Cartilaginous Endplate of Cervical Disk In Vivo: Feasibility and Correlation With Disk Degeneration in T2-Weighted Spin-Echo Sequence.

    Science.gov (United States)

    Kim, Yeo Ju; Cha, Jang Gyu; Shin, Yoon Sang; Chaudhari, Akshay S; Suh, Young Ju; Hwan Yoon, Seung; Gold, Garry E

    2018-05-01

    The purpose of this study was to evaluate the feasibility of 3D ultrashort TE (UTE) MRI in depicting the cartilaginous endplate (CEP) and its abnormalities and to investigate the association between CEP abnormalities and disk degeneration on T2-weighted spin-echo (SE) MR images in cervical disks in vivo. Eight healthy volunteers and 70 patients were examined using 3-T MRI with the 3D UTE cones trajectory technique (TR/TE, 16.1/0.032, 6.6). In the volunteer study, quantitative and qualitative assessments of CEP depiction were conducted for the 3D UTE and T2-weighted SE imaging. In the patient study, CEP abnormalities were analyzed. Intersequence agreement between the images obtained with the first-echo 3D UTE sequence and the images created by subtracting the second-echo from the first-echo 3D UTE sequence (subtracted 3D UTE) and the intraobserver and interobserver agreements for 3D UTE overall were also tested. The CEP abnormalities on the 3D UTE images correlated with the Miyazaki grading of the T2-weighted SE images. In the volunteer study, the CEP was well visualized on 3D UTE images but not on T2-weighted SE images (p evaluation of CEP abnormalities, intersequence agreements were substantial to almost perfect, intraobserver agreements were substantial to almost perfect, and interobserver agreements were moderate to substantial (p T2-weighted SE MRI.

  4. Jet-like correlations with direct-photon and neutral-pion triggers at √{sNN} = 200 GeV

    Science.gov (United States)

    Adamczyk, L.; Adkins, J. K.; Agakishiev, G.; Aggarwal, M. M.; Ahammed, Z.; Alekseev, I.; Anderson, D. M.; Aparin, A.; Arkhipkin, D.; Aschenauer, E. C.; Ashraf, M. U.; Attri, A.; Averichev, G. S.; Bai, X.; Bairathi, V.; Bellwied, R.; Bhasin, A.; Bhati, A. K.; Bhattarai, P.; Bielcik, J.; Bielcikova, J.; Bland, L. C.; Bordyuzhin, I. G.; Bouchet, J.; Brandenburg, J. D.; Brandin, A. V.; Bunzarov, I.; Butterworth, J.; Caines, H.; Calderón de la Barca Sánchez, M.; Campbell, J. M.; Cebra, D.; Chakaberia, I.; Chaloupka, P.; Chang, Z.; Chatterjee, A.; Chattopadhyay, S.; Chen, X.; Chen, J. H.; Cheng, J.; Cherney, M.; Christie, W.; Contin, G.; Crawford, H. J.; Das, S.; De Silva, L. C.; Debbe, R. R.; Dedovich, T. G.; Deng, J.; Derevschikov, A. A.; di Ruzza, B.; Didenko, L.; Dilks, C.; Dong, X.; Drachenberg, J. L.; Draper, J. E.; Du, C. M.; Dunkelberger, L. E.; Dunlop, J. C.; Efimov, L. G.; Engelage, J.; Eppley, G.; Esha, R.; Evdokimov, O.; Eyser, O.; Fatemi, R.; Fazio, S.; Federic, P.; Fedorisin, J.; Feng, Z.; Filip, P.; Fisyak, Y.; Flores, C. E.; Fulek, L.; Gagliardi, C. A.; Garand, D.; Geurts, F.; Gibson, A.; Girard, M.; Greiner, L.; Grosnick, D.; Gunarathne, D. S.; Guo, Y.; Gupta, S.; Gupta, A.; Guryn, W.; Hamad, A. I.; Hamed, A.; Haque, R.; Harris, J. W.; He, L.; Heppelmann, S.; Heppelmann, S.; Hirsch, A.; Hoffmann, G. W.; Horvat, S.; Huang, T.; Huang, B.; Huang, X.; Huang, H. Z.; Huck, P.; Humanic, T. J.; Igo, G.; Jacobs, W. W.; Jang, H.; Jentsch, A.; Jia, J.; Jiang, K.; Judd, E. G.; Kabana, S.; Kalinkin, D.; Kang, K.; Kauder, K.; Ke, H. W.; Keane, D.; Kechechyan, A.; Khan, Z. H.; Kikoła, D. P.; Kisel, I.; Kisiel, A.; Kochenda, L.; Koetke, D. D.; Kosarzewski, L. K.; Kraishan, A. F.; Kravtsov, P.; Krueger, K.; Kumar, L.; Lamont, M. A. C.; Landgraf, J. M.; Landry, K. D.; Lauret, J.; Lebedev, A.; Lednicky, R.; Lee, J. H.; Li, X.; Li, Y.; Li, C.; Li, W.; Li, X.; Lin, T.; Lisa, M. A.; Liu, F.; Liu, Y.; Ljubicic, T.; Llope, W. J.; Lomnitz, M.; Longacre, R. S.; Luo, X.; Luo, S.; Ma, G. L.; Ma, L.; Ma, Y. G.; Ma, R.; Magdy, N.; Majka, R.; Manion, A.; Margetis, S.; Markert, C.; Matis, H. S.; McDonald, D.; McKinzie, S.; Meehan, K.; Mei, J. C.; Miller, Z. W.; Minaev, N. G.; Mioduszewski, S.; Mishra, D.; Mohanty, B.; Mondal, M. M.; Morozov, D. A.; Mustafa, M. K.; Nandi, B. K.; Nasim, Md.; Nayak, T. K.; Nigmatkulov, G.; Niida, T.; Nogach, L. V.; Noh, S. Y.; Novak, J.; Nurushev, S. B.; Odyniec, G.; Ogawa, A.; Oh, K.; Okorokov, V. A.; Olvitt, D.; Page, B. S.; Pak, R.; Pan, Y. X.; Pandit, Y.; Panebratsev, Y.; Pawlik, B.; Pei, H.; Perkins, C.; Pile, P.; Pluta, J.; Poniatowska, K.; Porter, J.; Posik, M.; Poskanzer, A. M.; Pruthi, N. K.; Przybycien, M.; Putschke, J.; Qiu, H.; Quintero, A.; Ramachandran, S.; Ray, R. L.; Reed, R.; Ritter, H. G.; Roberts, J. B.; Rogachevskiy, O. V.; Romero, J. L.; Ruan, L.; Rusnak, J.; Rusnakova, O.; Sahoo, N. R.; Sahu, P. K.; Sakrejda, I.; Salur, S.; Sandweiss, J.; Sarkar, A.; Schambach, J.; Scharenberg, R. P.; Schmah, A. M.; Schmidke, W. B.; Schmitz, N.; Seger, J.; Seyboth, P.; Shah, N.; Shahaliev, E.; Shanmuganathan, P. V.; Shao, M.; Sharma, A.; Sharma, B.; Sharma, M. K.; Shen, W. Q.; Shi, Z.; Shi, S. S.; Shou, Q. Y.; Sichtermann, E. P.; Sikora, R.; Simko, M.; Singha, S.; Skoby, M. J.; Smirnov, D.; Smirnov, N.; Solyst, W.; Song, L.; Sorensen, P.; Spinka, H. M.; Srivastava, B.; Stanislaus, T. D. S.; Stepanov, M.; Stock, R.; Strikhanov, M.; Stringfellow, B.; Sumbera, M.; Summa, B.; Sun, Y.; Sun, Z.; Sun, X. M.; Surrow, B.; Svirida, D. N.; Tang, Z.; Tang, A. H.; Tarnowsky, T.; Tawfik, A.; Thäder, J.; Thomas, J. H.; Timmins, A. R.; Tlusty, D.; Todoroki, T.; Tokarev, M.; Trentalange, S.; Tribble, R. E.; Tribedy, P.; Tripathy, S. K.; Tsai, O. D.; Ullrich, T.; Underwood, D. G.; Upsal, I.; Van Buren, G.; van Nieuwenhuizen, G.; Vandenbroucke, M.; Varma, R.; Vasiliev, A. N.; Vertesi, R.; Videbæk, F.; Vokal, S.; Voloshin, S. A.; Vossen, A.; Wang, H.; Wang, F.; Wang, Y.; Wang, J. S.; Wang, G.; Wang, Y.; Webb, J. C.; Webb, G.; Wen, L.; Westfall, G. D.; Wieman, H.; Wissink, S. W.; Witt, R.; Wu, Y.; Xiao, Z. G.; Xie, W.; Xie, G.; Xin, K.; Xu, N.; Xu, Q. H.; Xu, Z.; Xu, J.; Xu, H.; Xu, Y. F.; Yang, S.; Yang, Y.; Yang, C.; Yang, Y.; Yang, Y.; Yang, Q.; Ye, Z.; Ye, Z.; Yi, L.; Yip, K.; Yoo, I.-K.; Yu, N.; Zbroszczyk, H.; Zha, W.; Zhang, Z.; Zhang, J. B.; Zhang, S.; Zhang, S.; Zhang, X. P.; Zhang, Y.; Zhang, J.; Zhang, J.; Zhao, J.; Zhong, C.; Zhou, L.; Zhu, X.; Zoulkarneeva, Y.; Zyzak, M.; STAR Collaboration

    2016-09-01

    Azimuthal correlations of charged hadrons with direct-photon (γdir) and neutral-pion (π0) trigger particles are analyzed in central Au+Au and minimum-bias p + p collisions at √{sNN} = 200 GeV in the STAR experiment. The charged-hadron per-trigger yields at mid-rapidity from central Au+Au collisions are compared with p + p collisions to quantify the suppression in Au+Au collisions. The suppression of the away-side associated-particle yields per γdir trigger is independent of the transverse momentum of the trigger particle (pTtrig), whereas the suppression is smaller at low transverse momentum of the associated charged hadrons (pTassoc). Within uncertainty, similar levels of suppression are observed for γdir and π0 triggers as a function of zT (≡ pTassoc/pTtrig). The results are compared with energy-loss-inspired theoretical model predictions. Our studies support previous conclusions that the lost energy reappears predominantly at low transverse momentum, regardless of the trigger energy.

  5. Classical density functional theory and the phase-field crystal method using a rational function to describe the two-body direct correlation function.

    Science.gov (United States)

    Pisutha-Arnond, N; Chan, V W L; Iyer, M; Gavini, V; Thornton, K

    2013-01-01

    We introduce a new approach to represent a two-body direct correlation function (DCF) in order to alleviate the computational demand of classical density functional theory (CDFT) and enhance the predictive capability of the phase-field crystal (PFC) method. The approach utilizes a rational function fit (RFF) to approximate the two-body DCF in Fourier space. We use the RFF to show that short-wavelength contributions of the two-body DCF play an important role in determining the thermodynamic properties of materials. We further show that using the RFF to empirically parametrize the two-body DCF allows us to obtain the thermodynamic properties of solids and liquids that agree with the results of CDFT simulations with the full two-body DCF without incurring significant computational costs. In addition, the RFF can also be used to improve the representation of the two-body DCF in the PFC method. Last, the RFF allows for a real-space reformulation of the CDFT and PFC method, which enables descriptions of nonperiodic systems and the use of nonuniform and adaptive grids.

  6. Defected red blood cell membranes and direct correlation with the uraemic milieu: the connection with the decreased red blood cell lifespan observed in haemodialysis patients

    International Nuclear Information System (INIS)

    Stamopoulos, D; Manios, E; Gogola, V; Grapsa, E; Bakirtzi, N

    2012-01-01

    Together with impaired production of erythropoietin and iron deficiency, the decreased lifespan of red blood cells (RBCs) is a main factor contributing to the chronic anaemia observed in haemodialysis (HD) patients. Atomic force microscopy is employed in this work to thoroughly survey the membrane of intact RBCs (iRBCs) of HD patients in comparison to those of healthy donors, aiming to obtain direct information on the structural status of RBCs that can be related to their decreased lifespan. We observed that the iRBC membrane of the HD patients is overpopulated with extended circular defects, termed ‘orifices’, that have typical dimension ranging between 0.2 and 1.0 μm. The ‘orifice’ index—that is, the mean population of ‘orifices’ per top membrane surface—exhibits a pronounced relative increase of order 54 ± 12% for the HD patients as compared to healthy donors. Interestingly, for the HD patients, the ‘orifice’ index, which relates to the structural status of the RBC membrane, correlates strongly with urea concentration, which is a basic index of the uraemic milieu. Thus, these results indicate that the uraemic milieu downgrades the structural status of the RBC membrane, possibly triggering biochemical processes that result in their premature elimination from the circulation. This process could decrease the lifespan of RBCs, as observed in HD patients. (paper)

  7. Jet-like correlations with direct-photon and neutral-pion triggers at sNN=200 GeV

    Directory of Open Access Journals (Sweden)

    L. Adamczyk

    2016-09-01

    Full Text Available Azimuthal correlations of charged hadrons with direct-photon (γdir and neutral-pion (π0 trigger particles are analyzed in central Au+Au and minimum-bias p+p collisions at sNN=200 GeV in the STAR experiment. The charged-hadron per-trigger yields at mid-rapidity from central Au+Au collisions are compared with p+p collisions to quantify the suppression in Au+Au collisions. The suppression of the away-side associated-particle yields per γdir trigger is independent of the transverse momentum of the trigger particle (pTtrig, whereas the suppression is smaller at low transverse momentum of the associated charged hadrons (pTassoc. Within uncertainty, similar levels of suppression are observed for γdir and π0 triggers as a function of zT (≡pTassoc/pTtrig. The results are compared with energy-loss-inspired theoretical model predictions. Our studies support previous conclusions that the lost energy reappears predominantly at low transverse momentum, regardless of the trigger energy.

  8. Characterization of Direct Current-Electrical Penetration Graph Waveforms and Correlation With the Probing Behavior of Matsumuratettix hiroglyphicus (Hemiptera: Cicadellidae), the Insect Vector of Sugarcane White Leaf Phytoplasma.

    Science.gov (United States)

    Roddee, J; Kobori, Y; Yorozuya, H; Hanboonsong, Y

    2017-06-01

    The leafhopper Matsumuratettix hiroglyphicus (Matsumura) (Hemiptera: Cicadellidae) is an important vector of phytoplasma causing white leaf disease in sugarcane. Thus, the aim of our study was to understand and describe the stylet-probing activities of this vector while feeding on sugarcane plants, by using direct current (DC) electrical penetration graph (EPG) monitoring. The EPG signals were classified into six distinct waveforms, according to amplitude, frequency, voltage level, and electrical origin of the observed traces during stylet penetration into the host plant tissues (probing). These six EPG waveforms of probing behavior comprise no stylet penetration (NP); stylet pathway through epidermis, mesophyll, and parenchymal cells (waveform A); contact at the bundle sheath layer (waveform B); salivation into phloem sieve elements (waveform C); phloem sap ingestion (waveform D); and short ingestion time of xylem sap (waveform E). The above waveform patterns were correlated with histological data of salivary sheath termini in plant tissue generated from insect stylet tips. The key findings of this study were that M. hiroglyphicus ingests the phloem sap at a relatively higher rate and for longer duration from any other cell type, suggesting that M. hiroglyphicus is mainly a phloem-feeder. Quantitative comparison of probing behavior revealed that females typically probe more frequently and longer in the phloem than males. Thus, females may acquire and inoculate greater amounts of phytoplasma than males, enhancing the efficiency of phytoplasma transmission and potentially exacerbating disease spreading. Overall, our study provides basic information on the probing behavior and transmission mechanism of M. hiroglyphicus. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Subcortical surgical anatomy of the lateral frontal region: human white matter dissection and correlations with functional insights provided by intraoperative direct brain stimulation: laboratory investigation.

    Science.gov (United States)

    De Benedictis, Alessandro; Sarubbo, Silvio; Duffau, Hugues

    2012-12-01

    Recent neuroimaging and surgical results support the crucial role of white matter in mediating motor and higher-level processing within the frontal lobe, while suggesting the limited compensatory capacity after damage to subcortical structures. Consequently, an accurate knowledge of the anatomofunctional organization of the pathways running within this region is mandatory for planning safe and effective surgical approaches to different diseases. The aim of this dissection study was to improve the neurosurgeon's awareness of the subcortical anatomofunctional architecture for a lateral approach to the frontal region, to optimize both resection and postoperative outcome. Ten human hemispheres (5 left, 5 right) were dissected according to the Klingler technique. Proceeding lateromedially, the main association and projection tracts as well as the deeper basal structures were identified. The authors describe the anatomy and the relationships among the exposed structures in both a systematic and topographical surgical perspective. Structural results were also correlated to the functional responses obtained during resections of infiltrative frontal tumors guided by direct cortico-subcortical electrostimulation with patients in the awake condition. The eloquent boundaries crucial for a safe frontal lobectomy or an extensive lesionectomy are as follows: 1) the motor cortex; 2) the pyramidal tract and premotor fibers in the posterior and posteromedial part of the surgical field; 3) the inferior frontooccipital fascicle and the superior longitudinal fascicle posterolaterally; and 4) underneath the inferior frontal gyrus, the head of the caudate nucleus, and the tip of the frontal horn of the lateral ventricle in the depth. Optimization of results following brain surgery, especially within the frontal lobe, requires a perfect knowledge of functional anatomy, not only at the cortical level but also with regard to subcortical white matter connectivity.

  10. Investigation of p,π+- charged particle correlations in π-C interactions at 5 GeV/c with emission of a particle in the backward direction

    International Nuclear Information System (INIS)

    Budagov, Yu.A.; Bayaramov, A.A.; Dzhelepov, V.P.; Dvornik, A.M.; Efremov, A.V.; Flyagin, V.B.; Lomakin, Yu.F.; Valkar, S.; Volodko, A.G.

    1976-01-01

    The π-C interactions at 5 GeV/c are studied. Angle correlation between two charged particles when a particle is emitted to the backward hemisphere has been investigated. Noticeable correlation appears if the angle between the two particles is 180 deg (lab.s.). It follows from this behaviour that the backward emission of a particle is due to the hard collision mechanism

  11. High local carcinogenic activity of 1,3-dimethyl-3-phenyl-1-nitrosourea and its inactivation by intravenous application in rats: comparison of in vivo findings with the in vitro direct and a combined in vivo/in vitro sister chromatid exchange assay in V79-E cells.

    Science.gov (United States)

    Thust, R; Martin, J; Mendel, J; Schreiber, D

    1987-02-01

    1,3-Dimethyl-3-phenyl-1-nitrosourea (DMPNU) is a very potent local carcinogen in rats and induces a 100% frequency of forestomach carcinomas when applied i.g. in two different dosages (10 applications of 0.3 or 0.03 mmol/kg body wt, respectively, at 14-day intervals), but it is inactive upon i.v. administration (10 applications of 0.03 mmol/kg body wt at 14-day intervals). By means of the direct sister chromatid exchange (SCE) assay in V79-E cells in the presence of rat blood, serum or plasma, respectively, as well as by a 'host-mediated' SCE assay (in which the agent was given i.v. to rats, and blood taken from the animal was checked for the recovery of genotoxic activity in cell cultures), we tried to elucidate the unexpected lack of carcinogenic activity of i.v. DMPNU. The direct SCE assay revealed a drastic reduction of DMPNU genotoxicity by rat blood, serum or plasma, respectively, which is abolished by the esterase inhibitor diisopropylfluorophosphate. In the 'host-mediated' SCE assay a genotoxic activity of DMPNU was only recoverable after a very high i.v. dose and when the blood added to the cell cultures had been taken from the rat heart within 1 min after DMPNU administration in vivo. 1-Methyl-1-nitrosourea (MNU) and 1-methyl-3-phenyl-1-nitrosourea (MPNU) were used as positive controls in these experiments and also gave a lower response than theoretically expected, but the relative loss of activity with the latter compounds was much lower than with DMPNU. It is assumed that an esterase in rat blood effectively decomposes this trisubstituted nitrosourea. Problems of the novel 'host-mediated' SCE assay are discussed.

  12. Site-directed mutagenesis, in vivo electroporation and mass spectrometry in search for determinants of the subcellular targeting of Rab7b paralogue in the model eukaryote Paramecium octaurelia.

    Science.gov (United States)

    Wyroba, E; Kwaśniak, P; Miller, K; Kobyłecki, K; Osińska, M

    2016-04-11

    Protein products of the paralogous genes resulting from the whole genome duplication may acquire new function. The role of post-translational modifications (PTM) in proper targeting of Paramecium Rab7b paralogue - distinct from that of Rab7a directly involved in phagocytosis - was studied using point mutagenesis, proteomic analysis and double immunofluorescence after in vivo electroporation of the mutagenized protein. Here we show that substitution of Thr200 by Ala200 resulted in diminished incorporation of [P32] by 37.4% and of 32 [C14-]UDP-glucose by 24%, respectively, into recombinant Rab7b_200 in comparison to the non-mutagenized control. Double confocal imaging revealed that Rab7b_200 was mistargeted upon electroporation into living cells contrary to non- mutagenized recombinant Rab7b correctly incorporated in the cytostome area. We identified the peptide ion at m/z=677.63+ characteristic for the glycan group attached to Thr200 in Rab7b using nano LC-MS/MS and comparing the peptide map of this protein with that after deglycosylation with the mixture of five enzymes of different specificity. Based on the mass of this peptide ion and quantitative radioactive assays with [P32]and  [C14-]UDP- glucose, the suggested composition of the adduct attached to Thr200 might be (Hex)1(HexNAc)1(Phos)3 or (HexNAc)1 (Deoxyhexose)1 (Phos)1 (HexA)1. These data indicate that PTM of Thr200 located in the hypervariable C-region of Rab7b in Paramecium is crucial for the proper localization/function of this protein. Moreover, these proteins differ also in other PTM: the number of phosphorylated amino acids in Rab7b is much higher than in Rab7a.

  13. Site‐directed mutagenesis, in vivo electroporation and mass spectrometry in search for determinants of the subcellular targeting of Rab7b paralogue in the model eukaryote Paramecium octaurelia

    Directory of Open Access Journals (Sweden)

    E. Wyroba

    2016-04-01

    Full Text Available Protein products of the paralogous genes resulting from the whole genome duplication may acquire new function. The role of post‐translational modifications (PTM in proper targeting of Paramecium Rab7b paralogue – distinct from that of Rab7a directly involved in phagocytosis ‐ was studied using point mutagenesis, proteomic analysis and double immunofluorescence after in vivo electroporation of the mutagenized protein. Here we show that substitution of Thr200 by Ala200 resulted in diminished incorporation of [P32] by 37.4% and of 32 [C14–]UDP‐glucose by 24%, respectively, into recombinant Rab7b_200 in comparison to the non‐mutagenized control. Double confocal imaging revealed that Rab7b_200 was mistargeted upon electroporation into living cells contrary to non‐ mutagenized recombinant Rab7b correctly incorporated in the cytostome area. We identified the peptide ion at m/z=677.63+ characteristic for the glycan group attached to Thr200 in Rab7b using nano LC‐MS/MS and comparing the peptide map of this protein with that after deglycosylation with the mixture of five enzymes of different specificity. Based on the mass of this peptide ion and quantitative radioactive assays with [P32]and  [C14‐]UDP‐ glucose, the suggested composition of the adduct attached to Thr200 might be (Hex1(HexNAc1(Phos3 or (HexNAc1 (Deoxyhexose1 (Phos1 (HexA1. These data indicate that PTM of Thr200 located in the hypervariable C‐region of Rab7b in Paramecium is crucial for the proper localization/function of this protein. Moreover, these proteins differ also in other PTM: the number of phosphorylated amino acids in Rab7b is much higher than in Rab7a.   

  14. Psychological Correlates of Teen Sexting in Three Countries--Direct and Indirect Associations between Self-Control, Self-Esteem, and Sexting

    Science.gov (United States)

    Wachs, Sebastian; Wright, Michelle F.; Wolf, Karsten D.

    2017-01-01

    The present study investigates frequency rates of sexting, and examines the associations of sexting with self-control and self-esteem as psychological correlates. The study sample included 1,818 adolescents between 12 and 17 years (M[subscript age] = 14.3, SD = 1.4) from Germany, the Netherlands, and Thailand. Across the three countries, the…

  15. The effect of radiofrequency ablation on different organs: Ex vivo and in vivo comparative studies

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yoo Na [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Rhim, Hyunchul, E-mail: rhimhc@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Choi, Dongil; Kim, Young-sun; Lee, Min Woo; Chang, Ilsoo; Lee, Won Jae; Lim, Hyo K. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of)

    2011-11-15

    Objective: The purposes of this study are to evaluate the ex vivo and in vivo efficacy of radiofrequency ablation (RFA) on different porcine tissues by the ablation of three different sites simultaneously. Materials and methods: A multichannel RFA system, enables three separate tumors to be ablated simultaneously, was used. RFA procedures were applied to normal porcine liver, kidney, and muscle together ex vivo (n = 12) and in vivo (n = 17). Pre-impedances, defined as baseline systemic impedances of tissues before beginning RFA, and the areas of ablation zones were measured and compared. Results: The areas of ablation zones among three organs had a significant difference in decreasing order as follows: liver, muscle, and kidney in the ex vivo study (p = 0.001); muscle, liver, and kidney in the in vivo study (p < 0.0001). The areas of ablation zones between ex vivo and in vivo had a significant difference in the liver and muscle (each p < 0.05). There was no significant correlation between the areas of ablation zones and pre-impedances in both studies. Conclusions: Renal RFA produced the smallest ablation zone in both in vivo and ex vivo studies. Muscular RFA demonstrated the largest ablation zone in the in vivo study, and hepatic RFA showed the largest ablation zone in the ex vivo study. This variability in the tissues should be considered for performing an optimized RFA for each organ site.

  16. General correlation and partial correlation analysis in finding interactions: with Spearman rank correlation and proportion correlation as correlation measures

    OpenAIRE

    WenJun Zhang; Xin Li

    2015-01-01

    Between-taxon interactions can be detected by calculating the sampling data of taxon sample type. In present study, Spearman rank correlation and proportion correlation are chosen as the general correlation measures, and their partial correlations are calculated and compared. The results show that for Spearman rank correlation measure, in all predicted candidate direct interactions by partial correlation, about 16.77% (x, 0-45.4%) of them are not successfully detected by Spearman rank correla...

  17. Stochastic resonance in a gain-noise model of a single-mode laser driven by pump noise and quantum noise with cross-correlation between real and imaginary parts under direct signal modulation

    Institute of Scientific and Technical Information of China (English)

    Chen Li-Mei; Cao Li; Wu Da-Jin

    2007-01-01

    Stochastic resonance (SR) is studied in a gain-noise model of a single-mode laser driven by a coloured pump noise and a quantum noise with cross-correlation between real and imaginary parts under a direct signal modulation. By using a linear approximation method, we find that the SR appears during the variation of signal-to-noise ratio (SNR)separately with the pump noise self-correlation time τ, the noise correlation coefficient between the real part and the imaginary part of the quantum noise λq, the attenuation coefficient γ and the deterministic steady-state intensity I0.In addition, it is found that the SR can be characterized not only by the dependence of SNR on the noise variables of τand λq, but also by the dependence of SNR on the laser system variables of γ and I0. Thus our investigation extends the characteristic quantity of SR proposed before.

  18. Radiation-induced bystander effects in vivo are sex specific

    International Nuclear Information System (INIS)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

    2008-01-01

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes

  19. Radiation-induced bystander effects in vivo are sex specific

    Energy Technology Data Exchange (ETDEWEB)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada); Kovalchuk, Olga [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada)], E-mail: olga.kovalchuk@uleth.ca

    2008-07-03

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

  20. Radiation-induced bystander effects in vivo are sex specific.

    Science.gov (United States)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

    2008-07-03

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naïve cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

  1. High p(T) direct photon and pi(0) triggered azimuthal jet correlations and measurement of k(T) for isolated direct photons in p plus p collisions at root s=200 GeV

    Czech Academy of Sciences Publication Activity Database

    Adare, A.; Afanasiev, S.; Aidala, C.; Kubart, J.; Mašek, L.; Mikeš, P.; Tomášek, Lukáš; Vrba, Václav

    2010-01-01

    Roč. 82, č. 7 (2010), "072001-1"-"072001-18" ISSN 1550-7998 R&D Projects: GA MŠk LC527; GA MŠk LA08015; GA MŠk LA08032 Institutional research plan: CEZ:AV0Z10100502 Keywords : jet: fragmentation * quark gluon: Compton scattering * scattering: heavy ion * photon: direct production * transverse momentum: high * PHENIX Subject RIV: BF - Elementary Particles and High Energy Physics Impact factor: 4.964, year: 2010 http://arxiv.org/pdf/arXiv:1006.1347

  2. Correlation spectrometer

    Science.gov (United States)

    Sinclair, Michael B [Albuquerque, NM; Pfeifer, Kent B [Los Lunas, NM; Flemming, Jeb H [Albuquerque, NM; Jones, Gary D [Tijeras, NM; Tigges, Chris P [Albuquerque, NM

    2010-04-13

    A correlation spectrometer can detect a large number of gaseous compounds, or chemical species, with a species-specific mask wheel. In this mode, the spectrometer is optimized for the direct measurement of individual target compounds. Additionally, the spectrometer can measure the transmission spectrum from a given sample of gas. In this mode, infrared light is passed through a gas sample and the infrared transmission signature of the gasses present is recorded and measured using Hadamard encoding techniques. The spectrometer can detect the transmission or emission spectra in any system where multiple species are present in a generally known volume.

  3. Imaging transcranial direct current stimulation (tDCS) of the prefrontal cortex-correlation or causality in stimulation-mediated effects?

    Science.gov (United States)

    Wörsching, Jana; Padberg, Frank; Ertl-Wagner, Birgit; Kumpf, Ulrike; Kirsch, Beatrice; Keeser, Daniel

    2016-10-01

    Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Study of direct single photons and correlated particles in proton-proton collisions at. sqrt. s = 62. 4 GeV

    Energy Technology Data Exchange (ETDEWEB)

    Angelis, A. L.S.; Besch, H. J.; Blumenfeld, B. J.

    1980-01-01

    As part of a study of large p/sub T/ phenomena in proton-proton collisions at the CERN ISR, a search for direct single photon production has been performed. A statistical division of the data sample into the fraction consistent with single photon production and the fraction due to multiphoton decays of neutral hadrons is accomplished by measuring the average conversion probability for the sample in a one radiation length thick converter. The fraction of the sample attributable to direct single photon production is < ..gamma../all > = 0.074 +- 0.012 for 6 GeV/c < p/sub T/ < 10 GeV/C, and < ..gamma../all > = 0.26 +- 0.04 for p/sub T/ > 10 GeV/c, with an additional systematic uncertainty of +- 0.05 for both values. It is found that single photons are produced preferentially with no accompanying particles on the same side. The ratio of positive to negative particles on the away side is found to be 3.7 +- 1.2 at high x/sub E/ and p/sub T/ for the single photon events.

  5. In vivo monitoring of skeletal aluminium burden in patients with renal failure

    International Nuclear Information System (INIS)

    Ellis, K.J.; Kelleher, S.; Raciti, A.; Savory, J.; Wills, M.

    1988-01-01

    In vivo neutron activation analysis was used to examine the total body and partial body (hand) aluminium levels in patients with end-stage renal failure. Patients maintained on chronic hemodialysis had higher mean body burdens of aluminium than did those clinically managed without dialysis. Approximately 70% of the patients examined indicated elevated levels of body or skeletal aluminium. A significant correlation was observed between the in vivo aluminium/calcium ratio obtained for the hand measurement and the increase in serum aluminium levels following a disferroxamine infusion test. The direct in vivo monitoring of hand Al/Ca values in patients may provide an alternate choice to bone biopsy for the detection of aluminium intoxication. (author) 15 refs.; 5 figs.; 2 tabs

  6. Monitoring and quantitative assessment of tumor burden using in vivo bioluminescence imaging

    Energy Technology Data Exchange (ETDEWEB)

    Chen, C.-C. [Cancer Research Division, National Health Research Institute, Miaoli 350, Taiwan (China); Hwang, Jeng-Jong [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jjhwang@ym.edu.tw; Ting, G. [Cancer Research Division, National Health Research Institute, Miaoli 350, Taiwan (China); Tseng, Y.-L. [Taiwan Liposome Company, Taipei 115, Taiwan (China); Wang, S.-J. [Department of Nuclear Medicine, Veterans General Hospital, Taipei 112, Taiwan (China); Whang-Peng, J. [Cancer Research Division, National Health Research Institute, Miaoli 350, Taiwan (China)

    2007-02-01

    In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating tumor growth. In this study, the kinetic of tumor growth has been assessed in C26 colon carcinoma bearing BALB/c mouse model. The ability of BLI to noninvasively quantitate the growth of subcutaneous tumors transplanted with C26 cells genetically engineered to stably express firefly luciferase and herpes simplex virus type-1 thymidine kinase (C26/tk-luc). A good correlation (R {sup 2}=0.998) of photon emission to the cell number was found in vitro. Tumor burden and tumor volume were monitored in vivo over time by quantitation of photon emission using Xenogen IVIS 50 and standard external caliper measurement, respectively. At various time intervals, tumor-bearing mice were imaged to determine the correlation of in vivo BLI to tumor volume. However, a correlation of BLI to tumor volume was observed when tumor volume was smaller than 1000 mm{sup 3} (R {sup 2}=0.907). {gamma} Scintigraphy combined with [{sup 131}I]FIAU was another imaging modality used for verifying the previous results. In conclusion, this study showed that bioluminescence imaging is a powerful and quantitative tool for the direct assay to monitor tumor growth in vivo. The dual reporter genes transfected tumor-bearing animal model can be applied in the evaluation of the efficacy of new developed anti-cancer drugs.

  7. Monitoring and quantitative assessment of tumor burden using in vivo bioluminescence imaging

    International Nuclear Information System (INIS)

    Chen, C.-C.; Hwang, Jeng-Jong; Ting, G.; Tseng, Y.-L.; Wang, S.-J.; Whang-Peng, J.

    2007-01-01

    In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating tumor growth. In this study, the kinetic of tumor growth has been assessed in C26 colon carcinoma bearing BALB/c mouse model. The ability of BLI to noninvasively quantitate the growth of subcutaneous tumors transplanted with C26 cells genetically engineered to stably express firefly luciferase and herpes simplex virus type-1 thymidine kinase (C26/tk-luc). A good correlation (R 2 =0.998) of photon emission to the cell number was found in vitro. Tumor burden and tumor volume were monitored in vivo over time by quantitation of photon emission using Xenogen IVIS 50 and standard external caliper measurement, respectively. At various time intervals, tumor-bearing mice were imaged to determine the correlation of in vivo BLI to tumor volume. However, a correlation of BLI to tumor volume was observed when tumor volume was smaller than 1000 mm 3 (R 2 =0.907). γ Scintigraphy combined with [ 131 I]FIAU was another imaging modality used for verifying the previous results. In conclusion, this study showed that bioluminescence imaging is a powerful and quantitative tool for the direct assay to monitor tumor growth in vivo. The dual reporter genes transfected tumor-bearing animal model can be applied in the evaluation of the efficacy of new developed anti-cancer drugs

  8. Diagnosis of lesions of the acetabular labrum, of the labral-chondral transition zone, and of the cartilage in femoroacetabular impingement: Correlation between direct magnetic resonance arthrography and hip arthroscopy.

    Science.gov (United States)

    Crespo Rodríguez, A M; de Lucas Villarrubia, J C; Pastrana Ledesma, M A; Millán Santos, I; Padrón, M

    2015-01-01

    To determine the sensitivity and accuracy of direct MR arthrography in the diagnosis of intra-articular lesions associated with femoroacetabular impingement. We used direct MR arthrography to study 51 patients with femoroacetabular impingement who underwent arthroscopic hip surgery. Surgery demonstrated 37 labral tears, 44 lesions in the labral-chondral transitional zone, and 40 lesions of the articular cartilage. We correlated the findings at preoperative direct MR arthrography with those of hip arthroscopy and calculated the sensitivity, specificity, positive predictive value, negative predictive value, and validity index for direct MR arthrography. The sensitivity and specificity of MR arthrography were 94.5% and 100%, respectively, for diagnosing labral tears, 100% and 87.5%, respectively, for diagnosing lesions of the labral-chondral transition zone, and 92.5% and 54.5%, respectively, for diagnosing lesions of the articular cartilage. The negative predictive value of MR arthrography for lesions of the labral-chondral transitional zone was 100%. MR arthrography accurately defined extensive lesions of the cartilage and the secondary osseous changes (the main factor in poor prognosis), although its diagnostic performance was not so good in small chondral lesions. In patients with femoroacetabular impingement, direct MR arthrography can adequately detect and characterize lesions of the acetabular labrum and of the labral-chondral transitional zone as well as extensive lesions of the articular cartilage and secondary osseous changes. Copyright © 2013 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

  9. Correlation of 3D Shift and 3D Tilt of the Patella in Patients With Recurrent Dislocation of the Patella and Healthy Volunteers: An In Vivo Analysis Based on 3-Dimensional Computer Models.

    Science.gov (United States)

    Yamada, Yuzo; Toritsuka, Yukiyoshi; Nakamura, Norimasa; Horibe, Shuji; Sugamoto, Kazuomi; Yoshikawa, Hideki; Shino, Konsei

    2017-11-01

    The concepts of lateral deviation and lateral inclination of the patella, characterized as shift and tilt, have been applied in combination to evaluate patellar malalignment in patients with patellar dislocation. It is not reasonable, however, to describe the 3-dimensional (3D) positional relation between the patella and the femur according to measurements made on 2-dimensional (2D) images. The current study sought to clarify the relation between lateral deviation and inclination of the patella in patients with recurrent dislocation of the patella (RDP) by redefining them via 3D computer models as 3D shift and 3D tilt. Descriptive laboratory study. Altogether, 60 knees from 56 patients with RDP and 15 knees from 10 healthy volunteers were evaluated. 3D shift and tilt of the patella were analyzed with 3D computer models created by magnetic resonance imaging scans obtained at 10° intervals of knee flexion (0°-50°). 3D shift was defined as the spatial distance between the patellar reference point and the midsagittal plane of the femur; it is expressed as a percentage of the interepicondylar width. 3D tilt was defined as the spatial angle between the patellar reference plane and the transepicondylar axis. Correlations between the 2 parameters were assessed with the Pearson correlation coefficient. The patients' mean Pearson correlation coefficient was 0.895 ± 0.186 (range, -0.073 to 0.997; median, 0.965). In all, 56 knees (93%) had coefficients >0.7 (strong correlation); 1 knee (2%), >0.4 (moderate correlation); 2 knees (3%), >0.2 (weak correlation); and 1 knee (2%), correlation). The mean correlation coefficient of the healthy volunteers was 0.645 ± 0.448 (range, -0.445 to 0.982; median, 0.834). A statistically significant difference was found in the distribution of the correlation coefficients between the patients and the healthy volunteers ( P = .0034). When distribution of the correlation coefficients obtained by the 3D analyses was compared with that by the 2

  10. Poly(2-ethyl-2-oxazoline) conjugates with doxorubicin for cancer therapy: In vitro and in vivo evaluation and direct comparison to poly[N-(2-hydroxypropyl)methacrylamide] analogues.

    Science.gov (United States)

    Sedlacek, Ondrej; Monnery, Bryn D; Mattova, Jana; Kucka, Jan; Panek, Jiri; Janouskova, Olga; Hocherl, Anita; Verbraeken, Bart; Vergaelen, Maarten; Zadinova, Marie; Hoogenboom, Richard; Hruby, Martin

    2017-11-01

    We designed and synthesized a new delivery system for the anticancer drug doxorubicin based on a biocompatible hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) carrier with linear architecture and narrow molar mass distribution. The drug is connected to the polymer backbone via an acid-sensitive hydrazone linker, which allows its triggered release in the tumor. The in vitro studies demonstrate successful cellular uptake of conjugates followed by release of the cytostatic cargo. In vivo experiments in EL4 lymphoma bearing mice revealed prolonged blood circulation, increased tumor accumulation and enhanced antitumor efficacy of the PEtOx conjugate having higher molecular weight (40 kDa) compared to the lower molecular weight (20 kDa) polymer. Finally, the in vitro and in vivo anti-cancer properties of the prepared PEtOx conjugates were critically compared with those of the analogous system based on the well-established PHPMA carrier. Despite the relatively slower intracellular uptake of PEtOx conjugates, resulting also in their lower cytotoxicity, there are no substantial differences in in vivo biodistribution and anti-cancer efficacy of both classes of polymer-Dox conjugates. Considering the synthetic advantages of poly(2-alkyl-2-oxazoline)s, the presented study demonstrates their potential as a versatile alternative to well-known PEO- or PHPMA-based materials for construction of drug delivery systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. In vitro and in vivo ocular safety and eye surface permanence determination by direct and Magnetic Resonance Imaging of ion-sensitive hydrogels based on gellan gum and kappa-carrageenan.

    Science.gov (United States)

    Fernández-Ferreiro, Anxo; González Barcia, Miguel; Gil-Martínez, María; Vieites-Prado, Alba; Lema, Isabel; Argibay, Barbara; Blanco Méndez, José; Lamas, Maria Jesus; Otero-Espinar, Francisco Javier

    2015-08-01

    Gellan gum, kappa-carrageenan and alginates are natural polysaccharides able to interact with different cations that can be used to elaborate ion-activated in situ gelling systems for different uses. The interaction between fluid solutions of these polysaccharides and cations presents into the tear made these biopolymers very interesting to elaborate ophthalmic drug delivery systems. The main purpose of this study is to evaluate the ability of mixtures of these polymers to obtain ion-activated ophthalmic in situ gelling systems with optimal properties for ocular use. To achieve this purpose different proportion of the biopolymers were analyzed using a mixture experimental design evaluating their transparency, mechanical properties and bioadhesion in the absence and presence of simulated tear fluid. Tear induces a rapid sol-to-gel phase transition in the mixtures forming a consistent hydrogel. The solution composed by 80% of gellan gum and 20% kappa-carrageenan showed the best mechanical and mucoadhesive properties. This mixture was evaluated for rheological behavior, microstructure, cytotoxicity, acute corneal irritancy, ex-vivo and in vivo ocular toxicity and in vivo corneal contact time using Magnetic Resonance Images (MRI) techniques. Result indicates that the system is safe at ophthalmic level and produces an extensive ocular permanence higher than 6h. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Synovial tissue hypoxia and inflammation in vivo.

    LENUS (Irish Health Repository)

    Ng, C T

    2012-02-01

    INTRODUCTION: Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO(2)) in patients with inflammatory arthritis with macroscopic\\/microscopic inflammation and local levels of proinflammatory mediators. METHODS: Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO(2) under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta), interferon gamma (IFNgamma), IL6, macrophage inflammatory protein 3alpha (MIP3alpha) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. RESULTS: The tPO(2) was 22.5 (range 3.2-54.1) mm Hg and correlated inversely with macroscopic synovitis (r=-0.421, p=0.02), sublining CD3 cells (-0.611, p<0.01) and sublining CD68 cells (r=-0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO(2) in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor alpha (TNFalpha), IL1beta, IFNgamma and MIP3alpha in patients with tPO(2) <20 mm Hg (all p values <0.05). CONCLUSIONS: This is the first study to show a direct in vivo correlation between synovial tPO(2), inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

  13. Thrombolytic effects of Douchi Fibrinolytic enzyme from Bacillus subtilis LD-8547 in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Yuan Jun

    2012-07-01

    Full Text Available Abstract Background Today, thrombosis is one of the most widely occurring diseases in modern life. Drugs with thrombolytic functions are the most effective methods in the treatment of thrombosis. Among them, Douchi fibrinolytic enzyme (DFE is a promising agent. DFE was isolated from Douchi, a typical and popular soybean-fermented food in China, and it can dissolve fibrin directly and efficiently. A strain, Bacillus subtilis LD-8547 produced DFE with high fibrinolytic activity has been isolated in our lab previously. Results In the study, thrombolytic effect of DFE from Bacillus subtilis LD-8547 was studied in vitro and in vivo systematically. The results showed that DFE played a significant role in thrombolysis and anticoagulation in vitro. And the thrombolytic effects correlated with DFE in a dose-dependent manner. In vivo, the acute toxicity assay showed that DFE had no obvious acute toxicity to mice. Test of carrageenan-induced thrombosis in mice indicated that the DFE significantly prevented tail thrombosis, and arterial thrombosis model test indicated that Douchi fibrinolytic enzyme DFE had thrombolytic effect on carotid thrombosis of rabbits in vivo. Other results in vivo indicated that DFE could increase bleeding and clotting time obviously. Conclusions The DFE isolated from Bacillus subtilis LD-8547 has obvious thrombolytic effects in vitro and in vivo. This function demonstrates that this enzyme can be a useful tool for preventing and treating clinical thrombus.

  14. Mechanical properties of porcine brain tissue in vivo and ex vivo estimated by MR elastography.

    Science.gov (United States)

    Guertler, Charlotte A; Okamoto, Ruth J; Schmidt, John L; Badachhape, Andrew A; Johnson, Curtis L; Bayly, Philip V

    2018-03-01

    The mechanical properties of brain tissue in vivo determine the response of the brain to rapid skull acceleration. These properties are thus of great interest to the developers of mathematical models of traumatic brain injury (TBI) or neurosurgical simulations. Animal models provide valuable insight that can improve TBI modeling. In this study we compare estimates of mechanical properties of the Yucatan mini-pig brain in vivo and ex vivo using magnetic resonance elastography (MRE) at multiple frequencies. MRE allows estimations of properties in soft tissue, either in vivo or ex vivo, by imaging harmonic shear wave propagation. Most direct measurements of brain mechanical properties have been performed using samples of brain tissue ex vivo. It has been observed that direct estimates of brain mechanical properties depend on the frequency and amplitude of loading, as well as the time post-mortem and condition of the sample. Using MRE in the same animals at overlapping frequencies, we observe that porcine brain tissue in vivo appears stiffer than porcine brain tissue samples ex vivo at frequencies of 100 Hz and 125 Hz, but measurements show closer agreement at lower frequencies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Macroeconomics correlations focused on foreign direct investments

    Directory of Open Access Journals (Sweden)

    Teodora ALECU

    2010-07-01

    Full Text Available This article is meant to reveal the way in which the theory of interconnections between systems and sub-systems partici-pating to the creation of economic value, which have been described by professor Paul Bran in his book Economics of Value is outlined in practice and how its analysis may help us to control the effects of the policies applied at the level of each macroeconomic sub-system.

  16. Correlation in atomic scattering

    International Nuclear Information System (INIS)

    McGuire, J.H.

    1987-01-01

    Correlation due to the Coulomb interactions between electrons in many-electron targets colliding with charged particles is formulated, and various approximate probability amplitudes are evaluated. In the limit that the electron-electron, 1/r/sub i//sub j/, correlation interactions are ignored or approximated by central potentials, the independent-electron approximation is obtained. Two types of correlations, or corrections to the independent-electron approximation due to 1/r/sub i//sub j/ terms, are identified: namely, static and scattering correlation. Static correlation is that contained in the asymptotic, e.g., bound-state, wave functions. Scattering correlation, arising from correlation in the scattering operator, is new and is considered in some detail. Expressions for a scattering correlation amplitude, static correlation or rearrangement amplitude, and independent-electron or direct amplitude are derived at high collision velocity and compared. At high velocities the direct and rearrangement amplitudes dominate. At very high velocities, ν, the rearrangement amplitude falls off less rapidly with ν than the direct amplitude which, however, is dominant as electron-electron correlation tends to zero. Comparisons with experimental observations are discussed

  17. A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage.

    Science.gov (United States)

    Lensing, Cody J; Adank, Danielle N; Wilber, Stacey L; Freeman, Katie T; Schnell, Sathya M; Speth, Robert C; Zarth, Adam T; Haskell-Luevano, Carrie

    2017-06-21

    Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro; however, studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH 2 , to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH 2 , on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an antiobesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2-8 h after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 h after administration (p < 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T 1/2 = 6.0 and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand's unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease

  18. Características morfológicas “in vivo” e da carcaça de cordeiros terminados em confinamento e suas correlações Morphological characteristics in vivo and carcass of lambs finished in feedlot and their correlations

    Directory of Open Access Journals (Sweden)

    Marcos Jun Iti Yokoo

    2010-09-01

    individually until they reached 32 kg of body weight, when they were slaughtered. It were realized morphological in vivo and carcass measurements, and ribeye area and fat thickness were measured for different methods. It were held some correlations between these measures. The roughage:concentrate ratio affected only the body condition, which was higher (3.85 in lambs that received 40% of roughafe in the diet, while the type of roughage affected conformation and carcass fat cover, higher in lambs fed with corn silage, by 3.65 and 3.50, respectively. The measurements of ribeye area and fat thickness obtained by different methods (ultrasound, caliper and planimeter were not affected by the roughage:concentrate ratio and type of roughage. The highest correlation among the methods for RA determination was between ultrasound and planimeter (0.56. The use of ultrasound to measure the ribeye area and fat thickness of lamb carcass was efficient, with similar values to those obtained directly from the carcass. It is recommended to conduct further studies assessing higher slaughter weights as used in this research, since the slaughter at 32kg for Ile de France breed did not provide the minimum fat thickness recommended for lamb carcasses, of 0.30cm

  19. Quantification of osmotic water transport in vivo using fluorescent albumin.

    Science.gov (United States)

    Morelle, Johann; Sow, Amadou; Vertommen, Didier; Jamar, François; Rippe, Bengt; Devuyst, Olivier

    2014-10-15

    Osmotic water transport across the peritoneal membrane is applied during peritoneal dialysis to remove the excess water accumulated in patients with end-stage renal disease. The discovery of aquaporin water channels and the generation of transgenic animals have stressed the need for novel and accurate methods to unravel molecular mechanisms of water permeability in vivo. Here, we describe the use of fluorescently labeled albumin as a reliable indicator of osmotic water transport across the peritoneal membrane in a well-established mouse model of peritoneal dialysis. After detailed evaluation of intraperitoneal tracer mass kinetics, the technique was validated against direct volumetry, considered as the gold standard. The pH-insensitive dye Alexa Fluor 555-albumin was applied to quantify osmotic water transport across the mouse peritoneal membrane resulting from modulating dialysate osmolality and genetic silencing of the water channel aquaporin-1 (AQP1). Quantification of osmotic water transport using Alexa Fluor 555-albumin closely correlated with direct volumetry and with estimations based on radioiodinated ((125)I) serum albumin (RISA). The low intraperitoneal pressure probably accounts for the negligible disappearance of the tracer from the peritoneal cavity in this model. Taken together, these data demonstrate the appropriateness of pH-insensitive Alexa Fluor 555-albumin as a practical and reliable intraperitoneal volume tracer to quantify osmotic water transport in vivo. Copyright © 2014 the American Physiological Society.

  20. In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

    Directory of Open Access Journals (Sweden)

    Gonzalo García-Rojo

    2017-07-01

    Full Text Available Acylpeptide hydrolase (APEH is a serine hydrolase that displays two catalytic activities, acting both as an exopeptidase toward short N-acylated peptides and as an endopeptidase toward oxidized peptides or proteins. It has been demonstrated that this enzyme can degrade monomers, dimers, and trimers of the Aβ1-40 peptide in the conditioned media of neuroblastoma cells. In a previous report, we showed that the specific inhibition of this enzyme by the organophosphate molecule dichlorvos (DDVP triggers an enhancement of long-term potentiation in rat hippocampal slices. In this study, we demonstrate that the same effect can be accomplished in vivo by sub-chronic treatment of young rats with a low dose of DDVP (0.1 mg/kg. Besides exhibiting a significant enhancement of LTP, the treated animals also showed improvements in parameters of spatial learning and memory. Interestingly, higher doses of DDVP such as 2 mg/kg did not prove to be beneficial for synaptic plasticity or behavior. Due to the fact that at 2 mg/kg we observed inhibition of both APEH and acetylcholinesterase, we interpret that in order to achieve positive effects on the measured parameters only APEH inhibition should be obtained. The treatment with both DDVP doses produced an increase in the endogenous concentration of Aβ1-40, although this was statistically significant only at the dose of 0.1 mg/kg. We propose that APEH represents an interesting pharmacological target for cognitive enhancement, acting through the modulation of the endogenous concentration of Aβ1-40.

  1. Overaccumulation of the chloroplast antisense RNA AS5 is correlated with decreased abundance of 5S rRNA in vivo and inefficient 5S rRNA maturation in vitro

    Science.gov (United States)

    Sharwood, Robert E.; Hotto, Amber M.; Bollenbach, Thomas J.; Stern, David B.

    2011-01-01

    Post-transcriptional regulation in the chloroplast is exerted by nucleus-encoded ribonucleases and RNA-binding proteins. One of these ribonucleases is RNR1, a 3′-to-5′ exoribonuclease of the RNase II family. We have previously shown that Arabidopsis rnr1-null mutants exhibit specific abnormalities in the expression of the rRNA operon, including the accumulation of precursor 23S, 16S, and 4.5S species and a concomitant decrease in the mature species. 5S rRNA transcripts, however, accumulate to a very low level in both precursor and mature forms, suggesting that they are unstable in the rnr1 background. Here we demonstrate that rnr1 plants overaccumulate an antisense RNA, AS5, that is complementary to the 5S rRNA, its intergenic spacer, and the downstream trnR gene, which encodes tRNAArg, raising the possibility that AS5 destabilizes 5S rRNA or its precursor and/or blocks rRNA maturation. To investigate this, we used an in vitro system that supports 5S rRNA and trnR processing. We show that AS5 inhibits 5S rRNA maturation from a 5S-trnR precursor, and shorter versions of AS5 demonstrate that inhibition requires intergenic sequences. To test whether the sense and antisense RNAs form double-stranded regions in vitro, treatment with the single-strand-specific mung bean nuclease was used. These results suggest that 5S–AS5 duplexes interfere with a sense-strand secondary structure near the endonucleolytic cleavage site downstream from the 5S rRNA coding region. We hypothesize that these duplexes are degraded by a dsRNA-specific ribonuclease in vivo, contributing to the 5S rRNA deficiency observed in rnr1. PMID:21148395

  2. In Vivo Imaging of Molecularly Targeted Phage

    Directory of Open Access Journals (Sweden)

    Kimberly A. Kelly

    2006-12-01

    Full Text Available Rapid identification of in vivo affinity ligands would have far-reaching applications for imaging specific molecular targets, in vivo systems imaging, and medical use. We have developed a high-throughput method for identifying and optimizing ligands to map and image biologic targets of interest in vivo. We directly labeled viable phage clones with far-red fluorochromes and comparatively imaged them in vivo by multichannel fluorescence ratio imaging. Using Secreted Protein Acidic and Rich in Cysteine (osteonectin and vascular cell adhesion molecule-1 as model targets, we show that: 1 fluorescently labeled phage retains target specificity on labeling; 2 in vivo distribution can be quantitated (detection thresholds of ~ 300 phage/mm3 tissue throughout the entire depth of the tumor using fluorescent tomographic imaging; and 3 fluorescently labeled phage itself can serve as a replenishable molecular imaging agent. The described method should find widespread application in the rapid in vivo discovery and validation of affinity ligands and, importantly, in the use of fluorochrome-labeled phage clones as in vivo imaging agents.

  3. Noninvasive visualization of in vivo release and intratumoral distribution of surrogate MR contrast agent using the dual MR contrast technique.

    Science.gov (United States)

    Onuki, Yoshinori; Jacobs, Igor; Artemov, Dmitri; Kato, Yoshinori

    2010-09-01

    A direct evaluation of the in vivo release profile of drugs from carriers is a clinical demand in drug delivery systems, because drug release characterized in vitro correlates poorly with in vivo release. The purpose of this study is to demonstrate the in vivo applicability of the dual MR contrast technique as a useful tool for noninvasive monitoring of the stability and the release profile of drug carriers, by visualizing in vivo release of the encapsulated surrogate MR contrast agent from carriers and its subsequent intratumoral distribution profile. The important aspect of this technique is that it incorporates both positive and negative contrast agents within a single carrier. GdDTPA, superparamagnetic iron oxide nanoparticles, and 5-fluorouracil were encapsulated in nano- and microspheres composed of poly(D,L-lactide-co-glycolide), which was used as a model carrier. In vivo studies were performed with orthotopic xenograft of human breast cancer. The MR-based technique demonstrated here has enabled visualization of the delivery of carriers, and release and intratumoral distribution of the encapsulated positive contrast agent. This study demonstrated proof-of-principle results for the noninvasive monitoring of in vivo release and distribution profiles of MR contrast agents, and thus, this technique will make a great contribution to the field. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  4. Spinodal Theory: A Common Rupturing Mechanism in Spinodal Dewetting and Surface Directed Phase Separation (Some Technological Aspects: Spatial Correlations and the Significance of Dipole-Quadrupole Interaction in Spinodal Dewetting)

    International Nuclear Information System (INIS)

    Singh, S.P.; Singh, S.P.

    2011-01-01

    The emerging structures in spinodal dewetting of thin nano films and spinodal decomposition of binary mixtures are found to be similar with certain differences attributed to the nonlinearities inherent in the wetting forces. This paper deals with the technological aspects of the spinodal processes by giving a brief account of the theory and to correlate the two phenomena termed as spinodal dewetting of thin nano films and surface-directed phase separation. The MC simulation micrographs at early stage of spinodal dewetting of a (linear) polymer film confined between two hard walls (using FENE potential between the beads on same chain and Morse potential between inter and intra chain beads) show similarities with surface-directed phase separation (using metropolis algorithm) in creation of holes. The spinodal dewetting is also criticized on the basis of global minimization of free energy emerging from dipole-quadrupole interactions. A novel molecular scale-driving mechanism coming from asymmetric interface formation in spinodal processes is also proposed. It can be believed that the modeling done with the films under confinement of two walls works as a classical mathematical Ansatz to the dipole-quadrupole interaction coming from quantum origins and giving rise to lateral interactions in the process reflecting a colossal behavior in thin nano films though weak in nature

  5. Spinodal Theory: A Common Rupturing Mechanism in Spinodal Dewetting and Surface Directed Phase Separation (Some Technological Aspects: Spatial Correlations and the Significance of Dipole-Quadrupole Interaction in Spinodal Dewetting

    Directory of Open Access Journals (Sweden)

    Satya Pal Singh

    2011-01-01

    Full Text Available The emerging structures in spinodal dewetting of thin nano films and spinodal decomposition of binary mixtures are found to be similar with certain differences attributed to the nonlinearities inherent in the wetting forces. This paper deals with the technological aspects of the spinodal processes by giving a brief account of the theory and to correlate the two phenomena termed as spinodal dewetting of thin nanofilms and surface-directed phase separation. The MC simulation micrographs at early stage of spinodal dewetting of a (linear polymer film confined between two hard walls (using FENE potential between the beads on same chain and Morse potential between inter and intra chain beads show similarities with surface-directed phase separation (using metropolis algorithm in creation of holes. The spinodal dewetting is also criticized on the basis of global minimization of free energy emerging from dipole-quadrupole interactions. A novel molecular scale-driving mechanism coming from asymmetric interface formation in spinodal processes is also proposed. It can be believed that the modeling done with the films under confinement of two walls works as a classical mathematical ansatz to the dipole-quadrupole interaction coming from quantum origins and giving rise to lateral interactions in the process reflecting a colossal behavior in thin nano films though weak in nature.

  6. In vivo analysis of the Notch receptor S1 cleavage.

    Directory of Open Access Journals (Sweden)

    Robert J Lake

    2009-08-01

    Full Text Available A ligand-independent cleavage (S1 in the extracellular domain of the mammalian Notch receptor results in what is considered to be the canonical heterodimeric form of Notch on the cell surface. The in vivo consequences and significance of this cleavage on Drosophila Notch signaling remain unclear and contradictory. We determined the cleavage site in Drosophila and examined its in vivo function by a transgenic analysis of receptors that cannot be cleaved. Our results demonstrate a correlation between loss of cleavage and loss of in vivo function of the Notch receptor, supporting the notion that S1 cleavage is an in vivo mechanism of Notch signal control.

  7. Passive in vivo elastography from skeletal muscle noise

    International Nuclear Information System (INIS)

    Sabra, Karim G.; Conti, Stephane; Roux, Philippe; Kuperman, W. A.

    2007-01-01

    Measuring the in vivo elastic properties of muscles (e.g., stiffness) provides a means for diagnosing and monitoring muscular activity. The authors demonstrated a passive in vivo elastography technique without an active external radiation source. This technique instead uses cross correlations of contracting skeletal muscle noise recorded with skin-mounted sensors. Each passive sensor becomes a virtual in vivo shear wave source. The results point to a low-cost, noninvasive technique for monitoring biomechanical in vivo muscle properties. The efficacy of the passive elastography technique originates from the high density of cross paths between all sensor pairs, potentially achieving the same sensitivity obtained from active elastography methods

  8. In vivo evaluation of biosensors volumetric bio-distribution for measurement of metabolic activity by X-ray correlation, fluorescence, Cerenkov image and radioisotope; Evaluacion in vivo de la biodistribucion volumetrica de biosensores para medicion de la actividad metabolica por correlacion de rayos X, fluorescencia, imagen Cerenkov y radioisotopica

    Energy Technology Data Exchange (ETDEWEB)

    Ramirez N, G. J.

    2016-07-01

    The aim of this study was to characterize the in vivo volumetric distribution of three folate based biosensors by different imaging modalities (X-ray, fluorescence, Cerenkov luminescence and radioisotopic imaging) through the development of a tri dimensional (3D) image reconstruction algorithm. The preclinical and multimodal Xtreme imaging system, with a Multimodal Animal Rotation System (Mars), was used to acquire bidimensional (2D) images, which were processed to obtain the 3D reconstruction. Images of mice at different times (biosensor distribution) were simultaneously obtained from the four imaging modalities. The filtered backprojection and inverse Radon transformation were used as main image-processing techniques. In the first instance, the algorithm developed in Mat lab was able to reconstruct in the 3D form the skeleton of the mice under study. Subsequently, the algorithm was able to get the volumetric profiles of {sup 99m}Tc-Folate-Bombesin (radioisotopic image), {sup 177}Lu-Folate-Bombesin (Cerenkov image), and FolateRSense 680 (fluorescence image) in the tumors and kidneys of the mice. No significant differences were detected between the volumetric quantifications using the standard measurement techniques and the quantifications obtained with the proposal made in this study, nor between the volumetric uptakes in the structures of interest. With the structures reconstructed in the 3D form, the fusion of anatomical (as the skeleton) and functional structures derived from the images of the biosensors uptake was achieved The imaging 3D reconstruction algorithm can be easily extrapolated to different 2D acquisition-type images. This characteristic flexibility of the algorithm developed in this study is an advantage in comparison to similar reconstruction methods. (Author)

  9. The in vivo biofilm

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Alhede, Maria; Alhede, Morten

    2013-01-01

    Bacteria can grow and proliferate either as single, independent cells or organized in aggregates commonly referred to as biofilms. When bacteria succeed in forming a biofilm within the human host, the infection often becomes very resistant to treatment and can develop into a chronic state. Biofilms...... have been studied for decades using various in vitro models, but it remains debatable whether such in vitro biofilms actually resemble in vivo biofilms in chronic infections. In vivo biofilms share several structural characteristics that differ from most in vitro biofilms. Additionally, the in vivo...... experimental time span and presence of host defenses differ from chronic infections and the chemical microenvironment of both in vivo and in vitro biofilms is seldom taken into account. In this review, we discuss why the current in vitro models of biofilms might be limited for describing infectious biofilms...

  10. Comparison of ex vivo stability of copeptin and vasopressin

    NARCIS (Netherlands)

    Heida, Judith E; Boesten, Lianne S M; Ettema, Esmée M; Muller Kobold, Anneke C.; Franssen, Casper F M; Gansevoort, Ron T; Zittema, Debbie

    BACKGROUND: Copeptin, part of the vasopressin precursor, is increasingly used as marker for vasopressin and is claimed to have better ex vivo stability. However, no study has directly compared the ex vivo stability of copeptin and vasopressin. METHODS: Blood of ten healthy volunteers was collected

  11. Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency.

    Science.gov (United States)

    Wang, X; Qiao, Y; Yang, L; Song, S; Han, Y; Tian, Y; Ding, M; Jin, H; Shao, F; Liu, A

    2017-11-01

    Leptin levels are increased in patients with systemic lupus erythematosus (SLE) but little is known on how this correlates with several disease characteristics including the frequency of regulatory T cells (Tregs). Here we compared serum leptin levels with frequency of circulating Tregs in 47 lupus patients vs. 25 healthy matched controls. Correlations with lupus disease activity were also analyzed, as well as Treg proliferation potential. It was found that leptin was remarkably increased in SLE patients as compared to controls, particularly in SLE patients with moderate and severe active SLE, and the increase correlated with disease activity. Importantly, increased leptin in lupus patients inversely correlated with the frequency of Tregs but not in controls, and leptin neutralization resulted in the expansion of Tregs ex vivo. Thus, hyperleptinemia in lupus patients correlates directly with disease activity and inversely with Treg frequency. The finding that leptin inhibition expands Tregs in SLE suggests possible inhibition of this molecule for an enhanced Treg function in the disease.

  12. Quantitative Analysis of HER2 Receptor Expression In Vivo by Near-Infrared Optical Imaging

    Directory of Open Access Journals (Sweden)

    Victor Chernomordik

    2010-07-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 overexpression in breast cancers is associated with poor prognosis and resistance to therapy. Current techniques for estimating this important characteristic use ex vivo assays that require tissue biopsies. We suggest a novel noninvasive method to characterize HER2 expression in vivo, using optical imaging, based on HER2-specific probes (albumin-binding domain–fused-(ZHER2:3422-Cys Affibody molecules [Affibody AB, Solna, Sweden], labeled with Alexa Fluor 750 [Molecular Probes, Invitrogen, Carlsbad, CA] that could be used concomitantly with HER2-targeted therapy. Subcutaneous tumor xenografts, expressing different levels of HER2, were imaged with a near-infrared fluorescence small-animal imaging system at several times postinjection of the probe. The compartmental ligand-receptor model was used to calculate HER2 expression from imaging data. Correlation between HER2 amplification/overexpression in tumor cells and parameters, directly estimated from the sequence of optical images, was observed (eg, experimental data for BT474 xenografts indicate that initial slope, characterizing the temporal dependence of the fluorescence intensity detected in the tumor, linearly depends on the HER2 expression, as measured ex vivo by an enzyme-linked immunosorbent assay for the same tumor. The results obtained from tumors expressing different levels of HER2 substantiate a similar relationship between the initial slope and HER2 amplification/overexpression. This work shows that optical imaging, combined with mathematical modeling, allows noninvasive monitoring of HER2 expression in vivo.

  13. Accounting for data variability, a key factor in in vivo/in vitro relationships: application to the skin sensitization potency (in vivo LLNA versus in vitro DPRA) example.

    Science.gov (United States)

    Dimitrov, S; Detroyer, A; Piroird, C; Gomes, C; Eilstein, J; Pauloin, T; Kuseva, C; Ivanova, H; Popova, I; Karakolev, Y; Ringeissen, S; Mekenyan, O

    2016-12-01

    When searching for alternative methods to animal testing, confidently rescaling an in vitro result to the corresponding in vivo classification is still a challenging problem. Although one of the most important factors affecting good correlation is sample characteristics, they are very rarely integrated into correlation studies. Usually, in these studies, it is implicitly assumed that both compared values are error-free numbers, which they are not. In this work, we propose a general methodology to analyze and integrate data variability and thus confidence estimation when rescaling from one test to another. The methodology is demonstrated through the case study of rescaling the in vitro Direct Peptide Reactivity Assay (DPRA) reactivity to the in vivo Local Lymph Node Assay (LLNA) skin sensitization potency classifications. In a first step, a comprehensive statistical analysis evaluating the reliability and variability of LLNA and DPRA as such was done. These results allowed us to link the concept of gray zones and confidence probability, which in turn represents a new perspective for a more precise knowledge of the classification of chemicals within their in vivo OR in vitro test. Next, the novelty and practical value of our methodology introducing variability into the threshold optimization between the in vitro AND in vivo test resides in the fact that it attributes a confidence probability to the predicted classification. The methodology, classification and screening approach presented in this study are not restricted to skin sensitization only. They could be helpful also for fate, toxicity and health hazard assessment where plenty of in vitro and in chemico assays and/or QSARs models are available. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  14. In vivo studies of opiate receptors

    International Nuclear Information System (INIS)

    Frost, J.J.; Dannals, R.F.; Duelfer, T.; Burns, H.D.; Ravert, H.T.; Langstroem, B.; Balasubramanian, V.; Wagner, H.N. Jr.

    1984-01-01

    To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented

  15. In vivo studies of opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Frost, J.J.; Dannals, R.F.; Duelfer, T.; Burns, H.D.; Ravert, H.T.; Langstroem, B.; Balasubramanian, V.; Wagner, H.N. Jr.

    1984-01-01

    To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented.

  16. Desmosomes In Vivo

    Directory of Open Access Journals (Sweden)

    David Garrod

    2010-01-01

    Full Text Available The structure, function, and regulation of desmosomal adhesion in vivo are discussed. Most desmosomes in tissues exhibit calcium-independent adhesion, which is strongly adhesive or “hyperadhesive”. This is fundamental to tissue strength. Almost all studies in culture are done on weakly adhesive, calcium-dependent desmosomes, although hyperadhesion can be readily obtained in confluent cell culture. Calcium dependence is a default condition in vivo, found in wounds and embryonic development. Hyperadhesion appears to be associated with an ordered arrangement of the extracellular domains of the desmosomal cadherins, which gives rise to the intercellular midline identified in ultrastructural studies. This in turn probably depends on molecular order in the desmosomal plaque. Protein kinase C downregulates hyperadhesion and there is preliminary evidence that it may also be regulated by tyrosine kinases. Downregulation of desmosomes in vivo may occur by internalisation of whole desmosomes rather than disassembly. Hyperadhesion has implications for diseases such as pemphigus.

  17. A Tat-conjugated Peptide Nucleic Acid Tat-PNA-DR Inhibits Hepatitis B Virus Replication In Vitro and In Vivo by Targeting LTR Direct Repeats of HBV RNA

    Science.gov (United States)

    Zeng, Zhengyang; Han, Shisong; Hong, Wei; Lang, Yange; Li, Fangfang; Liu, Yongxiang; Li, Zeyong; Wu, Yingliang; Li, Wenxin; Zhang, Xianzheng; Cao, Zhijian

    2016-01-01

    Hepatitis B virus (HBV) infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell-penetrating peptide-conjugated peptide nucleic acid (PNA), Tat-PNA-DR, was designed to target the direct repeat (DR) sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg), HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT) and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC). Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA-DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV. PMID:26978579

  18. A Tat-conjugated Peptide Nucleic Acid Tat-PNA-DR Inhibits Hepatitis B Virus Replication In Vitro and In Vivo by Targeting LTR Direct Repeats of HBV RNA

    Directory of Open Access Journals (Sweden)

    Zhengyang Zeng

    2016-01-01

    Full Text Available Hepatitis B virus (HBV infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell-penetrating peptide-conjugated peptide nucleic acid (PNA, Tat-PNA-DR, was designed to target the direct repeat (DR sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg, HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC. Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA-DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV.

  19. Particle correlations at ALICE

    Energy Technology Data Exchange (ETDEWEB)

    Erazmus, B.; Lednicky, R.; Lyuboshitz, V.; Martin, L.; Mikhailov, K.; Pluta, J.; Sinyukov, Yu.; Stavinsky, A.; Werner, K

    1998-12-31

    The ability of the ALICE detector for determination of the space-time characteristics of particle production in heavy-ion collisions at LHC from measurements of the correlation functions of identical and non-identical particles at small relative velocities is discussed. The possibility to use the correlations of non-identical particles for a direct determination of the delays in emission of various particle species at time scales as small as 10{sup -23} s is demonstrated. The influence of the multi-boson effects on pion multiplicities, single-pion spectra and two-pion correlation functions is discussed. (author) 63 refs.

  20. In-vivo quantitative measurement

    International Nuclear Information System (INIS)

    Ito, Takashi

    1992-01-01

    So far by positron CT, the quantitative analyses of oxygen consumption rate, blood flow distribution, glucose metabolic rate and so on have been carried out. The largest merit of using the positron CT is the observation and verification of mankind have become easy. Recently, accompanying the rapid development of the mapping tracers for central nervous receptors, the observation of many central nervous receptors by the positron CT has become feasible, and must expectation has been placed on the elucidation of brain functions. The conditions required for in vitro processes cannot be realized in strict sense in vivo. The quantitative measurement of in vivo tracer method is carried out by measuring the accumulation and movement of a tracer after its administration. The movement model of the mapping tracer for central nervous receptors is discussed. The quantitative analysis using a steady movement model, the measurement of dopamine receptors by reference method, the measurement of D 2 receptors using 11C-Racloprode by direct method, and the possibility of measuring dynamics bio-reaction are reported. (K.I.)

  1. A comparison of in vivo and in vitro methods for determining availability of iron from meals

    International Nuclear Information System (INIS)

    Schricker, B.R.; Miller, D.D.; Rasmussen, R.R.; Van Campen, D.

    1981-01-01

    A comparison is made between in vitro and human and rat in vivo methods for estimating food iron availability. Complex meals formulated to replicate meals used by Cook and Monsen (Am J Clin Nutr 1976;29:859) in human iron availability trials were used in the comparison. The meals were prepared by substituting pork, fish, cheese, egg, liver, or chicken for beef in two basic test meals and were evaluated for iron availability using in vitro and rat in vivo methods. When the criterion for comparison was the ability to show statistically significant differences between iron availability in the various meals, there was substantial agreement between the in vitro and human in vivo methods. There was less agreement between the human in vivo and the rat in vivo and between the in vivo and the rat in vivo and between the in vitro and the rat in vivo methods. Correlation analysis indicated significant agreement between in vitro and human in vivo methods. Correlation between the rat in vivo and human in vivo methods were also significant but correlations between the in vitro and rat in vivo methods were less significant and, in some cases, not significant. The comparison supports the contention that the in vitro method allows a rapid, inexpensive, and accurate estimation of nonheme iron availability in complex meals

  2. Formulation and In vitro/In vivo Evaluation of Sustained Release ...

    African Journals Online (AJOL)

    Conclusion: A fair correlation between in vitro dissolution and in vivo data was found. The results obtained indicate successful development of a sustained release formulation of diltiazem. Keywords: Diltiazem, Matrix tablet, Hydroxypropyl methylcellulose Eudragit, In vitro/in vivo correlation, Optimization ...

  3. Biopharmaceutical Classification System in Invitro/ In-vivo Correlation

    African Journals Online (AJOL)

    Drug development is a very laborious and expensive process. One of the major reasons for failure during the clinical phases of drug development is inadequate pharmacokinetic data on the drug candidate. Therefore, it would be advantageous if the pharmacokinetic properties of drug candidates be predicted beforehand.

  4. Pair Correlation Function Integrals

    DEFF Research Database (Denmark)

    Wedberg, Nils Hejle Rasmus Ingemar; O'Connell, John P.; Peters, Günther H.J.

    2011-01-01

    We describe a method for extending radial distribution functions obtained from molecular simulations of pure and mixed molecular fluids to arbitrary distances. The method allows total correlation function integrals to be reliably calculated from simulations of relatively small systems. The long......-distance behavior of radial distribution functions is determined by requiring that the corresponding direct correlation functions follow certain approximations at long distances. We have briefly described the method and tested its performance in previous communications [R. Wedberg, J. P. O’Connell, G. H. Peters......, and J. Abildskov, Mol. Simul. 36, 1243 (2010); Fluid Phase Equilib. 302, 32 (2011)], but describe here its theoretical basis more thoroughly and derive long-distance approximations for the direct correlation functions. We describe the numerical implementation of the method in detail, and report...

  5. Microstructural parcellation of the human cerebral cortex – from Brodmann's post-mortem map to in vivo mapping with high-field magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Stefan Geyer

    2011-02-01

    Full Text Available The year 2009 marked the 100th anniversary of the publication of the famous brain map of Korbinian Brodmann. Although a "classic" guide to microanatomical parcellation of the cerebral cortex, it is – from today's state-of-the-art neuroimaging perspective – problematic to use Brodmann's map as a structural guide to functional units in the cortex. In this article we discuss some of the reasons, especially the problematic compatibility of the "post-mortem world" of microstructural brain maps with the "in vivo world" of neuroimaging. We conclude with some prospects for the future of in vivo structural brain mapping: a new approach which has the enormous potential to make direct correlations between microstructure and function in living human brains: "in vivo Brodmann mapping" with high-field magnetic resonance imaging.

  6. Oncology In Vivo Data Integration for Hypothesis Generation

    Directory of Open Access Journals (Sweden)

    Wei Jia

    2012-06-01

    Full Text Available AstraZeneca’s Oncology in vivo data integration platform brings multidimensional data from animal model efficacy, pharmacokinetic and pharmacodynamic data to animal model profiling data and public in vivo studies. Using this platform, scientists can cluster model efficacy and model profiling data together, quickly identify responder profiles and correlate molecular characteristics to pharmacological response. Through meta-analysis, scientists can compare pharmacology between single and combination treatments, between different drug scheduling and administration routes.

  7. La Edad Se Correlaciona Directamente con la Fuerza de los Estereotipos de Género: Evidencia Obtenida en una Tarea de Memoria de Reconocimiento Age Correlates Directly With Gender Stereotype Strength: Evidence From a Recognition Memory Task

    Directory of Open Access Journals (Sweden)

    Sergio E Chaigneau

    2012-11-01

    Full Text Available Varias teorías predicen una correlación directa entre edad y estereotipos. Sin embargo, los estudios que muestran este efecto típicamente comparan adultos mayores (> 55-60 años con adultos jóvenes. Por contraste, en el estudio que se reporta participaron 79 individuos de 18 a 60 años de nivel socioeconómico alto, alumnos y profesores de una universidad privada en Santiago de Chile que respondieron a una invitación masiva. El trabajo se enfoca en los estereotipos de género, preguntando si los adultos medios (k 40 años también muestran un nivel más elevado de estereotipos que los jóvenes. Se utilizó una tarea de memoria en la que los participantes leían listas de oraciones que describían a hombres y mujeres realizando actividades estereotipadas y neutras, y debían luego reconocerlas en listas que incluían además oraciones distractoras. Los datos se analizaron con ANOVAs mixtos, revelando que la muestra como un todo exhibía un mejor rendimiento de memoria para estímulos estereotipados para género que para estímulos neutros y que, como se predijo, los adultos medios mostraron un efecto casi 2 veces mayor que los jóvenes.Several theories predict a direct correlation between age and stereotypes. However, studies that show this effect typically compare older adults (> 55-60 years of age with young adults. Contrastingly, in the current study participants were 79 high-SES individuals between 18 and 60 years of age, students and professors of a private university in Santiago de Chile, who responded to a mass email. The work reported here focuses on gender stereotypes and asks whether middle aged adults (k 40 years of age also show a higher level of stereotypes than adolescents and young adults. A recognition memory task was used, in which participants read lists of sentences describing men and women carrying out stereotyped and neutral daily activities, and then had to recognize them intermixed with distractor sentences. Data were

  8. Pharmaceutical applications of in vivo EPR

    International Nuclear Information System (INIS)

    Maeder, K.

    1998-01-01

    The aim of this article is to discuss the applications of in vivo EPR in the field of pharmacy. In addition to direct detection of free radical metabolites and measurement of oxygen, EPR can be used to characterize the mechanisms of drug release from biodegradable polymers. Unique information about drug concentration, the microenvironment (viscosity, polarity, pH) and biodistribution (by localized measurement or EPR Imaging) can be obtained. (author)

  9. Fusing in vivo and ex vivo NMR sources of information for brain tumor classification

    International Nuclear Information System (INIS)

    Croitor-Sava, A R; Laudadio, T; Sima, D M; Van Huffel, S; Martinez-Bisbal, M C; Celda, B; Piquer, J; Heerschap, A

    2011-01-01

    In this study we classify short echo-time brain magnetic resonance spectroscopic imaging (MRSI) data by applying a model-based canonical correlation analyses algorithm and by using, as prior knowledge, multimodal sources of information coming from high-resolution magic angle spinning (HR-MAS), MRSI and magnetic resonance imaging. The potential and limitations of fusing in vivo and ex vivo nuclear magnetic resonance sources to detect brain tumors is investigated. We present various modalities for multimodal data fusion, study the effect and the impact of using multimodal information for classifying MRSI brain glial tumors data and analyze which parameters influence the classification results by means of extensive simulation and in vivo studies. Special attention is drawn to the possibility of considering HR-MAS data as a complementary dataset when dealing with a lack of MRSI data needed to build a classifier. Results show that HR-MAS information can have added value in the process of classifying MRSI data

  10. In vivo X-ray fluorescence analysis

    International Nuclear Information System (INIS)

    Ahlgren, L.

    1980-02-01

    Measurements on five occupationally exposed persons have shown that it is possible to use X-ray fluorescence analysis for in vivo measurements of lead in the skeleton. The technique for calibrating in vivo X-ray fluorescence measurements of lead in bone tissue has been studied in detail and a two-component phantom simulating the bone and the soft tissue parts of the finger constructed. The technique has been used for in vivo measurements on 22 occupationally exposed persons. The minimum detectable concentration of lead in fingerbones was found to be around 20 μg x g -1 . The lead concentrations in their skeletons and blood were compared: the correlation was poor. The variations in lead concentrations in the skeleton have been studied in occupationally exposed persons and in samples from archaeological skeletons. The sensitivity and the minimum detectable concentration of cadmium in the kidney cortex in in vivo measurements has been studied by measurements on kidney models. The minimum detectable concentration was 20 μg x g -1 at a skin-kidney distance of 30 mm and 40 μg x g -1 at 40 mm. Five persons occupationally exposed were studied. (Author)

  11. Cannabinoid antagonist in nanostructured lipid carriers (NLCs): design, characterization and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Elisabetta; Ravani, Laura [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Drechsler, Markus [BIMF/Soft Matter Electron Microscopy, University of Bayreuth (Germany); Mariani, Paolo [Department of Life and Environmental Sciences and CNISM, Università Politecnica delle Marche, I-60100 Ancona (Italy); Contado, Catia [Department of Chemical and Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Ruokolainen, Janne [Department of Applied Physics, Aalto University, 00076 Aalto (Finland); Ratano, Patrizia; Campolongo, Patrizia [Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Roma (Italy); Trezza, Viviana [Department of Science, Roma Tre University, 00146 Roma (Italy); Nastruzzi, Claudio, E-mail: nas@unife.it [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Cortesi, Rita [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy)

    2015-03-01

    This study describes the preparation, characterization, and in vivo evaluation in rats of nanostructured lipid carriers (NLCs) encapsulating rimonabant (RMN) as prototypical cannabinoid antagonist. A study was conducted in order to optimize NLC production by melt and ultrasonication method. NLCs were prepared by alternatively adding the lipid phase into the aqueous one (direct protocol) or the aqueous phase into the lipid one (reverse protocol). RMN-NLCs have been characterized by cryogenic transmission electron microscopy (cryo-TEM), X-ray, photon correlation spectroscopy (PCS) and sedimentation field flow fractionation (SdFFF). Reverse NLCs were treated with polysorbate 80. RMN release kinetics have been determined in vitro by dialysis method. In vivo RMN biodistribution in rats was evaluated after intranasal (i.n.) administration of reverse RMN-NLC. The reverse protocol enabled to prevent the lost of lipid phase and to achieve higher RMN encapsulation efficacy (EE) with respect to the direct protocol (98% w/w versus 67% w/w). The use of different protocols did not affect NLC morphology and dimensional distribution. An in vitro dissolutive release rate of RMN was calculated. The in vivo data indicate that i.n. administration of RMN by reverse NLC treated with polysorbate 80 increased RMN concentration in the brain with respect to the drug in solution. The nanoencapsulation protocol presented here appears as an optimal strategy to improve the low solubility of cannabinoid compounds in an aqueous system suitable for in vivo administration. - Highlights: • Rimonabant (RMN) can be encapsulated in nanostructured lipid carriers (NLCs). • Nanoencapsulation improves RMN solubility in a stable physiologic aqueous formulation. • RMN is released in vitro from NLC by a controlled dissolutive release modality. • I.n. administration leads to higher RMN concentration in the brain with respect to plasma. • NLC increases RMN concentration in the brain with respect to

  12. Evaluation of drug penetration into the brain: a double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier

    International Nuclear Information System (INIS)

    Josserand, V.; Jego, B.; Duconge, F.; Tavitian, B.; Pelerin, H.; Ezan, E.; Mabondzo, A.; Bruin, B. de; Kuhnast, B.; Dolle, F.

    2004-01-01

    The blood brain barrier (BBB) passage of a set of radiopharmaceuticals candidates was measured both in vitro using a newly developed co-culture based model of human BBB and in vivo by positron emission tomography (PET). MATERIAL and METHODS: As an in vitro BBB model, a co-culture of primary human brain endothelial cells and primary human astrocytes was used. Dynamic PET studies were performed simultaneously on 4 anesthetized rats with the EXACT HR+ camera. Volumes of interest (VOI) were manually defined on the tomographic images in order to determine the pharmacokinetics of the compounds in various organs, including brain. The in vivo input function was measured by radioactivity counting of arterial blood samples. A two-compartment model analysis was used to compute the exchanging rate constants between blood and brain and to calculate the in vivo permeability coefficient. RESULTS: There was an excellent correlation between the in vitro and in vivo permeability coefficients (r = 0.99; p < 0.001) as well as between the in vivo distribution volume and the in vitro efflux /influx permeability coefficients ratio (r = 0.76). CONCLUSION: This double study evidenced a close relationship between the in vitro and the in vivo approaches for the assessment of the BBB passage. Hence, small animal PET imaging appeared suitable to screen drugs or radiopharmaceuticals candidates aimed at cerebral targets directly in the real-life situation in vivo. (author)

  13. Magnetic resonance imaging of trabecular and cortical bone in mice: comparison of high resolution in vivo and ex vivo MR images with corresponding histology

    International Nuclear Information System (INIS)

    Weber, Michael H.; Sharp, Jonathan C.; Latta, Peter; Sramek, Milos; Hassard, H. Thomas; Orr, F. William

    2005-01-01

    Measurements of bone morphometry and remodeling have been shown to reflect bone strength and can be used to diagnose degenerative bone disease. In this study, in vivo and ex vivo magnetic resonance imaging (MRI) techniques to assess trabecular and cortical bone properties have been compared to each other and to histology as a novel means for the quantification of bone. Femurs of C57Bl/6 mice were examined both in vivo and ex vivo on an 11.7 T MRI scanner, followed by histologic processing and morphometry. A thresholding analysis technique was applied to the MRI images to generate contour lines and to delineate the boundaries between bone and marrow. Using MRI, an optimal correlation with histology was obtained with an in vivo longitudinal sectioned short echo time gradient-echo versus an in vivo long echo time spin-echo sequence or an ex vivo pulse sequence. Gradient-echo images were acquired with a maximum in-plane resolution of 35 μm. Our results demonstrated that in both the in vivo and ex vivo data sets, the percent area of marrow increases and percent area of trabecular bone and cortical bone thickness decreases moving from the epiphyseal growth plate to the diaphysis. These changes, observed with MRI, correlate with the histological data. Investigations using in vivo MRI gradient-echo sequences consistently gave the best correlation with histology. Our quantitative evaluation using both ex vivo and in vivo MRI was found to be an effective means to visualize non-invasively the normal variation in trabecular and cortical bone as compared to a histological 'gold standard' The experiments validated in vivo MRI as a potential high resolution technique for investigating both soft tissue, such as marrow, and bone without radiation exposure

  14. A default Bayesian hypothesis test for correlations and partial correlations

    NARCIS (Netherlands)

    Wetzels, R.; Wagenmakers, E.J.

    2012-01-01

    We propose a default Bayesian hypothesis test for the presence of a correlation or a partial correlation. The test is a direct application of Bayesian techniques for variable selection in regression models. The test is easy to apply and yields practical advantages that the standard frequentist tests

  15. In Vivo Radiobioassay and Research Facility

    International Nuclear Information System (INIS)

    Lynch, Timothy P.

    2011-01-01

    Bioassay monitoring for intakes of radioactive material is an essential part of the internal dosimetry program for radiation workers at the Department of Energy's (DOE) Hanford Site. This monitoring program includes direct measurements of radionuclides in the body by detecting photons that exit the body and analyses of radionuclides in excreta samples. The specialized equipment and instrumentation required to make the direct measurements of these materials in the body are located at the In Vivo Radiobioassay and Research Facility (IVRRF). The IVRRF was originally built in 1960 and was designed expressly for the in vivo measurement of radioactive material in Hanford workers. Most routine in vivo measurements are performed annually and special measurements are performed as needed. The primary source terms at the Hanford Site include fission and activation products (primarily 137Cs and 90Sr), uranium, uranium progeny, and transuranic radionuclides. The facility currently houses five shielded counting systems, men's and women's change rooms and an instrument maintenance and repair shop. Four systems include high purity germanium detectors and one system utilizes large sodium iodide detectors. These systems are used to perform an average of 7,000 measurements annually. This includes approximately 5000 whole body measurements analyzed for fission and activation products and 2000 lung measurements analyzed for americium, uranium, and plutonium. Various other types of measurements are performed periodically to estimate activity in wounds, the thyroid, the liver, and the skeleton. The staff maintains the capability to detect and quantify activity in essentially any tissue or organ. The in vivo monitoring program that utilizes the facility is accredited by the Department of Energy Laboratory Accreditation Program for direct radiobioassay.

  16. In Vivo Assessment of Elasticity of Child Rib Cortical Bone Using Quantitative Computed Tomography

    Directory of Open Access Journals (Sweden)

    Y. Zhu

    2017-01-01

    Full Text Available Elasticity of the child rib cortical bone is poorly known due to the difficulties in obtaining specimens to perform conventional tests. It was shown on the femoral cortical bone that elasticity is strongly correlated with density for both children and adults through a unique relationship. Thus, it is assumed that the relationships between the elasticity and density of adult rib cortical bones could be expanded to include that of children. This study estimated in vivo the elasticity of the child rib cortical bone using quantitative computed tomography (QCT. Twenty-eight children (from 1 to 18 y.o. were considered. Calibrated QCT images were prescribed for various thoracic pathologies. The Hounsfield units were converted to bone mineral density (BMD. A relationship between the BMD and the elasticity of the rib cortical bone was applied to estimate the elasticity of children’s ribs in vivo. The estimated elasticity increases with growth (7.1 ± 2.5 GPa at 1 y.o. up to 11.6 ± 1.9 GPa at 18 y.o.. This data is in agreement with the few previous values obtained using direct measurements. This methodology paves the way for in vivo assessment of the elasticity of the child cortical bone based on calibrated QCT images.

  17. Cadmium analysis in vivo

    International Nuclear Information System (INIS)

    Bergman, R.

    1980-12-01

    The report describes the development of a method for in vivo Cd-analysis. The method is based on the analysis of the prompt gamma radiation which is emitted by neutron capture of the isotope Cd113. Different parts of the body can be analysed selectively by neutrons in the interval of 1 to 100 KeV. The results show that the level of Cd in Kidneys can be measured without exceeding the dose of 40 mrad and that only 20% uncertainty is introduced when analysing Cd. The development has been made at the R2 reactor in Studsvik using 25 KeV neutrons. (G.B.)

  18. Exploring sex differences in the adult zebra finch brain: In vivo diffusion tensor imaging and ex vivo super-resolution track density imaging.

    Science.gov (United States)

    Hamaide, Julie; De Groof, Geert; Van Steenkiste, Gwendolyn; Jeurissen, Ben; Van Audekerke, Johan; Naeyaert, Maarten; Van Ruijssevelt, Lisbeth; Cornil, Charlotte; Sijbers, Jan; Verhoye, Marleen; Van der Linden, Annemie

    2017-02-01

    Zebra finches are an excellent model to study the process of vocal learning, a complex socially-learned tool of communication that forms the basis of spoken human language. So far, structural investigation of the zebra finch brain has been performed ex vivo using invasive methods such as histology. These methods are highly specific, however, they strongly interfere with performing whole-brain analyses and exclude longitudinal studies aimed at establishing causal correlations between neuroplastic events and specific behavioral performances. Therefore, the aim of the current study was to implement an in vivo Diffusion Tensor Imaging (DTI) protocol sensitive enough to detect structural sex differences in the adult zebra finch brain. Voxel-wise comparison of male and female DTI parameter maps shows clear differences in several components of the song control system (i.e. Area X surroundings, the high vocal center (HVC) and the lateral magnocellular nucleus of the anterior nidopallium (LMAN)), which corroborate previous findings and are in line with the clear behavioral difference as only males sing. Furthermore, to obtain additional insights into the 3-dimensional organization of the zebra finch brain and clarify findings obtained by the in vivo study, ex vivo DTI data of the male and female brain were acquired as well, using a recently established super-resolution reconstruction (SRR) imaging strategy. Interestingly, the SRR-DTI approach led to a marked reduction in acquisition time without interfering with the (spatial and angular) resolution and SNR which enabled to acquire a data set characterized by a 78μm isotropic resolution including 90 diffusion gradient directions within 44h of scanning time. Based on the reconstructed SRR-DTI maps, whole brain probabilistic Track Density Imaging (TDI) was performed for the purpose of super resolved track density imaging, further pushing the resolution up to 40μm isotropic. The DTI and TDI maps realized atlas

  19. Stress and strain provide positional and directional cues in development.

    Directory of Open Access Journals (Sweden)

    Behruz Bozorg

    2014-01-01

    Full Text Available The morphogenesis of organs necessarily involves mechanical interactions and changes in mechanical properties of a tissue. A long standing question is how such changes are directed on a cellular scale while being coordinated at a tissular scale. Growing evidence suggests that mechanical cues are participating in the control of growth and morphogenesis during development. We introduce a mechanical model that represents the deposition of cellulose fibers in primary plant walls. In the model both the degree of material anisotropy and the anisotropy direction are regulated by stress anisotropy. We show that the finite element shell model and the simpler triangular biquadratic springs approach provide equally adequate descriptions of cell mechanics in tissue pressure simulations of the epidermis. In a growing organ, where circumferentially organized fibers act as a main controller of longitudinal growth, we show that the fiber direction can be correlated with both the maximal stress direction and the direction orthogonal to the maximal strain direction. However, when dynamic updates of the fiber direction are introduced, the mechanical stress provides a robust directional cue for the circumferential organization of the fibers, whereas the orthogonal to maximal strain model leads to an unstable situation where the fibers reorient longitudinally. Our investigation of the more complex shape and growth patterns in the shoot apical meristem where new organs are initiated shows that a stress based feedback on fiber directions is capable of reproducing the main features of in vivo cellulose fiber directions, deformations and material properties in different regions of the shoot. In particular, we show that this purely mechanical model can create radially distinct regions such that cells expand slowly and isotropically in the central zone while cells at the periphery expand more quickly and in the radial direction, which is a well established growth pattern

  20. Stress and strain provide positional and directional cues in development.

    Science.gov (United States)

    Bozorg, Behruz; Krupinski, Pawel; Jönsson, Henrik

    2014-01-01

    The morphogenesis of organs necessarily involves mechanical interactions and changes in mechanical properties of a tissue. A long standing question is how such changes are directed on a cellular scale while being coordinated at a tissular scale. Growing evidence suggests that mechanical cues are participating in the control of growth and morphogenesis during development. We introduce a mechanical model that represents the deposition of cellulose fibers in primary plant walls. In the model both the degree of material anisotropy and the anisotropy direction are regulated by stress anisotropy. We show that the finite element shell model and the simpler triangular biquadratic springs approach provide equally adequate descriptions of cell mechanics in tissue pressure simulations of the epidermis. In a growing organ, where circumferentially organized fibers act as a main controller of longitudinal growth, we show that the fiber direction can be correlated with both the maximal stress direction and the direction orthogonal to the maximal strain direction. However, when dynamic updates of the fiber direction are introduced, the mechanical stress provides a robust directional cue for the circumferential organization of the fibers, whereas the orthogonal to maximal strain model leads to an unstable situation where the fibers reorient longitudinally. Our investigation of the more complex shape and growth patterns in the shoot apical meristem where new organs are initiated shows that a stress based feedback on fiber directions is capable of reproducing the main features of in vivo cellulose fiber directions, deformations and material properties in different regions of the shoot. In particular, we show that this purely mechanical model can create radially distinct regions such that cells expand slowly and isotropically in the central zone while cells at the periphery expand more quickly and in the radial direction, which is a well established growth pattern in the meristem.

  1. Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: formulation and in vitro/in vivo evaluation.

    Science.gov (United States)

    Kassem, Mohamed A A; Elmeshad, Aliaa N; Fares, Ahmed R

    2014-03-10

    This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5×3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T(₅₀%)) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r²=0.9805) between fractions dissolved in vitro and fractions absorbed in vivo. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Search for correlations between the arrival directions of IceCube neutrino events and ultrahigh-energy cosmic rays detected by the Pierre Auger Observatory and the Telescope Array

    NARCIS (Netherlands)

    Collaboration, The IceCube; Aartsen, M. G.; Abraham, K.; Ackermann, M.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Ahrens, M.; Altmann, D.; Anderson, T.; Ansseau, I.; Archinger, M.; Arguelles, C.; Arlen, T. C.; Auffenberg, J.; Bai, X.; Barwick, S. W.; Baum, V.; Bay, R.; Beatty, J. J.; Tjus, J. Becker; Becker, K. -H.; Beiser, E.; Berghaus, P.; Berley, D.; Bernardini, E.; Bernhard, A.; Besson, D. Z.; Binder, G.; Bindig, D.; Bissok, M.; Blaufuss, E.; Blumenthal, J.; Boersma, D. J.; Bohm, C.; Börner, M.; Bos, F.; Bose, D.; Böser, S.; Botner, O.; Braun, J.; Brayeur, L.; Bretz, H. -P.; Buzinsky, N.; Casey, J.; Casier, M.; Cheung, E.; Chirkin, D.; Christov, A.; Clark, K.; Classen, L.; Coenders, S.; Cowen, D. F.; Silva, A. H. Cruz; Daughhetee, J.; Davis, J. C.; Day, M.; André, J. P. A. M. de; Clercq, C. De; Rosendo, E. del Pino; Dembinski, H.; Ridder, S. De; Desiati, P.; Vries, K. D. de; Wasseige, G. de; With, M. de; DeYoung, T.; Díaz-Vélez, J. C.; Lorenzo, V. di; Dumm, J. P.; Dunkman, M.; Eberhardt, B.; Ehrhardt, T.; Eichmann, B.; Euler, S.; Evenson, P. A.; Fahey, S.; Fazely, A. R.; Feintzeig, J.; Felde, J.; Filimonov, K.; Finley, C.; Fischer-Wasels, T.; Flis, S.; Fösig, C. -C.; Fuchs, T.; Gaisser, T. K.; Gaior, R.; Gallagher, J.; Gerhardt, L.; Ghorbani, K.; Gier, D.; Gladstone, L.; Glagla, M.; Glüsenkamp, T.; Goldschmidt, A.; Golup, G.; Gonzalez, J. G.; Góra, D.; Grant, D.; Griffith, Z.; Groß, A.; Ha, C.; Haack, C.; Ismail, A. Haj; Hallgren, A.; Halzen, F.; Hansen, E.; Hansmann, B.; Hanson, K.; Hebecker, D.; Heereman, D.; Helbing, K.; Hellauer, R.; Hickford, S.; Hignight, J.; Hill, G. C.; Hoffman, K. D.; Hoffmann, R.; Holzapfel, K.; Homeier, A.; Hoshina, K.; Huang, F.; Huber, M.; Huelsnitz, W.; Hulth, P. O.; Hultqvist, K.; In, S.; Ishihara, A.; Jacobi, E.; Japaridze, G. S.; Jeong, M.; Jero, K.; Jurkovic, M.; Kappes, A.; Karg, T.; Karle, A.; Kauer, M.; Keivani, A.; Kelley, J. L.; Kemp, J.; Kheirandish, A.; Kiryluk, J.; Kläs, J.; Klein, S. R.; Kohnen, G.; Koirala, R.; Kolanoski, H.; Konietz, R.; Köpke, L.; Kopper, C.; Kopper, S.; Koskinen, D. J.; Kowalski, M.; Krings, K.; Kroll, G.; Kroll, M.; Krückl, G.; Kunnen, J.; Kurahashi, N.; Kuwabara, T.; Labare, M.; Lanfranchi, J. L.; Larson, M. J.; Lesiak-Bzdak, M.; Leuermann, M.; Leuner, J.; Lu, L.; Lünemann, J.; Madsen, J.; Maggi, G.; Mahn, K. B. M.; Mandelartz, M.; Maruyama, R.; Mase, K.; Matis, H. S.; Maunu, R.; McNally, F.; Meagher, K.; Medici, M.; Meli, A.; Menne, T.; Merino, G.; Meures, T.; Miarecki, S.; Middell, E.; Mohrmann, L.; Montaruli, T.; Morse, R.; Nahnhauer, R.; Naumann, U.; Neer, G.; Niederhausen, H.; Nowicki, S. C.; Nygren, D. R.; Pollmann, A. Obertacke; Olivas, A.; Omairat, A.; O'Murchadha, A.; Palczewski, T.; Pandya, H.; Pankova, D. V.; Paul, L.; Pepper, J. A.; Heros, C. Pérez de los; Pfendner, C.; Pieloth, D.; Pinat, E.; Posselt, J.; Price, P. B.; Przybylski, G. T.; Quinnan, M.; Raab, C.; Rädel, L.; Rameez, M.; Rawlins, K.; Reimann, R.; Relich, M.; Resconi, E.; Rhode, W.; Richman, M.; Richter, S.; Riedel, B.; Robertson, S.; Rongen, M.; Rott, C.; Ruhe, T.; Ryckbosch, D.; Sabbatini, L.; Sander, H. -G.; Sandrock, A.; Sandroos, J.; Sarkar, S.; Schatto, K.; Schimp, M.; Schmidt, T.; Schoenen, S.; Schöneberg, S.; Schönwald, A.; Schulte, L.; Schumacher, L.; Seckel, D.; Seunarine, S.; Soldin, D.; Song, M.; Spiczak, G. M.; Spiering, C.; Stahlberg, M.; Stamatikos, M.; Stanev, T.; Stasik, A.; Steuer, A.; Stezelberger, T.; Stokstad, R. G.; Stößl, A.; Ström, R.; Strotjohann, N. L.; Sullivan, G. W.; Sutherland, M.; Taavola, H.; Taboada, I.; Tatar, J.; Ter-Antonyan, S.; Terliuk, A.; Tešić, G.; Tilav, S.; Toale, P. A.; Tobin, M. N.; Toscano, S.; Tosi, D.; Tselengidou, M.; Turcati, A.; Unger, E.; Usner, M.; Vallecorsa, S.; Vandenbroucke, J.; Eijndhoven, N. van; Vanheule, S.; Santen, J. van; Veenkamp, J.; Vehring, M.; Voge, M.; Vraeghe, M.; Walck, C.; Wallace, A.; Wallraff, M.; Wandkowsky, N.; Weaver, Ch; Wendt, C.; Westerhoff, S.; Whelan, B. J.; Wiebe, K.; Wiebusch, C. H.; Wille, L.; Williams, D. R.; Wissing, H.; Wolf, M.; Wood, T. R.; Woschnagg, K.; Xu, D. L.; Xu, X. W.; Xu, Y.; Yanez, J. P.; Yodh, G.; Yoshida, S.; Collaboration, M. Zoll The Pierre Auger; Aab, A.; Abreu, P.; Aglietta, M.; Ahn, E. J.; Samarai, I. Al; Albuquerque, I. F. M.; Allekotte, I.; Allison, P.; Almela, A.; Castillo, J. Alvarez; Alvarez-Muñiz, J.; Batista, R. Alves; Ambrosio, M.; Aminaei, A.; Anchordoqui, L.; Andrada, B.; Andringa, S.; Aramo, C.; Arqueros, F.; Arsene, N.; Asorey, H.; Assis, P.; Aublin, J.; Avila, G.; Awal, N.; Badescu, A. M.; Baus, C.; Beatty, J. J.; Becker, K. H.; Bellido, J. A.; Berat, C.; Bertaina, M. E.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blaess, S. G.; Blanco, A.; Blanco, M.; Blazek, J.; Bleve, C.; Blümer, H.; Boháčová, M.; Boncioli, D.; Bonifazi, C.; Borodai, N.; Botti, A. M.; Brack, J.; Brancus, I.; Bretz, T.; Bridgeman, A.; Briechle, F. L.; Buchholz, P.; Bueno, A.; Buitink, S.; Buscemi, M.; Caballero-Mora, K. S.; Caccianiga, B.; Caccianiga, L.; Candusso, M.; Caramete, L.; Caruso, R.; Castellina, A.; Cataldi, G.; Cazon, L.; Cester, R.; Chavez, A. G.; Chiavassa, A.; Chinellato, J. A.; Diaz, J. C. Chirinos; Chudoba, J.; Clay, R. W.; Colalillo, R.; Coleman, A.; Collica, L.; Coluccia, M. R.; Conceição, R.; Contreras, F.; Cooper, M. J.; Cordier, A.; Coutu, S.; Covault, C. E.; Dallier, R.; D'Amico, S.; Daniel, B.; Dasso, S.; Daumiller, K.; Dawson, B. R.; Almeida, R. M. de; Jong, S. J. de; Mauro, G. De; Neto, J. R. T. de Mello; Mitri, I. De; Oliveira, J. de; Souza, V. de; Debatin, J.; Peral, L. del; Deligny, O.; Dhital, N.; Giulio, C. Di; Matteo, A. Di; Castro, M. L. Díaz; Diogo, F.; Dobrigkeit, C.; Docters, W.; D'Olivo, J. C.; Dorofeev, A.; Anjos, R. C. dos; Dova, M. T.; Dundovic, A.; Ebr, J.; Engel, R.; Erdmann, M.; Erfani, M.; Escobar, C. O.; Espadanal, J.; Etchegoyen, A.; Falcke, H.; Fang, K.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Ferguson, A. P.; Fick, B.; Figueira, J. M.; Filevich, A.; Filipčič, A.; Fratu, O.; Freire, M. M.; Fujii, T.; Fuster, A.; Gallo, F.; García, B.; Garcia-Gamez, D.; Garcia-Pinto, D.; Gate, F.; Gemmeke, H.; Gherghel-Lascu, A.; Ghia, P. L.; Giaccari, U.; Giammarchi, M.; Giller, M.; Głas, D.; Glaser, C.; Glass, H.; Golup, G.; Berisso, M. Gómez; Vitale, P. F. Gómez; González, N.; Gookin, B.; Gordon, J.; Gorgi, A.; Gorham, P.; Gouffon, P.; Griffith, N.; Grillo, A. F.; Grubb, T. D.; Guarino, F.; Guedes, G. P.; Hampel, M. R.; Hansen, P.; Harari, D.; Harrison, T. A.; Harton, J. L.; Hasankiadeh, Q.; Haungs, A.; Hebbeker, T.; Heck, D.; Heimann, P.; Herve, A. E.; Hill, G. C.; Hojvat, C.; Hollon, N.; Holt, E.; Homola, P.; Hörandel, J. R.; Horvath, P.; Hrabovský, M.; Huege, T.; Insolia, A.; Isar, P. G.; Jandt, I.; Jansen, S.; Jarne, C.; Johnsen, J. A.; Josebachuili, M.; Kääpä, A.; Kambeitz, O.; Kampert, K. H.; Kasper, P.; Katkov, I.; Keilhauer, B.; Kemp, E.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Krause, R.; Krohm, N.; Kuempel, D.; Mezek, G. Kukec; Kunka, N.; Awad, A. Kuotb; LaHurd, D.; Latronico, L.; Lauer, R.; Lauscher, M.; Lautridou, P.; Lebrun, D.; Lebrun, P.; Oliveira, M. A. Leigui de; Letessier-Selvon, A.; Lhenry-Yvon, I.; Link, K.; Lopes, L.; López, R.; Casado, A. López; Lucero, A.; Malacari, M.; Mallamaci, M.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Marin, V.; Mariş, I. C.; Marsella, G.; Martello, D.; Martinez, H.; Bravo, O. Martínez; Meza, J. J. Masías; Mathes, H. J.; Mathys, S.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurizio, D.; Mayotte, E.; Mazur, P. O.; Medina, C.; Medina-Tanco, G.; Mello, V. B. B.; Melo, D.; Menshikov, A.; Messina, S.; Micheletti, M. I.; Middendorf, L.; Minaya, I. A.; Miramonti, L.; Mitrica, B.; Molina-Bueno, L.; Mollerach, S.; Montanet, F.; Morello, C.; Mostafá, M.; Moura, C. A.; Müller, G.; Muller, M. A.; Müller, S.; Naranjo, I.; Navas, S.; Necesal, P.; Nellen, L.; Nelles, A.; Neuser, J.; Nguyen, P. H.; Niculescu-Oglinzanu, M.; Niechciol, M.; Niemietz, L.; Niggemann, T.; Nitz, D.; Nosek, D.; Novotny, V.; Nožka, H.; Núñez, L. A.; Ochilo, L.; Oikonomou, F.; Olinto, A.; Pacheco, N.; Selmi-Dei, D. Pakk; Palatka, M.; Pallotta, J.; Papenbreer, P.; Parente, G.; Parra, A.; Paul, T.; Pech, M.; Pękala, J.; Pelayo, R.; Peña-Rodriguez, J.; Pepe, I. M.; Perrone, L.; Petermann, E.; Peters, C.; Petrera, S.; Phuntsok, J.; Piegaia, R.; Pierog, T.; Pieroni, P.; Pimenta, M.; Pirronello, V.; Platino, M.; Plum, M.; Porowski, C.; Prado, R. R.; Privitera, P.; Prouza, M.; Quel, E. J.; Querchfeld, S.; Quinn, S.; Rautenberg, J.; Ravel, O.; Ravignani, D.; Reinert, D.; Revenu, B.; Ridky, J.; Risse, M.; Ristori, P.; Rizi, V.; Carvalho, W. Rodrigues de; Rojo, J. Rodriguez; Rodríguez-Frías, M. D.; Rogozin, D.; Rosado, J.; Roth, M.; Roulet, E.; Rovero, A. C.; Saffi, S. J.; Saftoiu, A.; Salazar, H.; Saleh, A.; Greus, F. Salesa; Salina, G.; Gomez, J. D. Sanabria; Sánchez, F.; Sanchez-Lucas, P.; Santos, E. M.; Santos, E.; Sarazin, F.; Sarkar, B.; Sarmento, R.; Sarmiento-Cano, C.; Sato, R.; Scarso, C.; Schauer, M.; Scherini, V.; Schieler, H.; Schmidt, D.; Scholten, O.; Schoorlemmer, H.; Schovánek, P.; Schröder, F. G.; Schulz, A.; Schulz, J.; Schumacher, J.; Segreto, A.; Settimo, M.; Shadkam, A.; Shellard, R. C.; Sigl, G.; Sima, O.; Śmiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sonntag, S.; Sorokin, J.; Squartini, R.; Stanca, D.; Stanič, S.; Stapleton, J.; Stasielak, J.; Stephan, M.; Strafella, F.; Stutz, A.; Suarez, F.; Durán, M. Suarez; Suomijärvi, T.; Supanitsky, A. D.; Sutherland, M. S.; Swain, J.; Szadkowski, Z.; Taborda, O. A.; Tapia, A.; Tepe, A.; Theodoro, V. M.; Timmermans, C.; Peixoto, C. J. Todero; Toma, G.; Tomankova, L.; Tomé, B.; Tonachini, A.; Elipe, G. Torralba; Machado, D. Torres; Travnicek, P.; Trini, M.; Ulrich, R.; Unger, M.; Urban, M.; Galicia, J. F. Valdés; Valiño, I.; Valore, L.; Aar, G. van; Bodegom, P. van; Berg, A. M. van den; Vliet, A. van; Varela, E.; Cárdenas, B. Vargas; Varner, G.; Vasquez, R.; Vázquez, J. R.; Vázquez, R. A.; Veberič, D.; Verzi, V.; Vicha, J.; Videla, M.; Villaseñor, L.; Vorobiov, S.; Wahlberg, H.; Wainberg, O.; Walz, D.; Watson, A. A.; Weber, M.; Weidenhaupt, K.; Weindl, A.; Wiencke, L.; Wilczyński, H.; Winchen, T.; Wittkowski, D.; Wundheiler, B.; Wykes, S.; Yang, L.; Yapici, T.; Yushkov, A.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zepeda, A.; Zimmermann, B.; Ziolkowski, M.; Zong, Z.; Collaboration, F. Zuccarello The Telescope Array; Abbasi, R. U.; Abe, M.; Abu-Zayyad, T.; Allen, M.; Azuma, R.; Barcikowski, E.; Belz, J. W.; Bergman, D. R.; Blake, S. A.; Cady, R.; Chae, M. J.; Cheon, B. G.; Chiba, J.; Chikawa, M.; Cho, W. R.; Fujii, T.; Fukushima, M.; Goto, T.; Hanlon, W.; Hayashi, Y.; Hayashida, N.; Hibino, K.; Honda, K.; Ikeda, D.; Inoue, N.; Ishii, T.; Ishimori, R.; Ito, H.; Ivanov, D.; Jui, C. C. H.; Kadota, K.; Kakimoto, F.; Kalashev, O.; Kasahara, K.; Kawai, H.; Kawakami, S.; Kawana, S.; Kawata, K.; Kido, E.; Kim, H. B.; Kim, J. H.; Kim, J. H.; Kitamura, S.; Kitamura, Y.; Kuzmin, V.; Kwon, Y. J.; Lan, J.; Lim, S. I.; Lundquist, J. P.; Machida, K.; Martens, K.; Matsuda, T.; Matsuyama, T.; Matthews, J. N.; Minamino, M.; Mukai, Y.; Myers, I.; Nagasawa, K.; Nagataki, S.; Nakamura, T.; Nonaka, T.; Nozato, A.; Ogio, S.; Ogura, J.; Ohnishi, M.; Ohoka, H.; Oki, K.; Okuda, T.; Ono, M.; Oshima, A.; Ozawa, S.; Park, I. H.; Pshirkov, M. S.; Rodriguez, D. C.; Rubtsov, G.; Ryu, D.; Sagawa, H.; Sakurai, N.; Scott, L. M.; Shah, P. D.; Shibata, F.; Shibata, T.; Shimodaira, H.; Shin, B. K.; Shin, H. S.; Smith, J. D.; Sokolsky, P.; Springer, R. W.; Stokes, B. T.; Stratton, S. R.; Stroman, T. A.; Suzawa, T.; Takamura, M.; Takeda, M.; Takeishi, R.; Taketa, A.; Takita, M.; Tameda, Y.; Tanaka, H.; Tanaka, K.; Tanaka, M.; Thomas, S. B.; Thomson, G. B.; Tinyakov, P.; Tkachev, I.; Tokuno, H.; Tomida, T.; Troitsky, S.; Tsunesada, Y.; Tsutsumi, K.; Uchihori, Y.; Udo, S.; Urban, F.; Vasiloff, G.; Wong, T.; Yamane, R.; Yamaoka, H.; Yamazaki, K.; Yang, J.; Yashiro, K.; Yoneda, Y.; Yoshida, S.; Yoshii, H.; Zollinger, R.; Zundel, Z.

    2015-01-01

    This paper presents the results of different searches for correlations between very high-energy neutrino candidates detected by IceCube and the highest-energy cosmic rays measured by the Pierre Auger Observatory and the Telescope Array. We first consider samples of cascade neutrino events and of

  3. Cardiac biplane strain imaging: initial in vivo experience

    Energy Technology Data Exchange (ETDEWEB)

    Lopata, R G P; Nillesen, M M; Thijssen, J M; De Korte, C L [Clinical Physics Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Verrijp, C N; Lammens, M M Y; Van der Laak, J A W M [Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Singh, S K; Van Wetten, H B [Department of Cardiothoracic Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Kapusta, L [Pediatric Cardiology, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)], E-mail: R.Lopata@cukz.umcn.nl

    2010-02-21

    In this study, first we propose a biplane strain imaging method using a commercial ultrasound system, yielding estimation of the strain in three orthogonal directions. Secondly, an animal model of a child's heart was introduced that is suitable to simulate congenital heart disease and was used to test the method in vivo. The proposed approach can serve as a framework to monitor the development of cardiac hypertrophy and fibrosis. A 2D strain estimation technique using radio frequency (RF) ultrasound data was applied. Biplane image acquisition was performed at a relatively low frame rate (<100 Hz) using a commercial platform with an RF interface. For testing the method in vivo, biplane image sequences of the heart were recorded during the cardiac cycle in four dogs with an aortic stenosis. Initial results reveal the feasibility of measuring large radial, circumferential and longitudinal cumulative strain (up to 70%) at a frame rate of 100 Hz. Mean radial strain curves of a manually segmented region-of-interest in the infero-lateral wall show excellent correlation between the measured strain curves acquired in two perpendicular planes. Furthermore, the results show the feasibility and reproducibility of assessing radial, circumferential and longitudinal strains simultaneously. In this preliminary study, three beagles developed an elevated pressure gradient over the aortic valve ({delta}p: 100-200 mmHg) and myocardial hypertrophy. One dog did not develop any sign of hypertrophy ({delta}p = 20 mmHg). Initial strain (rate) results showed that the maximum strain (rate) decreased with increasing valvular stenosis (-50%), which is in accordance with previous studies. Histological findings corroborated these results and showed an increase in fibrotic tissue for the hearts with larger pressure gradients (100, 200 mmHg), as well as lower strain and strain rate values.

  4. Cardiac biplane strain imaging: initial in vivo experience

    International Nuclear Information System (INIS)

    Lopata, R G P; Nillesen, M M; Thijssen, J M; De Korte, C L; Verrijp, C N; Lammens, M M Y; Van der Laak, J A W M; Singh, S K; Van Wetten, H B; Kapusta, L

    2010-01-01

    In this study, first we propose a biplane strain imaging method using a commercial ultrasound system, yielding estimation of the strain in three orthogonal directions. Secondly, an animal model of a child's heart was introduced that is suitable to simulate congenital heart disease and was used to test the method in vivo. The proposed approach can serve as a framework to monitor the development of cardiac hypertrophy and fibrosis. A 2D strain estimation technique using radio frequency (RF) ultrasound data was applied. Biplane image acquisition was performed at a relatively low frame rate (<100 Hz) using a commercial platform with an RF interface. For testing the method in vivo, biplane image sequences of the heart were recorded during the cardiac cycle in four dogs with an aortic stenosis. Initial results reveal the feasibility of measuring large radial, circumferential and longitudinal cumulative strain (up to 70%) at a frame rate of 100 Hz. Mean radial strain curves of a manually segmented region-of-interest in the infero-lateral wall show excellent correlation between the measured strain curves acquired in two perpendicular planes. Furthermore, the results show the feasibility and reproducibility of assessing radial, circumferential and longitudinal strains simultaneously. In this preliminary study, three beagles developed an elevated pressure gradient over the aortic valve (Δp: 100-200 mmHg) and myocardial hypertrophy. One dog did not develop any sign of hypertrophy (Δp = 20 mmHg). Initial strain (rate) results showed that the maximum strain (rate) decreased with increasing valvular stenosis (-50%), which is in accordance with previous studies. Histological findings corroborated these results and showed an increase in fibrotic tissue for the hearts with larger pressure gradients (100, 200 mmHg), as well as lower strain and strain rate values.

  5. In vivo gluten challenge in coeliac disease

    Directory of Open Access Journals (Sweden)

    HJ Ellis

    2001-01-01

    Full Text Available In vivo gluten challenge has been used since the early 1950s to study the role of cereal fractions in celiac disease. While early studies relied on crude indicators of celiac toxicity, the advent of jejunal biopsy and sophisticated immunohistochemical techniques has allowed accurate studies to be performed. Studies to determine the nature of the cereal component that is toxic to patients with celiac disease have concentrated on wheat because of its nutritional importance. A number of in vitro studies indicated the presence of one or more celiac-activating epitopes with the N-terminus of the A-gliadin molecule. In vivo challenge with three synthetic peptides subsequently indicated the toxicity of a peptide corresponding to amino acids 31 to 49 of A-gliadin. In vivo gluten challenge is the gold standard for the assessment of celiac toxicity; however, jejunal biopsy is a relatively invasive procedure, thus, other methods have been investigated. Direct infusion of the rectum with gluten has been shown to result in an increase in mucosal intraepithelial lymphocytes, occurring only in celiac patients. This method has been used to study the celiac toxicity of gliadin subfractions. The in vitro technique of small intestinal biopsy organ culture is also a useful tool and appears to give the same results as in vivo challenge. The importance of tiny amounts of gliadin in the diet, such as that which occurs in wheat starch, has been studied by in vivo challenge; this technique has clarified the position of oats in the gluten-free diet. Several studies suggest that this cereal may be included in the diet of most adult celiac patients. Studies of the transport of gliadin across the enterocyte following ingestion or challenge suggest that gliadin may be metabolized by a different pathway in celiac disease. This could result in an abnormal presentation to the immune system, triggering a pathogenic rather than a tolerogenic response.

  6. EDITORIAL: Nanotechnology in vivo Nanotechnology in vivo

    Science.gov (United States)

    Demming, Anna

    2010-04-01

    -imaging labels [4]. A surface hydroxyl group renders silicon quantum dots soluble in water and the photoluminescence can be made stable with oxygen-passivation. In addition, researchers in Japan have demonstrated how the initially modest yield in the preparation of silicon quantum dots can be improved to tens of milligrams per batch, thus further promoting their application in bio-imaging [5]. In the search for non-toxic quantum dots, researchers at the Amrita Centre for Nanoscience in India have prepared heavy metal-free quantum dot bio-probes based on single phase ZnS [6]. The quantum dots are selectively doped with metals, transition metals and halides to provide tuneable luminescence properties, and they are surface conjugated with folic acid for cancer targeting. The quantum dots were demonstrated to be water-soluble, non-toxic in normal and cancer cell lines, and have bright, tuneable luminescence. So far most of the quantum dots developed for bio-imaging have had excitation and emission wavelengths in the visible spectrum, which is highly absorbed by tissue. This limits imaging with these quantum dots to superficial tissues. This week, researchers in China and the US reported work developing functionalized dots for in vivo tumour vasculature in the infrared part of the spectrum [7]. In addition the quantum dots were functionalised with glycine-aspartic acid (RGD) peptides, which target the vasculature of almost all types of growing tumours, unlike antibody- or aptamer-mediated targeting strategies that are specific to a particular cancer type. In this issue, researchers in China and the US demonstrate a novel type of contrast agent for ultrasonic tumour imaging [8]. Contrast-enhanced ultrasonic tumour imaging extends the diagnostic and imaging capabilities of traditional techniques. The use of nanoparticles as ultrasound contrast agents exploits the presence of open pores in the range of 380 to 780 nm in tumour blood vessels, which enhance the permeability and retention

  7. Direct Democracy

    DEFF Research Database (Denmark)

    Beramendi, Virginia; Ellis, Andrew; Kaufman, Bruno

    While many books on direct democracy have a regional or national approach, or simply focus on one of the many mechanisms associated with direct democracy, this Handbook delves into a global comparison of direct democracy mechanisms, including referendums, citizens' initiatives, agenda initiatives...... learned. In addition, the uniquely comprehensive world survey outlines direct democracy provisions in 214 countries and territories and indicates which, if any, of these provisions are used by each country or territory at both the national and sub-national levels. Furthermore, the world survey includes...

  8. Spin squeezing and quantum correlations

    Indian Academy of Sciences (India)

    2 states. A coherent spin-s state. (CSS) θ φ can then be thought of as having no quantum correlations as the constituent. 2s elementary spins point in the same direction ˆn(θ φ) which is the mean spin direction. 2. State classification and squeezing. In order to discuss squeezing, we begin with the squeezing condition itself.

  9. Optimum slicing of radical prostatectomy specimens for correlation between histopathology and medical images

    International Nuclear Information System (INIS)

    Chen, Li Hong; Ng, Wan Sing; Ho, Henry; Yuen, John; Cheng, Chris; Lazaro, Richie; Thng, Choon Hua

    2010-01-01

    There is a need for methods which enable precise correlation of histologic sections with in vivo prostate images. Such methods would allow direct comparison between imaging features and functional or histopathological heterogeneity of tumors. Correlation would be particularly useful for validating the accuracy of imaging modalities, developing imaging techniques, assessing image-guided therapy, etc. An optimum prostate slicing method for accurate correlation between the histopathological and medical imaging planes in terms of section angle, thickness and level was sought. Literature review (51 references from 1986-2009 were cited) was done on the various sectioning apparatus or techniques used to slice the prostate specimen for accurate correlation between histopathological data and medical imaging. Technology evaluation was performed with review and discussion of various methods used to section other organs and their possible applications for sectioning prostatectomy specimens. No consensus has been achieved on how the prostate should be dissected to achieve a good correlation. Various customized sectioning instruments and techniques working with different mechanism are used in different research institutes to improve the correlation. Some of the methods have convincingly shown significant potential for improving image-specimen correlation. However, the semisolid consistent property of prostate tissue and the lack of identifiable landmarks remain challenges to be overcome, especially for fresh prostate sectioning and microtomy without external fiducials. A standardized optimum protocol to dissect prostatectomy specimens is needed for the validation of medical imaging modalities by histologic correlation. These standards can enhance disease management by improving the comparability between different modalities. (orig.)

  10. In vivo endoscopic multi-beam optical coherence tomography

    Energy Technology Data Exchange (ETDEWEB)

    Standish, Beau A; Mariampillai, Adrian; Munce, Nigel R; Leung, Michael K K; Vitkin, I Alex [Deptartment of Medical Biophysics, University of Toronto, Toronto (Canada); Lee, Kenneth K C; Yang, Victor X D [Ontario Cancer Institute/University Health Network, Toronto (Canada)], E-mail: standish@ee.ryerson.ca

    2010-02-07

    A multichannel optical coherence tomography (multi-beam OCT) system and an in vivo endoscopic imaging probe were developed using a swept-source OCT system. The distal optics were micro-machined to produce a high numerical aperture, multi-focus fibre optic array. This combination resulted in a transverse design resolution of <10 {mu}m full width half maximum (FWHM) throughout the entire imaging range, while also increasing the signal intensity within the focus of the individual channels. The system was used in a pre-clinical rabbit study to acquire in vivo structural images of the colon and ex vivo images of the oesophagus and trachea. A good correlation between the structural multi-beam OCT images and H and E histology was achieved, demonstrating the feasibility of this high-resolution system and its potential for in vivo human endoscopic imaging.

  11. In vivo endoscopic multi-beam optical coherence tomography

    International Nuclear Information System (INIS)

    Standish, Beau A; Mariampillai, Adrian; Munce, Nigel R; Leung, Michael K K; Vitkin, I Alex; Lee, Kenneth K C; Yang, Victor X D

    2010-01-01

    A multichannel optical coherence tomography (multi-beam OCT) system and an in vivo endoscopic imaging probe were developed using a swept-source OCT system. The distal optics were micro-machined to produce a high numerical aperture, multi-focus fibre optic array. This combination resulted in a transverse design resolution of <10 μm full width half maximum (FWHM) throughout the entire imaging range, while also increasing the signal intensity within the focus of the individual channels. The system was used in a pre-clinical rabbit study to acquire in vivo structural images of the colon and ex vivo images of the oesophagus and trachea. A good correlation between the structural multi-beam OCT images and H and E histology was achieved, demonstrating the feasibility of this high-resolution system and its potential for in vivo human endoscopic imaging.

  12. Analysis of the in vivo confocal Raman spectral variability in human skin

    Science.gov (United States)

    Mogilevych, Borys; dos Santos, Laurita; Rangel, Joao L.; Grancianinov, Karen J. S.; Sousa, Mariane P.; Martin, Airton A.

    2015-06-01

    Biochemical composition of the skin changes in each layer and, therefore, the skin spectral profile vary with the depth. In this work, in vivo Confocal Raman spectroscopy studies were performed at different skin regions and depth profile (from the surface down to 10 μm) of the stratum corneum, to verify the variability and reproducibility of the intra- and interindividual Raman data. The Raman spectra were collected from seven healthy female study participants using a confocal Raman system from Rivers Diagnostic, with 785 nm excitation line and a CCD detector. Measurements were performed in the volar forearm region, at three different points at different depth, with the step of 2 μm. For each depth point, three spectra were acquired. Data analysis included the descriptive statistics (mean, standard deviation and residual) and Pearson's correlation coefficient calculation. Our results show that inter-individual variability is higher than intraindividual variability, and variability inside the SC is higher than on the skin surface. In all these cases we obtained r values, higher than 0.94, which correspond to high correlation between Raman spectra. It reinforces the possibility of the data reproducibility and direct comparison of in vivo results obtained with different study participants of the same age group and phototype.

  13. Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay

    Science.gov (United States)

    Schenk, B.; Würtinger, P.; Streif, W.; Sturm, W.; Fries, D.; Bachler, M.

    2016-01-01

    Background In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI). Methods Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation. Results When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM® thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV−t), and with all measured thrombin generation parameters. In vivo, CT, MaxV−t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax (+461% for PCC, +87.5% for aPCC). Conclusions Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents. Clinical trial registration EudracCT trial no. 213-00474-30. PMID:27623677

  14. Directing 101.

    Science.gov (United States)

    Pintoff, Ernest

    Providing an introduction to anyone considering directing as a field of study or career, this book takes a broad look at the process of directing and encourages students and professionals alike to look outside of the movie industry for inspiration. Chapters in the book discuss selecting and acquiring material; budgeting and financing; casting and…

  15. Direct and indirect methods for the quantification of leg volume: Comparison between water displacement volumetry, the disk model method and the frustum sign model method, using the correlation coefficient and the limits of agreement

    NARCIS (Netherlands)

    D.M.K.S. Kaulesar Sukul (D. M K S); P.Th. den Hoed (Pieter); T. Johannes (Tanja); R. van Dolder (R.); E. Benda (Eric)

    1993-01-01

    textabstractVolume changes can be measured either directly by water-displacement volumetry or by various indirect methods in which calculation of the volume is based on circumference measurements. The aim of the present study was to determine the most appropriate indirect method for lower leg volume

  16. Cells in Dengue Virus Infection In Vivo

    Directory of Open Access Journals (Sweden)

    Sansanee Noisakran

    2010-01-01

    Full Text Available Dengue has been recognized as one of the most important vector-borne emerging infectious diseases globally. Though dengue normally causes a self-limiting infection, some patients may develop a life-threatening illness, dengue hemorrhagic fever (DHF/dengue shock syndrome (DSS. The reason why DHF/DSS occurs in certain individuals is unclear. Studies in the endemic regions suggest that the preexisting antibodies are a risk factor for DHF/DSS. Viremia and thrombocytopenia are the key clinical features of dengue virus infection in patients. The amounts of virus circulating in patients are highly correlated with severe dengue disease, DHF/DSS. Also, the disturbance, mainly a transient depression, of hematological cells is a critical clinical finding in acute dengue patients. However, the cells responsible for the dengue viremia are unresolved in spite of the intensive efforts been made. Dengue virus appears to replicate and proliferate in many adapted cell lines, but these in vitro properties are extremely difficult to be reproduced in primary cells or in vivo. This paper summarizes reports on the permissive cells in vitro and in vivo and suggests a hematological cell lineage for dengue virus infection in vivo, with the hope that a new focus will shed light on further understanding of the complexities of dengue disease.

  17. Analysis of in vitro and in vivo function of total knee replacements using dynamic contact models

    Science.gov (United States)

    Zhao, Dong

    Despite the high incidence of osteoarthritis in human knee joint, its causes remain unknown. Total knee replacement (TKR) has been shown clinically to be effective in restoring the knee function. However, wear of ultra-high molecular weight polyethylene has limited the longevity of TKRs. To address these important issues, it is necessary to investigate the in vitro and in vivo function of total knee replacements using dynamic contact models. A multibody dynamic model of an AMTI knee simulator was developed. Incorporating a wear prediction model into the contact model based on elastic foundation theory enables the contact surface to take into account creep and wear during the dynamic simulation. Comparisons of the predicted damage depth, area, and volume lost with worn retrievals from a physical machine were made to validate the model. In vivo tibial force distributions during dynamic and high flexion activities were investigated using the dynamic contact model. In vivo medial and lateral contact forces experienced by a well-aligned instrumented knee implant, as well as upper and lower bounds on contact pressures for a variety of activities were studied. For all activities, the predicted medial and lateral contact forces were insensitive to the selected material model. For this patient, the load split during the mid-stance phase of gait and during stair is more equal than anticipated. The external knee adduction torque has been proposed as a surrogate measure for medial compartment load during gait. However, a direct link between these two quantities has not been demonstrated using in vivo measurement of medial compartment load. In vivo data collected from a subject with an instrumented knee implant were analyzed to evaluate this link. The subject performed five different overground gait motions (normal, fast, slow, wide, and toe out) while instrumented implant, video motion, and ground reaction data were simultaneously collected. The high correlation coefficient

  18. Directing Creativity

    DEFF Research Database (Denmark)

    Darsø, Lotte; Ibbotson, Piers

    2008-01-01

    In this article we argue that leaders facing complex challenges can learn from the arts, specifically that leaders can learn by examining how theatre directors direct creativity through creative constraints. We suggest that perceiving creativity as a boundary phenomenon is helpful for directing it....... Like leaders, who are caught in paradoxical situations where they have to manage production and logistics simultaneously with making space for creativity and innovation, theatre directors need to find the delicate balance between on one hand renewal of perceptions, acting and interaction...... and on the other hand getting ready for the opening night. We conclude that the art of directing creativity is linked to developing competencies of conscious presence, attention and vigilance, whereas the craft of directing creativity concerns communication, framing and choice....

  19. [Genomic research of traditional Chinese medicines in vivo metabolism].

    Science.gov (United States)

    Xiao, Shui-Ming; Bai, Rui; Zhang, Xiao-Yan

    2016-11-01

    Gene is the base of in vivo metabolism and effectiveness for traditional Chinese medicines (TCM), and the gene expression, regulation and modification are used as the research directions to perform the TCM multi-component, multi-link and multi-target in vivo metabolism studies, which will improve the research on TCM metabolic proecess, effect target and molecular mechanism. Humans are superorganisms with 1% genes inherited from parents and 99% genes from various parts of the human body, mainly coming from the microorganisms in intestinal flora. These indicate that genetically inherited human genome and "second genome" could affect the TCM in vivo metabolism from inheritance and "environmental" aspects respectively. In the present paper, typical case study was used to discuss related TCM in vivo metabolic genomics research, mainly including TCM genomics research and gut metagenomics research, as well as the personalized medicine evoked from the individual difference of above genomics (metagenomics). Copyright© by the Chinese Pharmaceutical Association.

  20. Direct Heat

    Energy Technology Data Exchange (ETDEWEB)

    Lienau, P J

    1990-01-01

    Potential resources and applications of earth heat in the form of geothermal energy are large. United States direct uses amount to 2,100 MWt thermal and worldwide 8,850 MWt above a reference temperature of 35 degrees Celsius. Space and district heating are the major direct uses of geothermal energy. Equipment employed in direct use projects is of standard manufacture and includes downhole and circulation pumps, transmission and distribution pipelines, heat exchangers and convectors, heat pumps and chillers. Direct uses of earth heat discussed are space and district heating, greenhouse heating and fish farming, process and industrial applications. The economic feasibility of direct use projects is governed by site specific factors such as location of user and resource, resource quality, system load factor and load density, as well as financing. Examples are presented of district heating in Klamath Falls, and Elko. Further developments of direct uses of geothermal energy will depend on matching user needs to the resource, and improving load factors and load density.

  1. Directed polymers versus directed percolation

    Science.gov (United States)

    Halpin-Healy, Timothy

    1998-10-01

    Universality plays a central role within the rubric of modern statistical mechanics, wherein an insightful continuum formulation rises above irrelevant microscopic details, capturing essential scaling behaviors. Nevertheless, occasions do arise where the lattice or another discrete aspect can constitute a formidable legacy. Directed polymers in random media, along with its close sibling, directed percolation, provide an intriguing case in point. Indeed, the deep blood relation between these two models may have sabotaged past efforts to fully characterize the Kardar-Parisi-Zhang universality class, to which the directed polymer belongs.

  2. Clinical evaluation of direct and photosensitized ultraviolet radiation damage to the lens

    International Nuclear Information System (INIS)

    Hockwin, O.; Lerman, S.

    1982-01-01

    We are reporting a new, objective, and quantitative method for monitoring age-related molecular changes in the human ocular lens in vivo, as expressed by increases in at least two (nontryptophan) fluorescence wavelengths. These fluorescence wavelengths appear to be caused by photochemically induced changes in the lens, and they reflect the ultraviolet (UV) filtering capacity of the patients' ocular lenses. These data correlate with previously reported in vitro lens fluorescence changes that are associated with the aging process. This method will also detect alterations in lenticular fluorescence caused by photosensitized as well as direct UV radiation damage

  3. Direct marketing

    Directory of Open Access Journals (Sweden)

    Čičić Muris

    2002-01-01

    Full Text Available Direct Marketing (DM is usually treated as unworthy activity, with actions at the edge of legality and activities minded cheating. Despite obvious problems regarding ethics and privacy threat, DM with its size, importance and role in a concept of integrated marketing communication deserves respect and sufficient analysis and review

  4. Valproic acid modulates platelet and coagulation function ex vivo

    DEFF Research Database (Denmark)

    Bambakidis, Ted; Dekker, Simone E; Halaweish, Ihab

    2017-01-01

    of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI...

  5. Direct numerical simulation of cellular-scale blood flow in microvascular networks

    Science.gov (United States)

    Balogh, Peter; Bagchi, Prosenjit

    2017-11-01

    A direct numerical simulation method is developed to study cellular-scale blood flow in physiologically realistic microvascular networks that are constructed in silico following published in vivo images and data, and are comprised of bifurcating, merging, and winding vessels. The model resolves large deformation of individual red blood cells (RBC) flowing in such complex networks. The vascular walls and deformable interfaces of the RBCs are modeled using the immersed-boundary methods. Time-averaged hemodynamic quantities obtained from the simulations agree quite well with published in vivo data. Our simulations reveal that in several vessels the flow rates and pressure drops could be negatively correlated. The flow resistance and hematocrit are also found to be negatively correlated in some vessels. These observations suggest a deviation from the classical Poiseuille's law in such vessels. The cells are observed to frequently jam at vascular bifurcations resulting in reductions in hematocrit and flow rate in the daughter and mother vessels. We find that RBC jamming results in several orders of magnitude increase in hemodynamic resistance, and thus provides an additional mechanism of increased in vivo blood viscosity as compared to that determined in vitro. Funded by NSF CBET 1604308.

  6. Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake.

    Science.gov (United States)

    Riccardi, Keith; Li, Zhenhong; Brown, Janice A; Gorgoglione, Matthew F; Niosi, Mark; Gosset, James; Huard, Kim; Erion, Derek M; Di, Li

    2016-10-01

    Unbound partition coefficient (Kpuu) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. Kpuu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transporter-transfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher Kpuu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high Kpuu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different Kpuu values in human hepatocytes (Kpuu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. Kpuu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (Km) of SLC13A5 was estimated to be 24 μM for PF-06649298 in human hepatocytes. In vitro Kpuu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo Kpuu of liver-to-plasma, illustrating the potential of this approach to predict in vivo Kpuu from in vitro systems. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Combined in vivo and ex vivo analysis of mesh mechanics in a porcine hernia model.

    Science.gov (United States)

    Kahan, Lindsey G; Lake, Spencer P; McAllister, Jared M; Tan, Wen Hui; Yu, Jennifer; Thompson, Dominic; Brunt, L Michael; Blatnik, Jeffrey A

    2018-02-01

    Hernia meshes exhibit variability in mechanical properties, and their mechanical match to tissue has not been comprehensively studied. We used an innovative imaging model of in vivo strain tracking and ex vivo mechanical analysis to assess effects of mesh properties on repaired abdominal walls in a porcine model. We hypothesized that meshes with dissimilar mechanical properties compared to native tissue would alter abdominal wall mechanics more than better-matched meshes. Seven mini-pigs underwent ventral hernia creation and subsequent open repair with one of two heavyweight polypropylene meshes. Following mesh implantation with attached radio-opaque beads, fluoroscopic images were taken at insufflation pressures from 5 to 30 mmHg on postoperative days 0, 7, and 28. At 28 days, animals were euthanized and ex vivo mechanical testing performed on full-thickness samples across repaired abdominal walls. Testing was conducted on 13 mini-pig controls, and on meshes separately. Stiffness and anisotropy (the ratio of stiffness in the transverse versus craniocaudal directions) were assessed. 3D reconstructions of repaired abdominal walls showed stretch patterns. As pressure increased, both meshes expanded, with no differences between groups. Over time, meshes contracted 17.65% (Mesh A) and 0.12% (Mesh B; p = 0.06). Mesh mechanics showed that Mesh A deviated from anisotropic native tissue more than Mesh B. Compared to native tissue, Mesh A was stiffer both transversely and craniocaudally. Explanted repaired abdominal walls of both treatment groups were stiffer than native tissue. Repaired tissue became less anisotropic over time, as mesh properties prevailed over native abdominal wall properties. This technique assessed 3D stretch at the mesh level in vivo in a porcine model. While the abdominal wall expanded, mesh-ingrown areas contracted, potentially indicating stresses at mesh edges. Ex vivo mechanics demonstrate that repaired tissue adopts mesh properties, suggesting

  8. Correlated binomial models and correlation structures

    International Nuclear Information System (INIS)

    Hisakado, Masato; Kitsukawa, Kenji; Mori, Shintaro

    2006-01-01

    We discuss a general method to construct correlated binomial distributions by imposing several consistent relations on the joint probability function. We obtain self-consistency relations for the conditional correlations and conditional probabilities. The beta-binomial distribution is derived by a strong symmetric assumption on the conditional correlations. Our derivation clarifies the 'correlation' structure of the beta-binomial distribution. It is also possible to study the correlation structures of other probability distributions of exchangeable (homogeneous) correlated Bernoulli random variables. We study some distribution functions and discuss their behaviours in terms of their correlation structures

  9. Biological evaluation of dental materials, in vitro and in vivo

    International Nuclear Information System (INIS)

    Kawahara, H.

    1982-01-01

    In this paper, the correlation between the user of tissue culture for in vitro tests and the tissue irritability and pupal response observed in in vitro tests, will be discussed. It would produce confusion if dental materials were standardised with the unreliable parameter of the living system in dynamic balance. Biological tests, both in vitro and in vivo, should be used for pre-standards testing, without any political control to establish physicochemical standards. As a first step, corrosion tests and the dissolution dosje of toxic components from the material in the tissue culture medium and/or artificial salvia should be standardised under conditions simulating the oral environment. The CNC method and photo-pattern analysis are used for the interpretation of cytotoxicity. The need for biological testing, both in vitro and in vivo, definitely exists in order to obtain physicochemical standards, with a biological simulation depending upon the feedback obtained from the results of in vitro and in vivo tests

  10. In vivo radiation sensitivity of glioblastoma multiforme

    International Nuclear Information System (INIS)

    Taghian, Alphonse; Freeman, Jill; Suit, Herman; DuBois, Willem; Budach, Wilfried; Baumann, Michael

    1995-01-01

    Purpose: Human glioblastoma (GBM) is one of the most resistant tumors to radiation. In previous reports, we have demonstrated a wide range of radiation sensitivity of GBM in vitro; that is, SF 2 values of 0.2 to 0.8. The great sensitivity of some of the cell lines is not in accord with the almost invariably fatal clinical outcome of patients with GBM. The sensitivity of cells in vitro pertains to cells cultured in optimal nutritional conditions. The TCD 50 (the radiation dose necessary to control 50% of the tumors locally) determined in lab animals is analogous to the use of radiation with curative intent in clinical radiation oncology. The aim of the present study was (a) to evaluate the sensitivity of GBM in vivo relative to that of other tumor types and (b) assess the relationship between the single dose TCD 50 of the xenografts and the sensitivity of the corresponding cell lines in vitro. Methods and Materials: The TCD 50 assay was used to study twelve human tumor lines. Four previously published values were added. A total of 10 GBM, 4 squamous cell carcinoma (SCC), 1 soft tissue sarcoma (STS), and 1 cancer colon (CC) are included in the analysis. For further suppression of the residual immune system, all the animals received 6 Gy whole-body irradiation 1 day before transplantation. Local tumor irradiations were given as a single dose, under conditions of clamp hypoxia using a Cs irradiator. Results: The TCD 50 values for the 10 GBM xenografts varied between 32.5 and 75.2 Gy, with an average of 47.2 ± 13.1 Gy. The TCD 50 values for the SCC were similar to those of the GBM and ranged from 40.7 and 54.4 Gy, with a mean of 46.8 ± 6.4. The difference between the average TCD 50 of GBM and SCC was not significant. The STS and CC xenografts had TCD 50 values of 46.0 and 49.2 Gy, respectively. No correlation was found between the TCD 50 in vivo and the SF 2 or D 0 in vitro. Conclusions: Our data on GBM xenografts showed a wide range of sensitivities to single dose

  11. In vivo radiation sensitivity of glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Taghian, Alphonse; Freeman, Jill; Suit, Herman; DuBois, Willem; Budach, Wilfried; Baumann, Michael

    1995-04-30

    Purpose: Human glioblastoma (GBM) is one of the most resistant tumors to radiation. In previous reports, we have demonstrated a wide range of radiation sensitivity of GBM in vitro; that is, SF{sub 2} values of 0.2 to 0.8. The great sensitivity of some of the cell lines is not in accord with the almost invariably fatal clinical outcome of patients with GBM. The sensitivity of cells in vitro pertains to cells cultured in optimal nutritional conditions. The TCD{sub 50} (the radiation dose necessary to control 50% of the tumors locally) determined in lab animals is analogous to the use of radiation with curative intent in clinical radiation oncology. The aim of the present study was (a) to evaluate the sensitivity of GBM in vivo relative to that of other tumor types and (b) assess the relationship between the single dose TCD{sub 50} of the xenografts and the sensitivity of the corresponding cell lines in vitro. Methods and Materials: The TCD{sub 50} assay was used to study twelve human tumor lines. Four previously published values were added. A total of 10 GBM, 4 squamous cell carcinoma (SCC), 1 soft tissue sarcoma (STS), and 1 cancer colon (CC) are included in the analysis. For further suppression of the residual immune system, all the animals received 6 Gy whole-body irradiation 1 day before transplantation. Local tumor irradiations were given as a single dose, under conditions of clamp hypoxia using a Cs irradiator. Results: The TCD{sub 50} values for the 10 GBM xenografts varied between 32.5 and 75.2 Gy, with an average of 47.2 {+-} 13.1 Gy. The TCD{sub 50} values for the SCC were similar to those of the GBM and ranged from 40.7 and 54.4 Gy, with a mean of 46.8 {+-} 6.4. The difference between the average TCD{sub 50} of GBM and SCC was not significant. The STS and CC xenografts had TCD{sub 50} values of 46.0 and 49.2 Gy, respectively. No correlation was found between the TCD{sub 50} in vivo and the SF{sub 2} or D{sub 0} in vitro. Conclusions: Our data on GBM

  12. In-vivo studies of new vector velocity and adaptive spectral estimators in medical ultrasound

    DEFF Research Database (Denmark)

    Hansen, Kristoffer Lindskov

    2010-01-01

    New ultrasound techniques for blood flow estimation have been investigated in-vivo. These are vector velocity estimators (Transverse Oscillation, Synthetic Transmit Aperture, Directional Beamforming and Plane Wave Excitation) and adaptive spectral estimators (Blood spectral Power Capon and Blood...

  13. Imaging the glutamatergic system in vivo - relevance to schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Bressan, R.A.; Pilowsky, L.S. [Inst. of Psychiatry, London (United Kingdom); Inst. of Nuclear Medicine, University College of London Medical School (United Kingdom)

    2000-11-01

    Schizophrenia is a devastating psychiatric illness. Its pathophysiology is not fully clarified. Animal data, in vitro and indirect in vivo imaging support glutamatergic N-methyl-D-aspartate (NMDA) receptor hypofunction in the disorder. A lack of suitable ligands has obstructed direct evaluation of the NMDA receptor hypofunction hypothesis of schizophrenia. Many research groups are working towards developing appropriate single-photon emission tomography and positron emission tomography ligands for the NMDA receptor. This paper briefly presents evidence for links between glutamatergic system dysfunction and schizophrenia. It reviews the radioligands to evaluate glutamatergic receptors in vivo and discusses issues in developing novel ligands for the glutamatergic system. (orig.)

  14. Imaging the glutamatergic system in vivo - relevance to schizophrenia

    International Nuclear Information System (INIS)

    Bressan, R.A.; Pilowsky, L.S.

    2000-01-01

    Schizophrenia is a devastating psychiatric illness. Its pathophysiology is not fully clarified. Animal data, in vitro and indirect in vivo imaging support glutamatergic N-methyl-D-aspartate (NMDA) receptor hypofunction in the disorder. A lack of suitable ligands has obstructed direct evaluation of the NMDA receptor hypofunction hypothesis of schizophrenia. Many research groups are working to