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Sample records for aaron yeow dfo

  1. The "Splendid Isolation" of Aaron T. Beck.

    PubMed

    Rosner, Rachael I

    2014-12-01

    Aaron T. Beck's Cognitive Therapy (CT) is a school of psychotherapy, conceived in the 1960s, that is celebrated by many clinicians for having provided the scientific antidote to all that was wrong with psychoanalysis. This essay situates the origins of CT in the crisis of legitimacy in psychiatry in the 1960s and 1970s, when, among many charges, psycho- analysts had to face the accusation that analysis was not adequately scientific. Beck actually began his career as both a psychoanalyst and an experimentalist. Contrary to common triumphalist accounts, Beck created CT to be a neutral space, not a partisan one, in turbulent times. Other notable psychoanalysts also sought compromise, rather than partisanship, to bridge the transition to biomedical science. The biographical approach of this essay to the origins of Beck's CT both situates him historiographically and articulates the complex experiences of a generation of psychoanalysts otherwise opaque to standard narratives. PMID:25665381

  2. Geophysicists: Jules Aarons (1921-2008)

    NASA Astrophysics Data System (ADS)

    Mendillo, Michael

    2009-03-01

    Jules Aarons, a pioneer in satellite radio beacon studies of the ionosphere, died peacefully at his home in Newton, Mass., on 21 November 2008 at age 87. When considering his college career, Jules was drawn toward the humanities, an interest subsequently redirected by his parents toward science as a more suitable way to earn a living, and then by the U.S. Army Air Corps toward radio technology as a more suitable way to win World War II. Both goals were readily accomplished, perhaps instilling in Jules the value of proper mentorship, that central aspect of his life that so dominates our recollections of him. After the war, and with a variety of options before him, Jules decided upon civilian government service at the U.S. Air Force's then new field station in Cambridge, Mass. This was the founding entity of the Air Force Cambridge Research Laboratory (AFCRL), and those five famous letters became identified with his professional career (1946-1981). With Russia's launch of Sputnik in 1957, the era of space-based radio communications began, and with it the need to understand the sporadic crackling and fading (``scintillations'') of radio transmissions from satellites to ground receiving stations. Wartime efforts also gave birth to radio astronomy. Jules fostered ways to fund the synergies he saw between the radio technologies of space science and those of ground-based radio astronomy in ways almost unimaginable today (and certainly not by former U.S. senator Mike Mansfield, whose 1973 amendment to the U.S. Congress's defense appropriations bill limited the financing of basic research by military agencies only to projects that have direct military consequences; the amendment resulted in a permanent restructuring of how U.S. Department of Defense (DOD) agencies fund university-based research).

  3. Primary Disaster Field Office (DFO), Lufkin, Texas

    NASA Technical Reports Server (NTRS)

    Wetherbee, James D.

    2005-01-01

    On February 1, 2003, the Space Shuttle Columbia broke apart during atmospheric re-entry on mission STS-107; the complexity of such an event cannot be underestimated. The Lufkin Disaster Field Office (DFO) served as the primary DFO for all operations, including staging assets and deploying field teams for search, recovery and security. There were many organizations that had operational experience with disaster recovery. Offers to help came from many groups including the White House Liaison Office, the Department of Defense (DOD), branches of local, state and federal government, the Federal Bureau of Investigation (FBI), the Federal Emergency Management Agency (FEMA), the Environmental Protection Agency (EPA), state police, fire departments, the Texas Forestry Service, the Texas Army National Guard, medical groups, various rescue forces, contractor companies, the Salvation Army, local businesses, and citizens of our country and especially East Texas. The challenge was to know how much help to accept and how to efficiently incorporate their valuable assistance into a comprehensive and cohesive operational plan. There were more than 2,000 people involved with search and recovery.

  4. 75 FR 7044 - Samuel Aaron, Inc., Long Island City, NY; Notice of Negative Determination Regarding Application...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-16

    ... Employment and Training Administration Samuel Aaron, Inc., Long Island City, NY; Notice of Negative... the Federal Register on January 25, 2010 (75 FR 3932). Pursuant to 29 CFR 90.18(c) reconsideration may... reconsideration of the decision. The TAA petition filed on behalf of workers at Samuel Aaron, Inc., Long...

  5. The 2009 Lindau Nobel Laureate Meeting: Aaron Ciechanover, Chemistry 2004

    PubMed Central

    Ciechanover, Aaron

    2009-01-01

    Aaron Ciechanover was born in Haifa, Israel in October 1947. He shared the Nobel Prize in Chemistry in 2004 with Avram Hershko and Irwin Rose for their discovery of ubiquitin-mediated protein degradation. When Ciechanover began his work on proteolysis, the field was outside the realm of scientific mainstream as many thought that the fundamental secrets relating to sequence specificity were relevant to the synthetic side, or code side. The notion that specific sequences could selectively guide a destructive process did not naturally occur to scientists including Ciechanover himself. The emergence of controversial evidence demonstrating a requirement for metabolic energy in intracellular protein degradation, refuted the idea that cellular proteolysis was an entirely exergonic process occurring in the lysosome and prompted Ciechanover, Hershko, and Rose to "launch an attack" on the system, in order to uncover true pathway. Later findings of Ciechanover and subsequent groups showed that not only was the process energy-dependent, but that 8% of the human genome is remarkably one large ubiquitin system. Following the recapitulation and reflection of his work, Ciechanover shares insights into his principal and philosophical approach to science and life altogether. The life and work of Aaron Ciechanover are deeply rooted and influenced by Judaism and Israel and it is therefore that with only brief intermission, Ciechanover spent his scientific career in Israel as he is - through his presence and work - able to contribute and shape presence and future of the State of Israel. PMID:19571788

  6. The 2008 Lindau Nobel Laureate Meeting: Aaron Ciechanover, Chemistry 2004.

    PubMed

    Ciechanover, Aaron

    2009-01-01

    Aaron Ciechanover was born in Haifa, Israel in October 1947. He shared the Nobel Prize in Chemistry in 2004 with Avram Hershko and Irwin Rose for their discovery of ubiquitin-mediated protein degradation. When Ciechanover began his work on proteolysis, the field was outside the realm of scientific mainstream as many thought that the fundamental secrets relating to sequence specificity were relevant to the synthetic side, or code side. The notion that specific sequences could selectively guide a destructive process did not naturally occur to scientists including Ciechanover himself. The emergence of controversial evidence demonstrating a requirement for metabollic energy in intracellular protein degradation, refuted the idea that cellular proteolysis was an entirely exergonic process occuring in the lysosme and prompted Ciechanover, Hershko, and Rose to "launch an attack" on the system, in order to uncover true pathway. Later findings of Ciechanover and subsequent groups showed that not only was the process energy-dependent, but that 8% of the human genome is remarkabley one large ubiquitin system. Following the recapitulation and reflection of his work, Ciechanover shares insights into his principal and philosophical approach to science and life alltogether. The life and work of Aaron Ciechanover are deeply rooted and influenced by Judaism and Israel and it is therefore that with only brief intermission, Ciechanover spent his scientific career in Israel as he is--through his presence and work--able to contribute and shape presence and future of the State of Israel. PMID:19571788

  7. Aaron Klug and the revolution in biomolecular structure determination.

    PubMed

    Amos, Linda A; Finch, John T

    2004-03-01

    Aaron Klug's group was one of the first to use a combination of X-ray diffraction and electron microscopy to study the structures of macromolecules. He helped to provide the intellectual framework for understanding the self-assembly of regular viruses and developed methods for analyzing their three-dimensional structures from electron microscope images, as well as the structures of helical polymers. He and his coworkers established the basic features of chromatin organization, including the structure of the repeating units (nucleosomes) and how they are stacked together. He studied a variety of molecules that interact with DNA or RNA, including disks of tobacco mosaic virus protein, a tRNA and a ribozyme, and also discovered the zinc-finger motif in nucleic acid-binding proteins. Thus, he has played a major part in developing the ideas and techniques that established structural molecular biology as an exciting new science during the second half of the twentieth century. PMID:15003624

  8. Culture in salutogenesis: the scholarship of Aaron Antonovsky.

    PubMed

    Benz, Carina; Bull, Torill; Mittelmark, Maurice; Vaandrager, Lenneke

    2014-12-01

    Aaron Antonovsky wrote extensively, although disjointedly, about the roles of culture in salutogenesis. This paper provides a synopsis of his work in this arena. A literature review identified those of his English language writings in which culture was a subject, and relevant text segments were analysed using an inductive followed by a deductive method. Using thematic network analysis, text segments were sorted inductively by open coding and then analysed. This was followed by deductive text segment coding guided by the constructs of the salutogenic model of health. The analysis revealed that Antonovsky had an expansive interest in the roles of culture in salutogenesis. His writings included attention to the role of culture in: (a) shaping life situations; (b) giving rise to stressors and resources; (c) contributing to life experiences of predictability, load balance and meaningful roles; (d) facilitating the development of the sense of coherence and (e) shaping perceptions of health and well-being. Antonovsky's writings about culture were sometimes conjectural, as well as being obviously influenced by his life experience in the USA and then in Israel, and by the spirit of the times in which he lived. However, he also drew extensively on his own and others' empiricism, leading him to view culture as an integral aspect of the salutogenic model of health. The present analysis provides salutogenesis scholars with a roadmap of Antonovsky's reflections, ponderings and conclusions about culture in the context of salutogenesis. It provides assistance in the form of an overview of Antonovsky's treatment of culture in the context of salutogenesis. PMID:24814861

  9. Culture in salutogenesis: the scholarship of Aaron Antonovsky

    PubMed Central

    Benz, Carina; Mittelmark, Maurice; Vaandrager, Lenneke

    2014-01-01

    Aaron Antonovsky wrote extensively, although disjointedly, about the roles of culture in salutogenesis. This paper provides a synopsis of his work in this arena. A literature review identified those of his English language writings in which culture was a subject, and relevant text segments were analysed using an inductive followed by a deductive method. Using thematic network analysis, text segments were sorted inductively by open coding and then analysed. This was followed by deductive text segment coding guided by the constructs of the salutogenic model of health. The analysis revealed that Antonovsky had an expansive interest in the roles of culture in salutogenesis. His writings included attention to the role of culture in: (a) shaping life situations; (b) giving rise to stressors and resources; (c) contributing to life experiences of predictability, load balance and meaningful roles; (d) facilitating the development of the sense of coherence and (e) shaping perceptions of health and well-being. Antonovsky’s writings about culture were sometimes conjectural, as well as being obviously influenced by his life experience in the USA and then in Israel, and by the spirit of the times in which he lived. However, he also drew extensively on his own and others’ empiricism, leading him to view culture as an integral aspect of the salutogenic model of health. The present analysis provides salutogenesis scholars with a roadmap of Antonovsky’s reflections, ponderings and conclusions about culture in the context of salutogenesis. It provides assistance in the form of an overview of Antonovsky’s treatment of culture in the context of salutogenesis. PMID:24814861

  10. Future-Minded: Aaron Schmidt--Thomas Ford Memorial Library, IL

    ERIC Educational Resources Information Center

    Library Journal, 2005

    2005-01-01

    Like many young people, Aaron Schmidt loves electronic gadgets. But not for their own sake. He believes the future of libraries depends on how well we meet the needs of today's young adults, who are far more tech-fluent than most librarians. As reference librarian and all-around technology guru at Thomas Ford Memorial Library, Schmidt created the…

  11. Computational Science as Part of Technology Education: An Interview with Aaron Clark

    ERIC Educational Resources Information Center

    Technology Teacher, 2008

    2008-01-01

    As teachers search for the most appropriate form of TIDE education for the future, they must consider as many alternatives as possible. One such alternative is computational science, which is described in detail in this interview with Dr. Aaron Clark of North Carolina State University. Dr. Clark recently agreed to this interview, with the primary…

  12. You Gotta Have a Gimmick: Aaron Coutu--Greenville Public Library, RI

    ERIC Educational Resources Information Center

    Library Journal, 2004

    2004-01-01

    This brief article describes the impact Aaron Coutu has had on the teens at the Greenville Public Library in Rhode Island. Coutu has gotten on the good side of many of the teens in the library since he is willing to undergo various personal humiliations, like shaving his head if they read 150 books (they read 196) or dyeing his hair green if they…

  13. Aaron Douglas and Hale Woodruff: African American Art Education, Gallery Work, and Expanded Pedagogy

    ERIC Educational Resources Information Center

    Bey, Sharif

    2011-01-01

    This analysis of archival materials discovered at Fisk and Atlanta Universities examines the teaching careers of Aaron Douglas and Hale Woodruff, two African American artists who came to prominence during the New Negro Movement in the 1920s and taught at historically Black universities in the 1930s and 1940s. These artists had a profound influence…

  14. Considering Pastoral Power: A Commentary on Aaron Schutz's "Rethinking Domination and Resistance: Challenging Postmodernism"

    ERIC Educational Resources Information Center

    Caughlan, Samantha

    2005-01-01

    In his "Rethinking Domination and Resistance: Challenging Postmodernism" ("Educational Researcher," January-February, 2004), Aaron Schutz questioned what he saw as postmodernism's fascination with the workings of pastoral modes of control, a preoccupation that prevents postmodernists from locating and opposing the disciplinary controls experienced…

  15. Desferal (DFO) induced Ga-67 washout from normal tissue, tumor and abscess in experimental animals

    SciTech Connect

    Oster, Z.H.; Som, P.; Atkins, H.L.; Brill, A.B.

    1980-01-01

    In the experimental animal, desferal (DFO) given intravenously washes out Ga-67 from all tissues. This effect is not uniform: blood activity is reduced very markedly, while liver activity is less affected. Maximal effect of DFO occurs if given close to the Ga-67 injection. When the time interval between the two is increased, the absolute amount of Ga-67 excreted in the urine in excess of the spontaneous excretion is reduced. Administration of DFO does not effect Ga-67 gastrointestinal excretion. In three animal tumor models (EMT-6 sarcoma in Balb/c mice, spontaneous adenocarcinoma in mice, and spontaneous adenocarcinoma in the rabbit) and in sterile abscess-bearing rats, the administration of DFO 24 hrs after Ga-67-citrate improves significantly the target-to-nontarget ratio. Animals given 50 mg/kg DFO I.V. after Ga-67 citrate showed a significant reduction in the whole-body activity as seen in a one-week follow up.

  16. Development of Ga-67 labeled DFO-DAS-fibrinogen conjugate as a thrombus imaging agent.

    PubMed

    Yamaoka, S

    1987-01-01

    A cluster method developed for labeling large molecular proteins with radioactive metal was applied for 67Ga-labeled fibrinogen. A large number of deferoxamine (DFO) was introduced to human fibrinogen using dialdehyde strarch (DAS) as a spacer-functional polymer. The synthesized DFO-DAS-fibrinogen mentioned above was easily labeled with GaCl3 (67Ga) solution (2 mCi/5 mg). The basic investigations found that 67Ga-DFO-DAS-fibrinogen was applicable to the diagnosis of thrombus, and clinical trials were carried out under the physician-sponsored IND. In our further investigation, improvement of the 67Ga-DFO-DAS-fibrinogen reagent was attempted to obtain high specific radioactivity. This was accomplished with the more familiar 67Ga citrate. From the results of a series of experiments, 67Ga-DFO-DAS-fibrinogen of a new composition labeled using 67Ga citrate with high specific radioactivity (2 mCi/3 mg) was prepared, and both reagents were evaluated as thrombus imaging agents from the chemical and biological aspects. The labeling efficiency and clottability of both 67Ga-DFO-DAS-fibrinogen conjugates were satisfactorily high, more than 95% and 80%, respectively. The biodistribution in rats showed that both 67Ga-DFO-DAS-fibrinogen conjugates were essentially the same. These results suggest that there are no significant differences between reagents. At present, the improved reagents are being supplied for the second clinical trials under physician-sponsored IND. PMID:3438481

  17. STS-26 press conference with crewmembers and JSC Director Aaron Cohen

    NASA Technical Reports Server (NTRS)

    1987-01-01

    STS-26 Discovery, Orbiter Vehicle (OV) 103, crew including Commander Frederick H. Hauck and Pilot Richard O. Covey and JSC Director Aaron Cohen participate in press conference held at JSC Auditorium and Public Affairs Facility Bldg 2. Hauck and Covey are shown with Cohen as they ponder queries from news media representatives during the first press conference for the group since the mission's announcement last week. Left to right are Covey, Hauck, and Cohen.

  18. STS-26 press conference with crewmembers and JSC Director Aaron Cohen

    NASA Technical Reports Server (NTRS)

    1987-01-01

    STS-26 Discovery, Orbiter Vehicle (OV) 103, crew including Commander Frederick H. Hauck, Pilot Richard O. Covey, Mission Specialist (MS) John M. Lounge, MS George D. Nelson, and MS David C. Hilmers and JSC Director Aaron Cohen participate in press conference held at JSC Auditorium and Public Affairs Facility Bldg 2. The five-man crew of NASA's recently announced STS-26 mission and Cohen answer questions from the news media. From the right are Cohen, Hauck, Covey, Lounge, Nelson, and Hilmers.

  19. Electron-Molecule Col1isions: Quantitative Approaches, and the Legacy of Aaron Temkin

    NASA Technical Reports Server (NTRS)

    Schneider, B.I.

    2007-01-01

    This article, on electron-molecule collisions, is dedicated to the legacy of my good friend and sometime collaborator, Aaron Temkin on his retirement from the NASA-Goddard Space Flight Center after many years of work at the highest intellectual level in the theoretical treatment of electron-atom and electron-molecule scattering. Aaron's contributions to the manner in which we think about electron-molecule collisions is clear to all of us who have worked in this field. I doubt that the great progress that has occurred in the computational treatment of such complex collision problems could have happened without these contributions. For a brief historical account, see the discussion of Temkin's contribution to electron-molecule scattering in the first article of this volume by Dr. A. K. Bhatia. In this article, I will concentrate on the application of the so called, non-adiabatic R-matrix theory, to vibrational excitation and dissociative attachment, although I will also present some results applying the Linear Algebraic and Kohn-Variational methods to vibrational excitation. As a starting point for almost all computationally effective approaches to electron-molecule collisions, is the fixed nuclei approximation. That is, one recognizes, just as one does with molecular bound states, that there is a separation of electronic(fast) and nuclear(s1ow) degrees of freedom. This separation makes it possible to "freeze" the nuclei in space, calculate the collision parameters for the frozen molecule and then, somehow to add back the vibrations and rotations. The manner in which this is done, depends on the details of the collision problem. It is the work of Aaron and a number of other researchers that has provided the guidance necessary to resolve these issues.

  20. Effects of the Microbial Siderophore DFO-B on Pb and Cd Speciation in Aqueous Solution

    SciTech Connect

    Mishra, Bhoopesh; Haack, Elizabeth A.; Maurice, Patricia A.; Bunker, Bruce A.

    2009-04-08

    This study investigates the complexation environments of aqueous Pb and Cd in the presence of the trihydroxamate microbial siderophore, desferrioxamine-B (DFO-B) as a function of pH. Complexation of aqueous Pb and Cd with DFO-B was predicted using equilibrium speciation calculation. Synchrotron-based X-ray absorption fine structure (XAFS) spectroscopy at Pb L(III) edge and Cd K edge was used to characterize Pb and Cd-DFO-B complexes at pH values predicted to best represent each of the metal-siderophore complexes. Pb was not found to be complexed measurably by DFO-B at pH 3.0, but was complexed by all three hydroxamate groups to form a totally 'caged' hexadentate structure at pH 7.5-9.0. At the intermediate pH value (pH 4.8), a mixture of Pb-DFOB complexes involving binding of the metal through one and two hydroxamate groups was observed. Cd, on the other hand, remained as hydrated Cd{sup 2+} at pH 5.0, occurred as a mixture of Cd-DFOB and inorganic species at pH 8.0, and was bound by three hydroxamate groups from DFO-B at pH 9.0. Overall, the solution species observed with EXAFS were consistent with those predicted thermodynamically. However, Pb speciation at higher pH values differed from that predicted and suggests that published constants underestimate the binding constant for complexation of Pb with all three hydroxamate groups of the DFO-B ligand. This molecular-level understanding of metal-siderophore solution coordination provides physical evidence for complexes of Pb and Cd with DFO-B, and is an important first step toward understanding processes at the microbial- and/or mineral-water interface in the presence of siderophores.

  1. Specific Sequestering Agents for the Actinides. 29. Stability of the Thorium(IV) Complexes of Desferrioxamine B (DFO) and Three Octadentate Catecholate or Hydroxypyridinonate DFO Derivatives: DFOMTA, DFOCAMC, and DFO-1,2-HOPO. Comparative Stability of the Plutonium(IV) DFOMTA Complex(1).

    PubMed

    Whisenhunt, Donald W.; Neu, Mary P.; Hou, Zhiguo; Xu, Jide; Hoffman, Darleane C.; Raymond, Kenneth N.

    1996-07-01

    The metal complex stability constants of Th(IV) with desferrioxamine B (DFO) and three octadentate derivatives [N-(2,3-dihydroxy-4-carboxybenzoyl)desferrioxamine B (DFOCAMC), N-(1,2-dihydro-1-hydroxy-2-oxopyridin-6-yl)carbonyl)desferrioxamine B (DFO-1,2-HOPO) and N-(2,3-dihydroxy-4-(methylamido)benzoyl)desferrioxamine B (DFOMTA)] have been determined. The formation constant of the Pu(IV)/DFOMTA complex has also been determined, and the formation constants have been estimated for the other Pu(IV) complexes of octadentate DFO derivatives. The DFO derivatives form 1:1 complexes with Th(IV) in aqueous solution. The solution chemistry of the Th(IV) complexes has been studied by spectrophotometric, potentiometric and proton NMR titrations. The Th(IV) formation constants are as follows (log K(f) values and esd's): DFO, 26.6(1); DFOMTA, 38.55(5); DFOCAMC, 37.2(3); DFO-1,2-HOPO, 33.7(4). The Pu(IV)/DFOMTA formation constant, determined by competitive spectrophotometric titration is (log K(f) value) 41.7(2). The estimation of the other Pu(IV) formation constants are as follows (log K(f) values): DFOCAMC, 40.4; DFO-1,2-HOPO, 36.9. The selectivity of DFO and the three derivatives for actinide(IV) ions is discussed. PMID:11666621

  2. Aaron T. Beck's drawings and the psychoanalytic origin story of cognitive therapy.

    PubMed

    Rosner, Rachael I

    2012-02-01

    In this essay the author challenges the standard origin story of cognitive therapy, namely, that its founder Aaron T. Beck broke with psychoanalysis to pursue a more pragmatic, parsimonious, and experimentalist cognitive model. It is true that Beck broke with psychoanalysis in large measure as a result of his experimental disconfirmation of key psychoanalytic ideas. His new school of cognitive therapy brought the experimental ethos into every corner of psychological life, extending outward into the largest multisite randomized controlled studies of psychotherapy ever attempted and inward into the deepest recesses of our private worlds. But newly discovered hand-sketched drawings from 1964 of the schema, a conceptual centerpiece of cognitive therapy, as well as unpublished personal correspondence show that Beck continued to think psychoanalytically even after he broke with psychoanalysis. The drawings urge us to consider an origin story much more complex than the one of inherited tradition. This new, multifaceted origin story of cognitive therapy reaches beyond sectarian disagreements and speaks to a broader understanding of the theoretical underpinnings of cognitive therapy. PMID:22530375

  3. The superoxide dismutase (SOD)-mimic manganese-deferoxamine (Mn-DFO) improves survival following hemorrhagic and endotoxic shock

    SciTech Connect

    de Garavilla, L.; Chermak, T.; Valentine, H.L.; Hanson, R.C. )

    1990-02-26

    The novel, low-molecular weight, organo-metallic complex Mn-DFO functions in vitro as an SOD-mimic effectively dismutating the superoxide radical. Oxygen-derived free radicals appear to be involved in the pathology of both endotoxic (ENDO) and hemorrhagic (HEM) shock whereby treatment with SOD is associated with improvements in survival. Therefore, the following models were utilized to evaluate the in vivo activity of Mn-DFO. Male rats (350-450g) were anesthetized with ketamine (100mg/kg, ip) and subjected to HEM hypotension by withdrawing approximately 40% of the animals' blood volume over a 10 minute period. MABP was maintained constant at 40mmHg for 60 minutes, followed by complete autoreinfusion. Survival was reduced to 20% in the control group at 24 hour post-reinfusion. A single post-shock dose of Mn-DFO (10mg/kg, iv) more than doubled the survival rate for up to 24 hour post-reinfusion as compared to control. Female mice (CFmal and-1, 20-25g) were challenged with 500ug of ENDO and 0.8ug of actinomycin/animal and dosed 1 hour pre and post with Mn-DFO (30mg/kg/dose, iv). Survival improved from 60% in the control group to 100% in the Mn-DFO group at 18 hours post ENDO challenge. Using a multiple dosing regimen, Mn-DFO significantly improved survival for up to 48 hours post-ENDO. Thus, unlike other SOD-mimics, Mn-DFO appears to exhibit in vivo activity.

  4. The Bioconjugation and Radiosynthesis of 89Zr-DFO-labeled Antibodies

    PubMed Central

    Zeglis, Brian M.; Lewis, Jason S.

    2015-01-01

    The exceptional affinity, specificity, and selectivity of antibodies make them extraordinarily attractive vectors for tumor-targeted PET radiopharmaceuticals. Due to their multi-day biological half-life, antibodies must be labeled with positron-emitting radionuclides with relatively long physical decay half-lives. Traditionally, the positron-emitting isotopes 124I (t1/2 = 4.18 d), 86Y (t1/2 = 14.7 hr), and 64Cu (t1/2 = 12.7 hr) have been used to label antibodies for PET imaging. More recently, however, the field has witnessed a dramatic increase in the use of the positron-emitting radiometal 89Zr in antibody-based PET imaging agents. 89Zr is a nearly ideal radioisotope for PET imaging with immunoconjugates, as it possesses a physical half-life (t1/2 = 78.4 hr) that is compatible with the in vivo pharmacokinetics of antibodies and emits a relatively low energy positron that produces high resolution images. Furthermore, antibodies can be straightforwardly labeled with 89Zr using the siderophore-derived chelator desferrioxamine (DFO). In this protocol, the prostate-specific membrane antigen targeting antibody J591 will be used as a model system to illustrate (1) the bioconjugation of the bifunctional chelator DFO-isothiocyanate to an antibody, (2) the radiosynthesis and purification of a 89Zr-DFO-mAb radioimmunoconjugate, and (3) in vivo PET imaging with an 89Zr-DFO-mAb radioimmunoconjugate in a murine model of cancer. PMID:25741890

  5. Aaron O. Wells, MD and the Medical Committee for Human Rights: reflections on a life of conscience.

    PubMed Central

    Wells, Aaron O.

    2004-01-01

    The southern civil rights movement compelled Dr. Aaron Wells and other doctors to find ways to use their skills in support of that movement. Through the Medical Committee for Human Rights (MCHR), healthcare workers provided a medical presence for civil rights protesters in the south during the 1960s. Formed at a time when racial segregation in professional medical associations, hospitals, and medical education was common, the MCHR also highlighted race-based inequities in American medicine. Dr. Wells, a man who lives a life of activism, was the first national president of the MCHR. During the summer of 2002, nearly 40 years after the founding of MCHR, Wells was interviewed about his experiences. Those reminiscences are the basis of this article. Images p1520-a PMID:15586659

  6. Effect of microbial siderophore DFO-B on Cd accumulation by Thlaspi caerulescens hyperaccumulator in the presence of zeolite.

    PubMed

    Karimzadeh, Lotfollah; Heilmeier, Hermann; Merkel, Broder J

    2012-07-01

    Hyperaccumulators are grown in contaminated soil and water in order that contaminants are taken up and accumulated. Transport of metals from soil to plant is initially dependent on the solubility and mobility of metals in soil solution which is controlled by soil and metal properties and plant physiology. Complexation with organic and inorganic ligands may increase mobility and availability of metals for plants. In this work the influence of desferrioxamine-B (DFO-B), which naturally is produced in the rhizosphere, and zeolite on Cd accumulation in root and shoot of Thlaspi caerulescens (Cd hyperaccumulator) was investigated. Plants were grown in pots with clean quartz sand, amended with 1% zeolite; treatment solutions included 0, 10, and 100 μM Cd and 70 μM DFO-B. Addition of zeolite to the quartz sand significantly reduced Cd concentration in plant tissues and translocation from root to shoot. On contrary, DFO-B considerably enhanced Cd sorption by roots and translocation to aerial part of plants. Treating the plants with zeolite and DFO-B together at 10 μM Cd resulted in reduction of the bioaccumulation factor but enhancement of Cd translocation from root to shoot at the rate of 13%. In contrast, at 100 μM Cd in the solution both bioaccumulation and translocation factors decreased. Total metal accumulation as a key factor for evaluating the efficiency of phytoremediation was highly influenced by treatments. Presence of zeolite in pots significantly decreased total Cd accumulation by plants, whereas, DFO-B clearly enhanced it. PMID:22572166

  7. 89Zr-DFO-J591 for immunoPET imaging of prostate-specific membrane antigen (PSMA) expression in vivo

    PubMed Central

    Holland, Jason P.; Divilov, Vadim; Bander, Neil H.; Smith-Jones, Peter M.; Larson, Steven M.; Lewis, Jason S.

    2010-01-01

    Zirconium-89 (t1/2 = 3.27 days) is a positron emitting radionuclide which displays excellent potential for use in the design and synthesis of radioimmunoconjugates for immunoPET. In these studies we report the preparation of 89Zr-DFO-J591, a novel 89Zr -labeled monoclonal antibody (mAb) construct for targeted immunoPET imaging and quantification of prostate-specific membrane antigen (PSMA) expression in vivo. Methods The in vivo behavior of [89Zr]Zr-chloride, [89Zr]Zr-oxalate and [89Zr]Zr-DFO was investigated by using PET imaging. High level computational studies using density functional theory (DFT) calculations have been used to investigate the electronic structure of [89Zr]Zr-DFO and probe the nature of the complex in aqueous conditions. J591 was functionalized with the hexadentate, tris-hydroxamate ligand desferrioxamine B (DFO) and radiolabeled with [89Zr]Zr-oxalate at room temperature. ImmunoPET imaging experiments in male, athymic nu/nu mice bearing sub-cutaneous LNCaP (PSMA positive) or PC-3 (PSMA negative) tumors were conducted. The change in 89Zr-DFO-J591 tissue uptake in response to high- and low-specific-activity formulations in the two tumor models was measured by using acute biodistribution studies and immunoPET. Results Basic characterization of three important reagents, [89Zr]Zr-chloride and [89Zr]Zr-oxalate, as well as the complex, [89Zr]Zr-DFO, demonstrated that the nature of the 89Zr species has a dramatic effect on the biodistribution and pharmacokinetics. DFT calculations provide a rationale for the observed high in vivo stability of 89Zr-DFO-labeled mAbs and suggest that in aqueous conditions, [89Zr]Zr-DFO forms a thermodynamically stable, 8-coordinate complex by coordination of two water molecules. 89Zr-DFO-J591 was produced in high radiochemical yield (>77%) with radiochemical purity >99% and a specific-activity of 181.7±1.1 MBq/mg (4.91±0.03 mCi/mg). In vitro assays demonstrated that 89Zr-DFO-J591 had an initial immunoreactive fraction of

  8. Experimental In Vitro Test of Differential `Femton' Oximetry (`DFO') Principle for Noninvasive Quantitative Diagnosis of Hypoxia

    NASA Astrophysics Data System (ADS)

    Druey, Chris; Radovic, Anna Z.; Maglich, Bogdan C.

    2010-03-01

    We report a high-resolution measurement of feasibility of noninvasive diagnosis of hypoxia via difference in γ rates from n + O --> O + γ + n between tumor, O1, and normal tissue, O2, using λDB 1 fm neutrons (`femtons'), which `count' atoms unaffected by molecular bonds. Q = (O1 -O2)/O1 quantifies hypoxia (<0), oxia (>0), and healthy tissue (=0). Hypoxic breast/prostate tumors have -0.80> Q <-0.96. DNA nucleotides dAdenosine, dCytosine and Thymidine, differing by 1 O atom, were irradiated with 14 MeV n's. We observed 1 atom as 0.012 ± .004 (3σ) γ rate difference. This implies that DFO would diagnose stand alone hypoxia Q = -0.10 and -0.25 with specificity 95% and 99%, respectively. As benchmark, we measured relative genome lengths of 2 mammal tissues to be Q = -0.12 ± .02, vs. 0.1 expected. These data suggest Femton Onco Physics as path to needle-less biopsy.

  9. 'The world is full of big bad wolves': investigating the experimental therapeutic spaces of R.D. Laing and Aaron Esterson.

    PubMed

    McGeachan, Cheryl

    2014-09-01

    In conjunction with the recent critical assessments of the life and work of R.D. Laing, this paper seeks to demonstrate what is revealed when Laing's work on families and created spaces of mental health care are examined through a geographical lens. The paper begins with an exploration of Laing's time at the Tavistock Clinic in London during the 1960s, and of the co-authored text with Aaron Esterson entitled, Sanity, Madness and the Family (1964). The study then seeks to demonstrate the importance Laing and his colleague placed on the time-space situatedness of patients and their worlds. Finally, an account is provided of Laing's and Esterson's spatial thinking in relation to their creation of both real and imagined spaces of therapeutic care. PMID:25114145

  10. ‘The world is full of big bad wolves’: investigating the experimental therapeutic spaces of R.D. Laing and Aaron Esterson

    PubMed Central

    2014-01-01

    In conjunction with the recent critical assessments of the life and work of R.D. Laing, this paper seeks to demonstrate what is revealed when Laing’s work on families and created spaces of mental health care are examined through a geographical lens. The paper begins with an exploration of Laing’s time at the Tavistock Clinic in London during the 1960s, and of the co-authored text with Aaron Esterson entitled, Sanity, Madness and the Family (1964). The study then seeks to demonstrate the importance Laing and his colleague placed on the time-space situatedness of patients and their worlds. Finally, an account is provided of Laing’s and Esterson’s spatial thinking in relation to their creation of both real and imagined spaces of therapeutic care. PMID:25114145

  11. Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

    PubMed Central

    Holland, Jason P.; Caldas-Lopes, Eloisi; Divilov, Vadim; Longo, Valerie A.; Taldone, Tony; Zatorska, Danuta; Chiosis, Gabriela; Lewis, Jason S.

    2010-01-01

    Background The positron-emitting radionuclide 89Zr (t1/2 = 3.17 days) was used to prepare 89Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted. Methodology/Principal Findings Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [89Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) tumor xenografts were conducted. The change in 89Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. 89Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3±2.1 MBq/mg (2.82±0.05 mCi/mg of mAb). In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87±0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68±13.06%ID/g; 71.71±10.35%ID/g and 85.18±11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of 89Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75±4.43%ID/g and 41.42±3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64±12.17%ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels. Conclusions/Significance The results indicate that 89Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors, and has

  12. Aaron's Law Act of 2013

    THOMAS, 113th Congress

    Rep. Lofgren, Zoe [D-CA-19

    2013-06-20

    07/15/2013 Referred to the Subcommittee on Crime, Terrorism, Homeland Security, and Investigations. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  13. Aaron's Solution, Instructor's Problem: Teaching Surface Analysis Using GIS

    ERIC Educational Resources Information Center

    Koch, Tom; Denike, Ken

    2007-01-01

    Teaching GIS is relatively simple, a matter of helping students develop familiarity with the software. Mapping as an aid to thinking is harder to instruct. This article presents a laboratory and lecture package developed to teach the utility of mapping in a course on spatial data analysis. Following a historical review of the use of surface…

  14. Patellar dislocation with genu valgum treated by DFO.

    PubMed

    Kwon, Jae Ho; Kim, Jong In; Seo, Dong-Hyun; Kang, Kyung-Woon; Nam, Ji Ho; Nha, Kyung-Wook

    2013-06-01

    Congenital habitual patellar dislocation is a rare condition of the knee where the patella dislocates during flexion and relocates during extension. The congenital form is permanent, irreducible, and presents at birth. It is characterized by a short quadriceps and a major patellofemoral dysplasia and short height. This article presents a rare case of a 27-year-old woman with recurring bilateral habitual dislocation of the patella after a failed previous proximal and distal realignment procedure. Clinical examinations of both knees revealed genu valgus knees and lateral joint pain that recurred after several previous operations. Radiographs of both knees showed patellar dislocation and genu valgum associated with patellofemoral dysplasia and osteoarthritis of the lateral compartment. Long-leg standing radiographs showed an anatomic tibiofemoral angle of right 13° and left 6° valgus and a mechanical tibiofemoral angle of right 8° and left 2° valgus and weight-bearing line of 65% on the right and 48% on the left. The authors performed a distal femoral closing wedging osteotomy to correct the valgus deformity, and then percutaneous lateral release and medial reefing were performed to stabilize the patellas of both knees simultaneously. PMID:23746026

  15. 76 FR 66969 - Aaron Gloskowski, D.O.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... unlawful distribution to others.'' Tony T. Bui, M.D., 75 FR 49979, 49989 (2010) (citations omitted.) As.... David W. Wang, 72 FR 54297, 54298 (2007); Sheran Arden Yeates, 71 FR 39130, 39131 (2006); Dominick A. Ricci, 58 FR 51104, 51105 (1993); Bobby Watts, 53 FR 11919, 11920 (1988). See also 21 U.S.C....

  16. Calcaneal Osteomyelitis Associated With a Severe Abscess

    PubMed Central

    Memis, Ali; Mutluoglu, Mesut; Öztürk, Sinan; Kara, Kemal; Ay, Hakan

    2016-01-01

    Diabetic foot osteomyelitis (DFO) is a common complication of the diabetic foot and the majority of minor and major amputations are preceded by DFO. The diagnosis and treatment of DFO are both challenging. Early recognition and comprehensive management of diabetic foot infections may obviate DFO, hence the dreadful consequence-resection of the infected bone. Herein, we present the successful management of a patient presenting with DFO and severe abscess formation of the heel. PMID:27104146

  17. Calcaneal Osteomyelitis Associated With a Severe Abscess.

    PubMed

    Memis, Ali; Mutluoglu, Mesut; Öztürk, Sinan; Kara, Kemal; Ay, Hakan

    2014-12-01

    Diabetic foot osteomyelitis (DFO) is a common complication of the diabetic foot and the majority of minor and major amputations are preceded by DFO. The diagnosis and treatment of DFO are both challenging. Early recognition and comprehensive management of diabetic foot infections may obviate DFO, hence the dreadful consequence-resection of the infected bone. Herein, we present the successful management of a patient presenting with DFO and severe abscess formation of the heel. PMID:27104146

  18. In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator.

    PubMed

    Hamilton, Jasmine L; Imran Ul-Haq, Muhammad; Abbina, Srinivas; Kalathottukaren, Manu Thomas; Lai, Benjamin F L; Hatef, Azadeh; Unniappan, Suraj; Kizhakkedathu, Jayachandran N

    2016-09-01

    Desferrioxamine (DFO) is currently in clinical use to remove iron from transfusion-dependent patients with β-thalassemia major, sickle-cell anemia and the myelodysplastic syndromes. However, its short half-life, burdensome, subcutaneous mode of administration and propensity to cause neurotoxicity at high doses greatly hinder its use. Thus, developing an optimized version of DFO with extended half-life, and reduced toxicity is a major goal. Using high molecular weight (MW), non-toxic, hyperbranched polyglycerol with high functionality, we demonstrate that the efficacy of DFO can be tuned with considerable reduction in toxicity. Using zebrafish embryos and mice, we tested toxicity, iron removal efficacy with low dosing and the biodistribution of ultra-long circulating DFO (ULC-DFO) conjugates. There was no significant difference in the mortality and development of zebrafish embryos upon exposure to ULC-DFO. Similarly, body weights and serum lactate dehydrogenase levels in mice treated with ULC-DFO remained within the normal range throughout the tolerance study. Moreover, ULC-DFO is significantly more effective than low MW DFO in promoting iron removal both from organs and via urine in iron overloaded mice despite using a moderate, once-weekly dosing schedule. This is probably due to the extended circulation half-life of ULC-DFO. The MW of ULC-DFO influences the accumulation and biodistribution, with highest MW (637 KDa) associated with up to 12% accumulation in the liver. In contrast, ULC-DFO with MWs of 75 KDa and lower were associated with relatively low organ accumulation, indicating that biodistribution of ULC-DFO can be tuned. Since ULC-DFO has improved iron removal properties, longer plasma retention time and possesses excellent biocompatibility, it represents a polymer conjugate with high clinical utility in comparison to DFO for the treatment of transfusion dependent iron overload. More importantly, ULC-DFO is anticipated to reduce the requirement for

  19. Eighth report of the Normandy Archaeological Project: 1975 excavations at the Eoff I site (40CF32), Aaron Shelton site (40CF69) and the Duke I site (40CF97)

    SciTech Connect

    Faulkner, C.H.; McCollough, C.R. . Dept. of Anthropology)

    1982-01-01

    This report discusses the research conducted during the last full field season for the Normandy Archaeological Project. There was a deep sense of urgency to use all available resources to continue to test crucial hypotheses about subsistence and settlement patterns of the Middle Woodland and Mississippian cultures in the lower and upper reservoir zones. The most salient of these hypotheses were prehistoric agricultural societies in the upper Duck Valley, and exploitative strategies of prehistoric hunters and gatherers in the upper Duck Valley differed in the lower and upper reservoir zones. Since the early Mississippian Banks phase and the late Middle Woodland Owl Hollow phase exhibited evidence for both food production and permanent settlement in the lower reservoir zone, a continued attempt was made to excavate those sites on which components of these two phase were found. Additional community pattern data and chronometric dates for the Banks phase were also sought since previously obtained radiocarbon assays indicated this was one of the earliest Mississippian cultures in the Middle South. The study of the origins and local development of this culture was also given priority status in Normandy Research. 145 refs., 33 figs., 94 tabs.

  20. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

    PubMed Central

    Boelaert, J R; de Locht, M; Van Cutsem, J; Kerrels, V; Cantinieaux, B; Verdonck, A; Van Landuyt, H W; Schneider, Y J

    1993-01-01

    This study investigates the pathophysiology of mucormycosis caused by Rhizopus, which has been reported in 46 dialysis patients, while treated with deferoxamine (DFO). This drug aggravates mucormycosis, which we experimentally induced in guinea pigs and which lead to a shortened animal survival (P < or = 0.01). The drug's effect on Rhizopus is not mediated through the polymorphonuclear cells. Fe.DFO, the iron chelate of DFO, abolishes the fungistatic effect of serum on Rhizopus and increases the in vitro growth of the fungus (P < or = 0.0001). This effect is present at Fe.DFO concentrations > or = 0.01 microM, at which fungal uptake of radioiron from 55Fe.DFO is observed. A 1,000-fold higher concentration of iron citrate is required to achieve a similar rate of radioiron uptake and of in vitro growth stimulation as observed with Fe.DFO. These in vitro effects of Fe.DFO (1 microM) in serum on radioiron uptake and on growth stimulation are more striking for Rhizopus than for Aspergillus fumigatus and are practically absent for Candida albicans. For these three fungal species, the rates of radioiron uptake from 55Fe.DFO and of growth stimulation in the presence of Fe.DFO in serum are directly related (r = 0.886). These results underscore the major role of Fe.DFO in the pathogenesis of DFO-related mucormycosis. Pharmacokinetic changes in uremia lead to a prolonged accumulation of Fe.DFO after DFO administration, which helps explain the increased sensitivity of dialysis patients to DFO-related mucormycosis. Images PMID:8486769

  1. Iron Chelation by Deferoxamine Prevents Renal Interstitial Fibrosis in Mice with Unilateral Ureteral Obstruction

    PubMed Central

    Tajima, Soichiro; Imao, Mizuki; Horinouchi, Yuya; Izawa-Ishizawa, Yuki; Kihira, Yoshitaka; Miyamoto, Licht; Ishizawa, Keisuke; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2014-01-01

    Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses. PMID:24586712

  2. Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.

    PubMed

    Ikeda, Yasumasa; Ozono, Iori; Tajima, Soichiro; Imao, Mizuki; Horinouchi, Yuya; Izawa-Ishizawa, Yuki; Kihira, Yoshitaka; Miyamoto, Licht; Ishizawa, Keisuke; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2014-01-01

    Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox) expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses. PMID:24586712

  3. Imaging PEG-like nanoprobes in tumor, transient ischemia, and inflammatory disease models.

    PubMed

    Wilks, Moses Q; Normandin, Marc D; Yuan, Hushan; Cho, Hoonsung; Guo, Yanyan; Herisson, Fanny; Ayata, Cenk; Wooten, Dustin W; El Fakhri, Georges; Josephson, Lee

    2015-06-17

    The iron chelator deferoxamine (DFO), approved for the treatment of iron overload, has been examined as a therapeutic in a variety of conditions which iron may exacerbate. To evaluate the potential of DFO-bearing PEG-like nanoprobes (DFO-PNs) as therapeutics, we determined their pharmacokinetics (PK) in normal mice, and imaged their accumulation in a tumor model and in models of transient brain ischemia and inflammation. DFO-PNs consist of a DFO, a Cy5.5, and PEG (5 kDa or 30 kDa) attached to Lys-Cys scaffold. Tumor uptake of a [(89)Zr]:DFO-PN(10) (30 kDa PEG, diameter 10 nm) was imaged by PET, surface fluorescence, and fluorescence microscopy. DFO-PN(10) was internalized by tumor cells (fluorescence microscopy) and by cultured cells (by FACS). [(89)Zr]:DFO-PN(4.3) (5 kDa PEG, diameter 4.3 nm) concentrated at incision generated inflammations but not at sites of transient brain ischemia. DFO-PNs are fluorescent, PK tunable forms of DFO that might be investigated as antitumor or anti-inflammatory agents. PMID:25971846

  4. Clinically achievable plasma deferoxamine concentrations are therapeutic in a rat model of Pneumocystis carinii pneumonia.

    PubMed Central

    Merali, S; Chin, K; Del Angel, L; Grady, R W; Armstrong, M; Clarkson, A B

    1995-01-01

    The iron-chelating drug deferoxamine (DFO) has been shown to be active in animal models of Pneumocystis carinii pneumonia (PCP), with effective daily intraperitoneal bolus dosages being 400 and 1,000 mg of DFO mesylate kg of body weight-1 in mouse and rat models, respectively. Continuous infusion produced a moderately improved response in a rat model. The data reported here demonstrate that the response achieved by continuous infusion of 195 and 335 mg of DFO mesylate kg-1 day-1 in the rat model is associated with mean concentrations in plasma of 1.3 and 2.5 micrograms of DFO ml-1 and mean concentrations in lung tissue of 4.9 and 6.0 micrograms of DFO g of lung tissue-1, respectively. Since current clinical use of DFO mesylate for the treatment of iron overload produces higher concentrations in the plasma of patients, DFO may prove to be a useful anti-PCP treatment. The 2.4- to 3.8-fold higher DFO concentration observed in lung tissue compared with that observed in plasma may be important in the response of PCP to DFO. PMID:8540710

  5. Deferoxamine restores callus size, mineralization and mechanical strength in fracture healing after radiotherapy

    PubMed Central

    Donneys, Alexis; Ahsan, Salman; Perosky, Joseph E.; Deshpande, Sagar S.; Tchanque-Fossuo, Catherine N.; Levi, Benjamin; Kozloff, Ken M.; Buchman, Steven R.

    2013-01-01

    Background Therapeutic augmentation of fracture site angiogenesis with Deferoxamine (DFO) has proven to increase vascularity, callus size and mineralization in long-bone fracture models. We posit that the addition of DFO would enhance pathological fracture healing in the setting of radiotherapy in a model where non-unions are the most common outcome. Methods Sprague-Dawley rats (n = 35) were divided into 3 groups. Fracture (Fx), radiated fracture (XFx) and radiated fracture + DFO (XFxDFO). Groups XFx and XFxDFO received a human equivalent dose of radiotherapy (7 Gy/day × 5 days = 35 Gy) 2 weeks prior to mandibular osteotomy and external fixation. The XFxDFO group received injections of DFO into the fracture callus after surgery. Following a 40-day healing period, mandibles were dissected, clinically assessed for bony-union, imaged with Micro-CT, and tension tested to failure. Results Compared to radiated fractures, metrics of callus size, mineralization and strength in DFO treated mandibles were significantly increased. These metrics were restored to a level demonstrating no statistical difference from control fractures. In addition we observed an increased rate of achieving bony unions in the XFxDFO treated group when compared to XFx (67% vs. 20% respectively). Conclusions Our data demonstrate near total restoration of callus size, mineralization, and biomechanical strength, as well as a 3-fold increase in the rate of union with the use of DFO. Our results suggest that the administration of DFO may have the potential for clinical translation as a new treatment paradigm for radiation induced pathologic fractures. Level of Evidence Animal study, not gradable for level of evidence. PMID:23629110

  6. Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use.

    PubMed

    Porter, J B; Rafique, R; Srichairatanakool, S; Davis, B A; Shah, F T; Hair, T; Evans, P

    2005-01-01

    Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes. PMID:16339661

  7. Macromol. Rapid Commun. 11/2016.

    PubMed

    Bagheri, Ali; Yeow, Jonathan; Arandiyan, Hamidreza; Xu, Jiangtao; Boyer, Cyrille; Lim, May

    2016-06-01

    Back Cover: Polymers featuring photoresponsive groups have been exploited as promising drug delivery systems. Light as spatially and temporally controllable external stimulus can be readily tuned and focused to trigger changes in the structure of polymer chains to provide "on-command" drug delivery. A benign synthesis route for a novel controlled polymerization, known as photoinduced electron/energy transfer-reversible addition-fragmentation (PET-RAFT) polymerization, is presented. Further details can be found in the article by A. Bagheri, J. Yeow, H. Arandiyan, J. Xu, C. Boyer,* and M. Limon page 905. PMID:27250999

  8. Gamma and pulse radiolysis investigation of the reaction of desferrioxamine with superoxide anions.

    PubMed

    Sabourault, D; Ribiere, C; Nordmann, R; Houee-Levin, C; Ferradini, C

    1989-12-01

    The kinetic scheme of the reaction of desferrioxamine (DFO) with O2-. was studied using pulse and gamma-radiolysis. The rate constant k(O2-. + DFO) is equal to 1.3 +/- 0.1 x 10(6) dm3 mol-1s-1 at pH 7.4. Studying the competition between DFO and ferricytochrome-c for O2-. generated by gamma-radiolysis, we observed that the nitroxide free radical resulting from the reaction of O2-. with DFO and the product(s) resulting from the decay of this nitroxide radical act inversely towards the cytochrome-c-Fe3+/cytochrome-c-Fe2+ redox couple. This explains the discrepancy between our value of k(O2-. + DFO) and the one measured previously using ferricytochrome-c for the detection of O2-. The reported results show that DFO acts as a powerful O2-. scavenger, and that the products resulting from the reaction of DFO with O2-. can initiate oxidative and/or reductive reactions that should be taken into account in interpreting the effects of DFO in vitro and in vivo. PMID:2574220

  9. 75 FR 25850 - Blue Ribbon Commission on America's Nuclear Future

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-10

    ... Ribbon Commission on America's Nuclear Future AGENCY: Department of Energy, Office of Nuclear Energy...- 0544; e-mail CommissionDFO@nuclear.energy.gov . Additional information may also be available at http... to CommissionDFO@nuclear.energy.gov , or post comments on the Commission Web site at...

  10. 76 FR 4646 - Blue Ribbon Commission on America's Nuclear Future

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-26

    ... Ribbon Commission on America's Nuclear Future AGENCY: Department of Energy, Office of Nuclear Energy... facsimile (202) 586- 0544; e-mail CommissionDFO@nuclear.energy.gov . Additional information will be... to CommissionDFO@nuclear.energy.gov , or post comments on the Commission Web site at...

  11. 75 FR 51025 - Blue Ribbon Commission on America's Nuclear Future, Reactor and Fuel Cycle Technology Subcommittee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-18

    ...: Department of Energy, Office of Nuclear Energy. ACTION: Notice of open meeting. SUMMARY: This notice...- 0544; e-mail CommissionDFO@nuclear.energy.gov . Additional information will be available at http://www... to CommissionDFO@nuclear.energy.gov , or post comments on the Commission Web site at...

  12. 78 FR 26636 - Notification of a Public Meeting of the Great Lakes Advisory Board

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-07

    ... public wishing further information regarding this meeting may contact Rita Cestaric, Designated Federal Officer (DFO), GLAB, by telephone at (312) 886-6815 or email at ] cestaric.rita@epa.gov . General.... Interested parties should contact Rita Cestaric, DFO, in writing (preferably via email) at the...

  13. Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of Rhizopus microsporus.

    PubMed

    de Locht, M; Boelaert, J R; Schneider, Y J

    1994-05-18

    Mucormycosis caused by the fungus Rhizopus has been documented in iron overloaded patients and more particularly in dialysis patients, both when treated with desferrioxamine B (DFO). This iron and aluminium chelator is thought to play a role in the pathogenesis of this infection. We therefore investigated in vitro the cellular pharmacology of iron chelated by DFO in the fungus Rhizopus. In a medium, designed for fungal cultivation, Rhizopus microsporus var. rhizopodiformis takes up iron from ferric-DFO complex (55Fe.DFO) and from 55Fe.rhizoferrin, the siderophore synthesized and secreted by Rhizopus [Drechsel et al., Biol. Metals 4: 238-243, 1991]. In both cases, iron accumulation is partially saturable with the duration of exposure and the chelator concentration. Fe.DFO binds to Rhizopus; iron becomes trapped and remains associated with the fungus, whereas the iron-depleted siderophore is released in the extracellular medium. In a medium designed for mammalian cell cultivation and in the absence of human serum, the fungal iron accumulation both from 55Fe.DFO and from 55Fe.rhizoferrin is proportional to the chelator concentration. Human serum at 40% does not influence the iron accumulation from Fe.DFO but it significantly affects that from Fe.rhizoferrin which, in the presence of serum, only occurs at concentration > 5 microM. This difference finds its explanation in the iron transfer observed between Fe.rhizoferrin and seric apotransferrin, the latter making the metal unavailable to Rhizopus. By contrast, no iron transfer takes place between Fe.DFO and apotransferrin, allowing fungal iron utilization from this complex, even at very low concentrations. The iron uptake, being inhibited by NaN3 and KCN, is energy-dependent; being inhibited by bipyridyl, it requires prior reduction of ferric iron; being unaffected by the covalent linkage of Fe.DFO to albumin, it does not require the entry of Fe.DFO within the fungus. These in vitro results strongly suggest that, upon

  14. The Vod Couple

    ERIC Educational Resources Information Center

    Schaffhauser, Dian

    2009-01-01

    This article features two high school chemistry teachers, Aaron Sams and Jonathan Bergmann, who have overturned conventional classroom instruction by using video podcasts to form the root of a new learning model. Thumbing through an issue of "MacWorld" a few years ago, Aaron Sams was struck by an article about an application called ProfCast that…

  15. 76 FR 27895 - Safety Zone; 2011 Memorial Day Tribute Fireworks, Lake Charlevoix, Boyne City, MI

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... rule, call or e-mail MST1 Aaron Woof, U.S. Coast Guard, Sector Sault Sainte Marie, telephone 906-253-2423, e-mail at Aaron.M.Woof@uscg.mil . If you have questions on viewing the docket, call Renee...

  16. Mind, Machine, and Creativity: An Artist's Perspective

    ERIC Educational Resources Information Center

    Sundararajan, Louise

    2014-01-01

    Harold Cohen is a renowned painter who has developed a computer program, AARON, to create art. While AARON has been hailed as one of the most creative AI programs, Cohen consistently rejects the claims of machine creativity. Questioning the possibility for AI to model human creativity, Cohen suggests in so many words that the human mind takes a…

  17. 75 FR 32932 - Combined Notice of Filings No. 1

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-10

    .... Applicants: Nexen Marketing, J. Aaron & Company. Description: Joint Petition for Temporary Waivers of... of Nexen Marketing U.S.A. Inc. and J. Aaron & Company. Filed Date: 05/21/2010. Accession Number... proceedings are accessible in the Commission's eLibrary system by clicking on the appropriate link in...

  18. 78 FR 26368 - Change in Bank Control Notices; Acquisitions of Shares of a Bank or Bank Holding Company

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-06

    ... 64198-0001: 1. Aaron W. Anderson, Topeka, Kansas; Angela Anderson Swift, Overland Park, Kansas; Emery... trusts: Aaron W. Anderson Trust; Angela Anderson Swift Trust; Emery Kent Fager Trust; John Fontron Fager... Ellen Anderson Trust; Andrew Timothy Swift Trust; Sarah Ann Swift Trust; Samuel James Swift...

  19. The Difficulties of a Young Gifted Child: Lessons from History.

    ERIC Educational Resources Information Center

    Diezmann, Carmel M.; Watters, James J.

    This paper presents a case study of Aaron, a 9-year-old Australian gifted student who has exhibited an outstanding interest and knowledge in science and mathematics, while at the same time displaying unusual behavioral and learning characteristics typified by inconsistent performance of many routine tasks. Aaron attends a moderately sized…

  20. Statement of Aaron Cohen, Director, Research and Engineering, Johnson Space Center and Chairman, Space Station Advanced Technology Advisory Committee, National Aeronautics and Space Administration, before the Subcommittee on Science, Technology, and Space, Committee on Commerce, Science, and Transportation, United States Senate

    NASA Technical Reports Server (NTRS)

    Cohen, A.

    1985-01-01

    The activities of NASA's Space Station Advanced Technology Advisory Committee is discussed. Advanced Technology Advisory Committee (ATAC) activities over the last year are reviewed in preparation of the report to Congress on the potential for advancing automation and robotics technology for the space station and for the U.S. economy.

  1. Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation.

    PubMed

    Fine, Jared M; Renner, Daniel B; Forsberg, Anna C; Cameron, Rachel A; Galick, Benjamin T; Le, Clint; Conway, Patrick M; Stroebel, Benjamin M; Frey, William H; Hanson, Leah R

    2015-01-01

    In addition to the hallmark accumulation of amyloid and hyper-phosphorylation of tau, brain changes in Alzheimer's disease are multifactorial including inflammation, oxidative stress, and metal dysregulation. Metal chelators have been explored as a less well known approach to treatment. One chelator currently being developed is deferoxamine (DFO), administered via the intranasal (IN) route. In the current study, APP/PS1 amyloid mice were treated with a chronic, low dose of IN DFO, subjected to a rigorous battery of behavior tests, and the mechanism of action was examined. Mice were treated 3x/week with 0.24 C IN DFO for 18 weeks from 36 to 54 weeks of age, 4 weeks of behavior tests were performed that included both working and reference memory, anxiolytic and motor behaviors, and finally brain tissues were analyzed for amyloid, protein oxidation, and other proteins affected by DFO. We found that IN DFO treatment significantly decreased loss of both reference and working memory in the Morris and radial arm water mazes (p < 0.05), and also decreased soluble Aβ40 and Aβ42 in cortex and hippocampus (p < 0.05). Further, IN DFO decreased activity of GSK3β, and led to decreases in oxidative stress (p < 0.05). These data demonstrate that low doses of IN DFO can modify several targets along the multiple pathways implicated in the neuropathology of Alzheimer's, making it an attractive candidate for the treatment of this heterogeneous disease. PMID:25445365

  2. Quantum chemical study of the Fe(III)-desferrioxamine B siderophore complex—Electronic structure, vibrational frequencies, and equilibrium Fe-isotope fractionation

    NASA Astrophysics Data System (ADS)

    Domagal-Goldman, S. D.; Paul, K. W.; Sparks, D. L.; Kubicki, J. D.

    2009-01-01

    This study presents molecular orbital/density functional theory (MO/DFT) calculations of the electronic structure, vibrational frequencies, and equilibrium isotope fractionation factors for iron desferrioxamine B (Fe-DFO-B) complexes in aqueous solution. In general, there was good agreement between the predicted properties of Fe(III)-DFO-B and previously published experimental and theoretical results. The predicted fractionation factor for equilibrium between Fe(III)-DFO-B and Fe(III)-catecholate at 22 °C, 0.68 ± 0.25‰, was in good agreement with a previously measured isotopic difference between bacterial cells and solution during the bacterial-mediated dissolution of hornblende [Brantley S. L., Liermann L. and Bullen T. D. (2001) Fractionation of Fe isotopes by soil microbes and organic acids. Geology29, 535-538]. Conceptually, this agreement is consistent with the notion that Fe is first removed from mineral surfaces via complexation with small organic acids (e.g., oxalate), subsequently sequestered by DFO-B in solution, and ultimately delivered to bacterial cells by Fe(III)-DFO-B complexes. The ability of DFO-B to discriminate between Fe(III) and Fe(II)/Al(III) was investigated with Natural Bond Orbital (NBO) analysis and geometry calculations of each metal-DFO-B complex. The results indicated that higher affinity for Fe(III) is not strictly a function of bond length but also the degree of Fe-O covalent bonding.

  3. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature

    PubMed Central

    Di Nicola, Maura; Barteselli, Giulio; Dell'Arti, Laura; Ratiglia, Roberto; Viola, Francesco

    2015-01-01

    Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease. PMID:26167477

  4. Deferoxamine alleviates liver fibrosis induced by CCl4 in rats.

    PubMed

    Mohammed, Aya; Abd Al Haleem, Ekram N; El-Bakly, Wesam M; El-Demerdash, Ebtehal

    2016-08-01

    Several chronic liver diseases can lead to the occurrence of hepatic fibrosis through the accumulation of iron, which causes induction of oxidative stress and consequently activation of fibrogenesis. The present study was designed to investigate the potential antifibrotic and anti-oxidant effects of deferoxamine (DFO), a well-known iron chelator in an experimental rat model of liver injury using carbon tetrachloride (CCl4 ). First, the potential effective dose of DFO was screened against CCl4 -induced acute hepatotoxicity. Then, rats were co-treated with DFO (300 mg/kg, i.p.) for 6 weeks starting from the third week of CCl4 induction of chronic hepatotoxicity. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress and fibrosis markers were assessed. It was found that treatment of animals with DFO significantly counteracted the changes in liver function; histopathological lesions and hepatic iron deposition that were induced by CCl4 . DFO also significantly counteracted the CCl4 -induced lipid peroxidation increase and reduction in antioxidant activities of superoxide dismutase and glutathione peroxidase enzymes. In addition, DFO ameliorated significantly liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cells (HSCs) activation marker; alpha smooth muscle actin and transforming growth factor-beta (TGF-β). Together, these findings indicate that DFO possesses a potent antifibrotic effect due to its antioxidant properties that counteracted oxidative stress and lipid peroxidation and restored antioxidant enzymes activities as well as reducing HSCs activation and fibrogenesis. PMID:27168353

  5. Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate.

    PubMed

    Rassu, Giovanna; Soddu, Elena; Cossu, Massimo; Brundu, Antonio; Cerri, Guido; Marchetti, Nicola; Ferraro, Luca; Regan, Raymond F; Giunchedi, Paolo; Gavini, Elisabetta; Dalpiaz, Alessandro

    2015-03-10

    We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-β-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 μm (DCH) to 3.47 ± 0.05 μm (MCD); the aerodynamic diameters were about 1.1 μm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron-like), but like DCH, it did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial-like). Nasal administration to rats of 200 μg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 μg/mL (DCH) to 14.37 ± 1.69 μg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-β-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure. PMID:25620068

  6. Preparation of Ga-67 labeled monoclonal antibodies using deferoxamine as a bifunctional chelating agent

    SciTech Connect

    Endo, K.; Furukawa, T.; Ohmomo, Y.; Sakahara, H.; Ohta, H.; Nakashima, T.; Okada, K.; Yoshida, O.; Yokoyama, A.; Torizuka, K.

    1984-01-01

    Ga-67 labeled monoclonal IgG or F(ab')/sub 2/ fragments against ..cap alpha..-fetoprotein and ..beta..-subunit of human choriogonadotropin (HCG), were prepared using Deferoxamine (DFO) as a bifunctional chelating agent. DFO, a well-known iron chelating agent, was conjugated with monoclonal antibodies (Ab) by a glutaraldehyde two step method and the effect of conjugation on the Ab activities was examined by RIA and Scatchard plot analysis. In both monoclonal Ab preparations, the conjugation reaction was favored as the pH increased. However, Ab-binding activities decreased as the molecular ratios of DFO to Ab increased. Preserved Ab activities were observed when Ab contained DFO per Ab molecule less than 2.1. At a ratio of over 3.3 DFO molecules per Ab, the maximal binding capacity rather than the affinity constant decreased. The inter-molecular cross linkage seemed to be responsible for the deactivation of binding activities. The obtained DFO-Ab conjugates, were then easily labeled with high efficiency and reproducibility and Ga-67 DFO-Ab complexes were highly stable both in vitro and in vivo. Thus, biodistribution of Ga-67 labeled F(ab')/sub 2/ fragments of monoclonal Ab to HCG ..beta..-subunit was attempted in nude mice transplanted with HCG-producing human teratocarcinoma. Tumor could be visualized, in spite of relatively high background imaging of liver, kidney and spleen. The use of DFO as a bifunctional chelating agent provided good evidence for its applicability to labeling monoclonal Ab with almost full retention of Ab activities. Further, availability of Ga-68 will make Ga-68 DFO-monoclonal Ab a very useful tool for positron tomography imaging of various tumors.

  7. Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate

    PubMed Central

    Rassu, Giovanna; Soddu, Elena; Cossu, Massimo; Brundu, Antonio; Cerri, Guido; Marchetti, Nicola; Ferraro, Luca; Regan, Raymond F.; Giunchedi, Paolo; Gavini, Elisabetta; Dalpiaz, Alessandro

    2015-01-01

    We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-β-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 μm (DCH) to 3.47 ± 0.05 μm (MCD); the aerodynamic diameters were about 1.1 μm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron like), but like DCH did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial like). Nasal administration to rats of 200 μg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 μg/mL (DCH) and 14.37 ± 1.69 μg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-β-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure. PMID:25620068

  8. Deferoxamine pretreatment prevents Cr(VI)-induced nephrotoxicity and oxidant stress: role of Cr(VI) chelation.

    PubMed

    Molina-Jijón, Eduardo; Zarco-Márquez, Guillermo; Medina-Campos, Omar Noel; Zataraín-Barrón, Zyanya Lucía; Hernández-Pando, Rogelio; Pinzón, Enrique; Zavaleta, Rosa Marina; Tapia, Edilia; Pedraza-Chaverri, José

    2012-01-27

    Deferoxamine (DFO) is a recognized iron chelator which has been shown to exert nephroprotection in models of toxic nephropathies. In the present work the potential protective effects of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress were evaluated. Rats were injected with a single injection (15mg/kg, s.c.) of potassium dichromate (K(2)Cr(2)O(7)). DFO was given as a single i.p. injection 30min before K(2)Cr(2)O(7) administration at three different doses (100, 200 and 400mg/kg). It was found that DFO pretreatment attenuated, in a dose-dependent way, K(2)Cr(2)O(7)-induced renal dysfunction and structural alterations evaluated by serum creatinine, blood urea nitrogen, creatinine clearance, proteinuria, plasma glutathione peroxidase activity, urinary excretion of N-acetyl-β-d-glucosaminidase and histological analyses. Furthermore, DFO prevented the K(2)Cr(2)O(7)-induced renal oxidant stress and the decrease in the activity of the antioxidant enzymes superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and catalase. Finally it was found that DFO, at 400mg/kg, decreases renal Cr(VI) content which prompted us to evaluate the potential Cr(VI) chelating properties of this compound. Indeed was found in an in vitro assay that DFO was an effective Cr(VI) chelator with an IC(50) of 800μg. In additional groups of rats was found that DFO posttreatment was ineffective to attenuate K(2)Cr(2)O(7)-induced nephrotoxicity and renal oxidant stress. Furthermore, DFO was unable to modify urinary excretion of total chromium. The nephroprotective effect of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress may be explained, at least partially, by the ability of DFO to chelate Cr(VI) and to attenuate renal Cr(VI) content. However, it cannot be excluded that the ability of DFO to chelate iron may also be involved in the protection observed in our study. PMID:22115772

  9. 75 FR 61781 - Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee on Planning and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-06

    ... ACRS meetings were published in the Federal Register on October 14, 2009, (74 FR 58268-58269). Detailed... obtained from the website cited above or by contacting the identified DFO. Moreover, in view of...

  10. 75 FR 28824 - Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee on Plant...

    Federal Register 2010, 2011, 2012, 2013, 2014

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  11. 77 FR 76074 - Advisory Committee on Veterans' Employment, Training and Employer Outreach (ACVETEO): Meeting

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  12. 78 FR 64931 - Advanced Scientific Computing Advisory Committee

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  13. 78 FR 50404 - Advanced Scientific Computing Advisory Committee

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  14. 76 FR 31945 - Advanced Scientific Computing Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-02

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  15. 78 FR 20093 - Notice of Availability for Public Comment on the U.S. Integrated Ocean Observing System Advisory...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-03

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    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-21

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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  19. Complexation of Pu(IV) with the natural siderophore desferrioxamine B and the redox properties of Pu(IV)(siderophore) complexes.

    PubMed

    Boukhalfa, Hakim; Reilly, Sean D; Neu, Mary P

    2007-02-01

    The bioavailability and mobility of Pu species can be profoundly affected by siderophores and other oxygen-rich organic ligands. Pu(IV)(siderophore) complexes are generally soluble and may constitute with other soluble organo-Pu(IV) complexes the main fraction of soluble Pu(IV) in the environment. In order to understand the impact of siderophores on the behavior of Pu species, it is important to characterize the formation and redox behavior of Pu(siderophore) complexes. In this work, desferrioxamine B (DFO-B) was investigated for its capacity to bind Pu(IV) as a model siderophore and the properties of the complexes formed were characterized by optical spectroscopy measurements. In a 1:1 Pu(IV)/DFO-B ratio, the complexes Pu(IV)(H2DFO-B)4+, Pu(IV)(H1DFO-B)3+, Pu(IV)(DFO-B)2+, and Pu(IV)(DFO-B)(OH)+ form with corresponding thermodynamic stability constants log beta1,1,2 = 35.48, log beta1,1,1 = 34.87, log beta1,1,0 = 33.98, and log beta1,1,-1 = 27.33, respectively. In the presence of excess DFO-B, the complex Pu(IV)H2(DFO-B)22+ forms with the formation constant log beta2,1,2 = 62.30. The redox potential of the complex Pu(IV)H2(DFO-B)22+ was determined by cyclic voltammetry to be E1/2 = -0.509 V, and the redox potential of the complex Pu(IV)(DFO-B)2+ was estimated to be E1/2 = -0.269 V. The redox properties of Pu(IV)(DFO-B)2+ complexes indicate that Pu(III)(siderophore) complexes are more than 20 orders of magnitude less stable than their Pu(IV) analogues. This indicates that under reducing conditions, stable Pu(siderophore) complexes are unlikely to persist. PMID:17257046

  20. Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.

    PubMed

    Guo, Chuang; Hao, Li-Juan; Yang, Zhao-Hui; Chai, Rui; Zhang, Shuai; Gu, Yu; Gao, Hui-Ling; Zhong, Man-Li; Wang, Tao; Li, Jia-Yi; Wang, Zhan-You

    2016-06-01

    Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator widely used in clinical settings, has been reported to improve motor deficits and dopaminergic neuronal survival in animal models of PD, DFO has poor penetration to cross the blood-brain barrier and elicits side effects. We evaluated whether an intranasal administration of DFO improves the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic neurons in the nigrostriatal axis and investigated the molecular mechanisms of intranasal DFO treatment in preventing MPTP-induced neurodegeneration. Treatment with DFO efficiently alleviated behavioral deficits, increased the survival of tyrosine hydroxylase (TH)-positive neurons, and decreased the action of astrocytes in the SN and striatum in an MPTP-induced PD mouse model. Interestingly, we found that DFO up-regulated the expression of HIF-1α protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of α-synuclein, divalent metal transporter with iron-responsive element (DMT1+IRE), and transferrin receptor (TFR). This was accompanied by a decrease in iron-positive cells in the SN and striatum of the DFO-treated group. We further revealed that DFO treatment significantly inhibited the MPTP-induced phosphorylation of the c-Jun N-terminal kinase (JNK) and differentially enhanced the phosphorylation of extracellular regulated protein kinases (ERK) and mitogen-activated protein kinase (MAPK)/P38 kinase. Additionally, the effects of DFO on increasing the Bcl-2/Bax ratio were further validated in vitro and in vivo. In SH-SY5Y cells, the DFO-mediated up-regulation of HIF-1α occurred via the activation of

  1. Volcanic synchronization of Dome Fuji and Dome C Antarctic deep ice cores over the past 216 kyr

    NASA Astrophysics Data System (ADS)

    Fujita, S.; Parrenin, F.; Severi, M.; Motoyama, H.; Wolff, E.

    2015-02-01

    Two deep ice cores, Dome Fuji (DF) and EPICA Dome C (EDC), drilled at remote dome summits in Antarctica, were synchronized to better understand their chronology. A total of 1401 volcanic tie points were identified covering the past 216 kyr. DFO2006, the chronology for the DF core characterized by strong constraining by the O2/N2 age markers, was compared with AICC2012, the chronology for 5 cores including the EDC core, and characterized by glaciological approaches combining ice flow modelling with various age markers. The age gaps between the two chronologies are within 2 kyr, except at Marine Isotope Stage (MIS) 5. DFO2006 gives ages older than AICC2012, with peak values of the gap of 4.5 and 3.1 kyr at MIS 5d and MIS 5b, respectively. Accordingly, ratios of duration DFO2006/AICC2012 are 85% at a period from the late stage of MIS 6 to MIS 5d and 114% at a period from MIS 5d to 5b. We then compared the DFO2006 with another chronology of the DF core, DFGT2006, characterized by glaciological approaches with weaker constraining by age markers. Features of the DFO2006/DFGT2006 age gaps are very similar to those of the DFO2006/AICC2012 age gaps. This fact lead us to hypothesize that a cause of the systematic DFO2006/AICC2012 age gaps at MIS 5 are associated with differences in the dating approaches. Besides, ages of speleothem records from China agreed well with DFO2006 at MIS 5c and 5d but not at MIS 5b. Thus, we hypothesize at least at MIS 5c and 5d, major sources of the gaps are systematic errors in surface mass balance estimation in the glaciological approach. Compatibility of the age markers should be carefully assessed in future.

  2. Interaction of Pseudomonas fluorescens with Eu(III) and Ce(IV) - Desferrioxamine Complexes

    NASA Astrophysics Data System (ADS)

    Yoshida, T.; Ozaki, T.; Ohnuki, T.; Francis, A.

    2002-12-01

    Naturally occurring chelating agents-, such as siderophores, are able to form complexes with actinides and enhance their solubility and mobility in the environment. Adsorption and/or biodegradation of chelated actinides by microorganisms are important processes which regulate their mobility in the natural environment. In this study, association of Eu(III), Ce(IV), and Fe(III) - desferrioxamine B (DFO) complexes with aerobic bacterium, Pseudomonas fluorescens (ATCC 55241), was investigated-, Eu(III) and Ce(IV) were used as analogues to trivalent and tetravalent actinides, respectively. When 20 μM of 1:1 Eu(III) - and Ce(IV) - DFO complexes were incubated with P. fluorescens in 0.1 M Tris-HCl buffer (pH = 7.3), the metals were removed from solution, with no change in DFO in solution. With decreasing metal/DFO molar ratio from 1 to 0.01, the accumulation of Eu(III) and Ce(IV) by P. fluorescens decreased. Kinetics study showed that accumulation of Eu(III) reached the maximum within 30 minutes, and then it decreased slightly with time. On the other hand, Ce(IV) accumulation proceeded in a parabolic process where the kinetics was slower than that of Eu(III) accumulation. In comparison to Eu(III) and Ce(IV), the removal of Fe(III) added as a DFO complex by P. fluorescens was not observed. The formation constants (log K) of Eu(III) - DFO and Fe(III) - DFO are reported to be 15 and 30.6, respectively. These results suggest that Eu(III) - DFO complex was dissociated in the presence of bacteria cells and was readily biosorbed.

  3. Phase I study using desferrioxamine and iron sorbitol citrate in an attempt to modulate the iron status of tumor cells to enhance doxorubicin activity.

    PubMed

    Voest, E E; Neijt, J P; Keunen, J E; Dekker, A W; van Asbeck, B S; Nortier, J W; Ros, F E; Marx, J J

    1993-01-01

    A novel approach to enhance the activity of doxorubicin is to increase the availability of cellular "chelatable" iron to participate in doxorubicin-mediated free-radical generation. To achieve this, we designed a regimen consisting of desferrioxamine (DFO, 50 mg/kg daily given as an i.v. infusion over 72 h) to increase cellular iron uptake. Thereafter, the combination of iron sorbitol citrate (ISC) and doxorubicin (as a single agent or as part of the CHOP regimen) was given. In a phase I study we investigated the toxicity of this regimen in nine patients with refractory malignant disease. Severe but reversible ocular toxicity (i.e., acute maculopathy) was observed in two patients. As these patients were the only ones who were pretreated with cisplatin, we caution against the use of DFO in cisplatin-pretreated patients. Severe phlebitis was encountered in five of nine patients. A partial remission was observed in two of four patients with refractory Non-Hodgkin's lymphoma who were treated with DFO, ISC, and doxorubicin as part of the CHOP regimen. We conclude that pretreatment with DFO and iron sorbitol citrate may be of benefit in the treatment of malignancies with doxorubicin-containing regimens, but ocular toxicity and severe phlebitis limits the use of DFO in this approach. The attachment of DFO to biocompatible polymers may be a method of overcoming the observed toxicity and warrants further study. PMID:8431969

  4. A Simple Small Size and Low Cost Sensor Based on Surface Plasmon Resonance for Selective Detection of Fe(III)

    PubMed Central

    Cennamo, Nunzio; Alberti, Giancarla; Pesavento, Maria; D'Agostino, Girolamo; Quattrini, Federico; Biesuz, Raffaela; Zeni, Luigi

    2014-01-01

    A simple, small size, and low cost sensor based on a Deferoxamine Self Assembled Monolayer (DFO-SAM) and Surface Plasmon Resonance (SPR) transduction, in connection with a Plastic Optical Fiber (POF), has been developed for the selective detection of Fe(III). DFO-SAM sensors based on appropriate electrochemical techniques can be frequently found in the scientific literature. In this work, we present the first example of a DFO-SAM sensor based on SPR in an optical fiber. The SPR sensing platform was realized by removing the cladding of a plastic optical fiber along half the circumference, spin coating a buffer of Microposit S1813 photoresist on the exposed core, and finally sputtering a thin gold film. The hydroxamate siderophore deferoxamine (DFO), having high binding affinity for Fe(III), is then used in its immobilized form, as self-assembled monolayer on the gold layer surface of the POF sensor. The results showed that the DFO-SAM-POF-sensor was able to sense the formation of the Fe(III)/DFO complex in the range of concentrations between 1 μm and 50 μm with a linearity range from 0 to 30 μm of Fe(III). The selectivity of the sensor was also proved by interference tests. PMID:24608007

  5. Synthesis and evaluation of oxidation-responsive alginate-deferoxamine conjugates with increased stability and low toxicity.

    PubMed

    Tian, Meng; Chen, Xi; Gu, Zhipeng; Li, Hao; Ma, Lu; Qi, Xin; Tan, Hong; You, Chao

    2016-06-25

    Deferoxamine is commonly used for iron-overload related diseases, its drawbacks such as instability and toxicity, however, significantly limited its utility in clinic. To address these issues, oxidation-responsive alginate-deferoxamine (Alg-DFO) conjugates were synthesized and their structure was characterized. The metabolism studies shown the conjugation of alginate significantly increased the stability of the DFO, with half-life more than 10 times longer than that of the free DFO. Moreover, the conjugates could not only quickly respond to oxidative stimuli and degradation, suggesting their potential to be cleared from the body by responding to iron-overload associated oxidative environment to avoid its accumulation and safety concern, but also protect iron binding capacity of the attached DFO from oxidation. The degradation mechanism for oxidative-response was proposed. In addition, the conjugates shown lower cytotoxicity compared to the free DFO. Taken together, the Alg-DFO conjugates synthesized in this work has promise for treating iron-overload related conditions. PMID:27083844

  6. Role of deferoxamine on enzymatic stress markers in an animal model of Alzheimer's disease after chronic aluminum exposure.

    PubMed

    Esparza, José L; Garcia, Tania; Gómez, Mercedes; Nogués, M Rosa; Giralt, Montserrat; Domingo, José L

    2011-06-01

    The effect of the chelator deferoxamine (DFO) on the activity of enzymatic stress markers was assessed in amyloid beta peptide (AβPP) transgenic mice, an animal model of Alzheimer's disease, after oral aluminum (Al) exposure for 6 months. AβPP transgenic (Tg2576) and C57BL6/SJL wild-type mice of 5 months of age were fed a diet supplemented with Al lactate (1 mg of Al/g food). Four groups of Tg2576 and wild-type animals were used: control, Al only, DFO only, and Al plus DFO. Mice in the DFO-treated groups received also subcutaneous injections of 0.20 mmol/kg/d of this chelating agent twice a week until the end of the study at 11 months of age. The hippocampus, cerebellum, and cortex were removed and processed to examine a number of oxidative stress markers. Furthermore, the expression of Cu-Zn superoxide dismutase, glutathione reductase, and catalase was evaluated by quantitative reverse transcriptase polymerase chain reaction analysis. Aluminum levels in the hippocampus of Tg2576 mice were higher than those found in cerebellum and cortex, while the main oxidative effects were evidenced in the presence of DFO only. Oral Al exposure of AβPP transgenic mice would have some potential to promote pro-oxidant events, while DFO administration would not help in preventing these deleterious effects. PMID:20455029

  7. Frequency of Sensory Neural Hearing Loss in Major Beta-Thalassemias in Southern Iran

    PubMed Central

    Faramarzi, Abolhassan; Karimi, Mehran; Heydari, Seyed-Taghi; Shishegar, Mahmoud; Kaviani, Masoud

    2010-01-01

    Objective The thalassemias are among the most common genetic disorders worldwide, occurring more frequently in the Mediterranean region. The aim of this study was to determined frequency of sensory-neural hearing loss in major ß- thalassemias transfusion dependent patients in south of Iran. Methods A cross sectional study on 308 cases of major beta-thalassemia patients referring to Thalassemia Center of Shiraz University of Medical Sciences between 2006–2007 years. The diagnosis of ß- thalassemia major was based on clinical history, complete blood count and hemoglobine electrophoresis. Clinical data such as serum ferritin level, deferoxamine (DFO) dose, mean daily doses of DFO (mg/kg) and audiometric variables was recorded. Findings Out of 308 cases, 283 (96.5%) had normal hearing and 10 (3.5%) sensorineural hearing loss. There was no statically significant difference between two groups regarding mean age, weight, age at the first blood transfusion, age at the first DFO infusion. Conclusion We found the lowest incidence of sensorineural hearing loss in a large population of patients suffered from major thalassemia who received DFO. We show that DFO is not ototoxic at a low dose. When considering all related literature, as a whole there has been much critical misrepresentation about DFO ototoxicity. PMID:23056722

  8. An evaluation of carrier agents for desferoxamine, an up-regulator of vascular endothelial growth factor.

    PubMed

    Hertzberg, Brian P; Holt, Joshua B; Graff, Ronald D; Gilbert, Shawn R; Dahners, Laurence E

    2013-05-01

    Avascularity and hypoxia result in avascular necrosis and play a negative role in fracture healing. The FDA-approved iron chelating agent, desferoxamine (DFO) in a liquid form, has been shown to induce angiogenesis and improve fracture healing through upregulation of the vascular endothelial growth factor. We were concerned that local injection of DFO would either fail to adequately deliver sufficient drug to the desired site or lead to undesired delivery to adjacent sites. Therefore, a sustained release delivery system was desirable to direct DFO to the intended site. Calcium sulfate pellets, collagen sponges, and demineralized cortical bone matrix were all evaluated as potentially controlled release systems for DFO using a fetal mouse metatarsal angiogenesis assay. Angiogenesis was analyzed using a vascularity grading scale, by measuring the mean vessel length of the 5 longest vessels, and by counting the mean number of vessels per metatarsal. Although there was some evidence of angiogenesis with all three carriers, DFO loaded CaSO4 pellets increased vascularity grading, the mean length of the five longest vessels, and the mean number of vessels, all by statistically significant margins versus the control. These results suggest that CaSO4 pellets could be used as a viable, nontoxic, controlled release system for DFO in clinical situations where increased angiogenesis and bone growth are desirable. PMID:22262572

  9. Desferrioxamine in warm reperfusion media decreases liver injury aggravated by cold storage

    PubMed Central

    Arthur, Peter G; Niu, Xian-Wa; Huang, Wen-Hua; DeBoer, Bastiaan; Lai, Ching Tat; Rossi, Enrico; Joseph, John; Jeffrey, Gary P

    2013-01-01

    AIM: To evaluate whether desferrioxamine decreases ischemia and perfusion injury aggravated by cold storage (CS) in a rat liver perfusion model. METHODS: Isolated rat livers were kept in CS in University of Wisconsin Solution for 20 h at 4 °C, then exposed to 25 min of warm ischemia (WI) at 37 °C followed by 2 h of warm perfusion (WP) at 37 °C with oxygenated (95% oxygen and 5% carbon dioxide) Krebs-Henseleit buffer. Desferrioxamine (DFO), an iron chelator, was added at different stages of storage, ischemia and perfusion: in CS only, in WI only, in WP only, in WI and perfusion, or in all stages. Effluent samples were collected after CS and after WI. Perfusate samples and bile were collected every 30 min (0, 0.5, 1, 1.5 and 2 h) during liver perfusion. Cellular injury was assessed by the determination of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) in the effluent and perfusate samples. Total iron was analysed in the perfusate samples. After WP, the liver was collected for the determination of liver swelling (wet to dry ratio) and liver morphological examination (hematoxylin and eosin staining). RESULTS: Increased CS time caused increased liver dysfunction during WP. After 2 h of WP, liver injury was indicated by increased release of AST (0.5 h CS: 9.4 ± 2.2 U/g liver vs 20 h CS: 45.9 ± 10.8 U/g liver, P < 0.05) and LDH (0.5 h CS: 59 ± 14 U/g liver vs 20 h CS: 297 ± 71 U/g liver, P < 0.05). There was an associated increase in iron release into the perfusate (0.5 h CS: 0.11 ± 0.03 μmoL/g liver vs 20 h CS: 0.58 ± 0.10 μmoL/g liver, P < 0.05) and reduction in bile flow (0.5 h CS: 194 ± 12 μL/g vs 20 h CS: 71 ± 8 μL/g liver, P < 0.05). When DFO was added during WI and WP following 20 h of CS, release of iron into the perfusate was decreased (DFO absent 0.58 ± 0.10 μmoL/g liver vs DFO present 0.31 ± 0.06 μmoL/g liver, P < 0.05), and liver function substantially improved with decreased release of AST (DFO absent 45.9 ± 10.8 U

  10. 77 FR 40863 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-11

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 5, 2012. Aaron Siegel... accurately describe the basis for exempting disclosure of classified information that is or may be...

  11. 76 FR 46767 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-03

    ..., 1996, 61 FR 6427). Dated: July 29, 2011. Aaron Siegel, Alternate OSD Federal Register Liaison Officer... Learning Suite provides a student management system that integrates Web-enabled courseware to...

  12. NASA Now Minute: Exercise Physiology: Countermeasures

    NASA Video Gallery

    Aaron Weaver, a biomedical engineer, discusses the importance of doingexercise while in space and provides a glimpse into one of NASA’slaboratories developing and improving the exercise equipme...

  13. 77 FR 40861 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-11

    ... (February 20, 1996, 61 FR 6427). Dated: July 5, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison... restricted access. Data is encrypted at rest, and backup data is encrypted and removed to a different...

  14. Staff Development in Reading: What the Experts Say.

    ERIC Educational Resources Information Center

    Vacca, Jo Anne

    1979-01-01

    Presents interviews of six prominent researchers (Ira Aaron, Harold Herber, Wayne Otto, Robert Ruddell, Roselmina Indrisano, and Olive Niles), which focused on the dynamics constituting effective staff development experiences. (HOD)

  15. Tricky correlations

    NASA Astrophysics Data System (ADS)

    Wesson, John

    2016-05-01

    In reply to Aaron Iftikhar's article “Is physics just for the rich?” (Forum, March p27), which discussed disparities in the numbers of physics students from some geographic areas and socioeconomic groups.

  16. Views of the Apollo 11 Twentieth Anniversary Black Tie reception

    NASA Technical Reports Server (NTRS)

    1989-01-01

    View from the Apollo 11 Twentieth Anniversary Black Tie reception at the downtown Houston Hyatt Regency Hotel. Scene show NASA/JSC Director Aaron Cohen talking with NASA Administrator Richard H. Truly and his wife, Cody.

  17. 75 FR 3904 - Change in Bank Control Notices; Acquisition of Shares of Bank or Bank Holding Companies

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-25

    ... Denney, Assistant Vice President) 1 Memorial Drive, Kansas City, Missouri 64198-0001: 1. Verlyn Joseph Herman, Jr., and Aaron Joseph Herman, both of Norton, Kansas; as members of a family group acting...

  18. 76 FR 35195 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ..., (February 20, 1996, 61 FR 6427). Dated: June 8, 2011. Aaron Siegel, Alternate OSD Federal Register Liaison...: SAF/XCPPI, 1800 Air Force Pentagon, Washington DC 20330-1800, or by phone at 703-...

  19. 78 FR 72878 - Revisions to Procedural Regulations Governing Filing, Indexing and Service by Oil Pipelines...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-04

    ... modified to be more descriptive. For more information, contact Aaron Kahn, Office of Energy Market... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Revisions to Procedural Regulations Governing Filing, Indexing and...

  20. Robot-Assisted Minimally Invasive Coronary Artery Bypass Surgery Operation

    MedlinePlus Videos and Cool Tools

    ... Most people rotate through and they do fine. Robotic surgery requires a little bit of expertise and ... physician assistant is [Aaron Murstoka]. Head nurse of robotics is [Sara Harrick]. And the rest of these ...

  1. 78 FR 60264 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-01

    ... leave or overtime and review post assignments. To serve as a management tool for statistical analysis..., 1996 (February 20, 1996, 61 FR 6427). Dated: September 25, 2013. Aaron Siegel, Alternate OSD...

  2. Medical Issues: Breathing

    MedlinePlus

    ... invasive ventilation. For long-term invasive ventilation, a tracheostomy tube is usually required. During a surgical procedure, ... soon as possible after diagnosis. Helpful Links Aaron's Tracheostomy webpage Acute Respiratory Illness Care Guidelines A Young ...

  3. Kennedy Space Center Wakes STS-135 Crew

    NASA Video Gallery

    The Flight Day 13 wakeup music was "Fanfare for the Common Man" by Aaron Copland played for Commander Chris Ferguson. It was followed by a prerecorded message from Kennedy Space Center employees. K...

  4. 77 FR 25993 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-02

    ...,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 27, 2012. Aaron Siegel, Alternate.... Robin Patterson, Department of the Navy, DNS-36, 2000 Navy Pentagon, Washington, DC 20350-2000 or...

  5. 77 FR 13574 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-07

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: March 2, 2012. Aaron Siegel, Alternate OSD Federal.... Robin Patterson, Department of the Navy, DNS-36, 2000 Navy Pentagon, Washington, DC 20350-2000 or...

  6. An Uninformative Truth: The Logic of Amarin's Off-Label Promotion.

    PubMed

    Hey, Spencer Phillips; Kesselheim, Aaron S

    2016-03-01

    Spencer Phillips Hey and Aaron Kesselheim propose that informativeness-asserting scientific facts-rather than truthfulness ought to be the standard for regulating commercial speech about pharmaceuticals. PMID:26978686

  7. Rfinity

    ScienceCinema

    Aaron R. Turner

    2010-01-08

    An innovation that offers a low-cost, plug-n-play option that enables virtually any wireless telecommunications device to safely store sensitive personal information and perform secure transactions. INL researchers include Steven McCown, Aaron Turner, Kur

  8. 77 FR 68746 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-16

    ...): DEPS will utilize Microsoft Office SharePoint Server as an integrated suite of server capabilities that... (February 20, 1996, 61 FR 6427). Dated: November 13, 2012. Aaron Siegel, Alternate OSD Federal...

  9. 76 FR 58788 - Privacy Act of 1974; Systems of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-22

    ... property is required. This system also serves as a transportation management information system for Navy... (February 20, 2996, 61 FR 6427). Dated: September 19, 2011. Aaron Siegel, Alternate OSD Federal...

  10. 77 FR 15361 - Notice of Amendment No. 001 to the Solicitation for Cooperative Agreement Applications (SCAA...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-15

    ..., 2012. Solicitations and Amendments are available at http://www.dla.mil/SmallBusiness/Pages/SCAA.aspx... Business Programs at PTAP@DLA.MIL . Dated: March 9, 2012. Aaron Siegel, Alternate OSD Federal...

  11. 76 FR 66051 - Availability of the Fiscal Year 2010 United States Special Operations Command (USSOCOM) Inventory...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-25

    ....socom.mil/sordac/Documents/USSOCOMFY10ServicesInventoryList.pdf . DATES: Inventory to be made publically... marian.duchesne@socom.mil . Dated: October 19, 2011. Aaron Siegel, Alternate OSD Federal Register...

  12. 77 FR 38274 - Availability of the Fiscal Year 2011 United States Special Operations Command (USSOCOM) Inventory...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-27

    ... USSOCOM public portal Web site at the following location: http://www.socom.mil/sordac/Documents/USSOCOM....duchesne.ctr@socom.mil . Dated: June 22, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison...

  13. NASA Now: Exercise Physiology: Countermeasures

    NASA Video Gallery

    Aaron Weaver is a biomedical engineer responsible for setting up and running experiments and recruiting test subjects in the Exercise Countermeasures Laboratory at NASA’s Glenn Research Center in...

  14. Rfinity

    SciTech Connect

    Aaron R. Turner

    2009-07-21

    An innovation that offers a low-cost, plug-n-play option that enables virtually any wireless telecommunications device to safely store sensitive personal information and perform secure transactions. INL researchers include Steven McCown, Aaron Turner, Kur

  15. 75 FR 30402 - National Environmental Justice Advisory Council; Notification of Public Teleconference and Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-01

    ... Comment AGENCY: Environmental Protection Agency. ACTION: Notification of Public Teleconference Meeting and....S. Environmental Protection Agency (EPA) hereby provides notice that the National Environmental... directed to Mr. Aaron Bell, U.S. Environmental Protection Agency, at 1200 Pennsylvania Avenue,...

  16. 78 FR 38015 - Department of Defense Task Force on the Care, Management, and Transition of Recovering Wounded...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-25

    ... Washington DC-Crystal City, 300 Army Navy Drive, Arlington, VA 22202. FOR FURTHER INFORMATION CONTACT: Mail... Moore, (703) 325-6640, by 5:00 p.m. EDT, Thursday, July 18, 2013. Dated: June 20, 2013. Aaron...

  17. Steady-state dissolution kinetics of aluminum-goethite in the presence of desferrioxamine-B and oxalate ligands.

    PubMed

    Cervini-Silva, Javiera; Sposito, Garrison

    2002-02-01

    This paper reports steady-state dissolution rates of synthetic low-substitution Al-goethites (mol % Al < 10) at pH 5 in the presence of the trihydroxamate siderophore, desferrioxamine B (DFO-B), and the common biological ligand, oxalate. The siderophore-promoted Fe release rate increased both with the level of Al substitution and with DFO-B concentration up to about 100 microM, after which a plateau occurred, suggesting a saturation effect from DFO-B adsorption as a precursor to dissolution. At concentrations above 200 microM, oxalate also enhanced the Fe release rate, which however was not influenced by Al substitution. For Al-goethites with mol % Al < 4, the Fe release rate in the presence of 40 microM DFO-B together with varying concentrations of oxalate was typically greater than the corresponding sum of dissolution rates in the presence of the two ligands alone. This synergism may be the combined result of the ability of oxalate to adsorb strongly at the goethite surface, thus promoting Fe release, and of the high selectivity of DFO for Fe(III). Ferric oxalate complexes formed during dissolution will likely lose Fe3+ by ligand substitution with DFO-B, leading to the production of Fe(HDFO-B)+ and uncomplexed oxalate, the latter of which, in turn, could adsorb to the goethite surface again. For Al-goethites with mol % Al > 4, synergism was not apparent, which may signal the effect of a decreased surface density of Fe-OH sites associated with Al for Fe substitution. The oxalate-promoted release rates of Al did not scale with those of Fe, indicating incongruent dissolution. However, Al release rates in the presence of DFO-B did scale approximately with those of Fe but were not affected by the concentration of siderophore. These results are consistent with the presence of Al(OH)3 inclusions in Al-goethite. PMID:11871546

  18. Improvement of rat islet viability during transplantation: validation of pharmacological approach to induce VEGF overexpression.

    PubMed

    Langlois, A; Bietiger, W; Seyfritz, E; Maillard, E; Vivot, K; Peronet, C; Meyer, N; Kessler, L; Jeandidier, N; Pinget, M; Sigrist, S

    2011-01-01

    Delayed and insufficient revascularization during islet transplantation deprives islets of oxygen and nutrients, resulting in graft failure. Vascular endothelial growth factor (VEGF) could play a critical role in islet revascularization. We aimed to develop pharmacological strategies for VEGF overexpression in pancreatic islets using the iron chelator deferoxamine (DFO), thus avoiding obstacles or safety risks associated with gene therapy. Rat pancreatic islets were infected in vivo using an adenovirus (ADE) encoding human VEGF gene (4.10(8) pfu/pancreas) or were incubated in the presence of DFO (10 μmol/L). In vitro viability, functionality, and the secretion of VEGF were evaluated in islets 1 and 3 days after treatment. Infected islets or islets incubated with DFO were transplanted into the liver of syngenic diabetic rats and the graft efficiency was estimated in vivo by measuring body weight, glycemia, C-peptide secretion, and animal survival over a period of 2 months. DFO induced transient VEGF overexpression over 3 days, whereas infection with ADE resulted in prolonged VEGF overexpression lasting 14 days; however, this was toxic and decreased islet viability and functionality. The in vivo study showed a decrease in rat deaths after the transplantation of islets treated with DFO or ADE compared with the sham and control group. ADE treatment improved body weight and C-peptide levels. Gene therapy and DFO improved metabolic control in diabetic rats after transplantation, but this effect was limited in the presence of DFO. The pharmacological approach is an interesting strategy for improving graft efficiency during transplantation, but this approach needs to be improved with drugs that are more specific. PMID:21294962

  19. Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice.

    PubMed

    Tajima, Soichiro; Ikeda, Yasumasa; Sawada, Kaori; Yamano, Noriko; Horinouchi, Yuya; Kihira, Yoshitaka; Ishizawa, Keisuke; Izawa-Ishizawa, Yuki; Kawazoe, Kazuyoshi; Tomita, Shuhei; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2012-01-01

    Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2'-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22(phox) expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22(phox) and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity. PMID:21917632

  20. Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study.

    PubMed

    Nouri, Fatemeh; Salehinejad, Parvin; Nematollahi-Mahani, Seyed Noureddin; Kamarul, Tunku; Zarrindast, Mohammad Reza; Sharifi, Ali Mohammad

    2016-07-01

    Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural-like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 µM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1α inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO-treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1α, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy. PMID:26242172

  1. PET imaging of epidermal growth factor receptor expression in tumours using 89Zr-labelled ZEGFR:2377 affibody molecules

    PubMed Central

    GAROUSI, JAVAD; ANDERSSON, KEN G.; MITRAN, BOGDAN; PICHL, MARIE-LOUISE; STÅHL, STEFAN; ORLOVA, ANNA; LÖFBLOM, JOHN; TOLMACHEV, VLADIMIR

    2016-01-01

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a positron-emitting radionuclide 89Zr. The 89Zr-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160±60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, 89Zr-DFO-ZEGFR:2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6±0.5% ID/g and tumour-to-blood ratio of 3.7±0.6 at 24 h after injection. 89Zr-DFO-ZEGFR:2377 provides higher tumour-to-organ ratios than anti-EGFR antibody 89Zr-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using 89Zr-DFO-ZEGFR:2377 at both 3 and 24 h after injection. In conclusion, 89Zr-DFO-ZEGFR:2377 is a potential probe for PET imaging of EGFR-expression in vivo. PMID:26847636

  2. PET imaging of epidermal growth factor receptor expression in tumours using 89Zr-labelled ZEGFR:2377 affibody molecules.

    PubMed

    Garousi, Javad; Andersson, Ken G; Mitran, Bogdan; Pichl, Marie-Louise; Ståhl, Stefan; Orlova, Anna; Löfblom, John; Tolmachev, Vladimir

    2016-04-01

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a positron-emitting radionuclide (89)Zr. The (89)Zr-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 ± 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, (89)Zr-DFO-ZEGFR:2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 ± 0.5% ID/g and tumour-to-blood ratio of 3.7 ± 0.6 at 24 h after injection. (89)Zr-DFO-ZEGFR:2377 provides higher tumour-to-organ ratios than anti-EGFR antibody (89)Zr-DFO-cetuximab at 48 h after injection. EGFR‑expressing tumours were clearly visualized by microPET using (89)Zr-DFO-ZEGFR:2377 at both 3 and 24 h after injection. In conclusion, 8(9)Zr-DFO-ZEGFR:2377 is a potential probe for PET imaging of EGFR-expression in vivo. PMID:26847636

  3. Consensus on surgical aspects of managing osteomyelitis in the diabetic foot

    PubMed Central

    Allahabadi, Sachin; Haroun, Kareem B.; Musher, Daniel M.; Lipsky, Benjamin A.; Barshes, Neal R.

    2016-01-01

    Background The aim of this study was to develop consensus statements that may help share or even establish ‘best practices’ in the surgical aspects of managing diabetic foot osteomyelitis (DFO) that can be applied in appropriate clinical situations pending the publication of more high-quality data. Methods We asked 14 panelists with expertise in DFO management to participate. Delphi methodology was used to develop consensus statements. First, a questionnaire elicited practices and beliefs concerning various aspects of the surgical management of DFO. Thereafter, we constructed 63 statements for analysis and, using a nine-point Likert scale, asked the panelists to indicate the extent to which they agreed or disagreed with the statements. We defined consensus as a mean score of greater than 7.0. Results The panelists reached consensus on 38 items after three rounds. Among these, seven provide guidance on initial diagnosis of DFO and selection of patients for surgical management. Another 15 statements provide guidance on specific aspects of operative management, including the timing of operations and the type of specimens to be obtained. Ten statements provide guidance on postoperative management, including wound closure and offloading, and six statements summarize the panelists’ agreement on general principles for surgical management of DFO. Conclusions Consensus statement on the perioperative management of DFO were formed with an expert panel comprised of a variety of surgical specialties. We believe these statements may serve as ‘best practice’ guidelines until properly performed studies provide more robust evidence to support or refute specific surgical management steps in DFO. PMID:27414481

  4. Sustained improvements in myocardial T2* over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine.

    PubMed

    Pennell, Dudley J; Porter, John B; Piga, Antonio; Lai, Yong-Rong; El-Beshlawy, Amal; Elalfy, Mohsen; Yesilipek, Akif; Kilinç, Yurdanur; Habr, Dany; Musallam, Khaled M; Shen, Junwu; Aydinok, Yesim

    2015-02-01

    Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938). PMID:25345697

  5. Alternative Chelator for 89Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)

    PubMed Central

    2015-01-01

    Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of mice suggests that 89Zr4+ is released from DFO in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of 89Zr-HOPO matched or surpassed that of 89Zr-DFO in every experiment. In healthy mice, 89Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for 89Zr-based PET imaging agents. PMID:24814511

  6. Adenoviral infection or deferoxamine? Two approaches to overexpress VEGF in beta-cell lines.

    PubMed

    Langlois, Allan; Bietiger, William; Sencier, Marie-Christine; Maillard, Elisa; Pinget, Michel; Kessler, Laurence; Sigrist, Severine

    2009-07-01

    Rapid and adequate revascularization of transplanted islets is important for their survival and function during transplantation. Vascular endothelial growth factor (VEGF) could play a critical role with respect to islet revascularization. The aim of this study was to compare two strategies that are used to overexpress VEGF in beta-cells: (1) gene therapy through adenoviral infection and (2) a pharmacological approach using deferoxamine (DFO). beta-Cell lines from rat insulinoma (RINm5F) were either infected using an adenovirus encoding the gene of human VEGF 165 or incubated with DFO. One day after treatment, the viability of RINm5F cells was preserved with 10 micromol/L of DFO (103.95 +/- 5.66% toward control; n = 4). In addition, adenoviral infection maintained the viability of cells for all the concentrations used. In both treatments, overexpression of VEGF was in a comparable level. Finally, the ratio of Bax/Bcl-2 indicated that the apoptosis increased in infected beta-cells whereas treatment with DFO seems to be antiapoptotic. Our results suggest that the use of DFO could be a realistic approach to improve the vascularization of islets during transplantation. PMID:19527112

  7. Composite chitosan/alginate hydrogel for controlled release of deferoxamine: A system to potentially treat iron dysregulation diseases.

    PubMed

    Rassu, Giovanna; Salis, Andrea; Porcu, Elena Piera; Giunchedi, Paolo; Roldo, Marta; Gavini, Elisabetta

    2016-01-20

    Recently, the potential application of deferoxamine (DFO) in several iron dysregulation diseases has been highlighted. However, DFO presents significant limitations in clinical use due to its poor absorption in the gut and very short plasma half-life. To overcome these problems, the feasibility of chitosan/alginate hydrogels as prolonged delivery systems of DFO was investigated. Hydrogel alone or co-formulated with poly(D,L-lactide-co-glycolide) microspheres were prepared and studied in vitro. The influence of the preparation methods on the performance of composite hydrogels on controlled DFO release was explored. Spray-dried microspheres based on poly(D,L-lactide-co-glycolide) were able to encapsulate DFO, a highly water soluble drug. Nevertheless, only the composite hydrogels managed to provide sustained drug release. The inclusion of microspheres into pre-formed chitosan/alginate hydrogel provided the most efficient delivery system; the drug released from microspheres is strongly entrapped in the hydrogel network and slowly released by diffusion. PMID:26572479

  8. Protective effects of desferrioxamine and deferiprone on the spleen tissue of aluminum intoxicated mice: A Fourier transform infrared spectroscopy study

    NASA Astrophysics Data System (ADS)

    Sivakumar, S.; Khatiwada, Chandra Prasad; Sivasubramanian, J.

    The present study was designed to examine the protective effects of the chelating agents desferrioxamine (DFO) and deferiprone (DFP) in aluminum intoxicated spleen tissue of mice by Fourier transform infrared (FTIR) spectroscopy. The finding revealed the alterations on the major biochemical constituents, such as lipids, proteins, phosphodiester and nucleic acids of the spleen tissue of mice at molecular level. The significant decreased in the peak areas of asymmetric and symmetric mode of the phosphodiester groups from control to aluminum intoxicated, but improved it by DFP and DFO + DFP treatments respectively for nearer control value. The bands ratio at I1081/I1232 significantly decreased from control to aluminum, but enhanced it by DFP and DFO + DFP respectively. This result suggests that DFO and DFP are the phosphodiesterase inhibitor, recovered from chronic growth of diseases in the spleen. Amide I and amide II peak area values decreased from control to aluminum intoxicated spleen tissue, but treated with DFP and DFO + DFP significantly improved. This result suggests an alteration in the protein profile. The absence of Olefinicdbnd CH stretching in aluminum intoxicated spleen suggests an altered lipid levels. Concentrations of trace elements were found by ICP-OES. Histopathological findings confirmed the biochemical observations of this study. The results of the FTIR study were found to be in agreement with biochemical studies and demonstrated that FTIR can be used successfully applied to toxicological studies at molecular level.

  9. Orofacial Praxis Abilities in Children with Speech Disorders

    PubMed Central

    Bertagnolli, Ana Paula Coitino; Gubiani, Marileda Barichello; Ceron, Marizete; Keske-Soares, Márcia

    2015-01-01

    Introduction Phonological development occurs in a gradual manner until the age of 7 years. The phonological system is constructed in a similar way for all children, despite presenting some variations in terms of age, paths taken, or repair strategies used. Objective To compare the orofacial praxis abilities of children with typical phonological development (DFT), children with phonetic-phonological impairment (DFoFe), and children with phonological impairment (DF), using two tests to assess the orofacial praxis abilities. Methods The sample consisted of 82 subjects between 4 and 8 years of age who attended public schools (from preschool to the second year of secondary school) in the city of Santa Maria, Brazil. Of these, 29 were diagnosed with DFT, 29 with DF, and 24 with DFoFe; much of this sample was male. Two tests of praxis abilities and assessment of the stomatognathic system were administered. Statistical analysis was performed using the chi-square test, with a significance level of 5%. Results Generally children with DFoFe underperformed in tests of praxis when compared with subjects with DF and DFT. Conclusion The results showed that children with DFoFe have more difficulty in orofacial praxis abilities than subjects in the other groups studied. This result could be expected, because subjects with DFoFe show changes in both phonetic and phonological levels of speech. PMID:26491472

  10. Effect of iron chelators on placental uptake and transfer of iron in rat

    SciTech Connect

    Wong, C.T.; McArdle, H.J.; Morgan, E.H.

    1987-05-01

    The uptake of radiolabeled transferrin and iron by the rat placenta has been studied using two approaches. The first involved injection of a ferrous or ferric iron chelator followed by injection of label. Neither chelator decreased the amount of labelled transferrin in the placenta after 2-h incubation and only bipyridine, a ferrous iron chelator, inhibited iron transport to the fetus. Deferoxamine (DFO), a ferric iron chelator, had no effect on iron transport to the fetus but reduced iron uptake by the liver. Both bipyridine and DFO increased iron excretion into the gut and by the urinary tract to the same degree into the gut, but there was a 10-fold greater urinary excretion with bipyridine than with DFO. Injection of iron attached to the chelators showed that neither bipyridine nor DFO could donate iron to the fetus as efficiently as transferrin. The mechanism involved was further investigated by studying the effect of the chelators on uptake of transferrin-bound iron by placental cells in culture. DFO inhibited iron accumulation more effectively than bipyridine in the cultured cells. The effect was not due to a decrease in the cycling time of the receptor. The results can be explained if the iron is released from the transferrin in intracellular vesicles in the ferrous form, where it may be chelated by bipyridine and prevented from passing to the fetus or converted to the ferric form once it is inside the cell matrix.

  11. Scavenging iron: a novel mechanism of plant immunity activation by microbial siderophores.

    PubMed

    Aznar, Aude; Chen, Nicolas W G; Rigault, Martine; Riache, Nassima; Joseph, Delphine; Desmaële, Didier; Mouille, Grégory; Boutet, Stéphanie; Soubigou-Taconnat, Ludivine; Renou, Jean-Pierre; Thomine, Sébastien; Expert, Dominique; Dellagi, Alia

    2014-04-01

    Siderophores are specific ferric iron chelators synthesized by virtually all microorganisms in response to iron deficiency. We have previously shown that they promote infection by the phytopathogenic enterobacteria Dickeya dadantii and Erwinia amylovora. Siderophores also have the ability to activate plant immunity. We have used complete Arabidopsis transcriptome microarrays to investigate the global transcriptional modifications in roots and leaves of Arabidopsis (Arabidopsis thaliana) plants after leaf treatment with the siderophore deferrioxamine (DFO). Physiological relevance of these transcriptional modifications was validated experimentally. Immunity and heavy-metal homeostasis were the major processes affected by DFO. These two physiological responses could be activated by a synthetic iron chelator ethylenediamine-di(o-hydroxyphenylacetic) acid, indicating that siderophores eliciting activities rely on their strong iron-chelating capacity. DFO was able to protect Arabidopsis against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. Siderophore treatment caused local modifications of iron distribution in leaf cells visible by ferrocyanide and diaminobenzidine-H₂O₂ staining. Metal quantifications showed that DFO causes a transient iron and zinc uptake at the root level, which is presumably mediated by the metal transporter iron regulated transporter1 (IRT1). Defense gene expression and callose deposition in response to DFO were compromised in an irt1 mutant. Consistently, plant susceptibility to D. dadantii was increased in the irt1 mutant. Our work shows that iron scavenging is a unique mechanism of immunity activation in plants. It highlights the strong relationship between heavy-metal homeostasis and immunity. PMID:24501001

  12. Scavenging Iron: A Novel Mechanism of Plant Immunity Activation by Microbial Siderophores1[C][W

    PubMed Central

    Aznar, Aude; Chen, Nicolas W.G.; Rigault, Martine; Riache, Nassima; Joseph, Delphine; Desmaële, Didier; Mouille, Grégory; Boutet, Stéphanie; Soubigou-Taconnat, Ludivine; Renou, Jean-Pierre; Thomine, Sébastien; Expert, Dominique; Dellagi, Alia

    2014-01-01

    Siderophores are specific ferric iron chelators synthesized by virtually all microorganisms in response to iron deficiency. We have previously shown that they promote infection by the phytopathogenic enterobacteria Dickeya dadantii and Erwinia amylovora. Siderophores also have the ability to activate plant immunity. We have used complete Arabidopsis transcriptome microarrays to investigate the global transcriptional modifications in roots and leaves of Arabidopsis (Arabidopsis thaliana) plants after leaf treatment with the siderophore deferrioxamine (DFO). Physiological relevance of these transcriptional modifications was validated experimentally. Immunity and heavy-metal homeostasis were the major processes affected by DFO. These two physiological responses could be activated by a synthetic iron chelator ethylenediamine-di(o-hydroxyphenylacetic) acid, indicating that siderophores eliciting activities rely on their strong iron-chelating capacity. DFO was able to protect Arabidopsis against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. Siderophore treatment caused local modifications of iron distribution in leaf cells visible by ferrocyanide and diaminobenzidine-H2O2 staining. Metal quantifications showed that DFO causes a transient iron and zinc uptake at the root level, which is presumably mediated by the metal transporter iron regulated transporter1 (IRT1). Defense gene expression and callose deposition in response to DFO were compromised in an irt1 mutant. Consistently, plant susceptibility to D. dadantii was increased in the irt1 mutant. Our work shows that iron scavenging is a unique mechanism of immunity activation in plants. It highlights the strong relationship between heavy-metal homeostasis and immunity. PMID:24501001

  13. Potential mobilization of platinum-group elements by siderophores in surface environments.

    PubMed

    Dahlheimer, Susan R; Neal, Clive R; Fein, Jeremy B

    2007-02-01

    The emission of platinum-group elements (PGEs) from catalytic converters has led to increased environmental abundances of Pt, Pd, and Rh; however, little is known about the environmental effects and fate of these metals. Organic ligands found in soils have the potential to increase the mobility of PGEs and potentially increase the bioavailability of the metals. Here, we assessed the abilities of microbially produced iron-chelating ligands (siderophores) to complex with the PGEs. Batch experiments using the synthetic siderophore desferrioxamine-B (DFO-B) and powdered metal or oxide forms of Pt, Pd, or Rh showed that DFO-B enhances the solubility of Pt and Pd due to the formation of Pt- and Pd-DFO-B aqueous complexes, with estimated minimum stability constants on the order of 10(17-18) and 10(20-24), respectively. Dissolution rates for Pd are comparable to other mineral dissolution rates with DFO-B. DFO-B had little to no effect on the dissolution of Rh metal or Rh2O3. Our results indicate that siderophores have the potential to increase the mobility of Pt and Pd in environments with limited activities of free trivalent cations. These results have implications for the fate of catalytic converter-emitted Pt and Pd, and support the need for further Pt and Pd toxicity and bioaccumulation studies. PMID:17328196

  14. SERS Activity of Silver Nanoparticles Functionalized with A Desferrioxamine B Derived Ligand for FE(III) Binding and Sensing

    NASA Astrophysics Data System (ADS)

    Galinetto, P.; Taglietti, A.; Pasotti, L.; Pallavicini, P.; Dacarro, G.; Giulotto, E.; Grandi, M. S.

    2016-01-01

    We report the SERS activity of colloidal silver nanoparticles functionalized with a ligand, derived from the siderophore desferrioxamine B (desferal, DFO), an iron chelator widely used in biological and medical applications. The ligand was equipped with a sulfur-containing moiety to ensure optimal binding with silver surfaces. By means of Raman and SERS effects we monitored the route of material preparation from the modified DFO-S molecule to the colloidal aggregates. The results indicate that the functionalization of the chelating agent does not affect its binding ability towards Fe(III). The resulting functionalized silver nanoparticles are a promising SERS tag for operation in biological environments. The Fe-O stretching signature, arising when DFO-S grafted to silver nanoparticles binds Fe(III), could provide a tool for cation sensing in solution.

  15. The coaxial gyrotron with two electron beams. II. Dual frequency operation

    SciTech Connect

    Liu Shenggang; Yuan Xuesong; Liu Diwei; Yan Yang; Zhang Yaxin; Li Hongfu; Zhong Renbin

    2007-10-15

    The dual frequency operation (DFO) of the coaxial gyrotron with two electron beams (CGTB) has been investigated in this part by means of both linear theory and computer simulation. In such an operation, the cavity is at degeneration and one beam works at the first harmonic while another at high harmonic. Making use of the coupled-mode theory, the dispersion equation considering the coupling of two beams and two modes has been obtained. The results of the numerical calculation and the particle in cell simulation show that CGTB with DFO can obtain high output power at two different frequencies simultaneously. In addition, the power of the high harmonic can be enhanced due to the nonlinear coupling between two beams, and some interesting and important phenomena of CGTB with DFO revealed in the paper are of significance in physics.

  16. Deferoxamine-induced increase in the intracellular iron levels in highly aggressive breast cancer cells leads to increased cell migration by enhancing TNF-α-dependent NF-κB signaling and TGF-β signaling.

    PubMed

    Liu, Ping; He, Kun; Song, Hongjiao; Ma, Zhufeng; Yin, Weihai; Xu, Lisa X

    2016-07-01

    Recent studies have suggested that excess iron accumulation may be a risk factor for breast cancer. However the role of iron in breast cancer metastasis has remained unclear. The major goal of our study is to investigate the roles of iron in breast cancer metastasis. We modulated the intracellular iron levels of human breast cancer cells, including the aggressive MDA-MB-231 cells and non-aggressive MCF-7 cells, by using Deferoxamine (DFO) - a most widely used iron chelator. We found that DFO treatment could deplete intracellular iron in MCF-7 cells. In contrast, DFO treatment led to a significant increase in the intracellular iron level in MDA-MB-231 cells. The MDA-MB-231 cells with the increased intracellular iron level exhibited increases in both mesenchymal markers and cell migration. Furthermore, the DFO-treated MDA-MB-231 cells showed increases in both tumor necrosis factor α (TNF-α)-induced nuclear factor kappa B (NF-κB) signaling and transforming growth factor-β (TGF-β) signaling, which could contribute to the enhanced cell migration. Collectively, our study has provided the first evidence suggesting that increased intracellular iron levels could lead to enhanced migration of aggressive breast cancer cells by increasing TNF-α-dependent NF-κB signaling and TGF-β signaling. Our study has also suggested that caution should be taken when DFO is applied for treating breast cancer cells, since DFO could produce differential effects on the intracellular iron levels for aggressive breast cancer cells and non-aggressive breast cancer cells. PMID:27138103

  17. Studies the alterations of biochemical and mineral contents in bone tissue of mus musculus due to aluminum toxicity and the protective action of desferrioxamine and deferiprone by FTIR, ICP-OES, SEM and XRD techniques

    NASA Astrophysics Data System (ADS)

    Sivakumar, S.; Khatiwada, Chandra Prasad; Sivasubramanian, J.

    The present study has attempt to analyze the changes in the biochemical and mineral contents of aluminum intoxicated bone and determine the protective action of desferrioxamine (DFO) and deferiprone (DFP) by using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), inductively coupled plasma optical emission spectroscopy (ICP-OES), and scanning electron microscopy (SEM) techniques for four groups of animals such as control (Group I), aluminum intoxicated (Group II), Al + DFP (Group III) and Al + DFO + DFP (Group IV) treated groups respectively. The FTIR spectra of the aluminum intoxicated bone showed significant alteration in the biochemical constituents. The bands ratio at I1400/I877 significantly decreased from control to aluminum, but enhanced it by Al + DFP to Al + DFO + DFP treated bone tissue for treatments of 16 weeks. This result suggests that DFO and DFP are the carbonate inhibitor, recovered from chronic growth of bone diseases and pathologies. The alteration of proteins profile indicated by Amide I and Amide II, where peak area values decreased from control to aluminum respectively, but enhanced by treated with DFP (p.o.) and DFO + DFP (i.p.) respectively. The XRD analysis showed a decrease in crystallinity due to aluminum toxicity. Further, the Ca, Mg, and P contents of the aluminum exposed bone were less than those of the control group, and enhanced by treatments with DFO and DFP. The concentrations of trace elements were found by ICP-OES. Therefore, present study suggests that due to aluminum toxicity severe loss of bone minerals, decrease in the biochemical constituents and changes in the surface morphology.

  18. XAFS Determination of Pb and Cd Speciation with Siderophores and the Metal/Siderophore/Kaolinite System

    SciTech Connect

    Mishra, Bhoopesh; Haack, Elizabeth A.; Vasconcelos, Igor F.; Maurice, Patricia A.; Bunker, Bruce A.

    2008-06-16

    We provide evidence for hexadentate complexes of Pb{sup 2+} and Cd{sup 2+} with the trihydroxamate siderophore desferrioxamine B (DFO-B) at pH 7.5, and 9.0, respectively. Analysis of the species of Pb{sup 2+} and Cd{sup 2+} adsorbed at the surface of kaolinite clay under the same pH conditions and in the presence of DFO-B indicate that Pb{sup 2+} is sorbed as a metal-siderophore complex while Cd{sup 2+} is not.

  19. Imaging of diabetic foot infections.

    PubMed

    Fridman, Robert; Bar-David, Tzvi; Kamen, Stewart; Staron, Ronald B; Leung, David K; Rasiej, Michael J

    2014-01-01

    Complications from diabetic foot infections are a leading cause of nontraumatic lower-extremity amputations. Nearly 85% of these amputations result from an infected foot ulcer. Osteomyelitis is present in approximately 20% of diabetic foot infections. It is imperative that clinicians make quick and successful diagnoses of diabetic foot osteomyelitis (DFO) because a delay in treatment may lead to worsening outcomes. Imaging studies, such as plain films, bone scans, musculoskeletal ultrasound, computerized tomography scans, magnetic resonance imaging, and positron emission tomography scans, aid in the diagnosis. However, there are several mimickers of DFO, which present problems to making a correct diagnosis. PMID:24296017

  20. 76 FR 53924 - Merchant Mariner Medical Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ..., issue of the Federal Register (73 FR 3316). Docket: For access to the docket to read background... medical research. Agenda Day 1 (1) Opening comments by Designated Federal Officer (DFO), Captain E. P... SECURITY Coast Guard Merchant Mariner Medical Advisory Committee AGENCY: Coast Guard, DHS. ACTION:...

  1. 77 FR 20834 - Merchant Mariner Medical Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-06

    ... qualifications of operators of commercial vessels, medical examiner education, and medical research. The meeting... Register (73 FR 3316). If you would like a copy of your material distributed to each member of the... medical research. Agenda: Day 1 (1) Opening comments by Designated Federal Officer (DFO), Captain E....

  2. Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

    PubMed Central

    Yalcintepe, Leman; Halis, Emre

    2016-01-01

    Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a “two-sided effect” in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent. PMID:26773173

  3. 78 FR 15928 - Forestry Research Advisory Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-13

    ... Time, Monday through Friday. SUPPLEMENTARY INFORMATION: Background In accordance with the provisions of... as necessary and at such times as designated by the Designated Federal Officer (DFO). No individual... country. Members of the Council will serve without compensation, but may be reimbursed for travel...

  4. 78 FR 9730 - Boston Harbor Islands Advisory Council Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-11

    ... National Park Service Boston Harbor Islands Advisory Council Meeting AGENCY: National Park Service... Islands Advisory Council. The agenda includes a presentation by Sally Snowman, 70th keeper of Boston Light... Jacobson, DFO, Boston Harbor Islands National Recreation Area, 408 Atlantic Avenue, Suite 228, Boston,...

  5. 78 FR 73547 - Medicare Program; Semi-Annual Meeting of the Advisory Panel on Hospital Outpatient Payment (HOP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ... Braver, 7500 Security Boulevard, Mail Stop: C4-05-17, Woodlawn, MD 21244-1850. Phone: (410) 786-3985..., DFO, CMS, CM, HAPG, DOC--HOP Panel 7500 Security Blvd., Mail Stop: C4-05-17, Woodlawn, MD...

  6. 75 FR 28823 - Advisory Committee on Reactor Safeguards (ACRS) Meeting of the ACRS Subcommittee on Planning and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-24

    ... ACRS meetings were published in the Federal Register on October 14, 2009 (74 FR 58268- 58269). Detailed... oral statements and/or written comments should notify the Designated Federal Official (DFO), Peter Wen (Telephone 301-415-2832 or E-mail ( Peter.Wen@nrc.gov ) five days prior to the meeting, if possible, so...

  7. 76 FR 3919 - National Offshore Safety Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ..., originally scheduled for Wednesday, January 12, 2011, from 11 a.m. to 12:30 p.m. EST, was cancelled due to... teleconference meeting will take place on Wednesday, February 9, 2011, from 11 a.m. to 12:30 p.m. EST. This... EST. FOR FURTHER INFORMATION CONTACT: Commander P.W. Clark, Designated Federal Officer (DFO) of...

  8. 78 FR 14299 - Notification of a Public Meeting of the Science Advisory Board Chemical Assessment Advisory...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ... committee in two Federal Register notices published on November 18, 2011 and August 29, 2012 (76 FR 223 pp. 71561-62; 77 FR 168 pp. 52330-31, respectively). Information about the formation of this SAB committee... may contact Dr. Suhair Shallal, Designated Federal Officer (DFO), SAB Staff Office, by...

  9. Transdermal deferoxamine prevents pressure-induced diabetic ulcers

    PubMed Central

    Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

    2015-01-01

    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID:25535360

  10. Investigation of biologically-designed metal-specific chelators for potential metal recovery and waste remediation applications.

    SciTech Connect

    Criscenti, Louise Jacqueline; Ockwig, Nathan W.

    2009-01-01

    Bacteria, algae and plants produce metal-specific chelators to capture required nutrient or toxic trace metals. Biological systems are thought to be very efficient, honed by evolutionary forces over time. Understanding the approaches used by living organisms to select for specific metals in the environment may lead to design of cheaper and more effective approaches for metal recovery and contaminant-metal remediation. In this study, the binding of a common siderophore, desferrioxamine B (DFO-B), to three aqueous metal cations, Fe(II), Fe(III), and UO{sub 2}(VI) was investigated using classical molecular dynamics. DFO-B has three acetohydroxamate groups and a terminal amine group that all deprotonate with increasing pH. For all three metals, complexes with DFO-B (-2) are the most stable and favored under alkaline conditions. Under more acidic conditions, the metal-DFO complexes involve chelation with both acetohydroxamate and acetylamine groups. The approach taken here allows for detailed investigation of metal binding to biologically-designed organic ligands.

  11. 78 FR 67205 - Advisory Committee on Reactor Safeguards; Procedures for Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-08

    .... Comments should be in the possession of the DFO 5 days prior to the meeting to allow time for reproduction... the meeting. Copies may be obtained upon payment of appropriate reproduction charges. ACRS meeting.... When Subcommittee meetings are held at locations other than at NRC facilities, reproduction...

  12. Iron Chelation Therapy in Thalassemia Syndromes

    PubMed Central

    Cianciulli, Paolo

    2009-01-01

    Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients. PMID:21415999

  13. 46 CFR 42.07-60 - Control.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Control. 42.07-60 Section 42.07-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES DOMESTIC AND FOREIGN VOYAGES BY SEA Control, Enforcement, and Rights of Appeal § 42.07-60 Control. (a) The Director, Field Operations (DFO) or the...

  14. 46 CFR 46.10-60 - Control.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Control. 46.10-60 Section 46.10-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES SUBDIVISION LOAD LINES FOR PASSENGER VESSELS Administration § 46.10-60 Control. The Director, Field Operations (DFO) or the Coast Guard District Commander...

  15. 46 CFR 42.07-60 - Control.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Control. 42.07-60 Section 42.07-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES DOMESTIC AND FOREIGN VOYAGES BY SEA Control, Enforcement, and Rights of Appeal § 42.07-60 Control. (a) The Director, Field Operations (DFO) or the...

  16. 46 CFR 42.07-60 - Control.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Control. 42.07-60 Section 42.07-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES DOMESTIC AND FOREIGN VOYAGES BY SEA Control, Enforcement, and Rights of Appeal § 42.07-60 Control. (a) The Director, Field Operations (DFO) or the...

  17. 46 CFR 46.10-60 - Control.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Control. 46.10-60 Section 46.10-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES SUBDIVISION LOAD LINES FOR PASSENGER VESSELS Administration § 46.10-60 Control. The Director, Field Operations (DFO) or the Coast Guard District Commander...

  18. 46 CFR 46.10-60 - Control.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Control. 46.10-60 Section 46.10-60 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) LOAD LINES SUBDIVISION LOAD LINES FOR PASSENGER VESSELS Administration § 46.10-60 Control. The Director, Field Operations (DFO) or the Coast Guard District Commander...

  19. 75 FR 81592 - Blue Ribbon Commission on America's Nuclear Future

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-28

    ... Ribbon Commission on America's Nuclear Future AGENCY: Department of Energy, Office of Nuclear Energy...) 586- 0544; e-mail CommissionDFO@nuclear.energy.gov . Additional information may also be available at.... Department of Energy, 1000 Independence Avenue, SW., Washington, DC 20585, e-mail to...

  20. 76 FR 71334 - Blue Ribbon Commission on America's Nuclear Future

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-17

    ... Ribbon Commission on America's Nuclear Future AGENCY: Office of Nuclear Energy, Department of Energy...; telephone (202) 586-4243; facsimile (202) 586- 0544; or email: CommissionDFO@nuclear.energy.gov . Additional... Energy, 1000 Independence Avenue SW., Washington DC 20585, or email:...

  1. 78 FR 18614 - National Offshore Safety Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-27

    ... our public dockets in the January 17, 2008, issue of the Federal Register (73 FR 3316). Docket: For... Wyndham Garden New Orleans Baronne Plaza Hotel, 201 Baronne Street, New Orleans, LA 70112, 1-504- 522-0083... Federal Official (DFO) of NOSAC, Commandant (CG-OES-2), U.S. Coast Guard, 2100 Second Street SW.,...

  2. Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1α pathway on the brain of APP/PS1 transgenic mice

    PubMed Central

    Guo, Chuang; Zhang, Yu-Xin; Wang, Tao; Zhong, Man-Li; Yang, Zhao-Hui; Hao, Li-Juan; Chai, Rui; Zhang, Shuai

    2015-01-01

    The widely recognized neuroprotective effect of iron chelators is contributed by their ability to prevent reactive oxygen species (ROS) generation via the Fenton reaction, which sequesters redox-active Fe. An additional neuroprotective mechanism of iron-chelating compounds is to regulate the transcriptional activator hypoxia-inducible factor 1α (HIF-1α). In the present study, we observed that intranasal administration of deferoxamine decreased beta-amyloid (Aβ) deposition and rescued synapse loss in the brain of Aβ precursor protein and presenilin-1 (APP/PS1) double transgenic mice. We found that deferoxamine (DFO) up-regulated HIF-1α mRNA expression and its protein level, and further induced the proteins that are encoded from HIF-1-adaptive genes, including transferrin receptor (TFR), divalent metal transporter 1 (DMT1), and brain-derived neurotrophic factor (BDNF). The effects of DFO on the induction and stabilization of HIF-1α were further confirmed in vitro. This was accompanied by a decrease of Fe in the CA3 region of the hippocampus. Western blotting studies revealed that DFO differentially enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/P38 kinase in vitro and in vivo. The results suggest that the DFO may up-regulate several HIF-1-dependent neuroprotective-adaptive genes in AD via activating P38/HIF-1α pathway, which may serve as important therapeutic targets to the disease. PMID:26082716

  3. 75 FR 35026 - Science Advisory Board Staff Office Request for Nominations of Experts for a Nutrient Criteria...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-21

    ... AGENCY Science Advisory Board Staff Office Request for Nominations of Experts for a Nutrient Criteria.... SUMMARY: The Science Advisory Board (SAB) Staff Office is requesting public nominations of experts to form..., Designated Federal Officer (DFO), EPA Science Advisory Board (1400F), 1200 Pennsylvania Avenue,...

  4. 75 FR 27554 - Science Advisory Board Staff Office; Request for Nominations of Experts for the SAB Arsenic...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ... AGENCY Science Advisory Board Staff Office; Request for Nominations of Experts for the SAB Arsenic Review...: The Science Advisory Board (SAB) Staff Office is requesting public nominations of experts to form an... Nominations may contact Dr. Sue Shallal, Designated Federal Officer (DFO), EPA Science Advisory Board...

  5. Evidences and controversies about recurrence of diabetic foot osteomyelitis: a personal view and an illustrated guide for understanding.

    PubMed

    Aragón-Sánchez, Javier

    2012-06-01

    Recurrence is one of the most worrying issues when dealing with diabetic foot osteomyelitis (DFO). In accordance with expert opinion in other areas of bone infection, it is accepted that very late relapse of apparently successfully treated osteomyelitis is not uncommon. However, the physiopathology of infections in large bones secondary to hematogenous osteomyelitis, infected prostheses, and open fractures is quite different from what is seen in the feet of patients with diabetes. The anatomy of the bones, the mechanism of infection and alterations in host defenses that are frequently seen in patients with diabetes may condition the onset, clinical course, and outcomes. Apparent eradication, disappearance of inflammatory signs, wound healing, bone healing based on image studies, and no recurrences during follow-up are common terms used for defining the success of therapy for DFO. Failure of initial surgical treatment, readmission to hospital, and new episodes of infection at the same or a contiguous site are considered as recurrence of osteomyelitis. Theoretically, bacteria living in the bone could be the source of clinical recurrence, but is it possible to obtain complete healing while bacteria remain alive in the bone in the feet of patients with diabetes? Can these bacteria grow and spread from the bone to the skin after years of healing? In the author's opinion, this type of long-term recurrence of DFO has not been well documented in the medical literature. It is the aim of this illustrated guide to review the evidence and controversies regarding the recurrence of DFO. PMID:22538269

  6. 78 FR 32645 - Notification of a Public Teleconference of the Great Lakes Advisory Board

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-31

    ... GLAB held a teleconference and meeting on May 21-22, 2013 (as noticed in 78 FR 26636-26637) to discuss...: Any member of the public wishing further information regarding this teleconference may contact Rita Cestaric, Designated Federal Officer (DFO), GLAB, by telephone at (312) 886-6815 or email at...

  7. Deferoxamine as a chelator for 67Ga in the preparation of antibody conjugates.

    PubMed

    Govindan, Serengulam V; Michel, Rosana B; Griffiths, Gary L; Goldenberg, David M; Mattes, M Jules

    2005-07-01

    (67)Ga antibodies (Abs) have been shown to be effective agents for single-cell killing due to the Auger electrons emitted, but their specific activities have not been as high as desired. We therefore evaluated deferoxamine (DFO) as a chelator, as opposed to the cyclic chelator NOTA, which was used previously. Use of DFO for Ab conjugation to (67)Ga was reported previously by several laboratories. DFO was conjugated to Abs by two methods, one using Ablysine conjugation and another using mild reduction of Abs to generate thiols in the hinge region. Labeling with (67)Ga was efficient, and the specific activities obtained under nonoptimized conditions were twice as high as those achieved previously. However, analysis of these conjugates revealed two problems that appear to prevent their further development. First, the stability was inadequate for the 3-day half-life of the nuclide. Second, the labels were poorly retained within cells after Ab internalization and catabolism. Also, it was found that stability was significantly affected by the incubation buffer used: buffers lacking physiological concentrations of divalent cations Ca and Mg resulted in much lower stability than buffers including them. In conclusion, DFO does not seem to be a suitable chelator for (67)Ga conjugation for our purposes. PMID:15982582

  8. 77 FR 19005 - Defense Business Board (DBB); Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-29

    ... of the Secretary Defense Business Board (DBB); Notice of Meeting AGENCY: DoD. ACTION: Meeting notice... Business Board (DBB). DATES: The public meeting of the Defense Business Board (hereafter referred to as... Board's Designated Federal Officer ] (DFO) is Phyllis Ferguson, Defense Business Board, 1155...

  9. Aeromedical Lessons from the Space Shuttle Columbia Accident Investigation

    NASA Technical Reports Server (NTRS)

    Pool, Sam L.

    2005-01-01

    This paper presents the aeromedical lessons learned from the Space Shuttle Columbia Accident Investigation. The contents include: 1) Introduction and Mission Response Team (MRT); 2) Primary Disaster Field Office (DFO); 3) Mishap Investigation Team (MIT); 4) Kennedy Space Center (KSC) Mishap Response Plan; 5) Armed Forces Institute of Pathology (AFIP); and 6) STS-107 Crew Surgeon.

  10. 77 FR 45699 - Advisory Committee On Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee On Economic...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-01

    ... ACRS meetings were published in the Federal Register on October 17, 2011, (76 FR 64126-64127). Detailed... and/or written comments should notify the Designated Federal Official (DFO), Christopher Brown (Telephone 301-415-7111 or Email: Christopher.Brown@nrc.gov ) five days prior to the meeting, if possible,...

  11. 78 FR 8202 - Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee on US-APWR...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-05

    ... ACRS meetings were published in the Federal Register on October 18, 2012, (77 FR 64146- 64147... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY... and/or written comments should notify the Designated Federal Official (DFO), Girija Shukla...

  12. 77 FR 58529 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-21

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... advisory committee meeting will take place: 1. Name of Committee: United States Military Academy Board of... statements should be sent to the Designated Federal Officer (DFO) at: United States Military Academy,...

  13. 77 FR 14006 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-08

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... advisory committee meeting will take place: 1. Name of Committee: United States Military Academy Board of.... Written statements should be sent to the Designated Federal Officer (DFO) at: United States...

  14. 76 FR 60816 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... advisory committee meeting will take place: 1. Name of Committee: United States Military Academy Board of... statements should be sent to the Designated Federal Officer (DFO) at: United States Military Academy,...

  15. 75 FR 3901 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-25

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... advisory committee meeting will take place: 1. Name of Committee: United States Military Academy Board of.... Written statements should be sent to the Designated Federal Officer (DFO) at: United States...

  16. 75 FR 7571 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-22

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... Committee: United States Military Academy Board of Visitors. 2. Date: Tuesday, March 9, 2010. 3. Time: 12:30... Designated Federal Officer (DFO) at: United States Military ] Academy, Office of the Secretary of the...

  17. 78 FR 13030 - Board of Visitors, United States Military Academy (USMA)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-26

    ... Department of the Army Board of Visitors, United States Military Academy (USMA) AGENCY: Department of the... advisory committee meeting will take place: 1. Name of Committee: United States Military Academy Board of... (DFO) at: United States Military Academy, Office of the Secretary of the General Staff (MASG),...

  18. 77 FR 27078 - Cancellation of May 8, 2012, Meeting of the Wekiva River System Advisory Management Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-08

    ..., 2012, 77 FR 23277, is cancelled. Instead, members of the Committee will meet on May 8, 2012, solely to share information and discuss preparations for the Wekiva Wild and Scenic River Plan Dedication Ceremony... INFORMATION CONTACT: Jaime Doubek-Racine, DFO, Wekiva Wild and Scenic River, RTCA Program, Florida...

  19. Increase of reactive oxygen species by desferrioxamine during experimental Chagas' disease

    PubMed Central

    Francisco, Amanda Fortes; de Abreu Vieira, Paula Melo; Arantes, Jerusa Marilda; Silva, Maisa; Pedrosa, Maria Lúcia; Elói-Santos, Silvana Maria; Martins-Filho, Olindo Assis; Teixeira-Carvalho, Andréa; Araújo, Márcio Sobreira Silva; Tafuri, Washington Luiz; Carneiro, Cláudia Martins

    2010-01-01

    Oxidative stress is common in inflammatory processes associated with many diseases including Chagas' disease. The aim of the present study was to evaluate, in a murine model, biomarkers of oxidative stress together with components of the antioxidant system in order to provide an overview of the mechanism of action of the iron chelator desferrioxamine (DFO). The study population comprised 48 male Swiss mice, half of which were treated daily by intraperitoneal injection of DFO over a 35-day period, while half were administered sterile water in a similar manner. On the 14th day of the experiment, 12 DFO-treated mice and an equal number of untreated mice were experimentally infected with Trypanosoma cruzi. Serum concentrations of nitric oxide and superoxide dismutase and hepatic levels of total glutathione, thiobarbituric acid reactive species and protein carbonyl, were determined on days 0, 7, 14 and 21 post-infection. The results obtained revealed that DFO enhances antioxidant activity in the host but also increases oxidative stress, indicating that the mode of action of the drug involves a positive contribution to the host together with an effect that is not beneficial to the parasite. PMID:20663295

  20. Combination of deferasirox and deferoxamine in clinical practice: an alternative scheme of chelation in thalassemia major patients.

    PubMed

    Cassinerio, E; Orofino, N; Roghi, A; Duca, L; Poggiali, E; Fraquelli, M; Zanaboni, L; Cappellini, M D

    2014-09-01

    The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs' starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 μM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable

  1. Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with 89Zr4+: comparison with desferrioxamine-B† †Electronic supplementary information (ESI) available: 1H and 13C NMR data, reverse phase HPLC and size exclusion HPLC chromatograms, phosphoimages of ITLC plates, ex vivo biodistribution data. See DOI: 10.1039/c4dt02978j Click here for additional data file.

    PubMed Central

    Meszaros, Levente K.; Paterson, Brett M.; Berry, David J.; Cooper, Maggie S.; Ma, Yongmin; Hider, Robert C.; Blower, Philip J.

    2015-01-01

    Due to its long half-life (78 h) and decay properties (77% electron capture, 23% β+, E max = 897 keV, E av = 397 keV, Eγ = 909 keV, Iγ = 100%) 89Zr is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H3DFO) are the most widely used bifunctional chelators for coordination of 89Zr4+ because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. 89Zr-DFO complexes are reportedly stable in vitro but there is evidence that 89Zr4+ is released in vivo, and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H3CP256 and its bifunctional maleimide derivative, H3YM103, for coordination of Zr4+ and compared the NMR spectra, and the 89Zr4+ radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H3DFO and its analogues. H3CP256 coordinates 89Zr4+ at carrier-free concentrations forming [89Zr(CP256)]+. Both H3DFO and H3CP256 were efficiently radiolabelled using [89Zr(C2O4)4]4– at ambient temperature in quantitative yield at pH 6–7 at millimolar concentrations of chelator. Competition experiments demonstrate that 89Zr4+ dissociates from [89Zr(DFO)]+ in the presence of one equivalent of H3CP256 (relative to H3DFO) at pH 6–7, resulting largely in [89Zr(CP256)]+. To assess the stability of H3DFO and H3YM103 immunoconjugates radiolabelled with 89Zr, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with 89Zr4+ in >98% yield at high specific activities and the labeled immunoconjugates were stable in serum with respect to dissociation of the radiometal. In vivo studies in mice indicate that 89Zr4+ dissociates from YM103-trastuzumab with significant amounts of activity becoming associated with bones and joints (25.88 ± 0.58% ID g–1 7

  2. Hemin Uptake and Release by Neurons and Glia

    PubMed Central

    Chen-Roetling, Jing; Cai, Ying; Lu, Xiangping; Regan, Raymond F.

    2013-01-01

    Hemin accumulates in intracerebral hematomas and may contribute to cell injury in adjacent tissue. Despite its relevance to hemorrhagic CNS insults, very little is known about hemin trafficking by neural cells. In the present study, hemin uptake and release were quantified in primary murine cortical cultures, and the effect of the hemin-binding compound deferoxamine (DFO) was assessed. Net uptake of 55Fe-hemin was similar in mixed neuron-glia, neuron, and glia cultures, but was 2.6–3.6-fold greater in microglia cultures. After washout, 40–60% of the isotope signal was released by mixed neuron-glia cultures into albumin-containing medium within 24 hours. Inhibiting hemin breakdown with tin protoporphyrin IX (SnPPIX) had minimal effect, while release of the fluorescent hemin analog zinc mesoporphyrin was quantitatively similar to that of 55Fe-hemin. Isotope was released most rapidly by neurons (52.2±7.2% at 2 hours), compared with glia (15.6±1.3%) and microglia (17.6±0.54%). DFO did not alter 55Fe-hemin uptake, but significantly increased its release. Mixed cultures treated with 10 μM hemin for 24 hours sustained widespread neuronal loss that was attenuated by DFO. Concomitant treatment with SnPPIX had no effect on either enhancement of isotope release by DFO or neuroprotection. These results suggest that in the presence of a physiologic albumin concentration, hemin uptake by neural cells is followed by considerable extracellular release. Enhancement of this release by DFO may contribute to its protective effect against hemin toxicity. PMID:24164169

  3. Imaging of hepatocellular carcinoma patient-derived xenografts using 89Zr-labeled anti-glypican-3 monoclonal antibody

    PubMed Central

    Yang, Xiaoyang; Liu, Hongguang; Sun, Chris K.; Natarajan, Arutselvan; Hu, Xiang; Wang, Xiaolin; Allegretta, Mark; Guttmann, Ronald D.; Gambhir, Sanjiv S.; Chua, Mei-Sze; Cheng, Zhen; So, Samuel K.

    2015-01-01

    Imaging probes for early detection of hepatocellular carcinoma (HCC) are highly desired to overcome current diagnostic limitations which lead to poor prognosis. The membrane protein glypican-3 (GPC3) is a potential molecular target for early HCC detection as it is over-expressed in >50% of HCCs, and is associated with early hepatocarcinogenesis. We synthesized the positron emission tomography (PET) probe 89Zr-DFO-1G12 by bioconjugating and radiolabeling the anti-GPC3 monoclonal antibody (clone 1G12) with 89Zr, and evaluated its tumor-targeting capacity. In vitro, 89Zr-DFO-1G12 was specifically taken up into GPC3-positive HCC cells only, but not in the GPC3-negative prostate cancer cell line (PC3). In vivo, 89Zr-DFO-1G12 specifically accumulated in subcutaneous GPC3-positive HCC xenografts only, but not in PC3 xenografts. Importantly, 89Zr-DFO-1G12 delineated orthotopic HCC xenografts from surrounding normal liver, with tumor/liver (T/L) ratios of 6.65 ± 1.33 for HepG2, and 4.29 ± 0.52 for Hep3B xenografts. It also delineated orthotopic xenografts derived from three GPC3-positive HCC patient specimens, with T/L ratios of 4.21 ± 0.64, 2.78 ± 0.26, and 2.31 ± 0.38 at 168 h p.i. Thus, 89Zr-DFO-1G12 is a highly translatable probe for the specific and high contrast imaging of GPC3-positive HCCs, which may aid early detection of HCC to allow timely intervention. PMID:24836949

  4. Imaging of hepatocellular carcinoma patient-derived xenografts using ⁸⁹Zr-labeled anti-glypican-3 monoclonal antibody.

    PubMed

    Yang, Xiaoyang; Liu, Hongguang; Sun, Chris K; Natarajan, Arutselvan; Hu, Xiang; Wang, Xiaolin; Allegretta, Mark; Guttmann, Ronald D; Gambhir, Sanjiv S; Chua, Mei-Sze; Cheng, Zhen; So, Samuel K

    2014-08-01

    Imaging probes for early detection of hepatocellular carcinoma (HCC) are highly desired to overcome current diagnostic limitations which lead to poor prognosis. The membrane protein glypican-3 (GPC3) is a potential molecular target for early HCC detection as it is over-expressed in >50% of HCCs, and is associated with early hepatocarcinogenesis. We synthesized the positron emission tomography (PET) probe (89)Zr-DFO-1G12 by bioconjugating and radiolabeling the anti-GPC3 monoclonal antibody (clone 1G12) with (89)Zr, and evaluated its tumor-targeting capacity. In vitro, (89)Zr-DFO-1G12 was specifically taken up into GPC3-positive HCC cells only, but not in the GPC3-negative prostate cancer cell line (PC3). In vivo, (89)Zr-DFO-1G12 specifically accumulated in subcutaneous GPC3-positive HCC xenografts only, but not in PC3 xenografts. Importantly, (89)Zr-DFO-1G12 delineated orthotopic HCC xenografts from surrounding normal liver, with tumor/liver (T/L) ratios of 6.65 ± 1.33 for HepG2, and 4.29 ± 0.52 for Hep3B xenografts. It also delineated orthotopic xenografts derived from three GPC3-positive HCC patient specimens, with T/L ratios of 4.21 ± 0.64, 2.78 ± 0.26, and 2.31 ± 0.38 at 168 h p.i. Thus, (89)Zr-DFO-1G12 is a highly translatable probe for the specific and high contrast imaging of GPC3-positive HCCs, which may aid early detection of HCC to allow timely intervention. PMID:24836949

  5. Move Over, SI: Minority Sports Magazine to Debut at Year's End

    ERIC Educational Resources Information Center

    Yates, Eleanor Lee

    2004-01-01

    A new magazine focusing exclusively on issues facing Black, Hispanic and other athletes of color is set to hit the news-stands at the end of the year. "The Color of Sports can fill a significant void and have a tremendous influence on shaping the agenda of the sports industry," says Aaron Brooks, one of the magazine's investors and quarterback for…

  6. 78 FR 69651 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-20

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: November 12, 2013. Aaron Siegel...: Ms. Theresa Lowery at Defense Intelligence Agency, DAN 1-C, 600 MacDill Blvd., Washington, DC 20340... Management Programs System location: Defense Intelligence Agency (DIA), 200 MacDill Blvd., Washington,...

  7. 77 FR 56625 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-13

    ..., 1996, 61 FR 6427). Dated: September 10, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. LDIA 06-0004 System name: Recall Rosters (April 16, 2010, 75 FR 19946... Intelligence Agency, DAN 1-C, 600 MacDill Blvd., Washington, DC 20340- 0001 or by phone at (202)...

  8. Developing the Vertex Formula Meaningfully

    ERIC Educational Resources Information Center

    Nebesniak, Amy L.; Burgoa, A. Aaron

    2015-01-01

    As teachers working with students in entry-level algebra classes, authors Amy Nebesniak and A. Aaron Burgoa realized that their instruction was a major factor in how their students viewed mathematics. They often presented students with abstract formulas that seemed to appear out of thin air. One instance occurred while they were teaching students…

  9. 76 FR 35197 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ... Maintaining Records About Individuals,'' February 20, 1996, 61 FR 6427. Dated: June 7, 2011. Aaron Siegel... Correspondence Course Program (ACCP) (July 25, 2008, 73 FR 43420). Changes: System Name: Delete entry and replace... is through Police patrols, installation fences, key card access, building-server room alarms...

  10. 77 FR 37006 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ... Individuals'', dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 15, 2012. Aaron Siegel... Satellite Communications (SATCOM) Management Enterprise (JSME). System location: Primary servers: Global... servers: U.S. Strategic Command (USSTRATCOM), Building 500, Suite BB30, 901 SAC Boulevard, Offutt...

  11. "The Social Network" and the Legal Environment of Business: An Opportunity for Student-Centered Learning

    ERIC Educational Resources Information Center

    McGill, Shelley

    2013-01-01

    Aaron Sorkin has a passion for words--his signature movie and television scripts are fast talking, jargon laced, word pictures that are instantly recognizable. "The Social Network," Sorkin's 2011 Academy Award Winning movie about the founding of Facebook, Inc., offers more than just witty banter; it provides an ideal teaching platform for…

  12. 77 FR 37004 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ..., 1996, 61 FR 6427). Dated: June 15, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer... that is being stored. Access to the computer system containing the records in this system is limited to... of the Secretary Privacy Act of 1974; System of Records AGENCY: National...

  13. 78 FR 31526 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-24

    ...)--Enterprise Workforce System (NEWS) (January 25, 2010, 75 FR 3899) Changes: Change system ID to ``NGA-003..., 1996 (February 20, 1996, 61 FR 6427). Dated: May 21, 2013. Aaron Siegel, Alternate OSD Federal Register... the risk of compromising the information that is being stored. Access to the computer...

  14. 78 FR 68039 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-13

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: November 6, 2013. Aaron Siegel, Alternate OSD... computer system containing the records in this system is limited to those individuals who have a need to... of the Secretary Privacy Act of 1974; System of Records AGENCY: National...

  15. Assessing and Changing Organizational Culture and Climate for Effective Services

    ERIC Educational Resources Information Center

    Glisson, Charles

    2007-01-01

    The 2007 Aaron Rosen Lecture was presented at the annual meeting of the Society for Social Work and Research, January 12, 2007, in San Francisco, CA. The lecture begins by describing the gap between what is known about efficacious treatments and other evidence-based practices on the one hand and the services that are provided in actual…

  16. Evaluating the Properties of the Evidence-Based Practice Attitude Scale (EBPAS) in Health Care

    ERIC Educational Resources Information Center

    Melas, Christos D.; Zampetakis, Leonidas A.; Dimopoulou, Anastasia; Moustakis, Vassilis

    2012-01-01

    The Evidence-Based Practice Attitude Scale (EBPAS; Aarons, 2004) is a relatively new construct for the study of attitudes toward the adoption of innovation and evidence-based practices (EBPs) in mental health service settings. Despite widespread interest in measuring the attitudes of health care providers in conjunction with the adoption of EBPs,…

  17. Friendship and the Public Stage: Revisiting Hannah Arendt's Resistance to "Political Education"

    ERIC Educational Resources Information Center

    Schutz, Aaron; Sandy, Marie G.

    2015-01-01

    Hannah Arendt's essays about the 1957 crisis over efforts of a group of youth, the "Little Rock Nine," to desegregate a high school in Little Rock, Arkansas, reveal a tension in her vision of the "public." In this article Aaron Schutz and Marie Sandy look closely at the experiences of the youth desegregating the school,…

  18. An Upstart Web Catalog Challenges an Academic-Library Giant

    ERIC Educational Resources Information Center

    Foster, Andrea L.

    2008-01-01

    21-year-old Aaron Swartz is attempting to turn the library world upside down. He is taking on the subscription-based WorldCat, the largest bibliographic database on the planet, by building a free online book catalog that anyone can update. Many academic librarians are wary of Mr. Swartz's project because it will allow nonlibrarians, who may be…

  19. Overcoming Risk: An Annotated Bibliography of Publications Developed by ERIC Clearinghouses.

    ERIC Educational Resources Information Center

    Schwartz, Wendy, Ed.; Howley, Craig, Ed.

    This publication contains two essays and an annotated bibliography of publications about risk. The entries in the bibliography were produced by the various clearinghouses in the ERIC system. The first essay, "Who Is at Risk? Definitions, Demographics, and Decisions," by Aaron M. Pallas, categorizes personal, family, and environmental factors that…

  20. Magna Carta for Community: Bay Mills Charters Schools throughout Michigan

    ERIC Educational Resources Information Center

    Reynolds, Jerry

    2009-01-01

    For most of a full career in sociology and education, Aaron Tadgerson has dwelt on the relationship between communities and the school systems that purport to serve them. The special problems of Indian education derive from that relationship. Tadgerson serves as the recruiter, retention, and land grant development coordinator for Bay Mills…

  1. 77 FR 29616 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-18

    ..., 1996, 61 FR 6427). Dated: May 14, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. DCIO 01 System name: Defense Industrial Base (DIB) Cyber Security/Information Assurance Records. System location: Director, Defense Industrial Base (DIB) Cyber...

  2. Subdiffusion kinetics of nanoprecipitate growth and destruction in solid solutions

    NASA Astrophysics Data System (ADS)

    Sibatov, R. T.; Svetukhin, V. V.

    2015-06-01

    Based on fractional differential generalizations of the Ham and Aaron-Kotler precipitation models, we study the kinetics of subdiffusion-limited growth and dissolution of new-phase precipitates. We obtain the time dependence of the number of impurities and dimensions of new-phase precipitates. The solutions agree with the Monte Carlo simulation results.

  3. 76 FR 38643 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-01

    ... (November 20, 2001, 66 FR 58132). Changes: System name: Delete entry and replace with ``Naval Inspector... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 28, 2011. Aaron Siegel, Alternate OSD Federal... determine whether information about themselves is contained in this system should address written...

  4. 76 FR 49753 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-11

    ... with Disabilities (June 21, 2006, 71 FR 35632). Changes: * * * * * ] System name: Delete entry and... available from the address in FOR FURTHER INFORMATION CONTACT. The proposed system report, as required by 5... (February 20, 1996, 61 FR 6427). Dated: August 5, 2011. Aaron Siegel, Alternate OSD Federal Register...

  5. 77 FR 29619 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-18

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: May 15, 2012. Aaron Siegel, Alternate OSD Federal... personnel. Categories of records in the system: Name, Social Security Number (SSN), gender, race/ethnicity... (citizenship, gender, date of birth, address, phone number, email address), medical information,...

  6. 78 FR 44931 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-25

    .... (February 20, 1996, 61 FR 6427). Dated: July 19, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison... with the ability to rapidly and effectively disseminate emergency alerts and notification information... the ability to rapidly and effectively disseminate emergency alerts and notification information...

  7. 78 FR 69393 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-19

    ... Geospatial-Intelligence Agency Enterprise Workforce System (May 24, 2013, 78 FR 31526) Changes...-Intelligence Agency (NGA), ATTN: Human Development Directorate, 7500 GEOINT Drive, Springfield, VA 22150...,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: November 12, 2013. Aaron...

  8. University Challenge

    ERIC Educational Resources Information Center

    Adults Learning, 2010

    2010-01-01

    The Browne review of higher education funding and student finance has been welcomed as "fair and progressive" by some and condemned as "elitist" and "socially disastrous" by others. In this article, some of the leading commentators and stakeholders from across the sector--Claire Callender, John Widdowson, Andy Westwood, Aaron Porter, Charles Levy,…

  9. 76 FR 52320 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-22

    ..., 1996 (February 20, 1996, 61 FR 6427). Dated: August 15, 2011. Aaron Siegel, Alternate OSD Federal... prefix (if appropriate), relationship to policy holder, and service branch classification. Sponsor Data... prefix or dependent suffix; or sponsor's name, Social Security Number (SSN) and/or DoD ID...

  10. 76 FR 61680 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). ] Dated: September 29, 2011. Aaron... War College (ATWC), 122 Forbes Avenue, Carlisle, PA 17013-5215. Commandant, Western Hemisphere... security is through police patrols, installation fences, key card access, building-server room alarms...

  11. Teaching Matters: Observations on Teacher Evaluations

    ERIC Educational Resources Information Center

    Hibler, David W.; Snyder, Jeffrey Aaron

    2015-01-01

    In this essay, the authors reflect on the ongoing teacher effectiveness debate. W. David Hibler is an experienced language arts teacher, who has taught in public high schools and middle schools in Alaska, North Carolina, and New York City. Jeffrey Aaron Snyder is a historian of education who writes about schooling in the twentieth-century United…

  12. 75 FR 36779 - Qualification of Drivers; Exemption Renewals; Vision

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-28

    ... renew exemptions at the end of the 2-year period. The comment period ended on May 17, 2010 (75 FR 19674.... Schnautz, Steve J. Sherar, Robert F. Skinner, Jr., William T. Smiley, Richard M. Smith, Robert A. Stoeckle, David N. Stubbs, Edward J. Sullivan, Aaron S. Taylor, Martin L. Taylor, Gary R. Thomas, William...

  13. 77 FR 38782 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-29

    ..., cell telephone phone, email address, bank or credit union name, city, state, and zip code, ABA routing..., 1996, 61 FR 6427). Dated: June 26, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer... Department of the Navy Privacy Act of 1974; System of Records AGENCY: Department of the Navy, DoD....

  14. 76 FR 51002 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-17

    ... Headquarters Services, 1155 Defense Pentagon, Washington, DC 20301- 1155, or by phone at (703) 588-6830..., 1996 (February 20, 1996, 61 FR 6427). Dated: August 12, 2011. Aaron Siegel, Alternate OSD Federal..., other names used, mailing address, email address, telephone numbers (home and/or cell), marital...

  15. 78 FR 73512 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ..., 1996, 61 FR 6427). Dated: December 3, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. N05880-2 System Name: Admiralty Claims Files (May 9, 2003, 68 FR 24959..., Washington, DC 20350-2000, or by phone at (202) 685-6545. SUPPLEMENTARY INFORMATION: The Department of...

  16. 78 FR 34352 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-07

    ... personal cell phone numbers, US government credit card number, personal and alternative email addresses..., 1996 (February 20, 1996, 61 FR 6427). Dated: June 3, 2013. Aaron Siegel, Alternate OSD Federal Register... of the Secretary Privacy Act of 1974; System of Records AGENCY: Office of the Secretary of...

  17. 77 FR 4798 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-31

    ...; home and work addresses; home and work email addresses; phone numbers (home, office, cell, and fax... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: January 26, 2012. Aaron Siegel, Alternate OSD... Department of the Navy Privacy Act of 1974; System of Records AGENCY: Department of the Navy, DoD....

  18. 77 FR 38598 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-28

    ..., (February 20, 1996, 61 FR 6427). Dated: June 25, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. CIG-23 System Name: Public Affairs Files (August 7, 2006, 71 FR 44667) Changes: * * * * * System name: Delete entry and replace with ``SCOUT and Public Affairs Files.''...

  19. Environmental Issues in Brazilian Society. Fulbright-Hays Seminars Abroad Program. June 26-July 31, 1994.

    ERIC Educational Resources Information Center

    Commission for Educational Exchange between the United States and Brazil, Brasilia.

    This book contains a review of the 1994 Fulbright-Hays Seminars Abroad Program along with lesson plans from 13 of the participants. The curriculum projects contained in this book include: (1) "The Brazilian Cinema: A Critical Appreciation of An Industry in Turmoil" (Aaron Braun); (2) "Reflections on the Relationship between Brazilian Communities…

  20. 78 FR 74122 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-10

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: December 5, 2013. Aaron Siegel, Alternate OSD...'s Records (December 30, 2008, 73 FR 79849). Changes: * * * * * Categories of individuals covered by... Integration and Chief Information Officer, ATTN: SAF/CIO A6, 1800 Air Force Pentagon, Washington, DC...

  1. 77 FR 31591 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-29

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: May 23, 2012. Aaron Siegel... General Records (December 2, 2008, 73 FR 73252). * * * * * Categories of records in the system: Delete... Office, Office of Warfighting Integration and Chief Information officer, ATTN: SAF/CIO A6, 1800 Air...

  2. Engl 1102: Literature and Composition: Handwriting and Typography

    ERIC Educational Resources Information Center

    Kashtan, Aaron

    2015-01-01

    Aaron Kashtan taught three sections of ENGL 1102, the second course in a mandatory first-year writing sequence with a heavy multimodal focus, during his first semester as a Marion L. Brittain Postdoctoral Fellow in the Department of Literature, Media and Communication at Georgia Tech. The specific subject matter for these sections was handwriting…

  3. 77 FR 56822 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-14

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: September 11, 2012. Aaron Siegel... Responsibility/Ethics File (July 30, 1999, 64 FR 41401). Changes: Delete entry and replace with ``N05800-2... Military Justice (UCMJ), or in Navy and Marine Corps administrative proceedings, or as legal...

  4. 78 FR 26623 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-07

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: May 2, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. A0600-8b AHRC System Name: Soldiers' Criminal History...; or may be obtained from the system manager. Record source categories: Subjects of...

  5. Internal Revenue Service General Counsel's Memorandum threatens tax exemption for charitable hospitals.

    PubMed

    Ball, D W

    1992-01-01

    A recent memorandum from the General Counsel of the Internal Revenue Service changes the standard against which tax exempt entities will be measured, which change can adversely affect charitable hospitals' tax exempt status. In addition, the memorandum makes clear that a violation of the Anti-Kickback statute, discussed in Mr. Aaron's article, is inconsistent with tax exempt status. PMID:10141602

  6. Views of the STS-5 Science Press briefing with Student Experimenters

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Views of the STS-5 Science Press briefing with Student Experimenters. Photos include Michelle Issel of Wallingfor, Connecticut showing her studen experiment dealing with the formation of crystals in a weightless environment (37862); Aaron Gillette of Winter Haven, Florida displaying his student experiment dealing with the growth of Porifera in zero gravity (37863).

  7. 76 FR 35859 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-20

    ... About Individuals,'' February 20, 1996, 61 FR 6427. Dated: June 13, 2011. Aaron Siegel, Alternate OSD... Records (July 25, 2008, 73 FR 43419). Changes: * * * * * System name: Delete entry and replace with... out unauthorized access. Paper records are maintained in locked file cabinets in a secure building...

  8. 78 FR 5792 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: January 23, 2013. Aaron Siegel, Alternate OSD... Reporting System (MRRS) (May 5, 2006, 71 FR 26481). Changes: * * * * * System Location: Delete entry and...: Delete entry and replace with ``For Marine Corps: Headquarters U.S. Marine Corps, PPO, PLN...

  9. 78 FR 72572 - Operational Contract Support

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-03

    ... FR 81807), the Department published an interim final rule and public comments were solicited. At the... more in any one year. Public Law 96-354, ``Regulatory Flexibility Act'' (5 U.S.C. 601) It has been... published December 29, 2011 (76 FR 81807), as final without change. Dated: November 18, 2013. Aaron...

  10. 78 FR 31528 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-24

    ...; and commissary patron profile information; social media (e.g. Facebook, Twitter, Flickr, YouTube... (February 20, 1996, 61 FR 6427). Dated: May 7, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. Z0035-01 System Name: Financial Transaction Data (December 28, 2007, 72...

  11. 78 FR 14278 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ..., 1996 (February 20, 1996, 61 FR 6427). Dated: February 28, 2013. Aaron Siegel, Alternate OSD Federal..., 2008; 73 FR 40304). Changes: * * * * * System name: Delete entry and replace with ``Debarment and... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE...

  12. Living the Dream of Green Acres: Boy with Autism Finds Acceptance and Success Thanks to 4-H

    ERIC Educational Resources Information Center

    Richardson, Ginny

    2006-01-01

    Twelve-year-old Aaron Zibricky, a member of the Lucky Clovers 4-H Club, entered his prize sheep, Star, in the 2005 Will County Fair in Illinois. Zibricky, who is diagnosed with autism, had worked and strived for this moment, putting in long hours feeding, cleaning and shearing the sheep and learning showmanship skills. No one was more elated at…

  13. 77 FR 69807 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-21

    ... (February 20, 1996, 61 FR 6427). Dated: November 15, 2012. Aaron Siegel, Alternate OSD Federal Register... System (DEERS), (August 3, 2011, 76 FR 46757). Changes: * * * * * System name: Delete entry and replace... cards; and to detect fraud and abuse of the benefit programs by claimants and providers to...

  14. 76 FR 65719 - Wyco Power and Water, Inc.; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-24

    ... River and one from Flaming Gorge Reservoir) to a storage terminus near Pueblo, Colorado. The pipeline would be located in Adams, Arapahoe, Elbert, El Paso, Larimer, Pueblo, and Weld Counties in Colorado... Green River; and (4) a terminus reservoir near Pueblo, Colorado. Applicant Contact: Aaron Million,...

  15. 77 FR 21975 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... in the performance of their duties. Passwords and User IDs are used to control access to the system...,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 9, 2012. Aaron Siegel, Alternate... functions. Authority for Maintenance of the System: Section 1080 of Public Law 111-84, The National...

  16. 77 FR 2052 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-13

    ...'', dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: January 10, 2012. Aaron Siegel, Alternate... leadership, former USSTRATCOM leadership and notable civilians in the local area, state government officials, US government leadership for Nebraska, Offutt AFB (55th Wing). Categories of records in the...

  17. 77 FR 25991 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-02

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 27, 2012. Aaron Siegel, Alternate OSD... leaders. It supports individual creativity, team collaboration, peer review, instructor-led and self... servicing the system in performance of their official duties. A risk assessment has been performed and...

  18. 77 FR 21973 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ..., 1996, 61 FR 6427). Dated: April 9, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. DSCA 02 System name: Regional International Outreach System (March 7, 2007, 72 FR... Collaboration Platform''. System location: Delete entry and replace with ``Amazon Web Services, LLC...

  19. 76 FR 28964 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-19

    ... (February 20, 1996, 61 FR 6427). Dated: May 15, 2011. Aaron Siegel, Alternate OSD Federal Register Liaison... other than military members.'' Safeguards: Delete entry and replace with ``Mass Communication Tool (MCT... terminals and rooms, guards, personnel screening, or visitor registers. eMarine Family Readiness (FR)...

  20. 77 FR 39488 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-03

    ... Individuals, ``dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 28, 2012. Aaron Siegel... Visas (October 13, 2009, 74 FR 52462). Changes: * * * * * System Location: Delete entry and replace with... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  1. 77 FR 21976 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 9, 2012. Aaron Siegel... (March 18, 2010, 75 FR 13089) Changes: * * * * * System name: Delete entry and replace with ``DIA... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  2. 77 FR 57076 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-17

    ..., 1996, 61 FR 6427). Dated: September 11, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. LDIA 0209 Litigation and Disposition Documentation (June 5, 2006, 71 FR... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  3. 78 FR 47308 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-05

    ..., 1996 (February 20, 1996, 61 FR 6427). Dated: July 31, 2013. Aaron Siegel, Alternate OSD Federal..., 2010, 75 FR 26201) Changes * * * * * Categories of individuals covered by the system: Delete entry and... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  4. 77 FR 22290 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-13

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 9, 2012. Aaron Siegel... Support System (September 6, 2007, 72 FR 51215) Changes: * * * * * System name: Delete entry and replace... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  5. 76 FR 35191 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ... (February 20, 1996, 61 FR 6427). Dated: June 9, 2011. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. LDIA 0660 Security Files (July 24, 2006, 71 FR 41784) * * * * * Changes... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  6. 77 FR 21974 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... Intelligence Virtual University (JIVU II) (March 24, 2008, 73 FR 15496) Changes: * * * * * System locations... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 9, 2012. Aaron Siegel... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Intelligence Agency,...

  7. Word Calling in 3rd and 4th Graders: Exploring Student and Teacher Characteristics

    ERIC Educational Resources Information Center

    Couzens, Lindsay Starr

    2013-01-01

    Reading difficulties in elementary school-aged children may occur when two components of reading--word identification, comprehension, or both of these skills--are weak or underdeveloped (Gough, 1972; Hoover & Gough, 1990; Joshi & Aaron, 2000; Savage, 2001). One type of reading difficulty that is frequently identified by teachers is known…

  8. 77 FR 27745 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-11

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: May 8, 2012. Aaron Siegel, Alternate OSD Federal...) Records (December 12, 2008, 73 FR 75692). Changes: * * * * * Categories of individuals covered by the.... Robin Patterson, Department of the Navy, DNS-36, 2000 Navy Pentagon, Washington, DC 20350-2000 or...

  9. 78 FR 34354 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-07

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 3, 2013. Aaron Siegel, Alternate OSD Federal... Systems (September 21, 2006, 71 FR 55173). Changes: * * * * * System location: Delete entry and replace... information. FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36),...

  10. 78 FR 35610 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-13

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 10, 2013. Aaron Siegel, Alternate OSD Federal... Tracking System (April 2, 2008, 73 FR 17961) Changes: * * * * * ] Categories of records in the system... information. FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36),...

  11. 78 FR 37801 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-24

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 19, 2013. Aaron Siegel, Alternate OSD Federal... System (ODIS) (July 26, 2010, 75 FR 43500). Changes: * * * * * Categories of records in the system... information. FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36),...

  12. 78 FR 61345 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-03

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: September 30, 2013. Aaron Siegel, Alternate OSD.../Interactive Detailing System (CMS/ID) Records (April 23, 2010, 75 FR 21260). Changes: * * * * * System name.... FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36), Department of...

  13. 78 FR 44102 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 18, 2013. Aaron Siegel, Alternate OSD Federal... Transportation Benefit Program (March 7, 2012, 77 FR 13574) Changes: * * * * * Categories of records in the... (DNS-36), Department of the Navy, 2000 Navy Pentagon, Washington, DC 20350-2000, or by phone at...

  14. 78 FR 37800 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-24

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 19, 2013. Aaron Siegel, Alternate OSD Federal... Information System (May 9, 2003, 68 FR 24959). Changes: * * * * * System name: Delete entry and replace with... information. FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36),...

  15. 78 FR 14284 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ...,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: February 28, 2013. Aaron Siegel... Management Information System (DMIS) (November 9, 2005, 70 FR 67995). Changes: * * * * * System location... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Contract Audit Agency,...

  16. 77 FR 2515 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-18

    ... System (MARS) Member Records (April 12, 1999, 64 FR 17636). * * * * * Changes: Delete entry and replace... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: January 12, 2012. Aaron Siegel, Alternate OSD... individual name, MARS call sign, amateur call sign, mailing address, Federal Communications license...

  17. 78 FR 43868 - Privacy Act of 1974; System of Records; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-22

    ... (78 FR 35606-35607), DoD published a notice altering a Privacy Act System of Records notice (NGA-013... (78 FR 35606-35607), DoD published a notice altering a Privacy Act System of Records notice (NGA-013... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 16, 2013. Aaron...

  18. Research in Sociology of Education and Socialization. Volume 10.

    ERIC Educational Resources Information Center

    Pallas, Aaron M., Ed.

    This volume is a mixture of research reviews, theoretical syntheses, and empirical analyses addressing issues in the sociology of education. Following an introduction by Aaron M. Pallas, the book is divided into eight chapters: (1) "The Sociology of Education: Its Development in the United States" (Robert Dreeben); (2) "In Comparative Isolation:…

  19. 78 FR 73515 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ..., 1996, 61 FR 6427). ] Dated: December 3, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison... (April 14, 1999, 64 FR 18410). Changes: * * * * * System ID: Delete entry and replace with ``NM01850-2... members. Records include name, Social Security Number (SSN), DoD ID Number, date of birth,...

  20. The Lighter Side of Staff Development

    ERIC Educational Resources Information Center

    Bacall, Aaron

    2004-01-01

    As educators, we often take ourselves a bit too seriously, so veteran educator and illustrator Aaron Bacall offers a little perspective with these lighthearted cartoons. Whether used as overheads for meetings or as an individual break in a busy day, this collection of whimsical glimpses at staff development will provide a moment to laugh and add a…

  1. Modern Czech Studies. Brown Slavic Contributions, Volume XIII.

    ERIC Educational Resources Information Center

    Levitsky, Alexander, Ed.; Fidler, Masako U., Ed.

    2000-01-01

    The following papers are included: "Responses to the Literature Papers" (Malynne M. Sternstein); "Kitsch and Irony in Kundera: 'The Joke' and 'The Unbearable Lightness of Being'" (Aaron Beaver); "Daniela Fischerova's 'The Message Table': (Lauren McConnell); "Rethinking the Grotesque in Hrabal's Fiction" Carnival as a Model for Closely Watching…

  2. Salutogenesis 30 Years Later: Where Do We Go from here?

    ERIC Educational Resources Information Center

    Becker, Craig M.; Glascoff, Mary Alice; Felts, W. Michael

    2010-01-01

    In 1979 Aaron Antonovsky introduced the concept of salutogenesis as the study of health development. This approach contrasted with the concept of pathogenesis or the study of disease development. Pathogenesis works retrospectively from disease to determine how individuals can avoid, manage, and/or eliminate that disease. Salutogenesis works…

  3. 76 FR 82283 - Privacy Act of 1974; Systems of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-30

    ...,' dated December 12, 2000, 65 FR 239. Dated: December 27, 2011. Aaron Siegel, Alternate OSD Federal..., 2010, 75 FR 2514). Changes: * * * * * Categories of individuals covered by the system: Delete entry and... identifiers or contact information. FOR FURTHER INFORMATION CONTACT: Ms. Anne Hill, NSA/CSS Freedom...

  4. 77 FR 56628 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-13

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: September 10, 2012. Aaron Siegel.... Kris Grein, National Security Agency/Central Security Service (NSA/CSS), Freedom of Information Act and... Blanket Routine Uses published at the beginning of the NSA/ CSS's compilation of record systems may...

  5. 78 FR 45913 - Privacy Act of 1974; Systems of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-30

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 25, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. GNSA 14 System Name: NSA/CSS Library Patron File Control System (August 19, 2009, 74 FR 41869) Changes: * * * * * System Location:...

  6. 78 FR 73509 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ... Reserve Component Soldiers and Units, and Air Force, Navy and Marine Corps requesting and scheduling... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: December 2, 2013. Aaron Siegel, Alternate OSD... (Air Force/Navy/Marine Corps) requesting and scheduling ``Army unit'' required training before...

  7. 78 FR 5787 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ..., 1996, 61 FR 6427). Dated: January 7, 2013. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense. LDIA 0450 System name: Drug-Free Workplace Files (September 9, 2009, 74 FR 46418..., unaccepted applicants, negative results, and other supporting data are maintained for three years after...

  8. 76 FR 50460 - Privacy Act of 1974; Notice of a Computer Matching Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-15

    ... Resources'' at 61 Federal Register (FR) 6435, February 20, 1996, and OMB guidelines pertaining to computer... Federal Register at 54 FR 25818 on June 19, 1989. The matching agreement, as required by 5 U.S.C. 552a(r... Individuals,' dated February 8, 1996 (61 FR 6435). Dated: August 9, 2011. Aaron Siegel, Alternate OSD...

  9. 76 FR 77811 - Privacy Act of 1974; Notice of a Computer Matching Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-14

    ... Federal Register at 54 FR 25818 on June 19, 1989. The matching agreement, as required by 5 U.S.C. 552a(r... Records about Individuals,' dated February 8, 1996 (61 FR 6435). ] Dated: December 9, 2011. Aaron Siegel... Rehabilitation and Employment Records--VA'' (58 VA 21/22/28), published at 74 FR 29275 (June 19, 2009), and...

  10. 78 FR 45513 - Privacy Act of 1974; Computer Matching Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-29

    ... FR 25818. The matching agreement, as required by 5 U.S.C. 552a(r) of the Privacy Act of 1974, and an... Individuals'', dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 24, 2013. Aaron Siegel... Base'', November 23, 2011, 76 FR 72391. 3. HHS will be disclosing, as applicable, to DMDC personal...

  11. 77 FR 271 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-04

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: December 29, 2011. Aaron Siegel, Alternate OSD... (December 4, 2009, 74 FR 63734). Changes: * * * * * System location(s): Delete entry and replace with... Albuquerque, Defense Threat Reduction Agency, 1680 Texas Street SE., Kirtland Air Force Base, Albuquerque,...

  12. 78 FR 70543 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-26

    ...,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: November 21, 2013. Aaron Siegel... records for the purpose of validation, analysis, and appraisal throughout the lifecycle. This system is...): To manage personnel and security records for the purpose of validation, analysis, and...

  13. 78 FR 14282 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: February 28, 2013. Aaron Siegel... Access Management System (TEAMS) (April 29, 2004, 69 FR 23497). Changes: * * * * * Categories of records... phone number, citizenship, position sensitivity, accession date, type and number of DCAA...

  14. The Technology of Unequal Rights for Women: Patent Drawings of a Voting Machine

    ERIC Educational Resources Information Center

    Hussey, Michael

    2008-01-01

    In 1878, Senator Aaron A. Sargent of California introduced to the Senate an amendment to the Constitution "Conferring upon Women the Right of Suffrage." Drafted by Susan B. Anthony, this same amendment would be introduced on a near-yearly basis until its final passage by Congress on May 19, 1919. Varying degrees of voting rights presented an…

  15. 76 FR 9853 - Notice of Final Federal Agency Actions on Proposed Highway in California

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-22

    .... Monday through Friday, phone number (909) 388-1804 or e-mail: aaron_burton@dot.ca.gov . For USACOE: Veronica Chan, Project Manager, Regulatory Division, 915 Wilshire Blvd., Los Angeles, CA 90017, phone number (213) 452-3410. SUPPLEMENTARY INFORMATION: Effective July 1, 2007, the Federal...

  16. 77 FR 26261 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-03

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 30, 2012. Aaron Siegel... Transportation Fringe Benefit Program--Outside the National Capital Region (September 22, 2009, 74 FR 48233... of the Secretary Privacy Act of 1974; System of Records AGENCY: Office of the Defense...

  17. 77 FR 26260 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-03

    ... (February 20, 1996, 61 FR 6427). Dated: April 30, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison... (February 3, 2010, 75 FR 5579). Changes: * * * * * System name: Add ``Enterprise'' after ``Agency''. System... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Logistics Agency, DoD....

  18. 78 FR 22854 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-17

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: April 1, 2013. Aaron Siegel... News Releases (June 24, 2011; 76 FR 37082). Changes: * * * * * System location: Delete entry and... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Logistics Agency, DoD....

  19. 78 FR 46326 - Proposed Collection: Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-31

    ... data will be useful in assessing the impact of DoD funding on STEM education at HBCU/MI. Number of... impact of DoD funding on STEM education at HBCU/MI. Dated: July 26, 2013. Aaron Siegel, Alternate OSD... graduate student Science, Technology, Engineering and Mathematics (STEM) participants. A numeric field...

  20. Travel to Learn: How, When, and Why to Apply for Overseas Professional Development

    ERIC Educational Resources Information Center

    Cook, Erika; Becker, Aaron

    2013-01-01

    In this article, Erika Cook and Aaron Becker suggest teachers travel to "unfamiliar" lands to not only breathe life into global lessons but also to gain new perspectives and experiences as educators. For teachers who dread teaching about an unfamiliar place or culture, Cook and Becker recommend considering the very real opportunities to…

  1. 78 FR 35607 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-13

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: June 10, 2013. Aaron Siegel, Alternate OSD Federal... and Tracking System (April 2, 2008, 73 FR 17959) Changes: * * * * * System location: Delete entry and... of response letter; or case file number.'' * * * * * Retention and disposal: Delete entry and...

  2. 76 FR 54743 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-02

    ..., 1996 (February 20, 1996, 61 FR 6427). Dated: August 29, 2011. Aaron Siegel, Alternate OSD Federal... Reporting System (DEERS), active foreign officers (Non-US Military Officers), Homeland Security employees... participation and support in matters of civil disturbance, disaster relief, and civil defense and...

  3. 77 FR 16019 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-19

    ... (February 20, 1996, 61 FR 6427). Dated: March 13, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison..., National Guard, National Guard retired personnel, Reserve personnel, Non-US citizens including military and... matters of civil disturbance, disaster relief, and civil defense and emergency action; records...

  4. 78 FR 17386 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-21

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: March 18, 2013. Aaron Siegel... (April 12, 2011; 76 FR 20341). Changes: * * * * * System location: Delete entry and replace with ``Public... of the Secretary Privacy Act of 1974; System of Records AGENCY: Defense Logistics Agency, DoD....

  5. 78 FR 17384 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-21

    ... Individuals,'' dated February 8, 1996 (February 20, 1996, 61 FR 6427). ] Dated: March 18, 2013. Aaron Siegel... Worksite Records (April 15, 2010; 75 FR 19624). Changes: * * * * * System name: Delete entry and replace...: Notice to alter a System of Records. SUMMARY: The Defense Logistics Agency proposes to alter a system...

  6. 77 FR 40865 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-11

    ... 8, 1996 (February 20, 1996, 61 FR 6427). Dated: July 5, 2012. Aaron Siegel, Alternate OSD Federal... Education Management System (PYTHON) System Location: U.S. Naval Postgraduate School (NPS), 1 University... Social Security Number (SSN). Safeguards: Access to the Python web interface occurs over...

  7. 75 FR 31464 - Notice of Public Meeting, Salem District Resource Advisory Committee Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-03

    ... with the Federal Land Policy and Management Act (FLPMA) and the Federal Advisory Committee Act of 1972..., land health, forest ecosystems, and infrastructure. Aaron G. Horton, District Manager. BILLING CODE... Bureau of Land Management Notice of Public Meeting, Salem District Resource Advisory Committee...

  8. Adult Fans of Comic Books: What They Get out of Reading

    ERIC Educational Resources Information Center

    Botzakis, Stergios

    2009-01-01

    This interview study is an exploration of the popular cultural and lifelong literacy practices of adult readers of comic books. Focusing on 4 participants from a pool of 12, the researcher used Kvale's (1996) method of meaning interpretation to analyze utterances and speak to the various uses reading held for these people. Aaron, Kyle, Peter, and…

  9. 78 FR 14283 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ... System-Active Component (March 21, 2006, 71 FR 14179). Changes: * * * * * System location: Delete entry... February 8, 1996 (February 20, 1996, 61 FR 6427). Dated: February 28, 2013. Aaron Siegel, Alternate OSD... ``Officers of the Air Force Reserve, Army Reserve, Navy Reserve and Air National Guard on extended...

  10. 78 FR 14286 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ..., Defense Finance and Accounting Service, Freedom of Information/Privacy Act Program Manager, Corporate... (February 20, 1996, 61 FR 6427). Dated: February 28, 2013. Aaron Siegel, Alternate OSD Federal Register..., 2007, 72 FR 30785). * * * * * Changes: Change System ID to read ``T7320a.'' * * * * *...

  11. 78 FR 5784 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ... February 8, 1996 (February 20, 1996, 61 FR 6427). ] Dated: January 23, 2013. Aaron Siegel, Alternate OSD... Accounting System (August 13, 2007, 72 FR 45231). * * * * * Changes: System Identifier: Delete entry and..., DoD. ACTION: Notice to alter a system of records. SUMMARY: The Defense Finance and Accounting...

  12. 77 FR 3235 - Proposed Collection; Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-23

    ... [Federal Register Volume 77, Number 14 (Monday, January 23, 2012)] [Notices] [Pages 3235-3236] [FR Doc No: 2012-1144] DEPARTMENT OF DEFENSE Office of the Secretary [Docket ID: DOD-2012-OS-0006...: January 17, 2012. Aaron Siegel, Alternate OSD Federal Register Liaison Officer, Department of Defense....

  13. 75 FR 65479 - National Environmental Justice Advisory Council; Notification of Public Meeting and Public Comment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-25

    ... AGENCY: Environmental Protection Agency. ACTION: Notification of Public Meeting. SUMMARY: Pursuant to the Federal Advisory Committee Act (FACA), Public Law 92-463, the U.S. Environmental Protection Agency (EPA... concerning the meeting should be directed to Mr. Aaron Bell, U.S. Environmental Protection Agency,...

  14. 78 FR 35609 - Privacy Act of 1974; System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-13

    ..., 1996 (February 20, 1996, 61 FR 6427). Dated: June 10, 2013. Aaron Siegel, Alternate OSD Federal... Management System (PRIMS) (August 13, 2007, 72 FR 45235). Changes: * * * * * System location: Delete entry... information. FOR FURTHER INFORMATION CONTACT: Ms. Robin Patterson, Head, PA/FOIA Office (DNS-36),...

  15. Synthesis, characterization, and biodistribution of multiple 89Zr-labeled pore-expanded mesoporous silica nanoparticles for PET

    NASA Astrophysics Data System (ADS)

    Miller, Larissa; Winter, Gordon; Baur, Benjamin; Witulla, Barbara; Solbach, Christoph; Reske, Sven; Lindén, Mika

    2014-04-01

    Functional nanoparticles are highly interesting imaging agents for positron emission tomography (PET) due to the possibility of multiple incorporation of positron emitting radionuclides thus increasing the signal strength. Furthermore, long-term nanoparticle biodistribution tests with increased signal-to-noise ratio can be achieved with nanoparticles carrying long-lived isotopes. Mesoporous silica nanoparticles, MSNs, have recently attracted a lot of interest as both imaging agents and carriers for drugs in vitro and in vivo. Here we present results related to the synthesis of PET imageable MSNs carrying the long-lived 89Zr isotope (half-life of 78.4 hours). Here, 89Zr4+ was immobilized through covalent attachment of the complexing agent p-isothiocyanatobenzyldesferrioxamine (DFO-NCS) to large-pore MSNs. Due to the presence of the high DFO content on the MSNs, quantitative 89Zr4+ labeling was achieved within just a few minutes, and no subsequent purification step was needed in order to remove non-complexed 89Zr4+. The stability of the 89Zr-labeled MSNs against leaching of 89Zr4+ was verified for 24 hours. The high signal strength of the 89Zr-DFO-MSNs was evidenced by successful PET imaging using a mouse model at particle loadings one order of magnitude lower than those previously applied in PET-MSN studies. The biodistribution followed the same trends as previously observed for MSNs of different sizes and surface functionalities. Taken together, our results suggest that 89Zr-DFO-MSNs are promising PET imaging agents for long-term in vivo imaging.Functional nanoparticles are highly interesting imaging agents for positron emission tomography (PET) due to the possibility of multiple incorporation of positron emitting radionuclides thus increasing the signal strength. Furthermore, long-term nanoparticle biodistribution tests with increased signal-to-noise ratio can be achieved with nanoparticles carrying long-lived isotopes. Mesoporous silica nanoparticles, MSNs, have

  16. Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas

    PubMed Central

    Oteo, M.; Romero, E.; Cámara, J. A.; de Martino, A.; Arroyo, A. G.; Morcillo, M. Á.; Squatrito, M.; Martinez-Torrecuadrada, J. L.; Mulero, F.

    2016-01-01

    Background A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. Methods An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments. Results 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. Conclusion A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In

  17. Pharmacological Suppression of CNS Scarring by Deferoxamine Reduces Lesion Volume and Increases Regeneration in an In Vitro Model for Astroglial-Fibrotic Scarring and in Rat Spinal Cord Injury In Vivo

    PubMed Central

    Krafft, Stefanie; Estrada, Veronica; Brazda, Nicole; Ziegler, Brigida; Faissner, Andreas; Müller, Hans Werner

    2015-01-01

    Lesion-induced scarring is a major impediment for regeneration of injured axons in the central nervous system (CNS). The collagen-rich glial-fibrous scar contains numerous axon growth inhibitory factors forming a regeneration-barrier for axons. We demonstrated previously that the combination of the iron chelator 2,2’-bipyridine-5,5’-decarboxylic acid (BPY-DCA) and 8-Br-cyclic AMP (cAMP) inhibits scar formation and collagen deposition, leading to enhanced axon regeneration and partial functional recovery after spinal cord injury. While BPY-DCA is not a clinical drug, the clinically approved iron chelator deferoxamine mesylate (DFO) may be a suitable alternative for anti-scarring treatment (AST). In order to prove the scar-suppressing efficacy of DFO we modified a recently published in vitro model for CNS scarring. The model comprises a co-culture system of cerebral astrocytes and meningeal fibroblasts, which form scar-like clusters when stimulated with transforming growth factor-β (TGF-β). We studied the mechanisms of TGF-β-induced CNS scarring and compared the efficiency of different putative pharmacological scar-reducing treatments, including BPY-DCA, DFO and cAMP as well as combinations thereof. We observed modulation of TGF-β-induced scarring at the level of fibroblast proliferation and contraction as well as specific changes in the expression of extracellular matrix molecules and axon growth inhibitory proteins. The individual and combinatorial pharmacological treatments had distinct effects on the cellular and molecular aspects of in vitro scarring. DFO could be identified as a putative anti-scarring treatment for CNS trauma. We subsequently validated this by local application of DFO to a dorsal hemisection in the rat thoracic spinal cord. DFO treatment led to significant reduction of scarring, slightly increased regeneration of corticospinal tract as well as ascending CGRP-positive axons and moderately improved locomotion. We conclude that the in

  18. Pharmacological Suppression of CNS Scarring by Deferoxamine Reduces Lesion Volume and Increases Regeneration in an In Vitro Model for Astroglial-Fibrotic Scarring and in Rat Spinal Cord Injury In Vivo.

    PubMed

    Vogelaar, Christina Francisca; König, Brigitte; Krafft, Stefanie; Estrada, Veronica; Brazda, Nicole; Ziegler, Brigida; Faissner, Andreas; Müller, Hans Werner

    2015-01-01

    Lesion-induced scarring is a major impediment for regeneration of injured axons in the central nervous system (CNS). The collagen-rich glial-fibrous scar contains numerous axon growth inhibitory factors forming a regeneration-barrier for axons. We demonstrated previously that the combination of the iron chelator 2,2'-bipyridine-5,5'-decarboxylic acid (BPY-DCA) and 8-Br-cyclic AMP (cAMP) inhibits scar formation and collagen deposition, leading to enhanced axon regeneration and partial functional recovery after spinal cord injury. While BPY-DCA is not a clinical drug, the clinically approved iron chelator deferoxamine mesylate (DFO) may be a suitable alternative for anti-scarring treatment (AST). In order to prove the scar-suppressing efficacy of DFO we modified a recently published in vitro model for CNS scarring. The model comprises a co-culture system of cerebral astrocytes and meningeal fibroblasts, which form scar-like clusters when stimulated with transforming growth factor-β (TGF-β). We studied the mechanisms of TGF-β-induced CNS scarring and compared the efficiency of different putative pharmacological scar-reducing treatments, including BPY-DCA, DFO and cAMP as well as combinations thereof. We observed modulation of TGF-β-induced scarring at the level of fibroblast proliferation and contraction as well as specific changes in the expression of extracellular matrix molecules and axon growth inhibitory proteins. The individual and combinatorial pharmacological treatments had distinct effects on the cellular and molecular aspects of in vitro scarring. DFO could be identified as a putative anti-scarring treatment for CNS trauma. We subsequently validated this by local application of DFO to a dorsal hemisection in the rat thoracic spinal cord. DFO treatment led to significant reduction of scarring, slightly increased regeneration of corticospinal tract as well as ascending CGRP-positive axons and moderately improved locomotion. We conclude that the in vitro

  19. The effect of iron overload and chelation on erythroid differentiation.

    PubMed

    Taoka, Kazuki; Kumano, Keiki; Nakamura, Fumihiko; Hosoi, Masataka; Goyama, Susumu; Imai, Yoichi; Hangaishi, Akira; Kurokawa, Mineo

    2012-02-01

    We investigated the mechanisms of hematopoietic disorders caused by iron overload and chelation, in particular, the inhibition of erythroblast differentiation. Murine c-kit(+) progenitor cells or human CD34(+) peripheral blood hematopoietic progenitors were differentiated in vitro to the erythroid lineage with free iron and/or an iron chelator. Under iron overload, formation of erythroid burst-forming unit colonies and differentiation to mature erythroblasts were significantly suppressed; these effects were canceled by iron chelation with deferoxamine (DFO). Moreover, excessive iron burden promoted apoptosis in immature erythroblasts by elevating intracellular reactive oxygen species (ROS). Interestingly, both DFO and a potent anti-oxidant agent reduced intracellular ROS levels and suppressed apoptosis, thus restoring differentiation to mature erythroblasts. Accordingly, intracellular ROS may represent a new therapeutic target in the treatment of iron overload. PMID:22193844

  20. Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils.

    PubMed

    Völlger, Lena; Akong-Moore, Kathryn; Cox, Linda; Goldmann, Oliver; Wang, Yanming; Schäfer, Simon T; Naim, Hassan Y; Nizet, Victor; von Köckritz-Blickwede, Maren

    2016-07-01

    Neutrophil extracellular trap (NET) formation is a significant innate immune defense mechanism against microbial infection that complements other neutrophil functions including phagocytosis and degranulation of antimicrobial peptides. NETs are decondensed chromatin structures in which antimicrobial components (histones, antimicrobial peptides and proteases) are deployed and mediate immobilization of microbes. Here we describe an effect of iron chelation on the phenotype of NET formation. Iron-chelating agent desferrioxamine (DFO) showed a modest but significant induction of NETs by freshly isolated human neutrophils as visualized and quantified by immunocytochemistry against histone-DNA complexes. Further analyses revealed that NET induction by iron chelation required NADPH-dependent production of reactive oxygen species (ROS) as well as protease and peptidyl-arginine-deiminase 4 (PAD4) activities, three key mechanistic pathways previously linked to NET formation. Our results demonstrate that iron chelation by DFO contributes to the formation of NETs and suggest a target for pharmacological manipulation of NET activity. PMID:27129288

  1. Latent Fingerprint Development on Thermal Paper Using Traditional Ninhydrin and 1,2-indanedione.

    PubMed

    Chen, Chun-Chieh; Yu, Yung-Chien; Lee, Henry C; Giang, Yun-Seng; Wang, Sheng-Meng

    2016-01-01

    Thermal paper poses a significant challenge to latent print development as it tends to change color when traditional fingerprint development formulations are applied to it. In this study, the optimal components of ninhydrin, 1,2-indanedione, 1,8-diazafluoren-9-one (DFO), and 5-methylthioninhydrin (5-MTN) for yielding clear fingerprints on thermal paper were determined by systematically adjusting the relative amounts of the reagents, polar solvents, and the nonpolar diluent petroleum ether, followed by validation on text-printed thermal paper. Specifically, 3.0% ethyl acetate as the polar solvent in petroleum ether was found to be the optimal combination; the optimal dilution ratios of ninhydrin, DFO, and 5-MTN original solutions with petroleum ether were 1 to 2, 11, and 7, respectively. The optimal concentration of 1,2-indanedione in petroleum ether was 0.125 g/L, with a string of 0.5% ethyl acetate in petroleum ether. PMID:26248596

  2. Bioaccumulations of aluminum and the effects of chelating agents on different organs of Cirrhinus mrigala.

    PubMed

    Sivakumar, S; Khatiwada, Chandra Prasad; Sivasubramanian, J

    2012-11-01

    The study of biological indicator organisms may be more informative than analyzing water or sediments for monitoring heavy metal pollution in the aquatic environment. Non-essential elements enter into the animals and accumulate at the different organs so that chelating agents are most versatile and effective antidotes to eliminate the metals toxicities. The aim of our present study is to find out bioaccumulations of aluminum and the effects of chelating agents DFO and DFP in Muscle, gill, kidney, brain and liver tissues of Cirrhinus mrigala by using inductively coupled atomic emission spectrometry (ICP-AES). This study determined that the accumulation pattern of aluminum is muscle > gill > kidney > brain > liver. The present result suggests that DFO and DFP reduce the aluminum concentration in the tissues of C. mrigala fish and both are efficient chelators. Aluminum toxicity is a widespread problem in all forms of life, including humans, animals, fish, plants, and causes wide spread degradation of the environment and health. PMID:23063109

  3. Immunoliposomes for Targeted Delivery of an Antifibrotic Drug.

    PubMed

    Schuster, Liane; Seifert, Oliver; Vollmer, Stefanie; Kontermann, Roland E; Schlosshauer, Burkhard; Hartmann, Hanna

    2015-09-01

    Excessive extracellular matrix formation in organs and tissues arises from an imbalance between the synthesis and degradation of matrix proteins, especially collagen. This condition interferes with proper wound healing and regeneration, and to date, no specific treatment is available. In the present study, we propose a targeted drug delivery system consisting of cell-specific immunoliposomes (ILs) loaded with deferoxamine (DFO) as an antifibrotic drug. ILs were functionalized with polyethylene glycol (PEG) to improve the steric stability and prolong their half-life. In addition, a single-chain Fv (scFv) antibody fragment that specifically targets fibroblast activation protein (FAP) was incorporated. An in vitro fibrosis model was employed to test this construct. This model consisted of highly activated pro-fibrotic fibroblasts with 2- to 6-fold induction of selected fibrosis markers: cell/matrix deposited collagen I, total soluble collagen, and α smooth muscle actin. The activation was accompanied by a significant and cell-specific elevation of FAP expression and activity, thereby confirming that FAP is an adequate target for antifibrotic drug delivery. Purified anti-FAP scFv was shown to bind specifically to these cells without influencing the FAP enzymatic activity. DFO was demonstrated to have a dose-dependent antifibrotic activity as quantified by collagen deposition. Specific binding and intracellular uptake of DiI-labeled ILs into the activated fibroblasts were shown by flow cytometry and microscopy. Finally, DFO-loaded ILs targeted to FAP caused a significant reduction in the collagen deposition, whereas no effect was observed using liposomes that lacked the targeting antibody fragment. These results suggest that the FAP-specific scFv-conjugated liposomes have considerable potential for cell-specific targeting applicable as a therapy for excessive collagen deposition during fibrosis. In general, through liposome encapsulation, bioactive molecules, such as

  4. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action.

    PubMed

    Lui, Goldie Y L; Obeidy, Peyman; Ford, Samuel J; Tselepis, Chris; Sharp, Danae M; Jansson, Patric J; Kalinowski, Danuta S; Kovacevic, Zaklina; Lovejoy, David B; Richardson, Des R

    2013-01-01

    Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors. PMID:23074173

  5. Synthesis, characterization, and biodistribution of multiple 89Zr-labeled pore-expanded mesoporous silica nanoparticles for PET.

    PubMed

    Miller, Larissa; Winter, Gordon; Baur, Benjamin; Witulla, Barbara; Solbach, Christoph; Reske, Sven; Lindén, Mika

    2014-05-01

    Functional nanoparticles are highly interesting imaging agents for positron emission tomography (PET) due to the possibility of multiple incorporation of positron emitting radionuclides thus increasing the signal strength. Furthermore, long-term nanoparticle biodistribution tests with increased signal-to-noise ratio can be achieved with nanoparticles carrying long-lived isotopes. Mesoporous silica nanoparticles, MSNs, have recently attracted a lot of interest as both imaging agents and carriers for drugs in vitro and in vivo. Here we present results related to the synthesis of PET imageable MSNs carrying the long-lived (89)Zr isotope (half-life of 78.4 hours). Here, (89)Zr(4+) was immobilized through covalent attachment of the complexing agent p-isothiocyanatobenzyldesferrioxamine (DFO-NCS) to large-pore MSNs. Due to the presence of the high DFO content on the MSNs, quantitative (89)Zr(4+) labeling was achieved within just a few minutes, and no subsequent purification step was needed in order to remove non-complexed (89)Zr(4+). The stability of the (89)Zr-labeled MSNs against leaching of (89)Zr(4+) was verified for 24 hours. The high signal strength of the (89)Zr-DFO-MSNs was evidenced by successful PET imaging using a mouse model at particle loadings one order of magnitude lower than those previously applied in PET-MSN studies. The biodistribution followed the same trends as previously observed for MSNs of different sizes and surface functionalities. Taken together, our results suggest that (89)Zr-DFO-MSNs are promising PET imaging agents for long-term in vivo imaging. PMID:24675844

  6. Difficult situations managing diabetic foot. Evidences and personal views: is to operate on patients with diabetic foot osteomyelitis old-fashioned?

    PubMed

    Senneville, Eric; Nguyen, Sophie

    2014-12-01

    Both medical and surgical approaches have been shown to be effective in the treatment of patients with diabetic foot osteomyelitis (DFO). In patients with risk factors of bad outcome such as major bone destruction, concomitant acute infections requiring drainage, problems in limb perfusion, highly resistant bacteria, and contraindication for or patient refusal of prolonged antibiotic therapy, the choice of surgery does not require further discussion. On the contrary, modest changes of bone on imaging assessment and no limiting factors as described above make medical treatment an attractive option for patients with DFO provided the rules of antibiotic treatment of chronic osteomyelitis are respected. The key question may not be to oppose surgery and medical treatment but to identify patients who need surgery and those who do not. There is currently no classification or score system that may allow physician to decide whether medical or surgical approach is best adapted to a given patient, and so both experience and skill of the multidisciplinary team appear paramount for guiding the choice of the best adapted ("tailored") strategy in a given patient. In this regard, it would be interesting to compare surgical and medical approaches for DFO that apparently may benefit from one or another (ie, bone lesions seen on plain radiographs of the foot but without bone fragmentation or multiple sites of osteomyelitis, no contraindication to prolonged antibiotic therapy, and location of bone involvement that may allow conservative surgery). Given the current available data on the therapeutic options of DFO, it appears that surgery for those patients is obviously not an old-fashioned option. PMID:25384914

  7. FTIR study of protective action of deferoxamine and deferiprone on the kidney tissues of aluminum loaded mice

    NASA Astrophysics Data System (ADS)

    Sivakumar, S.; Khatiwada, Chandra Prasad; Sivasubramanian, J.; Raja, B.

    2014-01-01

    The present study was designed to evaluate the FTIR spectra of the aluminum exposed kidney tissues and recovered by chelating agents DFO and DFP then showed significant alteration on the major biochemical constituents such as lipids, proteins and glycogen at molecular level. The significant increased in the peak area of glycogen from 0.006 ± 0.001 to 0.187 ± 0.032 may be the interruption of aluminum in the calcium metabolism and the reduced level of calcium. The peak area value of amide A significantly decreased from control (4.931 ± 1.446) to aluminum (1.234 ± 0.052), but improved by DFP and DFO + DFP from 2.658 ± 0.153 to 3.252 ± 0.070 respectively. Amide I and amide II peak area values also decreased from 1.690 ± 0.133 to 0.811 ± 0.192 and 1.158 ± 0.050 to 0.489 ± 0.047 but treated with DFP and DFO + DFP significantly improved. This result suggests an alteration in the protein profile. The absence of Olefinicdbnd CH stretching band, Cdbnd O stretching of triglycerides and ring breathing mode in the DNA bases in aluminum exposure kidney suggests an altered lipid levels. Treated with DFP and DFO + DFP mice were considerably increased in lipid peroxidative markers. Further, assessed the activities of enzymatic antioxidants and measured the levels of nonenzymatic antioxidants. Concentrations of trace elements were found by ICP-OES. Histopathology of chelating agents treated kidney showed reduced renal damage in aluminum induced mice. Thus, histopathological findings confirmed the biochemical observations of this study. This results demonstrated that FTIR spectroscopy can be successfully applied to toxicological and biotoxicology studies.

  8. Gram-negative diabetic foot osteomyelitis: risk factors and clinical presentation.

    PubMed

    Aragón-Sánchez, Javier; Lipsky, Benjamin A; Lázaro-Martínez, Jose L

    2013-03-01

    Osteomyelitis frequently complicates infections in the feet of patients with diabetes. Gram-positive cocci, especially Staphylococcus aureus, are the most commonly isolated pathogens, but gram-negative bacteria also cause some cases of diabetic foot osteomyelitis (DFO). These gram-negatives require different antibiotic regimens than those commonly directed at gram-positives. There are, however, few data on factors related to their presence and how they influence the clinical picture. We conducted a retrospective study to determine the variables associated with the isolation of gram-negative bacteria from bone samples in cases of DFO and the clinical presentation of these infections. Among 341 cases of DFO, 150 had a gram-negative isolate (alone or combined with a gram-positive isolate) comprising 44.0% of all patients and 50.8% of those with a positive bone culture. Compared with gram-positive infections, wounds with gram-negative organisms more often had a fetid odor, necrotic tissue, signs of soft tissue infection accompanying osteomyelitis, and clinically severe infection. By multivariate analysis, the predictive variables related to an increased likelihood of isolating gram-negatives from bone samples were glycated hemoglobin <7% (odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.1-3.5) and a wound caused by traumatic injury (OR = 2.0, 95% CI = 1.0-3.9). Overall, patients whose bone samples contained gram-negatives had a statistically significantly higher prevalence of leukocytosis and higher white blood cell counts than those without gram-negatives. In conclusion, gram-negative organisms were isolated in nearly half of our cases of DFO and were associated with more severe infections, higher white blood cell counts, lower glycated hemoglobin levels, and wounds of traumatic etiology. PMID:23446368

  9. Beliefs about chelation among thalassemia patients

    PubMed Central

    2012-01-01

    Background Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy. Methods The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks. Results Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p<0.001). Self-reported adherence to chelation was not associated with views about necessity or concerns, but negatively correlated with perceived sensitivity to DFO (Sensitive Soma scale; r=−0.23, p=0.01) and side effects of oral chelation (r=−0.14, p=0.04). High ferritin iron levels, potentially indicating lower adherence, were found in 41% of patients reporting low necessity of oral chelation compared to 24% reporting high necessity (p=0.048). Concerns about treatment were associated with lower quality of life and more symptoms of anxiety and depression. Conclusions Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. Clinicaltrials.gov identifier NCT00661804 PMID:23216870

  10. Activation of AP-1 and nuclear factor-kappaB transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes.

    PubMed

    Vollgraf, U; Wegner, M; Richter-Landsberg, C

    1999-12-01

    H2O2-induced onset and execution of programmed cell death in mature rat brain oligodendrocytes in culture is accompanied by the induction and nuclear translocation of the transcription factors AP-1 and nuclear factor-kappaB (NF-kappaB), both of which have been discussed as regulators of cell death and survival. Supershift analysis of nuclear extracts indicated that the AP-1 complex consists of c-Jun, c-Fos, JunD, and possibly JunB proteins, and that the NF-kappaB complex contains p50, p65, and c-Rel proteins. The first signs of DNA fragmentation were seen already during the first hour after the treatment. DNA fragmentation could be prevented by the antioxidants pyrrolidine dithiocarbamate and vitamin E, by the nuclease inhibitor aurintricarboxylic acid, and by preincubation with the iron chelator deferoxamine (DFO). Additionally, DFO protected oligodendrocytes from H2O2-induced cytotoxic effects as assessed by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and suppressed the formation of free radicals. DFO alone led to a slight increase and in combination with H2O2 synergistically induced DNA-binding activities of AP-1 and NF-kappaB in oligodendrocytes. Our data suggest that although low levels of H2O2 directly activate AP-1 and NF-kappaB and might contribute to signal transduction pathways promoting cell survival, the formation and action of hydroxyl radicals promote cell death mechanisms that can be attenuated by the iron chelator DFO. PMID:10582611

  11. Opening- and Closing-Wedge Distal Femoral Osteotomy

    PubMed Central

    Chahla, Jorge; Mitchell, Justin J.; Liechti, Daniel J.; Moatshe, Gilbert; Menge, Travis J.; Dean, Chase S.; LaPrade, Robert F.

    2016-01-01

    Background: Lateral compartment osteoarthritis of the knee can be a challenging pathology in the younger, active population due to limited treatment options and high patient expectations. Distal femoral osteotomy (DFO) has been reported to be a potential treatment option. Purpose: To perform a systematic review on the survival, outcomes, and complications of DFO for treatment of genu valgum with concomitant lateral compartment osteoarthritis of the knee. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review of the literature was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Registry of Controlled Trials, PubMed, and MEDLINE from 1980 to present. Inclusion criteria were as follows: outcomes of opening- and closing-wedge DFOs performed for treatment of genu valgum with concomitant lateral compartment osteoarthritis of the knee, English language, minimum 2-year follow-up, and human studies. Data abstracted from the selected studies included type of osteotomy (opening vs closing), survival rate, patient-reported and radiographic outcomes, and complications. Results: Fourteen studies met the inclusion criteria and were considered for the review. A total of 9 closing-wedge and 5 opening-wedge DFO studies were included. All were retrospective studies and reported good to excellent patient-reported outcomes after DFO. Survival decreased with increasing time from surgery, with 1 study reporting a 100% survival rate at 6.5 years, compared with 21.5% at 20 years in another study. A low rate of complications was reported throughout the review. Conclusion: Highly heterogeneous literature exists for both opening- and closing-wedge DFOs for the treatment of isolated lateral compartment osteoarthritis with valgus malalignment. A mean survival rate of 80% at 10-year follow-up was reported, supporting that this procedure can be a viable treatment option to delay or reduce the need for joint arthroplasty. A low

  12. RGS19 converts iron deprivation stress into a growth-inhibitory signal.

    PubMed

    Hwang, Junmo; Kim, Hyeng-Soo; Kang, Beom Sik; Kim, Do-Hyung; Ryoo, Zae Young; Choi, Sang-Un; Lee, Sanggyu

    2015-08-14

    Iron chelation is a promising therapeutic strategy for cancer that works, in part, by inducing overexpression of N-myc downstream-regulated gene 1 protein (NDRG1), a known growth inhibitor and metastasis suppressor. However, details of the signaling cascades that convert physical stress into a biological response remain elusive. We investigated the role of RGS19, a regulator of G-protein signaling, in iron chelator-induced NDRG1 overexpression in HeLa cells. Knockdown of RGS19 diminished the expression of genes involved in desferrioxamine (DFO)-induced growth inhibition. Conversely, overexpression of RGS19 enhanced the expression of these genes. Moreover, overexpression of RGS19 reduced cell viability. Overexpression of G-protein alpha subunit i3 (Gαi3) repressed the induction of NDRG1 expression. Selective inhibition of downstream targets of Gαi3 abrogated DFO-induced overexpression of NDRG1. DFO protected RGS19 from proteolysis induced by GAIP interacting protein N terminus (GIPN); moreover, an iron-deficient RGS19 mutant was stable in the presence of GIPN and retained GTPase-activating protein activity. RGS19 was co-purified with iron and showed unique UV-absorption characteristics frequently observed in iron-binding proteins. This study demonstrates that RGS19 senses cellular iron availability and is stabilized under iron-depleted conditions, resulting in the induction of a growth-inhibitory signal. PMID:26116529

  13. The Meniscus-Deficient Knee: Biomechanics, Evaluation, and Treatment Options.

    PubMed

    Rao, Allison J; Erickson, Brandon J; Cvetanovich, Gregory L; Yanke, Adam B; Bach, Bernard R; Cole, Brian J

    2015-10-01

    Meniscal tears are the most common knee injury, and partial meniscectomies are the most common orthopaedic surgical procedure. The injured meniscus has an impaired ability to distribute load and resist tibial translation. Partial or complete loss of the meniscus promotes early development of chondromalacia and osteoarthritis. The primary goal of treatment for meniscus-deficient knees is to provide symptomatic relief, ideally to delay advanced joint space narrowing, and ultimately, joint replacement. Surgical treatments, including meniscal allograft transplantation (MAT), high tibial osteotomy (HTO), and distal femoral osteotomy (DFO), are options that attempt to decrease the loads on the articular cartilage of the meniscus-deficient compartment by replacing meniscal tissue or altering joint alignment. Clinical and biomechanical studies have reported promising outcomes for MAT, HTO, and DFO in the postmeniscectomized knee. These procedures can be performed alone or in conjunction with ligament reconstruction or chondral procedures (reparative, restorative, or reconstructive) to optimize stability and longevity of the knee. Complications can include fracture, nonunion, patella baja, compartment syndrome, infection, and deep venous thrombosis. MAT, HTO, and DFO are effective options for young patients suffering from pain and functional limitations secondary to meniscal deficiency. PMID:26779547

  14. New insight into the influence of carob extract and gallic acid on hemin induced modulation of HT29 cell growth parameters.

    PubMed

    Klenow, Stefanie; Glei, Michael

    2009-09-01

    Red meat intake is associated with an increased risk of developing cancer. This is possibly related to the heme content of red meat. Plant derived polyphenols might protect from cancer development via their antioxidant activities. In this study, the impact of an aqueous extract of carob (CE) on hemin-modulated proliferation was investigated. CE, gallic acid (GA) and a known iron chelator (deferoxamine: DFO) significantly reduced the number of human colon cancer HT29 cells. CE and GA were more effective under serum-free conditions than in normal cell culture medium. These effects were abolished by addition of 1 microM hemin at low concentrations of CE and GA. At higher concentrations of CE and GA, both substances reduced cell number despite hemin supplementation. Effects of CE, GA and DFO on cell number could not be linked to iron chelation even though CE and DFO were capable of chelating iron. Furthermore, the effects of high CE concentration point to antioxidative effects other than iron chelation. However, a connection to a reduction of colorectal cancer risk due to consumption of meat with high heme content by CE could not be drawn, since the effective concentrations are beyond the physiologically relevant concentrations. PMID:19527781

  15. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases.

    PubMed

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  16. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases

    PubMed Central

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  17. The Meniscus-Deficient Knee

    PubMed Central

    Rao, Allison J.; Erickson, Brandon J.; Cvetanovich, Gregory L.; Yanke, Adam B.; Bach, Bernard R.; Cole, Brian J.

    2015-01-01

    Meniscal tears are the most common knee injury, and partial meniscectomies are the most common orthopaedic surgical procedure. The injured meniscus has an impaired ability to distribute load and resist tibial translation. Partial or complete loss of the meniscus promotes early development of chondromalacia and osteoarthritis. The primary goal of treatment for meniscus-deficient knees is to provide symptomatic relief, ideally to delay advanced joint space narrowing, and ultimately, joint replacement. Surgical treatments, including meniscal allograft transplantation (MAT), high tibial osteotomy (HTO), and distal femoral osteotomy (DFO), are options that attempt to decrease the loads on the articular cartilage of the meniscus-deficient compartment by replacing meniscal tissue or altering joint alignment. Clinical and biomechanical studies have reported promising outcomes for MAT, HTO, and DFO in the postmeniscectomized knee. These procedures can be performed alone or in conjunction with ligament reconstruction or chondral procedures (reparative, restorative, or reconstructive) to optimize stability and longevity of the knee. Complications can include fracture, nonunion, patella baja, compartment syndrome, infection, and deep venous thrombosis. MAT, HTO, and DFO are effective options for young patients suffering from pain and functional limitations secondary to meniscal deficiency. PMID:26779547

  18. Effect of metals and their antagonists on the radical intensity and cytotoxicity of ascorbates.

    PubMed

    Satoh, K; Ida, Y; Kochi, M; Tajima, M; Kashimata, M; Sakagami, H

    1997-01-01

    Five heavy metal antagonists were compared for their specificity of chelating action against copper (CuCl, CuCl2) and iron (FeCl2, FeCl3). ESR spectroscopy showed that both copper and iron significantly enhanced the radical intensity of ascorbate and sodium 5,6-benzylidene-L-ascorbate (SBA). Equimolar concentrations of dimercaprol efficiently chelated all these metals, thus significantly reducing their stimulation effects. On the other hand, the chelating action of penicillamine, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid was limited to CuCl and CuCl2 whereas deferoxamine mesylate (DFO) was a specific iron chelator. The cytotoxic activity of sodium ascorbate was augmented by DFO, but diminished by FeCl3. The simultaneous addition of DFO and FeCl3 counteracted each other, thus neutralizing their individual effects. The cytotoxic activity of both sodium ascorbate and SBA was significantly enhanced by CuCl2 and this stimulation effect of CuCl2 was effectively chelated by DTPA. The present study demonstrates the specificity of the chelating action of these five antagonists, suggesting the possible application of these different types of antagonists for the prevention of the pathogenic diseases catalyzed by the corresponding metals. PMID:9413172

  19. Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats

    PubMed Central

    Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Sripetchwandee, Jirapas; Srichairatanakool, Somdet; Fucharoen, Suthat; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2016-01-01

    Background Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated. Methods and Findings Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function. Conclusions The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats. PMID:27428732

  20. Super-oxidized solution (Dermacyn Wound Care) as adjuvant treatment in the postoperative management of complicated diabetic foot osteomyelitis: preliminary experience in a specialized department.

    PubMed

    Aragón-Sánchez, Javier; Lázaro-Martínez, Jose Luis; Quintana-Marrero, Yurena; Sanz-Corbalán, Irene; Hernández-Herrero, Maria J; Cabrera-Galván, Juan J

    2013-06-01

    Surgery is usually used to treat diabetic foot osteomyelitis (DFO), whether primarily or in cases in which antibiotics are not able to control infection. In many cases, the bone is only partially removed, which means that residual infection remains in the bone margins, and the wound is left open to heal by secondary intent. The use of culture-guided postoperative antibiotic treatment and adequate management of the wound must be addressed. No trials exist dealing with local treatment in the postoperative management of these cases of complicated DFO. We decided to test a super-oxidized solution, Dermacyn Wound Care (DWC; Oculus Innovative Sciences Netherlands BV, Sittard, Netherlands) to obtain preliminary experience in patients in whom infected bone remained in the surgical wounds. Our hypothesis was that DWC could be useful to control infection in the residual infected bone and surrounding soft tissues and would thus facilitate healing. Fourteen consecutive patients who underwent conservative surgery for DFO, in whom clean bone margins could not be assured, were treated in the postoperative period with DWC. Eleven cases were located in the forefoot, 6 on the first ray and the rest in lesser toes, 1 in the Lisfranc joint, and 2 on the calcaneus. No side effects appeared during treatment. Neither allergies nor skin dermatitis were found. Limb salvage was successfully achieved in 100% of the cases. Healing was achieved in a median period of 6.8 weeks. PMID:23446366

  1. Novel Bifunctional Cyclic Chelator for 89Zr Labeling–Radiolabeling and Targeting Properties of RGD Conjugates

    PubMed Central

    2015-01-01

    Within the last years 89Zr has attracted considerable attention as long-lived radionuclide for positron emission tomography (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αvß3 integrins were synthesized using different conjugation strategies and labeled with 89Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [89Zr]FSC-RGD conjugates or [89Zr]triacetylfusarinine C (TAFC). Quantitative 89Zr labeling was achieved within 90 min at room temperature. The distribution coefficients of the different radioligands indicate hydrophilic character. Compared to [89Zr]DFO, [89Zr]FSC derivatives showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging experiments showed efficient receptor-specific targeting of [89Zr]FSC-RGD conjugates. No bone uptake was observed analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of 89Zr-based PET imaging agents. PMID:25941834

  2. Mind, Machine, and Creativity: An Artist's Perspective

    PubMed Central

    Sundararajan, Louise

    2014-01-01

    Harold Cohen is a renowned painter who has developed a computer program, AARON, to create art. While AARON has been hailed as one of the most creative AI programs, Cohen consistently rejects the claims of machine creativity. Questioning the possibility for AI to model human creativity, Cohen suggests in so many words that the human mind takes a different route to creativity, a route that privileges the relational, rather than the computational, dimension of cognition. This unique perspective on the tangled web of mind, machine, and creativity is explored by an application of three relational models of the mind to an analysis of Cohen's talks and writings, which are available on his website: www.aaronshome.com. PMID:25541564

  3. Volcanic synchronization of Dome Fuji and Dome C Antarctic deep ice cores over the past 216 kyr

    NASA Astrophysics Data System (ADS)

    Fujita, S.; Parrenin, F.; Severi, M.; Motoyama, H.; Wolff, E. W.

    2015-10-01

    Two deep ice cores, Dome Fuji (DF) and EPICA Dome C (EDC), drilled at remote dome summits in Antarctica, were volcanically synchronized to improve our understanding of their chronologies. Within the past 216 kyr, 1401 volcanic tie points have been identified. DFO2006 is the chronology for the DF core that strictly follows O2 / N2 age constraints with interpolation using an ice flow model. AICC2012 is the chronology for five cores, including the EDC core, and is characterized by glaciological approaches combining ice flow modelling with various age markers. A precise comparison between the two chronologies was performed. The age differences between them are within 2 kyr, except at Marine Isotope Stage (MIS) 5. DFO2006 gives ages older than AICC2012, with peak values of 4.5 and 3.1 kyr at MIS 5d and MIS 5b, respectively. Accordingly, the ratios of duration (AICC2012 / DFO2006) range between 1.4 at MIS 5e and 0.7 at MIS 5a. When making a comparison with accurately dated speleothem records, the age of DFO2006 agrees well at MIS 5d, while the age of AICC2012 agrees well at MIS 5b, supporting their accuracy at these stages. In addition, we found that glaciological approaches tend to give chronologies with younger ages and with longer durations than age markers suggest at MIS 5d-6. Therefore, we hypothesize that the causes of the DFO2006-AICC2012 age differences at MIS 5 are (i) overestimation in surface mass balance at around MIS 5d-6 in the glaciological approach and (ii) an error in one of the O2 / N2 age constraints by ~ 3 kyr at MIS 5b. Overall, we improved our knowledge of the timing and duration of climatic stages at MIS 5. This new understanding will be incorporated into the production of the next common age scale. Additionally, we found that the deuterium signals of ice, δDice, at DF tends to lead the one at EDC, with the DF lead being more pronounced during cold periods. The lead of DF is by +710 years (maximum) at MIS 5d, -230 years (minimum) at MIS 7a and +60

  4. Iron chelation monotherapy in transfusion-dependent beta-thalassemia major patients: a comparative study of deferasirox and deferoxamine

    PubMed Central

    Hassan, Mohamed Abdel Malik; Tolba, Omar Atef

    2016-01-01

    Introduction Iron overload is the primary cause of mortality and morbidity in thalassemia major (TM) despite advances in chelation therapy. The aim of this study was to compare the effectiveness and safety of deferasirox (DFX) and deferoxamine (DFO) as iron-chelating agents in patients with transfusion-dependent β-thalassemia major. Methods This prospective randomized study included 60 patients with transfusion-dependent β-TM during the period from September 2014 to September 2015. Their ages were ≥ 6 years, and they had serum ferritin above 1500 μg/L and were on irregular DFO therapy. Patients had regular packed red cell transfusion in a dose of 10 mL/kg/session. They were randomized to receive DFX (single oral daily dose of 20–40 mg/kg/day) or DFO (20–50 mg/kg/day via subcutaneous infusion over 8–10 hours, 5 days a week). Iron overload was determined by serum ferritin level. The primary endpoint was decrease of serum ferritin level below 1500 μg/L. The secondary endpoint was drug safety. Results Both drugs significantly reduced serum ferritin (p < 0.001). At the end of follow-up, there were no significant differences between the two groups in serum ferritin levels (p = 0.673) and in percent reduction of ferritin (p = 0.315). There were no significant differences between the two groups in the total amount of blood transfusion (p = 0.166) and average iron intake (p = 0.227). There were no mortalities or any serious adverse effects, neutropenia, arthropathy, or pulmonary toxicity. Gastrointestinal upset and skin rash occurred more frequently with DFX than with DFO (p = 0.254 and 0.095, respectively). Conclusion With appropriate dosing and compliance with drugs, both DFX and DFO are generally well tolerated, safe, and effective in reducing serum ferritin levels in iron-overloaded, regularly-transfused thalassemia major patients. Therefore, oral DFX is recommended for more convenience and adherence to the treatment regimen. PMID:27382454

  5. MICROBIAL IMPACTS ON THE MIGRATION OF ACTINIDES -EFFECTS OF EXUDATES ON ADSORPTION-

    SciTech Connect

    OHNUKI,T.; OZAKI, T.; YOSHIDA, T.; NANKAWA, T.; KOZAI, N.; SAKAMOTO, F.; SUZUKI, Y.; FRANCIS, A.J.

    2006-10-18

    The interaction of actinides with microorganisms has been extensively studied to elucidate migration behavior of actinides in the environments. However, the mechanisms of interaction of microorganisms and actinides are poorly understood. They have been conducting basic science on microbial accumulation of actinides in order to elucidate the environmental behavior of actinides under relevant conditions. The effect of exudates from bacteria cells on the sorption of Eu(III) and Cm(III) by Chlorella vulgaris was studied by a batch method. The pH dependence of log K{sub d} of Eu(III) and Cm(III) for cellulose, major component of C. vulgaris cell, differed from that for C. vulgaris. On the contrary, log K{sub d} of Eu(III) and Cm(III) for cellulose in the solution containing exudates from C. vulgaris cells in a 0.5% NaCl solution showed a similar pH dependence to that by C. vulgaris. These results strongly suggested that exudates affect on the sorption of Eu(III) and Cm(III) on C. vulgaris. Effect of desferrioxamine B (DFO), one of exudates to chelate the insoluble Fe(III), on the sorption of Pu(IV), Th(IV) and Eu(III) by Pseudomonas fluorescens was studied. In the presence of DFO the sorption of Pu(IV), Th(IV) and Eu(III) on the cells increased with a decrease in pH from 7 to 4. In contrast, without DFO most of Pu(IV), Th(IV) and Eu(III) were precipitated from solution. Adsorption of DFO on the cells was negligible in the solution with and without metals. Adsorption of Pu(IV), Th(IV) and Eu(III) on P. fluorescens cells decreased in the order Eu(III) > Th(IV) > Pu(IV), which corresponds to increasing stability constant of the DFO complexes. These results indicate that Th(IV), Pu(IV) and Eu(III) dissociate when in contact with cells, after which the metals are adsorbed.

  6. Why there was a useful plausible analogy between geodesic domes and spherical viruses.

    PubMed

    Morgan, Gregory J

    2006-01-01

    In 1962, Donald Caspar and Aaron Klug published their classic theory of virus structure. They developed their theory with an explicit analogy between spherical viruses and Buckminster Fuller's geodesic domes. In this paper, I use the spherical virus-geodesic dome case to develop an account of analogy and deductive analogical inference based on the notion of an isomorphism. I also consider under what conditions there is a good reason to claim an experimentally untested analogy is plausible. PMID:17702504

  7. Virus design, 1955-1962: science meets art.

    PubMed

    Morgan, Gregory J

    2006-11-01

    ABSTRACT This paper traces the beginnings of structural virology in the mid-20th century, focusing especially on the synergy between models of virus structure and models within art, notably Buckminster Fuller's geodesic domes and Kenneth Snelson's tensegrity structures. As Donald Caspar and Aaron Klug sought to extend the Crick-Watson theory of spherical virus structure, they explored analogies between biology and architecture, eventually publishing the classic Caspar-Klug theory of virus structure in 1962. PMID:18943967

  8. Historical review: viruses, crystals and geodesic domes.

    PubMed

    Morgan, Gregory J

    2003-02-01

    In the mid 1950s, Francis Crick and James Watson attempted to explain the structure of spherical viruses. They hypothesized that spherical viruses consist of 60 identical equivalently situated subunits. Such an arrangement has icosahedral symmetry. Subsequent biophysical and electron micrographic data suggested that many viruses had >60 subunits. Drawing inspiration from architecture, Donald Caspar and Aaron Klug discovered a solution to the problem - they proposed that spherical viruses were structured like miniature geodesic domes. PMID:12575996

  9. JSC Officials in MCC Bldg 30 monitor STS-26 Discovery, OV-103, activity

    NASA Technical Reports Server (NTRS)

    1988-01-01

    JSC Officials, laughing, listen to crewmembers' commentary onboard Discovery, Orbiter Vehicle (OV) 103, during STS-26. In the Flight Control Room (FCR) of JSC's Mission Control Center (MCC) Bldg 30 and seated at the Mission Operations Directorate (MOD) console, MOD Director Eugene F. Kranz (foreground), wearing red, white and blue vest, smiles along with JSC Director Aaron Cohen and Flight Crew Operations Deputy Director Henry W. Hartsfield, Jr. (far right).

  10. 75 FR 41483 - Environmental Impacts Statements; Notice of Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-16

    ...-575-6060. Revision to FR Notice Published 04/16/2010: Extending Comment Period from 7/15/2010 to 8/30... to FR Notice Published 05/07/2010: Extending Comment Period from 6/21/2010 to 12/17/2010. EIS No.../09/2010, Contact: Aaron Snyder, 651-290-5489. Revision to FR Notice Published 06/11/2010:...

  11. The MOOC Moment and the End of Reform

    ERIC Educational Resources Information Center

    Bady, Aaron

    2013-01-01

    The Massive Open Online Courses (MOOC) phenomenon has happened very quickly and is also a shift in discourse. This article aims to slow things down and go through the last year or so with a bit more care than we're usually able to do in order to do a "close reading" of the year of the MOOC. Author Aaron Brady ventures an opinion to say…

  12. OIT Times Newsletter: Volume 3, Number 1, Winter 2000

    SciTech Connect

    Sousa, L.

    1999-12-16

    The Winter 2000 edition of the OIT Times newsletter, a quarterly publication produced by the Office of Industrial Technologies, highlights the 1999 start-up projects, announces the OIT solicitation schedule for FY2000, and features the success of the Ohio diecasting showcase. One of the quarterly highlights was Secretary Richardson's presentation of a Certificate of Partnership to Malden Mills CEO Aaron Feuerstein at the dedication of the plant's new, advanced cogeneration system.

  13. NASA GSFC Science Symposium on Atomic and Molecular Physics

    NASA Technical Reports Server (NTRS)

    Bhatia, Anand K. (Editor)

    2007-01-01

    This document is the proceedings of a conference on atomic and molecular physics in honor of the retirements of Dr. Aaron Temkin and Dr. Richard Drachman. The conference contained discussions on electron, positron, atomic, and positronium physics, as well as a discussion on muon catalyzed fusion. This proceedings document also contains photographs taken at the symposium, as well as speeches and a short biography made in tribute to the retirees.

  14. Style as Emergence (from What?)

    NASA Astrophysics Data System (ADS)

    Cohen, Harold

    I argue that an exclusively formal description of a painting cannot provide an adequate description of its style, nor can it express its style so vividly that the description can generate objects stylistically similar to the originals. While the characteristics through which we identify style certainly involve the formal, physical presence of the work, this is not without reference to the mindset of the artist and to the history of decisions that result in the presence of the work. By way of example, I will examine some original work that was generated, not with a computer program, but by a computer program, named AARON. Its work has a distinctive appearance, but one that lacks an obvious formal organizing principle. It would be impossible to simulate AARON convincingly without access to its history because, as I will show, it did not arise through any primary interest in formal configuration. In fact, the argument for purely formal analysis does not require that it uncovers the true history of the original, simply that the presumptive history generates a convincing simulation. Should we conclude from that argument that any given configuration could have been the result of some number of alternative histories? A dubious conclusion: I will argue that AARON's images result uniquely, not just from their making, but also from the long history of perceived goals and intentions, paths and detours, that resulted in the peculiarly idiosyncratic technology of their making.

  15. Medical Response, Search and Recovery during the Space Shuttle Columbia Accident Investigation

    NASA Technical Reports Server (NTRS)

    Stepaniak, Philip C.

    2010-01-01

    On February 1, 2003, the Space Shuttle Columbia broke apart during atmospheric re-entry on mission STS-107. After an event such as this, with high visibility and international interest, the operational challenge of recovering the crewmembers could not be underestimated. The Space Shuttle Program is organized to respond to a vehicle mishap using the resources of the Mishap Investigation Team (MIT). On the afternoon of Feb. 1, 2003, the MIT deployed to Barksdale Air Force Base (AFB), Louisiana. This location became the investigative center and interim storage location for crewmembers received from the Lufkin, Texas Disaster Field Office (DFO). The Lufkin DFO served as the primary area for all operations, including staging assets and deploying field teams for search, recovery and security of crewmember remains. More than 2,000 people from numerous organizations were involved with the recovery of the crew. All seven crewmembers of STS-107 were recovered and ceremonial last rights were administered. Astronaut and military personnel escorted the crew with honor to the MIT at Barksdale AFB, Louisiana. At Barksdale AFB a temporary morgue was established in an aircraft hangar and operated for approximately two weeks during which time coordination with the DFO field recovery teams, Armed Forces Institute of Pathology (AFIP) medical personnel, and the crew surgeons was on going. Families of crewmembers and NASA management were notified daily of the current findings. Working under the leadership of the MIT Lead, the medical team developed and executed a short-term plan to identify and relocate the crew with a military honor guard and protocol to the medical examiner at the Armed Forces Port Mortuary, Dover AFB, Delaware. After operations at Barksdale AFB were concluded the medical team transitioned back to Houston and a long-term plan was developed and implemented which involved the Air Force Mortuary Affairs at Randolph AFB, Texas. This plan was coordinated with search teams

  16. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.

    PubMed

    Elenbaas, Jared S; Maitra, Dhiman; Liu, Yang; Lentz, Stephen I; Nelson, Bradley; Hoenerhoff, Mark J; Shavit, Jordan A; Omary, M Bishr

    2016-05-01

    Protoporphyria is a metabolic disease that causes excess production of protoporphyrin IX (PP-IX), the final biosynthetic precursor to heme. Hepatic PP-IX accumulation may lead to end-stage liver disease. We tested the hypothesis that systemic administration of porphyrin precursors to zebrafish larvae results in protoporphyrin accumulation and a reproducible nongenetic porphyria model. Retro-orbital infusion of PP-IX or the iron chelator deferoxamine mesylate (DFO), with the first committed heme precursor α-aminolevulinic acid (ALA), generates high levels of PP-IX in zebrafish larvae. Exogenously infused or endogenously produced PP-IX accumulates preferentially in the liver of zebrafish larvae and peaks 1 to 3 d after infusion. Similar to patients with protoporphyria, PP-IX is excreted through the biliary system. Porphyrin accumulation in zebrafish liver causes multiorganelle protein aggregation as determined by mass spectrometry and immunoblotting. Endoplasmic reticulum stress and induction of autophagy were noted in zebrafish larvae and corroborated in 2 mouse models of protoporphyria. Furthermore, electron microscopy of zebrafish livers from larvae administered ALA + DFO showed hepatocyte autophagosomes, nuclear membrane ruffling, and porphyrin-containing vacuoles with endoplasmic reticulum distortion. In conclusion, systemic administration of the heme precursors PP-IX or ALA + DFO into zebrafish larvae provides a new model of acute protoporphyria with consequent hepatocyte protein aggregation and proteotoxic multiorganelle alterations and stress.-Elenbaas, J. S., Maitra, D., Liu, Y., Lentz, S. I., Nelson, B., Hoenerhoff, M. J., Shavit, J. A., Omary, M. B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress. PMID:26839379

  17. Coordination chemistry of two heavy metals: I, Ligand preferences in lead(II) complexation, toward the development of therapeutic agents for lead poisoning: II, Plutonium solubility and speciation relevant to the environment

    SciTech Connect

    Neu, M.P.

    1993-11-01

    The coordination chemistry and solution behavior of the toxic ions lead(II) and plutonium(IV, V, VI) have been investigated. The ligand pK{sub a}s and ligand-lead(II) stability constants of one hydroxamic acid and four thiohydroaxamic acids were determined. Solution thermodynamic results indicate that thiohydroxamic acids are more acidic and slightly better lead chelators than hydroxamates, e.g., N-methylthioaceto-hydroxamic acid, pK{sub a} = 5.94, log{beta}{sub 120} = 10.92; acetohydroxamic acid, pK{sub a} = 9.34, log{beta}{sub l20} = 9.52. The syntheses of lead complexes of two bulky hydroxamate ligands are presented. The X-ray crystal structures show the lead hydroxamates are di-bridged dimers with irregular five-coordinate geometry about the metal atom and a stereochemically active lone pair of electrons. Molecular orbital calculations of a lead hydroxamate and a highly symmetric pseudo octahedral lead complex were performed. The thermodynamic stability of plutonium(IV) complexes of the siderophore, desferrioxamine B (DFO), and two octadentate derivatives of DFO were investigated using competition spectrophotometric titrations. The stability constant measured for the plutonium(IV) complex of DFO-methylterephthalamide is log{beta}{sub 110} = 41.7. The solubility limited speciation of {sup 242}Pu as a function of time in near neutral carbonate solution was measured. Individual solutions of plutonium in a single oxidation state were added to individual solutions at pH = 6.0, T = 30.0, 1.93 mM dissolved carbonate, and sampled over intervals up to 150 days. Plutonium solubility was measured, and speciation was investigated using laser photoacoustic spectroscopy and chemical methods.

  18. On the value of satellite-based river discharge and river flood data

    NASA Astrophysics Data System (ADS)

    Kettner, A. J.; Brakenridge, R.; van Praag, E.; Borrero, S.; Slayback, D. A.; Young, C.; Cohen, S.; Prades, L.; de Groeve, T.

    2015-12-01

    Flooding is the most common natural hazard worldwide. According to the World Resources Institute, floods impact 21 million people every year and affect the global GDP by $96 billion. Providing accurate flood maps in near-real time (NRT) is critical to their utility to first responders. Also, in times of flooding, river gauging stations on location, if any, are of less use to monitor stage height as an approximation for water surface area, as often the stations themselves get washed out or peak water levels reach much beyond their design measuring capacity. In a joint effort with NASA Goddard Space Flight Center, the European Commission Joint Research Centre and the University of Alabama, the Dartmouth Flood Observatory (DFO) measures NRT: 1) river discharges, and 2) water inundation extents, both with a global coverage on a daily basis. Satellite-based passive microwave sensors and hydrological modeling are utilized to establish 'remote-sensing based discharge stations'. Once calibrated, daily discharge time series span from 1998 to the present. Also, the two MODIS instruments aboard the NASA Terra and Aqua satellites provide daily floodplain inundation extent with global coverage at a spatial resolution of 250m. DFO's mission is to provide easy access to NRT river and flood data products. Apart from the DFO web portal, several water extent products can be ingested by utilizing a Web Map Service (WMS), such as is established with for Latin America and the Caribbean (LAC) region through the GeoSUR program portal. This effort includes implementing over 100 satellite discharge stations showing in NRT if a river is flooding, normal, or in low flow. New collaborative efforts have resulted in flood hazard maps which display flood extent as well as exceedance probabilities. The record length of our sensors allows mapping the 1.5 year, 5 year and 25 year flood extent. These can provide key information to water management and disaster response entities.

  19. Lazaroid compounds prevent early but not late stages of oxidant-induced cell injury: potential explanation for the lack of efficacy of lazaroids in clinical trials.

    PubMed

    Huang, H; Patel, P B; Salahudeen, A K

    2001-01-01

    Earlier in vitro studies demonstrated the remarkable potency of the lazaroid compounds to prevent oxidant-induced early cell injury. However, the ability of lazaroid compounds to limit oxidative injury in vivo(including renal ischemia-reperfusion) has been less certain, and the early clinical trials using lazaroids to limit CNS injury or organ injury in the setting of transplantation have not been promising. Lazaroid compounds are potent inhibitors of lipid peroxidation, and their inability to influence other key injury processes, particularly during the late stages of cell injury, might partly explain the limited clinical efficacy. To test this, renal tubular (LLC-PK1) cells were incubated with 250 micromH(2)O(2)for 135 min, in the presence or absence of 2-methyl aminochroman (2-MAC, U-83836E), a lazaroid with potent ability to inhibit lipid peroxidation, or desferrioxamine, (DFO) an iron chelator with broader antioxidant efficacy. Cell injury, lipid peroxidation, DNA damage and ATP depletion were measured in the early (immediately after H(2)O(2)incubation) and late (24 h after H(2)O(2)incubation) stages of cell injury. In the early stage, 2-MAC suppressed H(2)O(2)-induced lipid peroxidation and LDH release, but not the DNA damage, ATP depletion or loss of cell replication. In contrast, DFO suppressed all of the measurements. In the late stages, despite continued suppression of lipid peroxidation, only DFO maintained significant cytoprotection against H(2)O(2), and this was accompanied by reduced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotection in the later stages of cell injury might provide at least a partial explanation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings. PMID:11207066

  20. Relationship among Chelator Adherence, Change in Chelators, and Quality of Life in Thalassemia

    PubMed Central

    Trachtenberg, Felicia L.; Gerstenberger, Eric; Xu, Yan; Mednick, Lauren; Sobota, Amy; Ware, Hannah; Thompson, Alexis A.; Neufeld, Ellis J.; Yamashita, Robert

    2015-01-01

    Purpose Thalassemia, a chronic blood disease, necessitates life-long adherence to blood transfusions and chelation therapy to reduce iron overload. We examine stability of Health-Related Quality of Life (HRQOL) in thalassemia and adherence to chelation therapy over time, especially after changes in chelator choice. Methods Thalassemia Longitudinal Cohort participants in the US, UK, and Canada completed the SF-36v2 (ages 14+), and the PF-28 CHQ (parents of children<14 years). Chelation adherence was defined as self-reported percent of doses administered in the last 4 weeks. Results 258 adults/adolescents (mean 29.7 years) and 133 children (mean 8.5 years) completed a mean of 2.8 years follow-up. Children made few chelator changes, whereas a mean of 2.2 changes was observed among the 37% of adults/adolescents who made chelator changes, mainly, due to patient preference or medical necessity. Physical HRQOL improved among those with lower iron burden (better health status) at baseline who made a single change in chelator, but declined among participants with multiple changes and/or high iron burden (worse health status). Mental health improved among participants with lower iron burden, but iron overload was negatively associated with social functioning. Adherence did not significantly change over follow-up except for an increase after a change from DFO infusion to oral deferasirox (p=0.03). Predictors of lower adherence for adults/adolescents at follow-up included side effects, smoking, younger age, problems preparing DFO, increased number of days per week DFO prescribed, and lower physical QOL. Conclusions Strategies to balance medical needs with family, work, and personal life may assist in adherence. PMID:24682717

  1. Clinical monitoring and management of complications related to chelation therapy in patients with β-thalassemia.

    PubMed

    Saliba, Antoine N; El Rassi, Fuad; Taher, Ali T

    2016-01-01

    Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with β-thalassemia in an attempt to reduce morbidity and mortality related to siderosis. Each of the approved iron chelating agents has its own advantages over the others and also has its own risks, whether related to over-chelation or not. In this review, we briefly discuss the methods to monitor the efficacy of iron chelation therapy (ICT) and the evidence behind the use of each iron chelating agent. We also portray the risks and complications associated with each iron chelating agent and recommend strategies to manage adverse events. PMID:26613264

  2. Modulation of Membrane Lipid Composition and Homeostasis in Salmon Hepatocytes Exposed to Hypoxia and Perfluorooctane Sulfonamide, Given Singly or in Combination

    PubMed Central

    Olufsen, Marianne; Cangialosi, Maria V.; Arukwe, Augustine

    2014-01-01

    The relative importance of environmental hypoxia due to global climate change on organismal ability to adapt to chemical insult and/or mechanisms of these responses is not well understood. Therefore, we have studied the effects of combined exposure to perfluorooctane sulfonamide (PFOSA) and chemically induced hypoxia on membrane lipid profile and homeostasis. Primary salmon hepatocytes were exposed to PFOSA at 0, 25 and 50 µM singly or in combination with either cobalt chloride (CoCl2: 0 and 150 µM) or deferroxamine (DFO: 0 and 100 µM) for 24 and 48 h. CoCl2 and DFO were used to induce cellular hypoxia because these two chemicals have been commonly used in animal experiments for this purpose and have been shown to increase hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) levels. Fatty acid (FA) profiles were determined by GC-MS, while gene expression patterns were determined by quantitative PCR. Hypoxic condition was confirmed with time-related increases of HIF-1α mRNA levels in CoCl2 and DFO exposed cells. In general, significant alterations of genes involved in lipid homeostasis were predominantly observed after 48 h exposure. Gene expression analysis showed that biological responses related to peroxisome proliferation (peroxisome proliferator-activated receptors (PPARs) and acyl coenzyme A (ACOX)) and FA desaturation (Δ5- and Δ6-desaturases: FAD5 and FAD6, respectively) and elongation (FAE) were elevated slightly by single exposure (i.e. either PFOSA, CoCl2 or DFO exposure alone), and these responses were potentiated in combined exposure conditions. Principal component analysis (PCA) showed a clustering of peroxisome proliferation responses at transcript levels and FA desaturation against membrane FAs levels whose changes were explained by PFOSA and chemically induced hypoxia exposures. Overall, our data show that most of the observed responses were stronger in combined stressor exposure conditions, compared to

  3. Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion.

    PubMed

    Lui, Goldie Y L; Kovacevic, Zaklina; V Menezes, Sharleen; Kalinowski, Danuta S; Merlot, Angelica M; Sahni, Sumit; Richardson, Des R

    2015-01-01

    Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway. PMID:25561562

  4. Self-assembled monolayers for studying enzyme immobilization and ion recognition

    NASA Astrophysics Data System (ADS)

    Kang, Jie

    This thesis explores the use of self-assembled monolayers on gold for studying enzyme immobilization and ion recognition. Chapter 1 serves as a general introduction to biosensing, self-assembled monolayers, protein immobilization, and surface characterization techniques. Chapter 2 through Chapter 5 describe the immobilization of a redox enzyme, glucose oxidase, to a variety of functional self-assembled monolayers by either noncovalent adsorption or covalent attachment. The characteristics of different immobilization methods are investigated, and the activity of the immobilized enzyme is assessed electrochemically. Chapter 2 presents detailed procedures for measuring glucose oxidase activity by an electrochemical technique---cyclic voltammetry. Chapter 3 describes the adsorption of glucose oxidase to hydrophobic and hydrophilic self-assembled monolayers (SAMs). Significant glucose oxidase adsorption to hydrophobic, methyl-terminated SAMs was observed, while long chain, hydrophilic SAMs terminated by hydroxyl and carboxyl groups resist enzyme adsorption. Chapter 4 examines the covalent attachment of glucose oxidase to N-hydroxysuccinimide ester (NHS ester)-terminated self-assembled monolayers. The reactivity of the surface NHS ester group is found to increase as its coverage is lowered. This observation is explained by the steric effect. Chapter 5 reports the electrostatic adsorption of glucose oxidase to self-assembled monolayers of cystamine. The adsorbed enzyme shows superior activity to enzyme immobilized by other means. The rate constants of surface enzyme catalysis are determined and compared with those of the enzyme in solution. Chapter 6 is concerned with iron (III) recognition by a self-assembled monolayer terminated with a siderophore group, desferrioxamine (H3DFO). We first demonstrate that the iron coverage of the ferrioxamine (FeDFO)-terminated SAM can be successfully assayed by cyclic voltammetry. We then present results for iron (III) binding to the H3

  5. Preclinical 89Zr Immuno-PET of High-Grade Serous Ovarian Cancer and Lymph Node Metastasis

    PubMed Central

    Sharma, Sai Kiran; Sevak, Kuntal K.; Monette, Sebastien; Carlin, Sean D.; Knight, James C.; Wuest, Frank R.; Sala, Evis; Zeglis, Brian M.; Lewis, Jason S.

    2016-01-01

    The elevation of cancer antigen 125 (CA125) levels in the serum of asymptomatic patients precedes the radiologic detection of high-grade serous ovarian cancer by at least 2 mo and the final clinical diagnosis by 5 mo. PET imaging of CA125 expression by ovarian cancer cells may enhance the evaluation of the extent of disease and provide a roadmap to surgery as well as detect recurrence and metastases. Methods 89Zr-labeled mAb-B43.13 was synthesized to target CA125 and evaluated via PET imaging and biodistribution studies in mice bearing OVCAR3 human ovarian adenocarcinoma xenografts. Ex vivo analysis of tumors and lymph nodes was performed via autoradiography, histopathology, and immunohistochemistry. Results PET imaging using 89Zr-DFO-mAb-B43.13 (DFO is desferrioxamine) clearly delineated CA125-positive OVCAR3 xenografts as early as 24 h after the administration of the radioimmunoconjugate. Biodistribution studies revealed accretion of 89Zr-DFO-mAb-B43.13 in the OVCAR3 tumors, ultimately reaching 22.3 ± 6.3 percentage injected dose per gram (%ID/g) at 72 h after injection. Most interestingly, activity concentrations greater than 50 %ID/g were observed in the ipsilateral lymph nodes of the xenograft-bearingmice. Histopathologic analysis of the immuno-PET–positive lymph nodes revealed the presence of grossly metastasized ovarian cancer cells within the lymphoid tissues. In control experiments, only low-level, non-specific uptake of 89Zr-labeled isotype IgG was observed in OVCAR3 tumors; similarly, low-activity concentrations of 89Zr-DFO-mAb-B43.13 accumulated in CA125-negative SKOV3 tumors. Conclusion Immuno-PET with 89Zr-labeled mAb-B43.13 is a potential strategy for the noninvasive delineation of extent of disease and may add value in treatment planning and treatment monitoring of high-grade serous ovarian cancer. PMID:26837339

  6. Toward the Effective and Efficient Measurement of Implementation Fidelity

    PubMed Central

    Schoenwald, Sonja K.; Garland, Ann F.; Chapman, Jason E.; Frazier, Stacy L.; Sheidow, Ashli J.; Southam-Gerow, Michael A.

    2011-01-01

    Implementation science in mental health is informed by other academic disciplines and industries. Conceptual and methodological territory charted in psychotherapy research is pertinent to two elements of the conceptual model of implementation posited by Aarons and colleagues (2010)—implementation fidelity and innovation feedback systems. Key characteristics of scientifically validated fidelity instruments, and of the feasibility of their use in routine care, are presented. The challenges of ensuring fidelity measurement methods are both effective (scientifically validated) and efficient (feasible and useful in routine care) are identified as are examples of implementation research attempting to balance these attributes of fidelity measurement. PMID:20957425

  7. Insurance Reimbursement: An Expert Discussion on Best Practices and Avoiding Pitfalls

    PubMed Central

    Niemtzow, Moderators: Richard C.; Sager, Marshall; Cooke, Participants: Claudia; Michelfelder, Aaron; Safayan, Ali

    2013-01-01

    Medical Acupuncture's Editor-in-Chief, Richard C. Niemtzow, MD, PhD, MPH, and Marshall Sagar, DO, DABMA, FAAMA, conducted a Roundtable Discussion with experienced medical acupuncturists—Claudia Cooke, MD, FACP, MPH, Aaron Michelfelder, MD, FAAFP, FAAMA, and Ali Safayan, MD—to discuss best insurance billing strategies related to their scope of practice and geographical locations, and related to compliance with the eventual changes from the Affordable Healthcare Act. This Roundtable offers valuable insight for frequently asked questions from both new and seasoned medical acupuncturists. The Journal welcomes further comments from the readership. PMID:24761183

  8. KSC-04PD-0837

    NASA Technical Reports Server (NTRS)

    2004-01-01

    KENNEDY SPACE CENTER, FLA. Center Director Jim Kennedy (right) talks to Aaron Fernander, principal of Ralph Bunche Middle School, a NASA Explorer School, in Atlanta, Ga. Kennedy is visiting NES sites to share Americas new vision for space exploration with the next generation of explorers. He was accompanied by astronaut Rick Linnehan on the visit. The purpose of the school visit is to talk with students about our destiny as explorers, NASAs stepping stone approach to exploring Earth, the Moon, Mars and beyond, how space impacts our lives, and how people and machines rely on each other in space.

  9. Eastern Renewable Generation Integration Study: Flexibility and High Penetrations of Wind and Solar; NREL (National Renewable Energy Laboratory)

    SciTech Connect

    Bloom, Aaron; Townsend, Aaron; Palchak, David

    2015-07-29

    Balancing wind and solar in a model is relatively easy. All you need to do is assume a very large system with infinite flexibility! But what if you don't have an infinitely flexible system? What if there are thousands of generators nestled in a handful of regions that are unlikely to change their operational practices? Would you still have enough flexibility to balance hundreds of gigawatts of wind and solar at a 5 minute level? At NREL, we think we can, and our industry partners agree. This presentation was presented at the IEEE Power and Energy Society General Meeting by Aaron Bloom, highlighting results of the Eastern Renewable Generation Integration Study.

  10. Mishap Investigation Team (MIT) - Barksdale AFB, Louisiana

    NASA Technical Reports Server (NTRS)

    Stepaniak, Philip

    2005-01-01

    The Shuttle Program is organized to support a Shuttle mishap using the resources of the MIT. The afternoon of Feb. 1, 2003, the MIT deployed to Barksdale AFB. This location became the investigative center and interim storage location for crewmembers received from the Lufkin Disaster Field Office (DFO). Working under the leadership of the MIT Lead, the medical team executed a short-term plan that included search, recovery, and identification including coordination with the Armed Forces Institute of Pathology Temporary operations was set up at Barksdale Air Force Base for two weeks. During this time, coordination with the DFO field recovery teams, AFIP personnel, and the crew surgeons was on going. In addition, the crewmember families and NASA management were updated daily. The medical team also dealt with public reports and questions concerning biological and chemical hazards, which were coordinated with SPACEHAB, Inc., Kennedy Space Center (KSC) Medical Operations and the Johnson Space Center (JSC) Space Medicine office. After operations at Barksdale were concluded the medical team transitioned back to Houston and a long-term search, recovery and identification plan was developed.

  11. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    SciTech Connect

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-10-25

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

  12. Oxidation-Induced Degradable Nanogels for Iron Chelation

    PubMed Central

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-01-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells. PMID:26868174

  13. Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease.

    PubMed

    Guo, Jun-Peng; Pan, Jin-Xiu; Xiong, Lei; Xia, Wen-Fang; Cui, Shun; Xiong, Wen-Cheng

    2015-01-01

    Patients of Alzheimer's disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation's effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO's inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits. PMID:26575486

  14. Incidence of hepatocellular carcinoma in patients with thalassemia who had hepatitis C.

    PubMed

    Ansari, Shahla; Azarkivan, Azita; Halagi, Farideh

    2013-01-01

    Hepatitis is the infections of a common cause disease among poly transfused patients. Hepatitis C is slowed progression and inducing HCC. This study assessed HCC incidences, the role of iron and possible antitumor activity of chelators in 170 thalassemia patients using deferoxamine (DFO) therapy. They are diagnosed with Hepatitis C due to positive PCR-RNA. They are Treated with IFN. The follow up program including tests every 3 Months and PCR-RNA, AFP and liver US every 6 months. Whenever there was suspicion of liver malignancy, Biopsy was performed. From the total of 170 patients,  59.4% were male, and 40.6% were female. Mean age of thalassemia diagnosis was 2.69±5.403 (1-41) years and mean Age of hepatitis diagnosis was 17.37±7.263 (3-51) years. 92.4 % of Patient's MT, 0.6 % SS, 2.9% TI. the viral genome was 1a3a. 73.5% of patients had first course of therapy. The frequency of AFP greater than 10 was 5.9%. And the incidence of HCC was 0.6 %(1/170) with a 95% confidence interval. The main risk factor for HCC was HCV infection in TM patients, but it was iron activity in TI patients. Iron chelation with DFO appeared to play a Protective role. PMID:23852846

  15. The role of iron in the proliferation of Drosophila l(2)mbn cells

    SciTech Connect

    Metzendorf, Christoph; Lind, Maria I.

    2010-09-24

    Research highlights: {yields} Establishment of a model system to study the role of iron during proliferation. {yields} Iron deprivation of insect tumorous cell line inhibits cell proliferation. {yields} Iron deprivation causes a reversible cell cycle arrest in G1/S-phase. {yields} Iron deprivation promotes decreased gene expression of cycE. -- Abstract: Iron is essential for life and is needed for cell proliferation and cell cycle progression. Iron deprivation results first in cell cycle arrest and then in apoptosis. The Drosophila tumorous larval hemocyte cell line l(2)mbn was used to study the sensitivity and cellular response to iron deprivation through the chelator desferrioxamine (DFO). At a concentration of 10 {mu}M DFO or more the proliferation was inhibited reversibly, while the amount of dead cells did not increase. FACS analysis showed that the cell cycle was arrested in G1/S-phase and the transcript level of cycE was decreased to less than 50% of control cells. These results show that iron chelation in this insect tumorous cell line causes a specific and coordinated cell cycle arrest.

  16. FT-Raman study of deferoxamine and deferiprone exhibits potent amelioration of structural changes in the liver tissues of mice due to aluminum exposure

    NASA Astrophysics Data System (ADS)

    Sivakumar, S.; Khatiwada, Chandra Prasad; Sivasubramanian, J.; Raja, B.

    2014-01-01

    The present study inform the alterations on major biochemical constituents such as lipids, proteins, nucleic acids and glycogen along with phosphodiester linkages, tryptophan bands, tyrosine doublet, disulfide bridge conformations, aliphatic hydrophobic residue, and salt bridges in liver tissues of mice using Fourier transform Raman spectroscopy. In amide I, amide II and amide III, the area value significant decrease due structural alteration in the protein, glycogen and triglycerides levels but chelating agents DFP and DFO upturned it. Morphology changes by aluminium induced alterations and recovery by chelating agents within liver tissues known by histopathological examination. Concentrations of trace elements were found by ICP-OES. FT-Raman study was revealed to be in agreement with biochemical studies and demonstrate that it can successfully specify the molecular alteration in liver tissues. The tyrosyl doublet ratio I899/I831 decreases more in aluminum intoxicated tissues but treatment with DFP and DFO + DFP brings back to nearer control value. This indicates more variation in the hydrogen bonding of the phenolic hydroxyl group due to aluminum poisoning. The decreased Raman intensity ratio (I3220/I3400) observed in the aluminum induced tissues suggests a decreased water domain size, which could be interpreted in terms of weaker hydrogen-bonded molecular species of water in the aluminum intoxicated liver tissues. Finally, FT-Raman spectroscopy might be a useful tool for obtained successfully to indicate the molecular level changes.

  17. Therapeutic effect of deferoxamine on iron overload-induced inhibition of osteogenesis in a zebrafish model.

    PubMed

    Chen, Bin; Yan, Yi-Lin; Liu, Chen; Bo, Lin; Li, Guang-Fei; Wang, Han; Xu, You-Jia

    2014-03-01

    Osteoporosis results from an imbalance in bone remodeling, in which osteoclastic bone resorption exceeds osteoblastic bone formation. Iron has recently been recognized as an independent risk factor for osteoporosis. Reportedly, excess iron could promote osteoclast differentiation and bone resorption through the production of reactive oxygen species (ROS). We evaluated the effect of iron on osteoblast differentiation and bone formation in zebrafish and further investigated the potential benefits of deferoxamine (DFO), a powerful iron chelator, in iron-overloaded zebrafish. The zebrafish model of iron overload described in this study demonstrated an apparent inhibition of bone formation, accompanied by decreased expression of osteoblast-specific genes (runx2a, runx2b, osteocalcin, osteopontin, ALP, and collagen type I). The negative effect of iron on osteoblastic activity and bone formation could be attributed to increased ROS generation and oxidative stress. Most importantly, we revealed that DFO was capable of removing whole-body iron and attenuating oxidative stress in iron-overloaded larval zebrafish, which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload. PMID:24414856

  18. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox.

    PubMed

    Kontoghiorghes, George J

    2008-01-01

    New developments in the area of iron and other metal metabolism and toxicity and the effects and uses of chelators have been presented at the 16th International Conference on Chelation (ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies, contradictory policies by regulatory authorities and ineffective policies by health authorities deprive thousands of thalassemia and other transfused patients of life saving iron chelating drugs and of efficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide a few months after the European Union (EU) authorities, and about 1 year after the Food and Drugs Administration (FDA), proceeded to its accelerated approval with no sufficient evidence that the drug was efficacious, especially for clearing excess cardiac iron, and also safe. Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxicities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriving thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g, L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of L1, DFO, and their combination in particular, appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron. PMID:18274978

  19. Diethylentriaminepenta acetic acid glucose conjugates as a cell permeable iron chelator

    PubMed Central

    Mosayebnia, Mona; Shafiee-Ardestani, Mehdi; Pasalar, Parvin; Mashayekhi, Mojgan; Amanlou, Massoud

    2014-01-01

    Objective: To find out whether DTPA-DG complex can enhance clearance of intracellular free iron. Materials and Methods: Diethylenetriaminepentaacetic acid-D-deoxy-glucosamine (DTPA-DG) was synthesized and examined for its activity as a cell-permeable iron chelator in human hepatocellular carcinoma (HEPG2) cell line exposed to high concentration of iron sulfate and compared with deferoxamine (DFO), a prototype iron chelator. The effect of DTPA-DG on cell viability was monitored using the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide MTT assay as well. Results: There was a significant increase of iron level after iron overload induction in HEPG2 cell culture. DTPA-DG presented a remarkable capacity to iron burden reducing with estimated 50% inhibitory concentration value of 65.77 nM. In fact, glycosyl moiety was gained access of DTPA to intracellular iron deposits through glucose transporter systems. Conclusion: DTPA-DG, more potent than DFO to sequester deposits of free iron with no profound toxic effect. The results suggest the potential of DTPA-DG in chelating iron and permitting its excretion from primary organ storage. PMID:24554907

  20. Siderophore production by pathogenic mucorales and uptake of deferoxamine B.

    PubMed

    Larcher, Gérald; Dias, Marylène; Razafimandimby, Bienvenue; Bomal, Danielle; Bouchara, Jean-Philippe

    2013-12-01

    Clinical reports have established that mucormycosis, mainly caused by Rhizopus spp., frequently occurs in patients treated with deferoxamine B (DFO, Desferal(®)) which is misappropriated by these fungi. Siderophore production by twenty mucoralean isolates was therefore investigated using a commercial iron-depleted culture medium. Siderophore production was detected for most of the isolates. Our experiments confirmed that feroxamine B (iron chelate of DFO) promoted in vitro growth of Rhizopus arrhizus. Electrophoretic analysis of somatic extracts revealed iron-regulated proteins of 60 and 32 kDa which were lacking in iron-depleted culture conditions. Using a fluorescent derivative of deferoxamine B, we showed by fluorescence microscopy the entry of the siderophore within the fungal cells, thus suggesting a shuttle mechanism encompassing the uptake of the entire siderophore-ion complex into the cell. This useful tool renders possible a better understanding of iron metabolism in Mucorales which could lead to the development of new diagnostic method or new antifungal therapy using siderophores as imaging contrast agents or active drug vectors. PMID:23982284

  1. An analysis of space scales for sea ice drift

    SciTech Connect

    Carrieres, T.

    1994-12-31

    Sea ice presents a hazard to navigation off Canada`s east coast from January to June. The Ice Centre Environment Canada (ICEC) which is part of the Atmospheric Environment Service monitors ice conditions in order to assist safe and efficient operations through or around the ice. The ice program depends on an advanced data acquisition, analysis and forecasting effort. Support for the latter is provided by kinematic models as well as a fairly simple dynamic sea ice model. In order to improve ICEC`s forecasting capabilities, the Department of Fisheries and Oceans (DFO) conducts ice modelling research and regular field experiments. The experiments provide a better understanding of the ice and also allow models to be validated and refined. The Bedford Institute of Oceanography (BIO, part of DFO) regularly deploys beacons on ice floes off the Labrador and Newfoundland coasts. These beacons provide environmental as well as location information through Service ARGOS. Documentation on the accuracy and information of the sensors is documented in Prinsenberg, 1993. The beacon locations are used here to infer an relatively unbiased representation of sea ice drift.

  2. Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin

    PubMed Central

    Li, Yanyan; Chen, Man; Xu, Yanyan; Yu, Xiao; Xiong, Ting; Du, Min; Sun, Jian; Liu, Liegang; Tang, Yuhan; Yao, Ping

    2016-01-01

    Iron, in its free ferrous states, can catalyze Fenton reaction to produce OH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD. PMID:27057276

  3. High Energy Theory Workshops and Visitors at the Michigan Center for Theoretical Physics FY15

    SciTech Connect

    Pierce, Aaron T.

    2015-09-18

    The String theory workshop was held from March 4-7, 2015 on the University of Michigan campus. Local organizers were Gordon Kane and Aaron Pierce. Piyush Kumar (Yale), Jim Halverson (KITP), Bobby Acharya (ICTP) and Sven Krippendorf (Oxford) served as external organizers.The meeting focused on the status of work to project 10 or 11 dimensional string/M theories onto our 4 spacetime dimensions (compactification). The workshop had 31 participants, half from outside the U.S. Participants were encouraged to focus on predictions for recent and forthcoming data, particularly for Higgs physics and LHC and dark matter, rather than on the traditional approach of embedding the Standard Model particles and forces. The Higgs boson sympoosium was locally organized by James Wells (chair), Aaron Pierce and Jianming Qian. Additional input in the early stages by Stefan Pokorski (Warsaw) who was unable to attend in the end. The workshop consistent of 22 talks from experts around the world, both theoretical and experimental. Experimentalists summarized the current state of knowledge of the Higgs boson and its varients. The theory talks ranged from technical calculations of Standard Model processes to speculative novel ideas. The YHET visitor program invited weekly young visitors to the University of Michigan campus to present their work. This year 24 participants came under the program, with 17 of them receiving at least partial support for their visits.

  4. Anti-Plasmodial Activity of Aroylhydrazone and Thiosemicarbazone Iron Chelators: Effect on Erythrocyte Membrane Integrity, Parasite Development and the Intracellular Labile Iron Pool

    PubMed Central

    Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B.; Kalinowski, Danuta S.; Lovejoy, David B.; Lane, Darius J. R.; Richardson, Des R.

    2013-01-01

    Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50 = 4.45 ± 1.70, 10.30 ± 4.40, and 3.64 ± 2.00 μM, respectively) than DFO (IC50 = 23.43 ± 3.40 μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activity, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization. PMID:24028863

  5. Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators: effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool.

    PubMed

    Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B; Kalinowski, Danuta S; Lovejoy, David B; Lane, Darius J R; Richardson, Des R

    2013-12-01

    Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50=4.45±1.70, 10.30±4.40, and 3.64±2.00μM, respectively) than DFO (IC50=23.43±3.40μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization. PMID:24028863

  6. Immune function in patients with beta thalassaemia receiving the orally active iron-chelating agent deferiprone.

    PubMed

    Loebstein, R; Dalal, I; Nisbet-Brown, E; Berkovitch, M; Meydan, N; Andrews, D; Loubser, M D; Koren, G; Roifman, C M; Olivieri, N F

    1997-09-01

    Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy. PMID:9332313

  7. A framework for optimization and quantification of uncertainty and sensitivity for developing carbon capture systems

    DOE PAGESBeta

    Eslick, John C.; Ng, Brenda; Gao, Qianwen; Tong, Charles H.; Sahinidis, Nikolaos V.; Miller, David C.

    2014-12-31

    Under the auspices of the U.S. Department of Energy’s Carbon Capture Simulation Initiative (CCSI), a Framework for Optimization and Quantification of Uncertainty and Sensitivity (FOQUS) has been developed. This tool enables carbon capture systems to be rapidly synthesized and rigorously optimized, in an environment that accounts for and propagates uncertainties in parameters and models. FOQUS currently enables (1) the development of surrogate algebraic models utilizing the ALAMO algorithm, which can be used for superstructure optimization to identify optimal process configurations, (2) simulation-based optimization utilizing derivative free optimization (DFO) algorithms with detailed black-box process models, and (3) rigorous uncertainty quantification throughmore » PSUADE. FOQUS utilizes another CCSI technology, the Turbine Science Gateway, to manage the thousands of simulated runs necessary for optimization and UQ. Thus, this computational framework has been demonstrated for the design and analysis of a solid sorbent based carbon capture system.« less

  8. Successful treatment of severe iron intoxication with gastrointestinal decontamination, deferoxamine, and hemodialysis.

    PubMed

    Gumber, Manoj R; Kute, Vivek B; Shah, Pankaj R; Vanikar, Aruna V; Patel, Himanshu V; Balwani, Manish R; Ghuge, Pramod P; Trivedi, Hargovind L

    2013-01-01

    Acute iron poisoning is a common and potentially serious problem in the pediatric population. Early recognition and treatment is crucial for a better outcome and to prevent morbidity and mortality. An 18-year-old female, who had accidental ingestion of 50 tablets of ferrous sulfate (100 mg of elemental iron per 335 mg tablet), 100 mg/kg of elemental iron, developed acute gastrointestinal and neurologic signs of toxicity and severe anion gap metabolic acidosis. The patient had received gastrointestinal decontamination, deferoxamine (DFO) infusion, and hemodialysis (HD) resulting in a decrease in serum iron concentration from 2150 to 160 mcg/dL at 24-h post-ingestion and improved mental status. Our cases demonstrate that HD may assist in decreasing serum iron concentration and improving clinical status in patients with massive overdose and life-threatening toxicity. PMID:23635030

  9. A framework for optimization and quantification of uncertainty and sensitivity for developing carbon capture systems

    SciTech Connect

    Eslick, John C.; Ng, Brenda; Gao, Qianwen; Tong, Charles H.; Sahinidis, Nikolaos V.; Miller, David C.

    2014-12-31

    Under the auspices of the U.S. Department of Energy’s Carbon Capture Simulation Initiative (CCSI), a Framework for Optimization and Quantification of Uncertainty and Sensitivity (FOQUS) has been developed. This tool enables carbon capture systems to be rapidly synthesized and rigorously optimized, in an environment that accounts for and propagates uncertainties in parameters and models. FOQUS currently enables (1) the development of surrogate algebraic models utilizing the ALAMO algorithm, which can be used for superstructure optimization to identify optimal process configurations, (2) simulation-based optimization utilizing derivative free optimization (DFO) algorithms with detailed black-box process models, and (3) rigorous uncertainty quantification through PSUADE. FOQUS utilizes another CCSI technology, the Turbine Science Gateway, to manage the thousands of simulated runs necessary for optimization and UQ. Thus, this computational framework has been demonstrated for the design and analysis of a solid sorbent based carbon capture system.

  10. Multidentate terephthalamidate and hydroxypyridonate ligands: towards new orally active chelators.

    PubMed

    Abergel, Rebecca J; Raymond, Kenneth N

    2011-01-01

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using (59)Fe, (238)Pu, and (241)Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity. PMID:21599440

  11. MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

    SciTech Connect

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-07-13

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

  12. Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer

    PubMed Central

    Houghton, Jacob L.; Zeglis, Brian M.; Abdel-Atti, Dalya; Aggeler, Robert; Sawada, Ritsuko; Agnew, Brian J.; Scholz, Wolfgang W.; Lewis, Jason S.

    2015-01-01

    Molecular imaging agents for preoperative positron emission tomography (PET) and near-infrared fluorescent (NIRF)-guided delineation of surgical margins could greatly enhance the diagnosis, staging, and resection of pancreatic cancer. PET and NIRF optical imaging offer complementary clinical applications, enabling the noninvasive whole-body imaging to localize disease and identification of tumor margins during surgery, respectively. We report the development of PET, NIRF, and dual-modal (PET/NIRF) imaging agents, using 5B1, a fully human monoclonal antibody that targets CA19.9, a well-established pancreatic cancer biomarker. Desferrioxamine (DFO) and/or a NIRF dye (FL) were conjugated to the heavy-chain glycans of 5B1, using a robust and reproducible site-specific (ss) labeling methodology to generate three constructs (ssDFO-5B1, ssFL-5B1, and ssdual-5B1) in which the immunoreactivity was not affected by the conjugation of either label. Each construct was evaluated in a s.c. xenograft model, using CA19.9-positive (BxPC3) and -negative (MIAPaCa-2) human pancreatic cancer cell lines. Each construct showed exceptional uptake and contrast in antigen-positive tumors with negligible nonspecific uptake in antigen-negative tumors. Additionally, the dual-modal construct was evaluated in an orthotopic murine pancreatic cancer model, using the human pancreatic cancer cell line, Suit-2. The ssdual-5B1 demonstrated a remarkable capacity to delineate metastases and to map the sentinel lymph nodes via tandem PET-computed tomography (PET/CT) and NIRF imaging. Fluorescence microscopy, histopathology, and autoradiography were performed on representative sections of excised tumors to visualize the distribution of the constructs within the tumors. These imaging tools have tremendous potential for further preclinical research and for clinical translation. PMID:26668398

  13. Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

    PubMed Central

    Kattamis, Antonis; Cappellini, M. Domenica; El-Beshlawy, Amal; Origa, Raffaella; Elalfy, Mohsen; Kilinç, Yurdanur; Perrotta, Silverio; Karakas, Zeynep; Viprakasit, Vip; Habr, Dany; Constantinovici, Niculae; Shen, Junwu; Porter, John B.

    2015-01-01

    Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (−52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227. PMID:25934475

  14. Hypoxia induces tumor and endothelial cell migration in a semaphorin 3F- and VEGF-dependent manner via transcriptional repression of their common receptor neuropilin 2.

    PubMed

    Coma, Silvia; Shimizu, Akio; Klagsbrun, Michael

    2011-01-01

    Neuropilin-2 (NRP2) is a receptor expressed by tumor cells and endothelial cells (EC) that binds both semaphorin 3F (SEMA3F), a potent inhibitor of tumor angiogenesis and metastasis, and vascular endothelial growth factor (VEGF), a potent stimulator of tumor angiogenesis. It was found that glioblastoma and melanoma cells repressed NRP2 expression when maintained under hypoxic conditions and after treatment with the hypoxia-mimetic agent desferrioxamine (DFO), at both the mRNA and protein levels. Silencing of HIF1-α, the hypoxia-induced subunit of the hypoxia inducible factor (HIF), abrogated DFO-induced NRP2 repression. Conversely, ectopic expression of HIF1-α directly repressed NRP2 promoter activity and expression. NRP2 is the sole receptor for SEMA3F. Loss of NRP2 expression in tumor cells inhibited SEMA3F-dependent activities, such as inactivation of RhoA, depolymerization of F-actin, and inhibition of tumor cell migration. On the other hand, loss of NRP2 expression in tumor cells increased VEGF protein levels in conditioned media, with no effects on VEGF mRNA levels. This increase in VEGF protein levels promoted paracrine activation of EC, including VEGF receptor-2 phosphorylation, and activation of downstream signaling proteins such as p44/42 MAPK and p38 MAPK. In addition, the elevated VEGF levels induced EC migration and sprouting, two key steps of tumor angiogenesis in vivo. It was concluded that hypoxia regulates VEGF and SEMA3F activities through transcriptional repression of their common receptor NRP2, providing a novel mechanism by which hypoxia induces tumor angiogenesis, growth and metastasis. PMID:21610314

  15. X-ray absorption spectroscopy of aqueous aluminum-organic complexes.

    PubMed

    Hay, Michael B; Myneni, Satish C B

    2010-05-27

    Aqueous-phase X-ray absorption near-edge structure (XANES) spectra were collected on dissolved Al complexes with organic ligands, including desferrioxamine B, EDTA, acetohydroxamate, malate, oxalate, and salicylate. Spectral interpretations were made using the density functional theory-based modeling package StoBe. The goals of this work were to study the geometric and electronic structural characteristics of these complexes relative to Al(H(2)O)(6)(3+) and to examine the utility of the aqueous Al XANES technique as a tool for probing Al speciation and structure. In the case of EDTA, aqueous Fourier-transform infrared spectroscopy was also used to corroborate the structures of the Al(EDTA)(-) and AlOH(EDTA)(2-) complexes. Synthetic XANES spectra calculated with StoBe reproduced the observed spectral differences between Al(H(2)O)(6)(3+), Al(dfoB)(+), and Al(EDTA)(-). The narrower XANES feature observed for Al(dfoB)(+) relative to Al(H(2)O)(6)(3+) can be attributed to a weaker splitting of the Al 3p-O 2p interactions in the former, while Al(EDTA)(-) exhibits split Al 3p-ligand interactions that likely result from the mixed O/N coordination. In complexes with mixed aqua/organic-oxygen ligation (Al-acetohydroxamate, Al-malate, Al-oxalate, and Al-salicylate), spectra exhibit linear, systematic changes in peak width as a function of H(2)O to organic ligand ratio in the Al coordination sphere. These results highlight the sensitivity of the aqueous Al K-edge XANES spectrum to coordination environment and demonstrate its utility as an experimental probe for future studies of Al speciation in complex solutions. PMID:20443586

  16. Flood mapping by combining the strengths of optical and Sentinel active radar remote sensing

    NASA Astrophysics Data System (ADS)

    Winsemius, H. C.; Brakenridge, G. R.; Westerhoff, R.; Huizinga, J.; Villars, N.; Bishop, C.

    2012-04-01

    Flood mapping with remote sensing plays an important role in large scale disaster management procedures. For this purpose, the Dartmouth Flood Observatory (DFO) gained experience since 1993 with the production of flood maps from optical satellite imagery and has currently established, together with NASA collaborators, a fully automated, global, near real-time service. Another consortium is also presently working on an automated, near real-time, global flood mapping procedure called the 'Global Flood Observatory' (GFO), which will make use of high resolution Sentinel data. The procedure is currently tested on Envisat active radar (ASAR) imagery. Both the DFO and GFO projects provide open data output of their data and maps. The optical and radar approaches to flood mapping each have advantages and suffer from shortcomings. Optical remote sensing via the U.S. MODIS and VIIRS sensors is constrained by cloud cover but can attain a high revisit frequency (>2 /day), whereas the Envisat ASAR is not affected by cloud cover, but uses a lower revisit frequency (generally once/3 days, depending on the location). In this contribution, we demonstrate the combination of both approaches into one flood mapping result. This results in improved flood mapping in a case study over the Chao Phraya basin (Bangkok surroundings) during the recent October-November 2011 extreme flooding. The combined map shows that during overpass, ASAR reveals flooded regions over cloud-obscured areas, which clearly follow elevated features in the landscape such as roads, embankments and railways. Meanwhile, the high frequency of delivery of the optical information ensures timely information. Also, the quite different water classification methods used for the optical and ASAR data sources show good agreement and have been successfully merged into one GIS data product. This can also be automatically generated and disseminated on a global basis.

  17. Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

    PubMed Central

    N.Tinianow, Jeff; Pandya, Darpan N.; Pailloux, Sylvie L.; Ogasawara, Annie; Vanderbilt, Alexander N.; Gill, Herman S.; Williams, Simon-P.; Wadas, Thaddeus J.; Magda, Darren; Marik, Jan

    2016-01-01

    A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89Zr; subsequently, it was used as a bi-functional chelator for preparation of 89Zr-labeled antibodies. Quantitative chelation of 89Zr4+ with the octadentate ligand forming 89ZrL complex was achieved under mild conditions within 15 minutes. The 89Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89Zr4+ from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89Zr-labeled monoclonal antibodies for immunoPET studies. PMID:26941844

  18. The clinical spectrum of renal osteodystrophy in 57 chronic hemodialysis patients: a correlation between biochemical parameters and bone pathology findings.

    PubMed

    Chazan, J A; Libbey, N P; London, M R; Pono, L; Abuelo, J G

    1991-02-01

    Fifty-nine chronic hemodialysis patients who had been on dialysis for an average of 77 months underwent bone biopsies and the pathologic findings were correlated with biochemical and demographic data. All but two had evidence of renal osteodystrophy, 23 with osteitis fibrosa (OF), 19 with osteomalacia and/or adynamic disease (OM/AD), and 15 with mixed osteodystrophy (MOD). Patients in each group were similar with regard to age, sex distribution, duration of dialysis, unstimulated serum aluminum, calcium and phosphorus. Patients with osteitis fibrosa (OF) had statistically higher DFO stimulated aluminum, alkaline phosphatase and PTHC levels than the other two groups although there was marked individual variation. The bone biopsies were also evaluated for the amount of aluminum deposited in the osteoid seam. All 23 of the patients with OF and 11 of the 15 patients with MOD had no, mild, or minimal aluminum deposition but 12 of the 19 patients with OM/AD had moderate to marked aluminum deposition. Patients with minimal to mild aluminum deposition were similar in age, duration of dialysis, sex distribution, unstimulated and DFO stimulated aluminum levels, calcium, phosphorus, alkaline phosphatase to those with moderate to marked deposition but had significantly higher parathormone levels. All patients had been treated in a similar fashion regarding diet, oral phosphate binders and vitamin D; therefore, the observed differences in bone pathology were not readily explicable. However, patients who were found to have osteitis fibrosa and those with minimal to mild aluminum deposition had significantly higher parathormone levels when compared with patients in the other groups at the inception of dialysis. PMID:2019018

  19. Alveolar macrophage cytokine response to air pollution particles: Oxidant mechanisms

    SciTech Connect

    Imrich, Amy; Ning Yaoyu; Lawrence, Joy; Coull, Brent; Gitin, Elena; Knutson, Mitchell; Kobzik, Lester . E-mail: lkobzik@hsph.harvard.edu

    2007-02-01

    Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-L-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 {mu}M) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H{sub 2}O{sub 2} generated by glucose oxidase, 10 {mu}M/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H{sub 2}O{sub 2}. The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H{sub 2}O{sub 2} but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H{sub 2}O{sub 2}-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H{sub 2}O{sub 2} released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.

  20. Iron depletion increases manganese uptake and potentiates apoptosis through ER stress

    PubMed Central

    Seo, Young Ah; Li, Yuan; Wessling-Resnick, Marianne

    2013-01-01

    Iron deficiency is a risk factor for manganese (Mn) accumulation. Excess Mn promotes neurotoxicity but the mechanisms involved and whether iron depletion might affect these pathways is unknown. To study Mn intoxication in vivo, iron deficient and control rats were intranasally instilled with 60 mg MnCl2/kg over 3 weeks. TUNEL staining of olfactory tissue revealed that Mn exposure induced apoptosis and that iron deficiency potentiated this effect. In vitro studies using the dopaminergic SH-SY5Y cell line confirmed that Mn-induced apoptosis was enhanced by iron depletion using the iron chelator desferrioxamine. Mn has been reported to induce apoptosis through endoplasmic reticulum stress. In SH-SY5Y cells, Mn exposure induced the ER stress genes glucose regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP). Increased phosphorylation of the eukaryotic translation initiation factor 2α (phospho-eIF2α) was also observed. These effects were accompanied by the activation of ER resident enzyme caspase-12, and the downstream apoptotic effector caspase-3 was also activated. All of the Mn-induced responses were enhanced by DFO treatment. Inhibitors of ER stress and caspases significantly blocked Mn-induced apoptosis and its potentiation by DFO, indicating that ER stress and subsequent caspase activation underlie cell death. Taken together, these data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency most likely through upregulation of DMT1. PMID:23764342

  1. Chemical Determinants of antimalarial activity of reversed siderophores.

    PubMed Central

    Tsafack, A; Libman, J; Shanzer, A; Cabantchik, Z I

    1996-01-01

    Reversed siderophores (RSFs) are artificial hydroxamate-based iron chelators designed after the natural siderophore ferrichrome. The modular molecular design of RSF derivatives allowed the synthesis of various congeners with controlled iron-binding capacities and partition coefficients. These two physicochemical properties were assessed by a novel fluorescent method and were found to be the major determinants of RSF permeation across erythrocyte membranes and scavenging of compartmentalized iron. The partition coefficient apparently conferred upon RSFs two major features: (i) the ability to rapidly access iron pools of in vitro-grown Plasmodium falciparum at all developmental stages and to mobilize intracellular iron and transfer it to the medium and (ii) the ability to suppress parasite growth at all developmental stages. These features of RSFs were assessed by quantitative determination of the structure-activity relationships of the biological activities and partition coefficients spanning a wide range of values. The most effective RSF containing the aromatic group of phenylalanine (RSFm2phe) showed 50% inhibitory concentration of 0.60 +/- 0.03 nmol/ml in a 48-h test and a 2-h onset of inhibition of ring development at 5 nmol/ml. The lipophilic compound RSFm2phe and the lipophilic and esterase-cleavable compound RSFm2pee inhibited parasite growth at all developmental stages whether inhibition was assessed in a continuous mode or after discontinuing drug administration. The antimalarial effects of RSFm2phe and cleavable RSFm2pee were potentiated in the presence of desferrioxamine (DFO) at concentrations at which DFO alone had no effect on parasite growth. These studies provide experimental evidence indicating that the effective and persistent antimalarial actions of RSFs are associated with drug access to infected cells and scavenging of iron from intracellular parasites. Moreover, the optimal antimalarial actions of RSFs are apparently also determined by improved

  2. Alveolar macrophage cytokine response to air pollution particles: oxidant mechanisms

    PubMed Central

    Imrich, Amy; Ning, YaoYu; Lawrence, Joy; Coull, Brent; Gitin, Elena; Knutson, Mitchell; Kobzik, Lester

    2007-01-01

    Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-acetyl cysteine (20mM), dimethyl thiourea (20 mM) and catalase (5 uM) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H2O2 generated by glucose oxidase, 10 uM/hr), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H2O2. The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H2O2 but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H2O2-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H2O2 released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity. PMID:17222881

  3. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30–40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO–L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption. PMID:26893541

  4. Reactive Oxygen Species are involved in BMP-Induced Dendritic Growth in Cultured Rat Sympathetic Neurons

    PubMed Central

    Chandrasekaran, Vidya; Lea, Charlotte; Sosa, Jose Carlo; Higgins, Dennis; Lein, Pamela J.

    2015-01-01

    Previous studies have shown that bone morphogenetic proteins (BMPs) promote dendritic growth in sympathetic neurons; however, the downstream signaling molecules that mediate the dendrite promoting activity of BMPs are not well characterized. Here we test the hypothesis that reactive oxygen species (ROS)-mediated signaling links BMP receptor activation to dendritic growth. In cultured rat sympathetic neurons, exposure to any of three mechanistically distinct antioxidants, diphenylene iodinium (DPI), nordihydroguiaretic acid (NGA) or desferroxamine (DFO), blocked de novo BMP-induced dendritic growth. Addition of DPI to cultures previously induced with BMP to extend dendrites caused dendritic retraction while DFO and NGA prevented further growth of dendrites. The inhibition of the dendrite promoting activity of BMPs by antioxidants was concentration-dependent and occurred without altering axonal growth or neuronal cell survival. Antioxidant treatment did not block BMP activation of SMAD 1,5 as determined by nuclear localization of these SMADs. While BMP treatment did not cause a detectable increase in intracellular ROS in cultured sympathetic neurons as assessed using fluorescent indicator dyes, BMP treatment increased the oxygen consumption rate in cultured sympathetic neurons as determined using the Seahorse XF24 Analyzer, suggesting increased mitochondrial activity. In addition, BMPs upregulated expression of NADPH oxidase 2 (NOX2) and either pharmacological inhibition or siRNA knockdown of NOX2 significantly decreased BMP-7 induced dendritic growth. Collectively, these data support the hypothesis that ROS are involved in the downstream signaling events that mediate BMP7-induced dendritic growth in sympathetic neurons, and suggest that ROS-mediated signaling positively modulates dendritic complexity in peripheral neurons. PMID:26079955

  5. Facilitation of human osteoblast apoptosis by sulindac and indomethacin under hypoxic injury.

    PubMed

    Liu, Cheng; Tsai, An-Ly; Chen, Yen-Chu; Fan, Shih-Chen; Huang, Chun-Hsien; Wu, Chia-Ching; Chang, Chih-Han

    2012-01-01

    Hypoxic-ischemia injury occurs after trauma causes consequential bone necrosis. Non-steroid anti-inflammatory drugs (NSAIDs) are frequently used in orthopedic clinics for pain relief. However, the underlying mechanism and outcome for usage of NSAIDs is poorly understood. To investigate the damage and loss of osteoblast function in hypoxia, two hypoxia mimetics, cobalt chloride (CoCl(2)) and desferrioxamine (DFO), were used to create an in vitro hypoxic microenvironment. The cell damage was observed by decreases of cell viability and increases in cyclooxygenase-2 and cleaved poly(ADP-ribose) polymerase (PARP). Cell apoptosis was confirmed by WST-1 cytotoxic assays and flow cytometry. The functional expression of osteoblast in alkaline phosphatase (ALP) activity was significantly decreased by CoCl(2) and inhibited when treated with DFO. To simulate the use of NSAID after hypoxic injury, four types of anti-inflammatory drugs, sulindac sulfide (SUL), indomethacin (IND), aspirin (Asp), and sodium salicylate (NaS), were applied to osteoblasts after 1 h of hypoxia mimetic treatment. SUL and IND further enhanced cell death after hypoxia. ALP activity was totally abolished in hypoxic osteoblasts under IND treatment. Facilitation of osteoblast apoptosis occurred regardless of IND dosage under hypoxic conditions. To investigate osteoblast in vivo, local hypoxia was created by fracture of tibia and then treated the injured mice with IND by oral feeding. IND-induced osteoblast apoptosis was confirmed by positive staining of TUNEL assay in fractured mice. Significant delay of fracture healing in bone tissue was also observed with the treatment of IND. These results provide information pertaining to choosing appropriate anti-inflammatory drugs for orthopedic patients. PMID:21882223

  6. Dissemination of satellite-based river discharge and flood data

    NASA Astrophysics Data System (ADS)

    Kettner, A. J.; Brakenridge, G. R.; van Praag, E.; de Groeve, T.; Slayback, D. A.; Cohen, S.

    2014-12-01

    In collaboration with NASA Goddard Spaceflight Center and the European Commission Joint Research Centre, the Dartmouth Flood Observatory (DFO) daily measures and distributes: 1) river discharges, and 2) near real-time flood extents with a global coverage. Satellite-based passive microwave sensors and hydrological modeling are utilized to establish 'remote-sensing based discharge stations', and observed time series cover 1998 to the present. The advantages over in-situ gauged discharges are: a) easy access to remote or due to political reasons isolated locations, b) relatively low maintenance costs to maintain a continuous observational record, and c) the capability to obtain measurements during floods, hazardous conditions that often impair or destroy in-situ stations. Two MODIS instruments aboard the NASA Terra and Aqua satellites provide global flood extent coverage at a spatial resolution of 250m. Cloud cover hampers flood extent detection; therefore we ingest 6 images (the Terra and Aqua images of each day, for three days), in combination with a cloud shadow filter, to provide daily global flood extent updates. The Flood Observatory has always made it a high priority to visualize and share its data and products through its website. Recent collaborative efforts with e.g. GeoSUR have enhanced accessibility of DFO data. A web map service has been implemented to automatically disseminate geo-referenced flood extent products into client-side GIS software. For example, for Latin America and the Caribbean region, the GeoSUR portal now displays current flood extent maps, which can be integrated and visualized with other relevant geographical data. Furthermore, the flood state of satellite-observed river discharge sites are displayed through the portal as well. Additional efforts include implementing Open Geospatial Consortium (OGC) standards to incorporate Water Markup Language (WaterML) data exchange mechanisms to further facilitate the distribution of the satellite

  7. The Eltrombopag antitumor effect on hepatocellular carcinoma.

    PubMed

    Kurokawa, Tomohiro; Murata, Soichiro; Zheng, Yun-Wen; Iwasaki, Kenichi; Kohno, Keisuke; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

    2015-11-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  8. The Eltrombopag antitumor effect on hepatocellular carcinoma

    PubMed Central

    KUROKAWA, TOMOHIRO; MURATA, SOICHIRO; ZHENG, YUN-WEN; IWASAKI, KENICHI; KOHNO, KEISUKE; FUKUNAGA, KIYOSHI; OHKOHCHI, NOBUHIRO

    2015-01-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  9. High-dose methylprednisolone treatment of laser-induced retinal injury exacerbates acute inflammation and long-term scarring

    NASA Astrophysics Data System (ADS)

    Schuschereba, Steven T.; Cross, Michael E.; Scales, David K.; Pizarro, Jose M.; Edsall, Peter R.; Stuck, Bruce E.; Marshall, John

    1999-06-01

    Purpose. To evaluate therapeutics for attenuating retinal laser injury. Methods. New Zealand Red rabbits (n=76) were pretreated (IV) with either a single dose of hydroxyethyl starch conjugated deferoxamine (HES-DFO, n=29) (6.1 ml/kg, 16.4 mg/ml) or methylprednisolone sodium succinate (MP, n=22) (30 mg/kg, followed by taper of 30, 20, 20, and 10 mg/kg/day for a total of 5d). Controls were untreated (n=25). Fifteen min later, animals were irradiated with a multiline cw argon laser (285 mW, 10 msec pulse durations, 16 lesions/eye). Funduscopy, fluorescein angiography, histology, and morphometry were performed at 10 min, 1h, 3h, 24h, 1 mo, and 6 mo after irradiation. Leukocytes were counted at lesion centers for retinal and choroidal compartments at 1, 3, and 24h. Results. At 3h, percent area incrase for the lesions was highest for MP (44%) and lowest for HES-DFO (16%)(p<0.05). In hemorrhagic lesions, MP treatment resulted in the highest increase of retinal neotrophils by 24h (p<0.05), and by 1 and 6 mo extensive chorio-retinal scarring occurred in nonhemorrhagic and hemorrhagic lesions. Also, no benefit was demonstrated on sparing of photoreceptors with MP treatment. Conclusions. Treatment of laser-induced retinal injury with methylprednisolone (MP) exacerbates acute inflammation and long-term chorio-retinal scarring; however, hydroxyethyl starch conjugated deferoxamine therapy ameliorates these aspects of injury. Data suggest caution in the use of MP therapy for laser injuries.

  10. Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload.

    PubMed

    Aydinok, Yesim; Kattamis, Antonis; Cappellini, M Domenica; El-Beshlawy, Amal; Origa, Raffaella; Elalfy, Mohsen; Kilinç, Yurdanur; Perrotta, Silverio; Karakas, Zeynep; Viprakasit, Vip; Habr, Dany; Constantinovici, Niculae; Shen, Junwu; Porter, John B

    2015-06-18

    Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227. PMID:25934475

  11. Iron chelators ICL670 and 311 inhibit HIV-1 transcription.

    PubMed

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R; Ray, Patricio E; Gordeuk, Victor R; Nekhai, Sergei

    2007-10-25

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics. PMID:17631934

  12. Evidence suggesting a role for hydroxyl radical in gentamicin-induced acute renal failure in rats.

    PubMed Central

    Walker, P D; Shah, S V

    1988-01-01

    The protective effect of hydroxyl radical scavengers and iron chelators has strongly implicated the hydroxyl radical in several models of tissue injury. Based on in vitro studies showing gentamicin-enhanced generation of reactive oxygen metabolites in renal cortical mitochondria, we examined the effect of hydroxyl radical scavengers and iron chelators in gentamicin-induced acute renal failure. Rats treated with gentamicin (G) alone (100 mg/kg, s.c. x 8 d) developed advanced renal failure (BUN 215 +/- 30 mg/dl) compared to saline-treated controls (BUN 16 +/- 1 mg/dl, P less than 0.001). In contrast, rats treated with gentamicin and either dimethylthiourea (DMTU, an hydroxyl radical scavenger, 125 mg/kg, i.p. twice a day) or deferoxamine (DFO, an iron chelator, 20 mg/day by osmotic pump) had significantly lower BUN (G + DMTU 48.8 +/- 8 mg/dl, P less than 0.001, n = 8; G + DFO 30 +/- 7 mg/dl, P less than 0.001, n = 8). In separate experiments, treatment with two other hydroxyl radical scavengers (dimethyl sulfoxide or sodium benzoate) and a second iron chelator (2,3,dihydroxybenzoic acid) had a similar protective effect on renal function (as measured by both BUN and creatinine). In addition, histological evidence of damage was markedly reduced by the interventional agents. Finally, concurrent treatment with DMTU prevented the gentamicin induced increase in renal cortical malondialdehyde content (G: 4.4 +/- 0.2 nmol/mg; G + DMTU: 3.1 +/- 0.2 nmol/mg, P less than 0.0001, n = 8) suggesting that the protective effect of DMTU was related to free radical mechanisms rather than to some other effect. Taken together, these data strongly support a role for hydroxyl radical or a similar oxidant in gentamicin-induced acute renal failure. Images PMID:3123518

  13. Iron depletion in HCT116 cells diminishes the upregulatory effect of phenethyl isothiocyanate on heme oxygenase-1.

    PubMed

    Bolloskis, Michael P; Carvalho, Fabiana P; Loo, George

    2016-04-15

    Some of the health-promoting properties of cruciferous vegetables are thought to be partly attributed to isothiocyanates. These phytochemicals can upregulate the expression of certain cytoprotective stress genes, but it is unknown if a particular nutrient is involved. Herein, the objective was to ascertain if adequate iron is needed for enabling HCT116 cells to optimally express heme oxygenase-1 (HO-1) when induced by phenethyl isothiocyanate (PEITC). PEITC increased HO-1 expression and also nuclear translocation of Nrf2, which is a transcription factor known to activate the HO-1 gene. However, in HCT116 cells that were made iron-deficient by depleting intracellular iron with deferoxamine (DFO), PEITC was less able to increase HO-1 expression and nuclear translocation of Nrf2. These suppressive effects of DFO were overcome by replenishing the iron-deficient cells with the missing iron. To elucidate these findings, it was found that PEITC-induced HO-1 upregulation can be inhibited with thiol antioxidants (glutathione and N-acetylcysteine). Furthermore, NADPH oxidase inhibitors (diphenyleneiodonium and apocynin) and a superoxide scavenger (Tiron) each inhibited PEITC-induced HO-1 upregulation. In doing so, diphenyleneiodonium was the most potent and also inhibited nuclear translocation of redox-sensitive Nrf2. Collectively, the results imply that the HO-1 upregulation by PEITC involves an iron-dependent, oxidant signaling pathway. Therefore, it is concluded that ample iron is required to enable PEITC to fully upregulate HO-1 expression in HCT116 cells. As such, it is conceivable that iron-deficient individuals may not reap the full health benefits of eating PEITC-containing cruciferous vegetables that via HO-1 may help protect against multiple chronic diseases. PMID:26945724

  14. Clinically Approved Iron Chelators Influence Zebrafish Mortality, Hatching Morphology and Cardiac Function

    PubMed Central

    Hamilton, Jasmine L.; Hatef, Azadeh; Imran ul-haq, Muhammad; Nair, Neelima; Unniappan, Suraj; Kizhakkedathu, Jayachandran N.

    2014-01-01

    Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity. PMID:25329065

  15. Assessment of trophic status in Changjiang (Yangtze) River estuary

    NASA Astrophysics Data System (ADS)

    Wang, Baodong

    2007-07-01

    The integrated methodology for the assessment of estuarine trophic status (ASSETS), which was extended and refined from the United States National Estuarine Eutrophication Assessment (NEEA), is a multi-parameter assessment system and has been widely used in eutrophication assessment in estuarine and coastal waters. The ASSETS was applied to evaluate the trophic status of the Changjiang (Yangtze) River estuary, one of the largest estuaries in the world. The following main results were obtained: (i) The estuarine export potential is “moderate susceptibility” due to the “moderate” dilution potential and “moderate” flushing potential; (ii) The overall human influence (OHI) index classified the impact of nutrients in the system as “high” due to the high level of nutrient discharge by the river which channels anthropogenic impacts in the catchments to the estuarine system; (iii) The overall eutrophic condition (OEC) in the estuary was classified into the “high” category due to frequent occurrence of nuisance and toxic algal blooms in the mixing and seawater zones; (iv) Since the nutrient loadings (e.g., DIN) in the river is expected to continue to increase in the near future following the population increase and rapid economic growth throughout the drainage basin, the nutrient-related symptoms in the estuary are likely to substantially worsen, which leads to the “worsen high” category for the definition of future outlook (DFO). The combinations of the three components (i.e., OHI, OEC, and DFO) lead to an overall grade as “bad” for the trophic status in the Changjiang River estuary.

  16. Social Network Analysis for Program Implementation

    PubMed Central

    Valente, Thomas W.; Palinkas, Lawrence A.; Czaja, Sara; Chu, Kar-Hai; Brown, C. Hendricks

    2015-01-01

    This paper introduces the use of social network analysis theory and tools for implementation research. The social network perspective is useful for understanding, monitoring, influencing, or evaluating the implementation process when programs, policies, practices, or principles are designed and scaled up or adapted to different settings. We briefly describe common barriers to implementation success and relate them to the social networks of implementation stakeholders. We introduce a few simple measures commonly used in social network analysis and discuss how these measures can be used in program implementation. Using the four stage model of program implementation (exploration, adoption, implementation, and sustainment) proposed by Aarons and colleagues [1] and our experience in developing multi-sector partnerships involving community leaders, organizations, practitioners, and researchers, we show how network measures can be used at each stage to monitor, intervene, and improve the implementation process. Examples are provided to illustrate these concepts. We conclude with expected benefits and challenges associated with this approach. PMID:26110842

  17. G-quadruplexes and their regulatory roles in biology.

    PubMed

    Rhodes, Daniela; Lipps, Hans J

    2015-10-15

    'If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo' (Statement by Aaron Klug over 30 years ago).During the last decade, four-stranded helical structures called G-quadruplex (or G4) have emerged from being a structural curiosity observed in vitro, to being recognized as a possible nucleic acid based mechanism for regulating multiple biological processes in vivo. The sequencing of many genomes has revealed that they are rich in sequence motifs that have the potential to form G-quadruplexes and that their location is non-random, correlating with functionally important genomic regions. In this short review, we summarize recent evidence for the in vivo presence and function of DNA and RNA G-quadruplexes in various cellular pathways including DNA replication, gene expression and telomere maintenance. We also highlight remaining open questions that will have to be addressed in the future. PMID:26350216

  18. G-quadruplexes and their regulatory roles in biology

    PubMed Central

    Rhodes, Daniela; Lipps, Hans J.

    2015-01-01

    ‘If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo’ (Statement by Aaron Klug over 30 years ago). During the last decade, four-stranded helical structures called G-quadruplex (or G4) have emerged from being a structural curiosity observed in vitro, to being recognized as a possible nucleic acid based mechanism for regulating multiple biological processes in vivo. The sequencing of many genomes has revealed that they are rich in sequence motifs that have the potential to form G-quadruplexes and that their location is non-random, correlating with functionally important genomic regions. In this short review, we summarize recent evidence for the in vivo presence and function of DNA and RNA G-quadruplexes in various cellular pathways including DNA replication, gene expression and telomere maintenance. We also highlight remaining open questions that will have to be addressed in the future. PMID:26350216

  19. [The 2004 Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation].

    PubMed

    Neefjes, J; Groothuis, T A M; Dantuma, N P

    2004-12-25

    This year's Nobel Prize in Chemistry has been awarded to Aaron Ciechanover, Avram Herskho and Irwin Rose for the discovery of ubiquitin-mediated protein degradation. In a series of groundbreaking experiments these scientists described the basic principles for a unique posttranslational modification based on the conjugation of the small protein ubiquitin to proteins deemed for degradation. Although ubiquitin started in 1980 as an unusual modification of certain proteins, it is now clear that it functions as a signal for degradation when it forms a polymer. Hundreds of proteins are involved in the controlled destruction of ubiquitin-labelled proteins in the cell. And hundreds of other proteins are involved in protein modification by mono-ubiquitin, so that other processes, such as the formation of another degradation compartment, the lysosome, can proceed normally. PMID:15646859

  20. Ubiquitin--the kiss of death goes Nobel. Will you be quitting?

    PubMed

    Behuliak, M; Celec, P; Gardlik, R; Palffy, R

    2005-01-01

    The Nobel prize in chemistry 2004 was given to Aaron Ciechanover, Avram Hershko and Irwin Rose for their discovery of the ubiquitin mediated proteolysis. Years of research have shown that the ubiquitin pathway plays a crucial role in the cellular metabolism and its regulation. These scientists together with Alexander Varshavsky have identified the most important elements of this pathway as well as their interactions. The ubiquitin pathway degrades intracellular proteins with an ubiquitin chain being the tag that marks proteins assigned for degradation. This process is mediated by ubiquitin-activating enzyme (El), ubiquitin-conjugating enzymes (E2) and ubiquitin-protein ligases (E3). Mono-ubiquitination and deubiquitination play a classic regulatory role in numerous processes including cell-cycle, transcription, translation, DNA repair, stress response etc. This article tries to summarize current knowledge on the molecular basis of the ubiqutin pathway. (Fig. 1, Ref. 52.) PMID:16026142

  1. The meteoric rise of regulated intracellular proteolysis.

    PubMed

    Mayer, R J

    2000-11-01

    It is often the case in biology that research into breaking things down lags behind research into synthesizing them, and this is certainly true for intracellular proteolysis. Now that we recognize that intracellular proteolysis, triggered by attaching multiple copies of a small protein called ubiquitin to target proteins, is fundamental to life, it is hard to believe that 20 years ago this field was little more than a backwater of biochemistry studied by a handful of laboratories. Among the few were Avram Hershko, Aaron Ciechanover and Alexander Varshavsky, who were recently awarded the Albert Lasker award for basic medical research for discovering the importance of protein degradation in cellular physiology. This Timeline traces how they and their collaborators triggered the rapid movement of ubiquitin-mediated proteolysis to centre stage. PMID:11253367

  2. NASA DEVELOP students

    NASA Technical Reports Server (NTRS)

    2008-01-01

    NASA DEVELOP students at Stennis Space Center recently held a midterm review with George Crozier, who serves as a science adviser to the team. The team also was joined by Jamie Favors of the Mobile (Ala.) County Health Department DEVELOP Team; Cheri Miller, the team's NASA adviser; and Kenton Ross, a team science adviser. Students participating in the meeting included: Lauren Childs, Jason Jones, Maddie Brozen, Matt Batina, Jenn Frey, Angie Maki and Aaron Brooks. The primary purpose of the meeting was to update Crozier on the status of the team's work for the summer 2008 term and discuss plans for the fiscal year 2009 project proposal. This included discussion of a possible project to study the effects of hurricanes on the Florida panhandle. DEVELOP is a NASA-sponsored, student-led, student-run program focused on developing projects to help communities.

  3. Satisfaction with Counseling among Black Males in Transition from the Foster Care System

    PubMed Central

    Scott, Lionel D.; Munson, Michelle R.; White, Tony

    2009-01-01

    Using the Multidimensional Adolescent Satisfaction Scale (Garland, Saltzman, & Aarons, 2000), satisfaction with counseling and associated variables were examined among Black males (n = 47) transitioning from the foster care system. Potential associated variables assessed were foster care custody status, counseling status, diagnosis of major depression and disruptive behavior disorder based DSM-IV criteria, history of placement in congregate care settings, attitudes toward mental health services, stigma beliefs, and masculine norms. Results from simultaneous multiple regression analysis showed that attitudes toward mental health services contributed significantly to satisfaction with counseling. Specifically, Black males who expressed more positive attitudes toward mental health services in terms of confidence in mental health professionals and the therapeutic process reported greater satisfaction. Implications and future research directions are discussed. PMID:20046996

  4. Transport of subsurface bacteria in porous media. Final report

    SciTech Connect

    Arnold, R.G.; Baygents, J.C.; Ogden, K.L.

    1998-05-01

    The aims of our project have not changed significantly since the original proposal. Our primary goals were to support field experiments by screening strains of bacteria to find favorable transport characteristics among field isolates and to estimate collision efficiencies for those bacteria in typical Oyster site sediments. The data we obtained were disseminated to other members of the subprogram. For example, Tim Ginn of PNL incorporated our results into his field model; Aaron Mills used our work for comparison purposes; and John Wilson used our results to determine if there is a correlation between facies type and cell adhesion. Copies of all information were also sent to Mary DeFlaun of Envirogen for incorporation into the Sample Tables. In addition to the originally proposed work, we performed longer column studies, examining the effects of aluminum, iron, and water chemistry on bacterial transport, and beginning to understand the role of electrostatic interactions as determinants of biocolloid/collector affinity.

  5. Reaction efficiency of diffusion-controlled processes on finite aperiodic planar arrays. II. Potential effects

    NASA Astrophysics Data System (ADS)

    Garza-López, Roberto A.; Brzezinski, Jack; Low, Daniel; Gomez, Ulysses; Raju, Swaroop; Ramirez, Craig; Kozak, John J.

    2009-08-01

    We continue our study of diffusion-reaction processes on finite aperiodic lattices, viz., the Penrose lattice and a Girih tiling. Focusing on bimolecular reactions, we mobilize the theory of finite Markov processes to document the effect of attractive forces on the reaction efficiency. Considering both a short-range square-well potential and a longer-range 1/ r S ( S = 4, 6) potential, we find that irreversible reactive encounters between reactants on a Girih platelet are kinetically advantaged relative to processes on a Penrose platelet. This result generalizes the conclusion reached in our earlier study [Roberto A. Garza-López, Aaron Kaufman, Reena Patel, Joseph Chang, Jack Brzezinski, John J. Kozak, Chem. Phys. Lett. 459 (2008) 137] where entropic factors (only) were assessed.

  6. The Need for Specific Penalties for Hacking in Criminal Law

    PubMed Central

    Oh, Sangkyo; Lee, Kyungho

    2014-01-01

    In spite of the fact that hacking is a widely used term, it is still not legally established. Moreover, the definition of the concept of hacking has been deployed in a wide variety of ways in national literature. This ambiguity has led to various side effects. Recently in the United States, reforms collectively known as Aaron's Law were proposed as intended amendments to the Computer Fraud and Abuse Act (CFAA). Most experts expect that this change will put the brakes on the CFAA as a severe punishment policy, and result in a drop in controversial court decisions. In this study, we analyze the definitions and the penalties for hacking for each country and compare them with the national law and then make suggestions through more specific legislation. We expect it will reduce legal controversy and prevent excessive punishment. PMID:25032236

  7. Adolescence: booze, brains, and behavior.

    PubMed

    Monti, Peter M; Miranda, Robert; Nixon, Kimberly; Sher, Kenneth J; Swartzwelder, H Scott; Tapert, Susan F; White, Aaron; Crews, Fulton T

    2005-02-01

    This article represents the proceedings of a symposium at the 2004 Research Society on Alcoholism meeting in Vancouver, British Columbia, Canada, organized and chaired by Peter M. Monti and Fulton T. Crews. The presentations and presenters were (1) Introduction, by Peter M. Monti; (2) Adolescent Binge Drinking Causes Life-Long Changes in Brain, by Fulton T. Crews and Kim Nixon; (3) Functional Neuroimaging Studies in Human Adolescent Drinkers, by Susan F. Tapert; (4) Abnormal Emotional Reactivity as a Risk Factor for Alcoholism, by Robert Miranda, Jr.; (5) Alcohol-Induced Memory Impairments, Including Blackouts, and the Changing Adolescent Brain, by Aaron M. White and H. Scott Swartzwelder; and (6) Discussion, by Kenneth Sher. PMID:15714044

  8. Suffering and salutogenesis.

    PubMed

    Oliveira, Clara Costa

    2015-06-01

    In considering pain and suffering, some considerations will appear about epistemological beliefs shaping the clinical practices of health-care workers. With this, we try to understand the usual omission of human suffering in the training of many health professionals. So, we emphasize the role of the pathogenic paradigm in how human suffering is viewed in health care. In contrast to those who see suffering only as pathogenic, we defend that suffering can be a source of significant learning for both the sufferer as well as those who undertake caring in certain circumstances. We therefore argue that it is necessary to educate for health and not only for illness, choosing a holistic paradigm: Aaron Antonovky's salutogenic model that encloses positive aspects of human suffering when it is lived with an internal sense of coherence. PMID:25073763

  9. Osteopilus septentrionalis (Cuban treefrog)

    USGS Publications Warehouse

    Glorioso, Brad M.; Steece, Aaron; Lemann, Zachary K.; Lazare, Remy; Beck, James W.

    2016-01-01

    USA: LOUISIANA: St. Tammany Parish: on private property on Allen Road in Slidell (ca. 30.262°N, 89.741°W; WGS 84). 2 April 2013. Aaron Steece. Verified by Hardin Waddle. Florida Museum of Natural History (UF 177727, photo voucher). New parish record. This adult was found ca. 2 m high on a branch at the edge of a wooded area behind a house. It was photographed and released, as the species identity and significance was unknown. The origin of this individual is unknown. The homeowner stated that he bought nursery plants often, but checked them thoroughly as he put them indoors. Since this initial finding, the homeowner learned more about Cuban Treefrogs and searched for them on many occasions at this location for two years, but detected no additional Cuban Treefrogs.

  10. The fall and rise of the history of recent chemistry.

    PubMed

    Morris, Peter J T

    2011-11-01

    This paper defines the history of recent chemistry, and then charts the disappearance of the history of recent chemistry ("how we got here" history) from general histories of chemistry by the late 1930s. It is also shown how the history of recent chemistry in the early decades of the twentieth century was very much the history of physical chemistry. The revival of the history of recent chemistry is attributed to Eduard Farber and Aaron lhde. Several attempts have been made since the early 1980s to promote the history of recent chemistry, with mixed results. The current situation is assessed, and the paper concludes with a proposal for the entrenchment of the subject. PMID:22397156

  11. Social network analysis for program implementation.

    PubMed

    Valente, Thomas W; Palinkas, Lawrence A; Czaja, Sara; Chu, Kar-Hai; Brown, C Hendricks

    2015-01-01

    This paper introduces the use of social network analysis theory and tools for implementation research. The social network perspective is useful for understanding, monitoring, influencing, or evaluating the implementation process when programs, policies, practices, or principles are designed and scaled up or adapted to different settings. We briefly describe common barriers to implementation success and relate them to the social networks of implementation stakeholders. We introduce a few simple measures commonly used in social network analysis and discuss how these measures can be used in program implementation. Using the four stage model of program implementation (exploration, adoption, implementation, and sustainment) proposed by Aarons and colleagues [1] and our experience in developing multi-sector partnerships involving community leaders, organizations, practitioners, and researchers, we show how network measures can be used at each stage to monitor, intervene, and improve the implementation process. Examples are provided to illustrate these concepts. We conclude with expected benefits and challenges associated with this approach. PMID:26110842

  12. Beyond Depression: Towards a Process-Based Approach to Research, Diagnosis, and Treatment

    PubMed Central

    Forgeard, Marie J. C.; Haigh, Emily A. P.; Beck, Aaron T.; Davidson, Richard J.; Henn, Fritz A.; Maier, Steven F.; Mayberg, Helen S.; Seligman, Martin E. P.

    2012-01-01

    Despite decades of research on the etiology and treatment of depression, a significant proportion of the population is affected by the disorder, fails to respond to treatment and is plagued by relapse. Six prominent scientists, Aaron Beck, Richard Davidson, Fritz Henn, Steven Maier, Helen Mayberg, and Martin Seligman, gathered to discuss the current state of scientific knowledge on depression, and in particular on the basic neurobiological and psychopathological processes at play in the disorder. These general themes were addressed: 1) the relevance of learned helplessness as a basic process involved in the development of depression; 2) the limitations of our current taxonomy of psychological disorders; 3) the need to work towards a psychobiological process-based taxonomy; and 4) the clinical implications of implementing such a process-based taxonomy. PMID:22509072

  13. KSC-04PD-0851

    NASA Technical Reports Server (NTRS)

    2004-01-01

    KENNEDY SPACE CENTER, FLA. Center Director Jim Kennedy (center) and Principal Aaron Fernander (right) visit a classroom in Ralph Bunche Middle School, a NASA Explorer School, in Atlanta, Ga. At left is Ralph Thomas, assistant administrator for Small and Disadvantaged Business Utilization at NASA. Kennedy is visiting NES sites to share Americas new vision for space exploration with the next generation of explorers. He was accompanied by astronaut Rick Linnehan on the visit. The purpose of the school visit is to talk with students about our destiny as explorers, NASAs stepping stone approach to exploring Earth, the Moon, Mars and beyond, how space impacts our lives, and how people and machines rely on each other in space.

  14. The need for specific penalties for hacking in criminal law.

    PubMed

    Oh, Sangkyo; Lee, Kyungho

    2014-01-01

    In spite of the fact that hacking is a widely used term, it is still not legally established. Moreover, the definition of the concept of hacking has been deployed in a wide variety of ways in national literature. This ambiguity has led to various side effects. Recently in the United States, reforms collectively known as Aaron's Law were proposed as intended amendments to the Computer Fraud and Abuse Act (CFAA). Most experts expect that this change will put the brakes on the CFAA as a severe punishment policy, and result in a drop in controversial court decisions. In this study, we analyze the definitions and the penalties for hacking for each country and compare them with the national law and then make suggestions through more specific legislation. We expect it will reduce legal controversy and prevent excessive punishment. PMID:25032236

  15. Higher-Order Mixed Finite Element Methods for Time Domain Electromagnetics

    SciTech Connect

    White, D; Stowell, M; Koning, J; Rieben, R; Fisher, A; Champagne, N; Madsen, N

    2004-02-06

    This is the final report for LDRD 01-ERD-005. The Principal Investigator was Niel Madsen of the Defense Sciences Engineering Division (DSED). Collaborators included Daniel White, Joe Koning and Nathan Champagne of DSED, Mark Stowell of Center for Applications Development and Software Engineering (CADSE), and Ph.D. students Rob Rieben and Aaron Fisher at the UC Davis Department of Applied Science. It should be noted that the students were partially supported by the LLNL Student-Employee Graduate Research Fellow program. We begin with an Introduction which provides background and motivation for this research effort. Section II contains high-level description of our Approach, and Section III summarizes our key research Accomplishments. A description of the Software deliverables is provided in Section IV, and Section V includes simulation Validation and Results. It should be noted we do not get into the mathematical details in this report, rather these can be found in our publications which are listed in Section III.

  16. Landsat Radiometry Project

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This final report summarizes three years of work characterizing the radiometry of the Landsat 4, 5 and 7 Thematic Mappers. It is divided into six sections that are representative of the major areas of effort: 1) Internal Calibrator Lamp Monitoring; 2) Vicarious Calibration; 3) Relative Gain Analysis; 4) Outgassing; 5) Landsat 4 Absolute Calibration; and 6) Landsat 5 Scene Invariant Analysis. Each section provides a summary overview of the work that has been performed at SDSU. Major results are highlighted. In several cases, references are given to publications that have developed from this work, Several team members contributed to this report: Tim Ruggles, Dave Aaron, Shriharsha Madhavan, Esad Micijevic, Cory Mettler, and Jim Dewald. At the end of the report is a summary section.

  17. Beyond Depression: Towards a Process-Based Approach to Research, Diagnosis, and Treatment.

    PubMed

    Forgeard, Marie J C; Haigh, Emily A P; Beck, Aaron T; Davidson, Richard J; Henn, Fritz A; Maier, Steven F; Mayberg, Helen S; Seligman, Martin E P

    2011-12-01

    Despite decades of research on the etiology and treatment of depression, a significant proportion of the population is affected by the disorder, fails to respond to treatment and is plagued by relapse. Six prominent scientists, Aaron Beck, Richard Davidson, Fritz Henn, Steven Maier, Helen Mayberg, and Martin Seligman, gathered to discuss the current state of scientific knowledge on depression, and in particular on the basic neurobiological and psychopathological processes at play in the disorder. These general themes were addressed: 1) the relevance of learned helplessness as a basic process involved in the development of depression; 2) the limitations of our current taxonomy of psychological disorders; 3) the need to work towards a psychobiological process-based taxonomy; and 4) the clinical implications of implementing such a process-based taxonomy. PMID:22509072

  18. Longitude dependent response of the GPS derived ionospheric ROTI to geomagnetic storms

    NASA Astrophysics Data System (ADS)

    Tanna, H. J.; Pathak, K. N.

    2014-08-01

    The local time dependent effects of geomagnetic storm on the ionospheric TEC and Rate of change of TEC Index (ROTI) are studied here using the GPS data for four different low latitude stations: Ogaswara, Japan (24.29 °N, 153.91 °E; Geomagnetic: 17.21 °N, 136.16 °W); Surat, India (21.16 °N, 72.78 °E; Geomagnetic: 12.88 °N, 146.91 °E); Bogota, Colombia (4.64 °N, -74.09 °E; Geomagnetic: 14.42 °N, 1.67 °W); and Kokee park Waimea, Hawaii, US (22.12 °N, -159.67 °E; Geomagnetic: 22.13 °N, 91.19 °W). The solar wind velocity and geomagnetic indices: Dst, Kp and IMF Bz are utilized to validate the geomagnetic storms registered during the years 2011 and 2012. Using the GPS based TEC data and computed values of ROTI, the storm induced ionospheric irregularities generation and inhibition has been studied for all stations. The present study suggests that, the F-region irregularities of a scale length of few kilometers over the magnetic equator are locally affected by geomagnetic storms. This study also shows a good agreement (70-84 %) with the Aaron's criteria (Aarons, Radio Sci., 26:1131-1149, 1991; Biktash, Ann. Geophys., 19:731-739, 2004) as significant absence and enhancement of ROTI was found to be influenced by the local time of the negative peak of Dst index association.

  19. Convergent Close-Coupling Approach to Electron-Atom Collisions

    NASA Technical Reports Server (NTRS)

    Bray, Igor; Stelbovics, Andris

    2007-01-01

    It was with great pleasure and honour to accept the invitation to make a presentation at the symposium celebrating the life-long work of Aaron Temkin and Richard Drachman. The work of Aaron Temkin was particularly influential on our own during the development of the CCC method for electron-atom collisions. There are a number of key problems that need to be dealt with when developing a general computational approach to such collisions. Traditionally, the electron energy range was subdivided into the low, intermediate, and high energies. At the low energies only a finite number of channels are open and variational or close-coupling techniques could be used to obtain accurate results. At high energies an infinite number of discrete channels and the target continuum are open, but perturbative techniques are able to yield accurate results. However, at the intermediate energies perturbative techniques fail and computational approaches need to be found for treating the infinite number of open channels. In addition, there are also problems associated with the identical nature of electrons and the difficulty of implementing the boundary conditions for ionization processes. The beauty of the Temkin-Poet model of electron-hydrogen scattering is that it simplifies the full computational problem by neglecting any non-zero orbital angular momenta in the partial-wave expansion, without loosing the complexity associated with the above-mentioned problems. The unique nature of the problem allowed for accurate solution leading to benchmark results which could then be used to test the much more general approaches to electron-atom collision problems. The immense value of the Temkin-Poet model is readily summarised by the fact that the initial papers of Temkin and Poet have been collectively cited around 250 times to date and are still being cited in present times. Many of the citations came from our own work during the course of the development of the CCC method, which we now describe.

  20. Siderophore Promoted Dissolution of a Series of Mn-Substituted Goethites

    NASA Astrophysics Data System (ADS)

    Holmstrom, S. J.; Sposito, G.

    2005-12-01

    The presence of organic ligands, like siderophores, can strongly influence mineral dissolution. Recent research suggests that at least some siderophores enhance mineral dissolution by formation of surface complexes with Fe and Mn. The impact of biogeochemical weathering caused by exudates of plants, fungi and bacteria containing siderophores has been discussed. We have studied the dissolution kinetics of Mn-substituted goethites (mol % Mn < 11) in the presences of 80 μM desferrioxamine B (DFO-B), a common and well-studied hydroxamate siderophore that has been identified in both terrestrial and marine environments and which forms very stable 1:1 complexes with Fe(III) or Mn(III). (The stability constants at I = 0.1 are 1030.6 and 1028.3, respectively.) A series of Mn-substituted goethites (α-MnxFe1-xOOH) were synthesized from ferrihydrite in the presence of Mn(II) in alkaline media. The Fe(III) in octahedral positions in the mineral structure was partially replaced by Mn, which was confirmed visually by the change to darker color when the content of Mn increased and proved by infra-red spectroscopy and X-ray diffraction studies of the samples. Substitution of Fe in the goethite by Mn caused a change in the cell dimensions. The calculated unit cell edge lengths a and c decreased, while b increased, for the Mn-goethites compared to pure goethite. The difference of the unit cell parameters between the pure goethite and the Mn-substituted goethites increased with increased Mn content, providing further confirmation that Fe had been substituted by Mn incorporated into the goethite structure. X-ray absorption near-edge structure spectroscopy analysis of the Mn-substituted goethites showed that the oxidation state of Mn in the samples was, as expected, Mn(III), even when Mn-goethites were prepared from Mn(II) solutions. Both SEM and TEM micrographs showed that the Mn-substituted goethite crystals had the same acicular shape as pure goethite. The specific surface area

  1. Cerenkov luminescence imaging of medical isotopes

    PubMed Central

    Ruggiero, Alessandro; Holland, Jason P.; Lewis, Jason S.; Grimm, Jan

    2011-01-01

    The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies. Methods In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters 18F, 64Cu, 89Zr, and 124I; β-emitter 131I; and α-particle emitter 225Ac for potential use in CLI. The novel radiolabeled monoclonal antibody 89Zr-desferrioxamine B-[DFO-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies. Results Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-,β-, and α-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of 89Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities. Conclusion These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear

  2. Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy

    PubMed Central

    De Sanctis, Vincenzo; Elsedfy, Heba; Soliman, Ashraf T.; Elhakim, Ihab Zaki; Kattamis, Christos; Soliman, Nada A.; Elalaily, Rania

    2016-01-01

    Introduction It is well known that the older generation of adult TM patients has a higher incidence of morbidities and co-morbidities. At present, little information is available on adult TM patients with multiple endocrine complications (MEC). The main objectives of this longitudinal retrospective survey were: 1) to establish the incidence and progression of MEC (3 or more) in TM patients; 2) to compare the clinical, laboratory and imaging data to a sex and age-matched group of TM patients without MEC; 3) to assess the influence of iron overload represented by serum ferritin (peak and mean annual value at the last endocrine observation). Patients and methods The study was started in January 1974 and was completed by the same physician at the end of December 2015. The registry database of the regularly followed TM patients from diagnosis included 145 adults (> 18 years). All TM patients were of Italian ethnic origin. Eleven out of 145 patients (7.5 %) developed MEC. Twenty-four other patients (12 females and 12 males) had a normal endocrine function (16.5 %) and served as controls. Results In our survey, four important, relevant aspects emerged in the MEC group. These included the late age at the start of chelation therapy with desferrioxamine mesylate (DFO); the higher serum ferritin peak (8521.8 ± 5958.9 vs 3575.2 ± 1801.4 ng/ml); the upper proportion of splenectomized (81.8 % vs. 28.5%) patients and poor compliance registered mainly during the peripubertal and pubertal age (72.7 % vs.16.6 %) in TM patients developing MEC versus those without endocrine complications. Furthermore, a negative correlation was observed in all TM patients between LIC and final height (r: −0.424; p = 0.031). Conclusions Our study supports the view that simultaneous involvement of more than one endocrine gland is not uncommon (7.5 %). It mainly occurred in TM patients who started chelation therapy with DFO late in life and who had irregular/poor compliance to treatment. Therefore

  3. Stimulating angiogenesis mitigates the unloading-induced reduction in osteogenesis in early-stage bone repair in rats

    PubMed Central

    Matsumoto, Takeshi; Sato, Shota

    2015-01-01

    Accelerating fracture healing during bed rest allows early mobilization and avoids prolonged fracture healing times. We tested the hypothesis that stimulating angiogenesis with deferoxamine (DFO) mitigates the unloading-induced reduction in early-stage bone repair. Rats aged 12 weeks were subjected to cortical drilling on their tibial diaphysis under anesthesia and treated with hindlimb unloading (HU), HU and DFO administration (DFOHU), or weight bearing (WB) for 5 or 10 days (HU5/10, DFOHU5/10, WB5/10; n = 8 per groups) until sacrifice for vascular casting with a zirconium dioxide-based contrast agent. Taking advantage of its absorption discontinuity at the K-absorption edge, vascular and bone images in the drill-hole defects were acquired by synchrotron radiation subtraction CT. Bone repair was reduced in HU rats. The bone volume fraction (B.Vf) was 88% smaller in HU5 and 42% smaller in HU10 than in WB5/10. The bone segment densities (B.Seg) were 97% smaller in HU5 and 141% larger in HU10 than in WB5/10, and bone thickness (B.Th) was 38% smaller in HU10 than in WB10. The vascular volume fraction (V.Vf) was 35% and the mean vessel diameter (V.D) was 13% smaller in HU10 than in WB10. When compared according to categorized vessel sizes, V.Vf in the diameter ranges 20–30, 30–40, and >40 μm were smaller in HU10 than in WB10, and V.Seg in the diameter range >40 μm was smaller in HU10 than in WB10. In contrast, there was no difference in B.Vf between DFOHU5/10 and WB5/10 and in V.Vf between DFOHU10 and WB10, though B.Seg remained 86% smaller in DFOHU5 and 94% larger in DFOHU10 than in WB5/10, and B.Th and V.D were 23% and 14% lower in DFOHU10 than in WB10. Vessel size-specific V.Vf in the diameter ranges 10–20 and 20–30 μm was larger in DFOHU5 than in HU5. In conclusion, the enhanced angiogenic ingrowth mitigates the reduction in bone repair during mechanical unloading. PMID:25780087

  4. Intercomparison of Operational Ocean Forecasting Systems in the framework of GODAE

    NASA Astrophysics Data System (ADS)

    Hernandez, F.

    2009-04-01

    representation, either due to model and forcing fields errors, or assimilation scheme efficiency. Comparisons to sea-ice satellite products also evidence discrepancies linked to model, forcing and assimilation strategies of each forecasting system. Key words: Intercomparison, ocean analysis, operational oceanography, system assessment, metrics, validation GODAE Intercomparison Team: L. Bertino (NERSC/Norway), G. Brassington (BMRC/Australia), E. Chassignet (FSU/USA), J. Cummings (NRL/USA), F. Davidson (DFO/Canda), M. Drévillon (CERFACS/France), P. Hacker (IPRC/USA), M. Kamachi (MRI/Japan), J.-M. Lellouche (CERFACS/France), K. A. Lisæter (NERSC/Norway), R. Mahdon (UKMO/UK), M. Martin (UKMO/UK), A. Ratsimandresy (DFO/Canada), and C. Regnier (Mercator Ocean/France)

  5. The metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), inhibits stress-induced autophagy in cancer cells.

    PubMed

    Sahni, Sumit; Bae, Dong-Hun; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Jansson, Patric J; Richardson, Des R

    2014-04-01

    N-myc downstream regulated gene 1 (NDRG1) is a potent metastasis suppressor with an undefined role in the stress response. Autophagy is a pro-survival pathway and can be regulated via the protein kinase-like endoplasmic reticulum kinase (PERK)/eIF2α-mediated endoplasmic reticulum (ER) stress pathway. Hence, we investigated the role of NDRG1 in stress-induced autophagy as a mechanism of inhibiting metastasis via the induction of apoptosis. As thiosemicarbazone chelators induce stress and up-regulate NDRG1 to inhibit metastasis, we studied their effects on the ER stress response and autophagy. This was important to assess, as little is understood regarding the role of the stress induced by iron depletion and its role in autophagy. We observed that the chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which forms redox-active iron and copper complexes, effectively induced ER stress as shown by activation of the PERK/eIF2α pathway. Dp44mT also increased the expression of the autophagic marker, LC3-II, and this was dependent on activation of the PERK/eIF2α axis, as silencing PERK prevented LC3-II accumulation. The effect of Dp44mT on LC3-II expression was at least partially due to iron-depletion, as this effect was also demonstrated with the classical iron chelator, desferrioxamine (DFO), and was not observed for the DFO-iron complex. NDRG1 overexpression also inhibited basal autophagic initiation and the ER stress-mediated autophagic pathway via suppression of the PERK/eIF2α axis. Moreover, NDRG1-mediated suppression of the pro-survival autophagic pathway probably plays a role in its anti-metastatic effects by inducing apoptosis. In fact, multiple pro-apoptotic markers were increased, whereas anti-apoptotic Bcl-2 was decreased upon NDRG1 overexpression. This study demonstrates the role of NDRG1 as an autophagic inhibitor that is important for understanding its mechanism of action. PMID:24532803

  6. Quantitative analysis of the anti-proliferative activity of combinations of selected iron-chelating agents and clinically used anti-neoplastic drugs.

    PubMed

    Potuckova, Eliska; Jansova, Hana; Machacek, Miloslav; Vavrova, Anna; Haskova, Pavlina; Tichotova, Lucie; Richardson, Vera; Kalinowski, Danuta S; Richardson, Des R; Simunek, Tomas

    2014-01-01

    Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA

  7. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes.

    PubMed

    Ruggiero, Alessandro; Villa, Carlos H; Holland, Jason P; Sprinkle, Shanna R; May, Chad; Lewis, Jason S; Scheinberg, David A; McDevitt, Michael R

    2010-01-01

    Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT-([(225)Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([(89)Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that

  8. The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo.

    PubMed

    Lee, Jehn-Chuan; Chiang, Kun-Chun; Feng, Tsui-Hsia; Chen, Yu-Jen; Chuang, Sung-Ting; Tsui, Ke-Hung; Chung, Li-Chuan; Juang, Horng-Heng

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment. PMID:27589737

  9. Amyloid β25-35 induced ROS-burst through NADPH oxidase is sensitive to iron chelation in microglial Bv2 cells.

    PubMed

    Part, Kristin; Künnis-Beres, Kai; Poska, Helen; Land, Tiit; Shimmo, Ruth; Zetterström Fernaeus, Sandra

    2015-12-10

    Iron chelation therapy and inhibition of glial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can both represent possible routes for Alzheimer's disease modifying therapies. The metal hypothesis is largely focused on direct binding of metals to the N-terminal hydrophilic 1-16 domain peptides of Amyloid beta (Aβ) and how they jointly give rise to reactive oxygen species (ROS) production. The cytotoxic effects of Aβ through ROS and metals are mainly studied in neuronal cells using full-length Aβ1-40/42 peptides. Here we study cellularly-derived ROS during 2-60min in response to non-metal associated mid domain Aβ25-35 in microglial Bv2 cells by fluorescence based spectroscopy. We analyze if Aβ25-35 induce ROS production through NADPH oxidase and if the production is sensitive to iron chelation. NADPH oxidase inhibitor diphenyliodonium (DPI) is used to confirm the production of ROS through NADPH oxidase. We modulate cellular iron homeostasis by applying cell permeable iron chelators desferrioxamine (DFO) and deferiprone (DFP). NADPH oxidase subunit gp91-phox level was analyzed by Western blotting. Our results show that Aβ25-35 induces strong ROS production through NADPH oxidase in Bv2 microglial cells. Intracellular iron depletion resulted in restrained Aβ25-35 induced ROS. PMID:26505916

  10. Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design.

    PubMed

    Holland, Jason P; Vasdev, Neil

    2014-07-14

    The reaction of [(89)Zr(C2O4)4](4-) with the tris-hydroxamate ligand desferrioxamine B (DFO) provides the basis of radiolabelling biological vectors such as antibodies and proteins with the radionuclide (89)Zr for positron emission tomography imaging. In this work, density functional theory methods were used to investigate the mechanism of reaction from [Zr(C2O4)4](4-) to Zr(MeAHA)4 by ligand substitution with N-methyl acetohydroxamate (MeAHA). Calculations were performed under simulated basic and acidic conditions. Ligand substitution under basic conditions was found to be thermodynamically feasible with an overall calculated change in solvation free energy, ΔGsol = -97 kJ mol(-1) using the B3LYP/DGDZVP methodology and a water continuum solvation model. In contrast, an acid-mediated mechanism of ligand substitution was found to be thermodynamically non-feasible. Molecular orbital analysis provides a rationale for the difference in thermodynamic stability between [Zr(C2O4)4](4-) and Zr(MeAHA)4. Overall, the DFT calculations are consistent with observed experimental (89)Zr-radiolabelling reactions and suggest that computational methods may prove useful in designing novel chelates for increasing the thermodynamic and kinetic stability of (89)Zr-complexes in vivo. PMID:24722728

  11. Enhancing protoporphyrin IX-induced PDT

    NASA Astrophysics Data System (ADS)

    Curnow, Alison; Pye, Andrew; Campbell, Sandra

    2009-06-01

    Photodynamic therapy (PDT) using porphyrin precursors is commonly used in dermatology. Evidence indicates that good clinical outcomes (associated with excellent cosmesis) can be achieved in superficial precancers and basal cell carcinoma (BCC), however, efficacy appears less favorable for thicker nodular BCC (nBCC) unless multiple PDT treatment cycles are performed. Enhancement is therefore required if nBCC lesions are to be treated effectively with a single PDT treatment. The most common technique currently being routinely employed clinically is the use of aminolevulinic acid (ALA) esters (usually methyl (MAL) or hexyl (HAL)). Standard dermatological PDT employing these porphyrin precursors already manipulates the normal heme biosynthesis pathway resulting in a temporary accumulation of the natural photosensitizer, protoporphyrin IX (PpIX). Further manipulation using iron chelating agents is possible however. In normal and malignant human cells in vitro, the novel iron chelating agent CP94 produced greater PPIX fluorescence when administered with ALA or MAL than either congener produced alone. CP94 was also significantly more effective than the clinically established iron chelating agent desferrioxamine (DFO). Topical application of ALA+CP94 to clinical nBCC lesions was a simple and safe treatment modification which produced a significant increase in clinical clearance when CP94 was included in the cream.

  12. Mechanism of the toxicity induced by natural humic acid on human vascular endothelial cells.

    PubMed

    Kihara, Yusuke; Yustiawati; Tanaka, Masato; Gumiri, Sulmin; Ardianor; Hosokawa, Toshiyuki; Tanaka, Shunitz; Saito, Takeshi; Kurasaki, Masaaki

    2014-08-01

    Humic acid (HA), a group of high-molecular weight organic compounds characterized by an ability to bind heavy metals, is normally found in natural water. Although the impairment of vascular endothelial cells in the presence of humic substances has been reported to be involved in some diseases, the mechanisms responsible for this involvement remain unclear. In this study, we examined the cytotoxicity of HA obtained from peatland in Central Kalimantan, Indonesia, to human vascular endothelial cells, as well as the mechanisms behind these effects. It was found that 50 mg/L HA showed cytotoxicity, which we considered to be mediated by apoptosis through the mitochondrial pathway because of an increase in the expression of caspases 6 and 9 in response to HA administration. In addition, this cytotoxicity was enhanced when cells in this experimental system were exposed to oxidative stress, while it was decreased by the addition of vitamin C. Thus, we conclude that the apoptosis induced by HA depends upon oxidative stress. Furthermore, an iron chelator, DFO, showed a tendency to decrease HA-induced cytotoxicity, suggesting that iron may potentially mediate HA-induced oxidative stress. In conclusion, long-term consumption of HA-rich water obtained from our study area may cause damage to endothelial cells and subsequent chronic health problems. PMID:23042718

  13. An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy.

    PubMed

    Tavaré, Richard; Escuin-Ordinas, Helena; Mok, Stephen; McCracken, Melissa N; Zettlitz, Kirstin A; Salazar, Felix B; Witte, Owen N; Ribas, Antoni; Wu, Anna M

    2016-01-01

    The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys-diabody ((89)Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8(+) T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti-PD-L1). The ability of anti-CD8 immuno-PET to provide whole body information regarding therapy-induced alterations of this dynamic T-cell population provides new opportunities to evaluate antitumor immune responses of immunotherapies currently being evaluated in the clinic. PMID:26573799

  14. Aluminium induced structural, metabolic alterations and protective effects of desferrioxamine in the brain tissue of mice: An FTIR study

    NASA Astrophysics Data System (ADS)

    Sivakumar, S.; Sivasubramanian, J.; Raja, B.

    2012-12-01

    In this study, we intended to made a new approach to evaluate aluminium induced metabolic changes in mice brain tissue using Fourier transform infrared spectroscopy. Results demonstrate that FTIR can successfully indicate the molecular changes that occur in all groups. The overall findings demonstrate the alterations on the major biochemical constituents, such as lipids, proteins and nucleic acids of the brain tissues of mice. The significant decrease in the area value of amide A peak and Olefinicdbnd CH stretching band suggests an alteration in the protein profile and lipid levels due to aluminium exposure, respectively. The significant shift in the amide I and amide II protein peaks may indicate the progression of aluminium induced Alzheimer's disease. Further the administration of DFO significantly improved the level of protein and brought back the amide I and II peaks nearer to the control value. Histopathological results also revealed impairment of Aluminium induced alterations in brain tissue. The results of the FTIR study were found to be in agreement with biochemical studies.

  15. Automated Ground Umbilical Systems (AGUS) Project

    NASA Technical Reports Server (NTRS)

    Gosselin, Armand M.

    2007-01-01

    All space vehicles require ground umbilical systems for servicing. Servicing requirements can include, but are not limited to, electrical power and control, propellant loading and venting, pneumatic system supply, hazard gas detection and purging as well as systems checkout capabilities. Of the various types of umbilicals, all require several common subsystems. These typically include an alignment system, mating and locking system, fluid connectors, electrical connectors and control !checkout systems. These systems have been designed to various levels of detail based on the needs for manual and/or automation requirements. The Automated Ground Umbilical Systems (AGUS) project is a multi-phase initiative to develop design performance requirements and concepts for launch system umbilicals. The automation aspect minimizes operational time and labor in ground umbilical processing while maintaining reliability. This current phase of the project reviews the design, development, testing and operations of ground umbilicals built for the Saturn, Shuttle, X-33 and Atlas V programs. Based on the design and operations lessons learned from these systems, umbilicals can be optimized for specific applications. The product of this study is a document containing details of existing systems and requirements for future automated umbilical systems with emphasis on design-for-operations (DFO).

  16. Hypoxia induces PDK4 gene expression through induction of the orphan nuclear receptor ERRγ.

    PubMed

    Lee, Ja Hee; Kim, Eun-Jin; Kim, Don-Kyu; Lee, Ji-Min; Park, Seung Bum; Lee, In-Kyu; Harris, Robert A; Lee, Mi-Ock; Choi, Hueng-Sik

    2012-01-01

    Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia. PMID:23050013

  17. Hypoxia Induces PDK4 Gene Expression through Induction of the Orphan Nuclear Receptor ERRγ

    PubMed Central

    Lee, Ji-Min; Park, Seung Bum; Lee, In-Kyu; Harris, Robert A.; Lee, Mi-Ock; Choi, Hueng-Sik

    2012-01-01

    Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia–mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia. PMID:23050013

  18. Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1α Upregulation-Mediated β-Catenin Activation in Endometriosis.

    PubMed

    Xiong, Wenqian; Zhang, Ling; Xiong, Yao; Liu, Hengwei; Liu, Yi

    2016-04-01

    Endometriosis is a common benign gynecological disease defined as the presence of endometrial tissue outside the uterine cavity. The aim of this study was to identify the molecular mechanism underlying hypoxia-induced increases in invasive ability of human endometrial stromal cells (HESCs). Herein, we show that the expression levels of hypoxia-inducible factor lα (HIF-1α) and β-catenin were greater in ectopic endometriotic tissue compared with eutopic tissue from controls. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in β-catenin expression and its dephosphorylation. Hypoxia/HIF-1α also activated the β-catenin/T-cell factor (TCF) signaling pathway and the expression of target genes, vascular endothelial growth factor and matrix metalloproteinase 9, and knockdown of HIF-1α or β-catenin abrogated hypoxia-induced increases in HESC invasiveness. These results suggest that HIF-1α interacting with β-catenin/TCF signaling pathway, which is activated by hypoxia, may provide new insights into the etiology of endometriosis. PMID:26482209

  19. Evidence for Hydroxamate Siderophores and Other N-Containing Organic Compounds Controlling (239,240)Pu Immobilization and Remobilization in a Wetland Sediment.

    PubMed

    Xu, Chen; Zhang, Saijin; Kaplan, Daniel I; Ho, Yi-Fang; Schwehr, Kathleen A; Roberts, Kimberly A; Chen, Hongmei; DiDonato, Nicole; Athon, Matthew; Hatcher, Patrick G; Santschi, Peter H

    2015-10-01

    Pu concentrations in wetland surface sediments collected downstream of a former nuclear processing facility in F-Area of the Savannah River Site (SRS), USA, were ∼2.5 times greater than those measured in the associated upland aquifer sediments; similarly, the Pu concentration solid/water ratios were orders of magnitude greater in the wetland than in the low-organic matter content aquifer soils. Sediment Pu concentrations were correlated to total organic carbon and total nitrogen contents and even more strongly to hydroxamate siderophore (HS) concentrations. The HS were detected in the particulate or colloidal phases of the sediments but not in the low molecular weight fractions (<1000 Da). Macromolecules which scavenged the majority of the potentially mobile Pu were further separated from the bulk mobile organic matter fraction ("water extract") via an isoelectric focusing experiment (IEF). An electrospray ionization Fourier-transform ion cyclotron resonance ultrahigh resolution mass spectrometry (ESI FTICR-MS) spectral comparison of the IEF extract and a siderophore standard (desferrioxamine; DFO) suggested the presence of HS functionalities in the IEF extract. This study suggests that while HS are a very minor component in the sediment particulate/colloidal fractions, their concentrations greatly exceed those of ambient Pu, and HS may play an especially important role in Pu immobilization/remobilization in wetland sediments. PMID:26313339

  20. A linear geospatial streamflow modeling system for data sparse environments

    USGS Publications Warehouse

    Asante, Kwabena O.; Arlan, Guleid A.; Pervez, Md Shahriar; Rowland, James

    2008-01-01

    In many river basins around the world, inaccessibility of flow data is a major obstacle to water resource studies and operational monitoring. This paper describes a geospatial streamflow modeling system which is parameterized with global terrain, soils and land cover data and run operationally with satellite‐derived precipitation and evapotranspiration datasets. Simple linear methods transfer water through the subsurface, overland and river flow phases, and the resulting flows are expressed in terms of standard deviations from mean annual flow. In sample applications, the modeling system was used to simulate flow variations in the Congo, Niger, Nile, Zambezi, Orange and Lake Chad basins between 1998 and 2005, and the resulting flows were compared with mean monthly values from the open‐access Global River Discharge Database. While the uncalibrated model cannot predict the absolute magnitude of flow, it can quantify flow anomalies in terms of relative departures from mean flow. Most of the severe flood events identified in the flow anomalies were independently verified by the Dartmouth Flood Observatory (DFO) and the Emergency Disaster Database (EM‐DAT). Despite its limitations, the modeling system is valuable for rapid characterization of the relative magnitude of flood hazards and seasonal flow changes in data sparse settings.

  1. Introduction and Mission Response Team (MRT)

    NASA Technical Reports Server (NTRS)

    Pool, Sam

    2005-01-01

    On February 1, 2003 the Space Shuttle Columbia, returning to Earth with a crew of seven astronauts, disintegrated along a track extending from California to Louisiana. Observers on the ground filmed breakup of the spacecraft. Debris fell along a 567 statute mile track from Littlefield, Texas to Fort Polk, Louisiana; the largest ever recorded debris field. At the time of the accident the National Aeronautics and Space Administration (NASA) flight surgeon on-duty at the Mission Control Center (MCC) in Houston, Texas initiated the medical contingency response. The DOD surgeon at Patrick Air Force Base was notified, NASA medical personnel were recalled and the services of Armed Forces Institute of Pathology (AFIP) were requested. Subsequent to the accident the NASA flight surgeons that had supported the crew on orbit now provided medical support to the crewmember s families. Federal Emergency Management Agency (FEMA), the National Transportation Safety Board (NTSB), the Federal Bureau of Investigation (FBI) and numerous other federal, state and local agencies along with the citizens of Texas and Louisiana responded to the disaster. Search and recovery was managed from a Disaster Field Office (DFO) established in Lufkin, Texas. Mishap Investigation Team (MIT) medical operations were managed from Barksdale Air Force Base, Louisiana. Accident investigation teams (Columbia Accident Investigation Task Force (CAITF) and Columbia Accident Investigation Board (CAIB)) appointed immediately after the disaster included current and former authorities in space medicine. In August 2003, the CAIB concluded its investigation and released its findings in a report published in February 2004.

  2. Effects of salts on oxidative stability of lipids in Tween-20 stabilized oil-in-water emulsions.

    PubMed

    Cui, Leqi; Cho, Hyung Taek; McClements, D Julian; Decker, Eric A; Park, Yeonhwa

    2016-04-15

    Lipid oxidation in oil-in-water (O/W) emulsions is an important factor determining the shelf life of food products. Salts are often present in many types of emulsion based food products. However, there is limited information on influence of salts on lipid oxidation in O/W emulsions. Thus, the purpose of this study was to examine the effects of sodium and potassium chloride on lipid oxidation in O/W emulsions. Tween 20 stabilized corn O/W emulsions at pH 7.0 were prepared with different concentrations of sodium chloride with or without the metal chelators. NaCl did not cause any changes in emulsion droplet size. NaCl dose-dependently promoted lipid oxidation as measured by the lipid oxidation product, hexanal. Both deferoxamine (DFO) and ethylenediaminetetraacetic acid (EDTA) reduced lipid oxidation in emulsions with NaCl, with EDTA being more effective. Potassium chloride showed similar impact on lipid oxidation as sodium chloride. These results suggest that salts are able to promote lipid oxidation in emulsions and this effect can be controlled by metal chelators. PMID:26675849

  3. Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics.

    PubMed

    Pretorius, Etheresia; Bester, Janette; Vermeulen, Natasha; Alummoottil, Sajee; Soma, Prashilla; Buys, Antoinette V; Kell, Douglas B

    2015-01-01

    We have noted in previous work, in a variety of inflammatory diseases, where iron dysregulation occurs, a strong tendency for erythrocytes to lose their normal discoid shape and to adopt a skewed morphology (as judged by their axial ratios in the light microscope and by their ultrastructure in the SEM). Similarly, the polymerization of fibrinogen, as induced in vitro by added thrombin, leads not to the common 'spaghetti-like' structures but to dense matted deposits. Type 2 diabetes is a known inflammatory disease. In the present work, we found that the axial ratio of the erythrocytes of poorly controlled (as suggested by increased HbA1c levels) type 2 diabetics was significantly increased, and that their fibrin morphologies were again highly aberrant. As judged by scanning electron microscopy and in the atomic force microscope, these could be reversed, to some degree, by the addition of the iron chelators deferoxamine (DFO) or deferasirox (DFX). As well as their demonstrated diagnostic significance, these morphological indicators may have prognostic value. PMID:25848817

  4. Effective combination therapy of deferiprone and deferoxamine for the rapid clearance of excess cardiac IRON and the prevention of heart disease in thalassemia. The Protocol of the International Committee on Oral Chelators.

    PubMed

    Kolnagou, Annita; Kontoghiorghes, George J

    2006-01-01

    The International Committee on Oral Chelators (ICOC) combination therapy protocol involving the administration of deferiprone (L1) during the day (80-110 mg/kg/day) and deferoxamine (DFO) (40-60 mg/kg at least 3 days/week) during the night for 8-12 hours using a pump, or the whole 24 hours using an elastomeric pump infuser, has been tested in 11 thalassemia patients (seven males, four females) over a period of 9-28 months. The patients had variable serum ferritin levels (0.54-4.6 mg/L) and cardiac iron load ranging from normal to severe siderosis levels (MRI T2*: 4.7-45 ms). There was a substantial overall reduction in serum ferritin levels (0.17-2.16 mg/L) and normalization of cardiac iron (MRI T2* >20 ms) in all patients. In two patients with severe and moderate cardiac iron load range levels, cardiac iron normalization was achieved within 9-10 months. Two patients on L1 monotherapy (80-120 mg/kg/day) maintained normal range MRI T2* cardiac iron levels over the same period. The ICOC combination therapy protocol appears to be the most effective and least cumbersome form of chelation treatment for the rapid clearance of excess iron from the heart. PMID:16798649

  5. Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells.

    PubMed

    Latunde-Dada, Gladys O; Takeuchi, Ken; Simpson, Robert J; McKie, Andrew T

    2006-12-22

    Haem released from digestion and breakdown of meat products provides an important source of dietary iron, which is readily absorbed in the proximal intestine. The recent cloning and characterization of a haem carrier protein 1 (HCP 1) has provided a candidate intestinal haem transporter. The current studies describe the expression and functional analysis of HCP1 in cultured Caco-2 cells, a commonly used model of human intestinal cells. HCP1 mRNA expression in other cell types was also studied. The uptake of (55)Fe labeled haem was determined in cells under different experimental conditions and HCP1 expression was measured by RT-PCR and immunohistochemistry. mRNA and protein expressions increased in Caco-2 cells transduced with HCP1 adenoviral plasmid, and consequently (55)Fe haem uptake was higher in these cells. Haem uptake was also increased in fully differentiated Caco-2 cells compared to undifferentiated cells. Preincubation of cells with desferrioxamine (DFO, to deplete cells of iron) had no effect on HCP1 expression or haem uptake. Treatment with CdCl(2) (to induce haem oxygenase, HO-1) enhanced HCP1 expression and increased haem uptake into the cells. HCP1 expression and function were found to be adaptive to the rate of haem degradation by HO-1. Furthermore, HCP1 expression in different cells implies a functional role in tissues other than the duodenum. PMID:17156779

  6. Performance of 1,2-indanedione and the need for sequential treatment of fingerprints.

    PubMed

    Mangle, Milery Figuera; Xu, Xioama; de Puit, M

    2015-09-01

    The use of 1,2-indanedione-ZnCl2 (IND-Zn) for the visualisation of fingermarks on porous materials has been widely accepted. The use of the reagent in comparison with others has been well described. To what extent IND or IND-Zn reacts with amino acids, in comparison to ninhydrin, has not been described to date. In this technical note we describe the analysis of amino acids with LCMS with the purpose of understanding the reactivity of ninhydrin, IND-Zn and the sequence thereof. The consumption of amino acids by these visualisation reagents is a feature we propose to use for calculations on the reactivity of these reagents. By using recently developed methods for the quantification of amino acids, we determined the consumption of these entities by visualisation reagents. We show that the differences in reactivity between IND and ninhydrin are not as big as the differences between 1,8-diazafluoren-9-one (DFO) and ninhydrin. We also show that it is of great importance to use IND-Zn and ninhydrin in sequence, in order to fully consume the amino acids present in fingermarks. PMID:26385717

  7. Structural, electrical, magnetic and 57Fe Mössbauer study of polycrystalline multiferroic DyFeO3

    NASA Astrophysics Data System (ADS)

    Reddy, S. Shravan Kumar; Raju, N.; Reddy, Ch. Gopal; Reddy, P. Yadagiri; Reddy, K. Rama; Reddy, V. Raghavendra

    2015-12-01

    Structural, Raman spectroscopy, leakage current density, temperature dependent magnetization and Mössbauer measurements of polycrystalline DyFeO3 (DFO) prepared through sol-gel route are reported in this paper. Phase purity and structure of the prepared sample is confirmed from x-ray diffraction and Raman spectroscopy measurements. The room temperature leakage current density (J-E) measurements indicate that Ohmic contribution and space charge limited conduction are the dominating mechanisms at low and high applied electric fields respectively. Signatures of Fe3+ spin reorientation transition (TSR) and the antiferromagnetic ordering of Dy3+ ions are observed from the temperature dependent (10-350 K) magnetization data. The M-H data measured at 2 K shows the field induced metamagnetic transition. Internal hyperfine field obtained from temperature dependent (5-300 K) 57Fe Mössbauer measurements is observed to decrease below the TSR and further found to increase till 5 K indicating the contribution of Dy3+ magnetic ordering on the hyperfine field of Fe nucleus.

  8. Effects of Size-Fractionated Particulate Matter on Cellular Oxidant Radical Generation in Human Bronchial Epithelial BEAS-2B Cells.

    PubMed

    Guan, Longfei; Rui, Wei; Bai, Ru; Zhang, Wei; Zhang, Fang; Ding, Wenjun

    2016-01-01

    The aim of the present study was to investigate the effects of size-fractionated (i.e., <1; 1-2.5, and 2.5-10 µm in an aerodynamic diameter) ambient particulate matter (PM) on reactive oxygen species (ROS) activity and cell viability in human bronchial epithelial cells (BEAS-2B). The PM samples were collected from an urban site (uPM) in Beijing and a steel factory site (sPM) in Anshan, China, from March 2013 to December 2014. Metal elements, organic and elemental carbon, and water-soluble inorganic ions in the uPM and sPM were analyzed. The cell viability and ROS generation in PM-exposed BEAS-2B cells were measured by MTS and DCFH-DA. The results showed that both uPM and sPM caused a decrease in the cell viability and an increase in ROS generation. The level of ROS measured in sPM1.0 was approximately triple that in uPM1.0. The results of correlation analysis showed that the ROS activity and cytotoxicity were related to different PM composition. Moreover, deferoxamine (DFO) significantly prevented the increase of ROS generation and the decrease of cell viability. Taken together, our results suggest that the metals absorbed on PM induced oxidant radical generation in BEAS-2B cells that could lead to impairment of pulmonary function. PMID:27171105

  9. Formation of reactive oxygen species in rat epithelial cells upon stimulation with fly ash.

    PubMed

    Voelkel, K; Krug, H F; Diabaté, S

    2003-02-01

    Fly ash was used as a model for ambient particulate matter which is under suspicion to cause adverse pulmonary health effects. The fly ash was pre-sized and contained only particles < 20 microm including an ultrafine fraction (< 100 nm) that contributed 31% to the particle number. In our study, we investigated the influence of fly ash on the promotion of early inflammatory reactions like the formation of reactive oxygen species (ROS) in rat lung epithelial cells (RLE-6TN). Furthermore, we determined the formation of nitric oxide (NO). The cells show a clear dose-response relationship concerning the formation of ROS with regard to the mass of particles applied. Lipopolysaccharide (LPS) added as a co-stimulus did not increase the formation of ROS induced by fly ash. Furthermore, in LPS (0.1 microg/ml) and tumour necrosis factor-alpha (TNF-alpha; 1 ng/ml) pre-treated cells no increase in reactive oxygen species comparable to fly ash alone is observable. In presence of the metal chelator, desferrioxamine (DFO), ROS formation can be significantly reduced. Neither fly ash nor LPS induced a significant NO release in RLE-6TN cells. PMID:12682424

  10. Effects of Size-Fractionated Particulate Matter on Cellular Oxidant Radical Generation in Human Bronchial Epithelial BEAS-2B Cells

    PubMed Central

    Guan, Longfei; Rui, Wei; Bai, Ru; Zhang, Wei; Zhang, Fang; Ding, Wenjun

    2016-01-01

    The aim of the present study was to investigate the effects of size-fractionated (i.e., <1; 1–2.5, and 2.5–10 µm in an aerodynamic diameter) ambient particulate matter (PM) on reactive oxygen species (ROS) activity and cell viability in human bronchial epithelial cells (BEAS-2B). The PM samples were collected from an urban site (uPM) in Beijing and a steel factory site (sPM) in Anshan, China, from March 2013 to December 2014. Metal elements, organic and elemental carbon, and water-soluble inorganic ions in the uPM and sPM were analyzed. The cell viability and ROS generation in PM-exposed BEAS-2B cells were measured by MTS and DCFH-DA. The results showed that both uPM and sPM caused a decrease in the cell viability and an increase in ROS generation. The level of ROS measured in sPM1.0 was approximately triple that in uPM1.0. The results of correlation analysis showed that the ROS activity and cytotoxicity were related to different PM composition. Moreover, deferoxamine (DFO) significantly prevented the increase of ROS generation and the decrease of cell viability. Taken together, our results suggest that the metals absorbed on PM induced oxidant radical generation in BEAS-2B cells that could lead to impairment of pulmonary function. PMID:27171105

  11. Hydroelectric redevelopment maintains heritage values

    SciTech Connect

    Bulkovshteyn, L.; Chidiac, M.; Hall, W.

    1995-12-31

    The Seymour GS is an 80 year old generating station on the historic Trent-Severn Waterway in Ontario, Canada. The rehabilitation at Seymour was approved by Provincial and Federal authorities on condition that the original appearance of the building be maintained. The capacity of the Generating Station (GS) is being uprated from 3.15 MW to 5.7 MW, by replacing five vertical double runner Francis units with five horizontal Kaplan turbines. The replacement of vertical Francis units with horizontal Kaplan units, necessitated an extensive and innovative demolition approach for the substructure modification. The new turbines required a powerhouse base slab 3.5 m below the grade of the original slab. This required removal of the existing slabs and foundation rock along with most of the interior powerhouse walls. The type of modification and demolition were carefully chosen to accommodate a very tight schedule dictated by the requirement of the Federal Department of Fisheries and Oceans (DFO), where in-water work is restricted to certain months of the year.

  12. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons

    PubMed Central

    Aguirre, Pabla; Mena, Natalia P.; Carrasco, Carlos M.; Muñoz, Yorka; Pérez-Henríquez, Patricio; Morales, Rodrigo A.; Cassels, Bruce K.; Méndez-Gálvez, Carolina; García-Beltrán, Olimpo; González-Billault, Christian; Núñez, Marco T.

    2015-01-01

    Neuronal death in Parkinson’s disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2’-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death. PMID:26658949

  13. Concurrent expression of heme oxygenase-1 and p53 in human retinal pigment epithelial cell line

    SciTech Connect

    Lee, Sang Yull; Jo, Hong Jae; Kim, Kang Mi; Song, Ju Dong; Chung, Hun Taeg; Park, Young Chul

    2008-01-25

    Heme oxygenase-1 (HO-1) is a stress-responsive protein that is known to regulate cellular functions such as cell proliferation, inflammation, and apoptosis. Here, we investigated the effects of HO activity on the expression of p53 in the human retinal pigment epithelium (RPE) cell line ARPE-19. Cobalt protoporphyrin (CoPP) induced the expression of both HO-1 and p53 without significant toxicity to the cells. In addition, the blockage of HO activity with the iron chelator DFO or with HO-1 siRNA inhibited the CoPP-induced expression of p53. Similarly, zinc protoporphyrin (ZnPP), an inhibitor of HO, suppressed p53 expression in ARPE-19 cells, although ZnPP increased the level of HO-1 protein while inhibiting HO activity. Also, CoPP-induced p53 expression was not affected by the formation of reactive oxygen species (ROS). Based on these results, we conclude that HO activity is involved in the regulation of p53 expression in a ROS-independent mechanism, and also suggest that the expression of p53 in ARPE-19 cells is associated with heme metabolites such as biliverdin/bilirubin, carbon monoxide, and iron produced by the activity of HO.

  14. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

    PubMed Central

    Delagrange, Philippe; Krause, Diana N.; Sugden, David; Cardinali, Daniel P.; Olcese, James

    2010-01-01

    The hormone melatonin (5-methoxy-N-acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT1 and MT2, that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer. PMID:20605968

  15. [The Bilbao declaration: international meeting on the law concerning the human genome project].

    PubMed

    1994-06-01

    The Bilbao statement was the result of a work meeting, held the day before the closing session by a group of representative experts, formed by general chairmen and meeting organizers. The compelled and necessary consent gave rise to the document that was read and communicated to the world's public opinion during the closing act on may 26, 1993. Notwithstanding, the working group considered that the divulged version was provisory and committed to continue the task of re-elaborating the statement. The aim was to complete and improve it, taking the greatest advantage of the important meeting achievements. The document that is next reproduced is the definitive integral version of the Bilbao Statement. The expert group that takes the responsibility of this Statement is Jean Dausset, Nobel Prize of Medicine (1980); Carleton Gajdusek, Nobel Prize of Medicine (1976); Santiago Grisolía president of UNESCO committee for the Genome Project; Michael Kirby, President of the Court of Appeal of the Supreme Court of New South Wales, Australia; Aaron Klug, member of the Constitutional Council, Paris, France; Rafael Mendizábal, Judge of the Constitutional Court, Madrid, Spain; Juan Bautista Pardo, President of the Superior Court of Justice of the Basque Country and Carlos María Romeo Casabona, Director of the Chair of Law and Human Genome of the University of Deusto (Bilbao). PMID:7732218

  16. The discovery of ubiquitin-dependent proteolysis

    PubMed Central

    Wilkinson, Keith D.

    2005-01-01

    In early 1980, Irwin A. Rose, Avram Hershko, and Aaron Ciechanover published two papers in PNAS that reported the astounding observation that energy-dependent intracellular proteolysis was far more complicated than the previously accepted models of lysosomal proteolysis or the action of ATP-dependent proteases such as bacterial lon. In fact, it has turned out to be even more complicated than they could have suspected. The general model of covalently attaching a small protein as a targeting signal has proved to be every bit as important to eukaryotic cells as the better understood modifications such as phosphorylation or acetylation. The key player in this modification, a small protein called ubiquitin (APF-1 in these papers), is the founding member of a large family of proteins containing the β-grasp fold and is used as a posttranslational targeting signal to modify the structure, function, and/or localization of other proteins. The story of this discovery is a textbook example of the confluence of intellectual curiosity, unselfish collaboration, chance, luck, and preparation. PMID:16230621

  17. The discovery of ubiquitin-dependent proteolysis.

    PubMed

    Wilkinson, Keith D

    2005-10-25

    In early 1980, Irwin A. Rose, Avram Hershko, and Aaron Ciechanover published two papers in PNAS that reported the astounding observation that energy-dependent intracellular proteolysis was far more complicated than the previously accepted models of lysosomal proteolysis or the action of ATP-dependent proteases such as bacterial lon. In fact, it has turned out to be even more complicated than they could have suspected. The general model of covalently attaching a small protein as a targeting signal has proved to be every bit as important to eukaryotic cells as the better understood modifications such as phosphorylation or acetylation. The key player in this modification, a small protein called ubiquitin (APF-1 in these papers), is the founding member of a large family of proteins containing the beta-grasp fold and is used as a posttranslational targeting signal to modify the structure, function, and/or localization of other proteins. The story of this discovery is a textbook example of the confluence of intellectual curiosity, unselfish collaboration, chance, luck, and preparation. PMID:16230621

  18. Ubiquitin: molecular modeling and simulations.

    PubMed

    Ganoth, Assaf; Tsfadia, Yossi; Wiener, Reuven

    2013-11-01

    The synthesis and destruction of proteins are imperative for maintaining their cellular homeostasis. In the 1970s, Aaron Ciechanover, Avram Hershko, and Irwin Rose discovered that certain proteins are tagged by ubiquitin before degradation, a discovery that awarded them the 2004 Nobel Prize in Chemistry. Compelling data gathered during the last several decades show that ubiquitin plays a vital role not only in protein degradation but also in many cellular functions including DNA repair processes, cell cycle regulation, cell growth, immune system functionality, hormone-mediated signaling in plants, vesicular trafficking pathways, regulation of histone modification and viral budding. Due to the involvement of ubiquitin in such a large number of diverse cellular processes, flaws and impairments in the ubiquitin system were found to be linked to cancer, neurodegenerative diseases, genetic disorders, and immunological disorders. Hence, deciphering the dynamics and complexity of the ubiquitin system is of significant importance. In addition to experimental techniques, computational methodologies have been gaining increasing influence in protein research and are used to uncover the structure, stability, folding, mechanism of action and interactions of proteins. Notably, molecular modeling and molecular dynamics simulations have become powerful tools that bridge the gap between structure and function while providing dynamic insights and illustrating essential mechanistic characteristics. In this study, we present an overview of molecular modeling and simulations of ubiquitin and the ubiquitin system, evaluate the status of the field, and offer our perspective on future progress in this area of research. PMID:24113788

  19. Regulation of the G1 to S transition by the ubiquitin pathway.

    PubMed

    DeSalle, L M; Pagano, M

    2001-02-16

    This year the most prestigious prize in medical sciences, the Lasker Award, has been presented to the three scientists who discovered the ubiquitin pathway: Aaron Ciechanover, Avram Hershko, and Alexander Varshavsky [Nature Med. 6 (2000) 1073-1081]. During a time when the scientific community was focused on understanding how proteins were synthesized, they intently pursued the novel idea that cells were programmed to selectively destroy proteins. Their work led to the identification of an elaborate system of protein degradation targeting a myriad of cellular substrates. A small protein called ubiquitin is at the center of this process. Although the ubiquitin pathway was first described in the early 1980s, it has only more recently advanced to the forefront of basic research as a significant regulatory network within the cell. The field continues to grow as new ubiquitination enzymes and novel functions of this system are identified. Scientists are focused on elucidating the mechanisms by which cells deploy the ubiquitin pathway to control levels of selected proteins, such as cell cycle regulatory proteins, transcription factors and signaling molecules. Accelerated or decelerated rates of degradation of particular substrates participate in the genesis of many human diseases. Thus, understanding the mechanisms that confer specificity to the ubiquitin system will allow the development of novel therapeutic approaches to target aberrations in this pathway underlying tumorigenesis and other human pathologies. PMID:11223033

  20. Memoir and performance: social change and self life-writing among men who are gay pornography producers and actors.

    PubMed

    Cohler, Bertram J

    2004-01-01

    Identity may be understood both as a life-story, either told or written as memoir or autobiography, and also as a practice such as producing or acting in gay pornographic film, but always within the context of social and historical change. Study of the memoirs of gay men who have been actors and/or producers of gay pornographic films across three generation cohorts provides an opportunity for understanding the interplay of social change and life circumstances in making gay identity. This perspective on identity is illustrated through the study of the memoirs of three men from different cohorts who have produced and acted in gay pornographic films: Wakefield Poole, born in 1936; Scott O'Hara, born in 1961; and Aaron Lawrence, born in 1971. Differences in style and content of both memoir and practice in gay pornographic films reflect changing social expectations regarding men who have sex with men following the emergence of the gay rights movement and the AIDS epidemic. PMID:15451702

  1. The Physics Force- Physics for ages 6 to 106.

    NASA Astrophysics Data System (ADS)

    Dahlberg, E. Dan

    2006-03-01

    The Physics Force is a very successful and entertaining outreach program of the Institute of Technology in the University of Minnesota developed to make science exciting and fun for students of all ages, from 6 to 106. Although all attendees, including high school and college students and guests from retirement homes, praise our performances, the primary focus is on K-6 students. The original Force consists of six k-12 teachers, Hank Ryan, Jon Barber, Jack Netland, Fred Orsted, Aaron Pinski, and Jay Dornfeld and Dan Dahlberg of the University of Minnesota Physics Department. The Force performed variations of The Physics Circus, our most popular show, at Disney's Epcot Center, parts of it were shown on Newton's Apple and several of us have performed demonstrations on the Knoff-Hoff Show, a very successful German T.V. science program. The goal of The Physics Force is to show students and the public Science is Fun, Science is Interesting, and Science is Understandable. By all measures we have available, we are extremely successful in reaching our goals. In the last three year cycle of our University support almost 100,000 residents of Minnesota (or about 2% of the total population) saw a Physics Force performance; it appears we will surpass those numbers in the present cycle.

  2. CZTSSe: Materials and Physics Challenges

    NASA Astrophysics Data System (ADS)

    Gunawan, Oki

    2011-03-01

    Thin-film photovoltaic (PV) technologies led by CdTe and Cu(In,Ga) Se 2 (CIGS) are enjoying growing market share, due to their high performance and cost competitiveness, in the quest for renewable energy for the future. However the reliance on non-earth abundant elements tellurium and indium in these technologies presents a potential obstacle to ultimate terawatt deployment. We recently demonstrated kesterite Cu 2 ZnSn(Se,S)4 (CZTSSe) solar cells, comprised of the earth abundant metals copper, zinc and tin, with world record efficiency of 9.7%. In this talk we present a comprehensive device characterization study that pinpoints the key performance bottlenecks in these cells. We find strong buffer-absorber interface recombination and low minority carrier lifetimes that limit the open circuit voltage and a high and diverging device series resistance at lower temperature that suggests a blocking back contact that may limit the fill factor. These findings help to identify key areas for improvement for these CZTSSe cells in the pursuit of a high performance terawatt-scalable PV technology. In collaboration with Teodor K. Todorov, Aaron Barkhouse, Kejia Wang, David B. Mitzi, Supratik Guha, IBM T J Watson Research Center.

  3. Cross-Spectral Signatures in Global Helioseismology Data of Large-Scale Flow in the Sun

    NASA Astrophysics Data System (ADS)

    Woodard, M. F.

    2005-05-01

    Large-scale flows in the Sun's interior have been studied using a variety of helioseismic techniques, including spectral analysis of spherical harmonic time series of photospheric velocity oscillations. Detailed maps of differential rotation have been obtained from measurements of the frequencies of resonance peaks in the power spectra. Flows can also affect power spectra in subtler ways, e.g., by their influence on the widths of resonance peaks. In addition to their spectral signature, flows and other aspherical perturbations also produce cross-spectral signatures, via the mode-coupling effect of a flow. Cross power spectra of time series of coefficients in the spherical-harmonic decomposition of SOHO/MDI medium-ℓ velocity images have been computed and are being compared with theoretical predictions. The results of a preliminary comparison of observed and theoretically predicted cross spectra for differential rotation and meridional circulation will be presented. A program to systematically map large-scale solar internal flow using cross-spectral data will be described. The author acknowledges useful discussions with colleagues, especially Doug Braun, Yuhong Fan, Aaron Birch, and Jesper Schou. He is also grateful to Jesper Schou for help in acquiring MDI data products and to NASA for support under contract NAS5-3114. The Solar Oscillations Investigation- Michelson Doppler Imager experiment on SOHO is supported by NASA contract NAG5-3077 at Stanford University. SOHO is a project of international cooperation between ESA and NASA.

  4. S-TI-S Josephson junction networks: a platform for exploring and exploiting topological states and Majorana fermions

    NASA Astrophysics Data System (ADS)

    van Harlingen, Dale J.

    We are studying the transport properties of hybrid superconductor-topological insulator nanoscale devices fabricated by depositing superconductor electrodes onto the surface of topological insulators. In top-gated lateral Nb-Bi2Se3-Nb junctions, we have measured the Josephson supercurrent and conductance as a function of geometry, temperature, and gate voltage in order to determine the nature of the electronic transport. The supercurrent exhibits a sharp drop as a function of gate voltage that may be explained by the relocation of the topological surface state from above to below trivial conducting surface states formed by band-banding near the surface. We find that the magnetic field modulation of the supercurrent in Josephson junctions and dc SQUIDs exhibits anomalous features consistent with a 4 π-periodic sin(φ/2)-component in the junction current-phase relation that may arise from the nucleation of Majorana bound states in the junction. We are exploring circuits for imaging, manipulating, and braiding these exotic excitations and schemes for reading out their parity. In collaboration with Aaron Finck, Erik Huemiller, Cihan Kurter, Vladimir Orlyanchik, Martin Stehno, and Can Zhang.

  5. Adapting and using quality management methods to improve health promotion.

    PubMed

    Becker, Craig M; Glascoff, Mary A; Felts, William Michael; Kent, Christopher

    2015-01-01

    Although the western world is the most technologically advanced civilization to date, it is also the most addicted, obese, medicated, and in-debt adult population in history. Experts had predicted that the 21st century would be a time of better health and prosperity. Although wealth has increased, our quest to quell health problems using a pathogenic approach without understanding the interconnectedness of everyone and everything has damaged personal and planetary health. While current efforts help identify and eliminate causes of problems, they do not facilitate the creation of health and well-being as would be done with a salutogenic approach. Sociologist Aaron Antonovsky coined the term salutogenesis in 1979. It is derived from salus, which is Latin for health, and genesis, meaning to give birth. Salutogenesis, the study of the origins and creation of health, provides a method to identify an interconnected way to enhance well-being. Salutogenesis provides a framework for a method of practice to improve health promotion efforts. This article illustrates how quality management methods can be used to guide health promotion efforts focused on improving health beyond the absence of disease. PMID:25777291

  6. Peptide neuroregulators: the opioid system as a model.

    PubMed

    Barchas, J D; Evans, C; Elliott, G R; Berger, P A

    1985-01-01

    Aaron Lerner's work provides a stunning set of examples of substances that help to transmit information in the brain and body. His characterization of alpha-MSH and melatonin and his sparking of interest in the further discovery of previously unknown substances have been of inestimable value for the field of neurobiology. Efforts such as those that Lerner undertook so successfully in the field of investigative dermatology now constitute a major research thrust in the field of behavioral neurochemistry and are directly related to advances in psychiatry and neurology. This review considers aspects of research on the neuropeptides, with particular attention to the endogenous opioid (morphine-like) peptides that are active on neural tissue. Neuropeptide research can be categorized broadly as efforts to discover and characterize new families and classes of active agents, investigations of their genetic and molecular processing, and studies of their relationships to behavior in animals and human beings. This review selectively considers some key research questions and strategies that arise from such research. PMID:2938344

  7. PRO-140 (Progenics).

    PubMed

    Poli, G

    2001-09-01

    PRO-140, a monoclonal antibody against the HIV coreceptor CCR5, is under investigation by Progenics and the Aaron Diamond AIDS Research Center (ADARC) as a potential treatment for HIV infection [211441], [286246], [286247]. Phase I/II trials were expected to commence during 2001 [395621], [409142], despite being initially planned for 2000 [322637], [361819], [365216], [375598], [408483]. In January 1998, ADARC and Progenics reported that the HIV binding site on the CCR5 coreceptor is distinct from betachemokine binding domains, which they claimed may allow for the development of therapeutics with fewer side effects [273391], 421256]. In vitro studies have shown PRO-140 potently blocked all of 17 primary HIV isolates that use CCR5 as a fusion coreceptor [342173]. In October 2000, Progenics was awarded an SBIR grant to fund a 2-year project exploring the breadth, potency and durability of PRO-140 therapy in laboratory and animal models of HIV infection. This project was a collaboration between Progenics, Weill Medical College of Cornell University and the Scripps Research Institute [385982]. In May 1999, the company entered into an agreement with Protein Design Labs (PDL) for the humanization by PDL of PRO-140 [325445]. In November 1997, Progenics was awarded a 600,000 dollars grant from the NIAID for the examination of new approaches to HIV vaccine design based on CCR5 [268407]. PMID:15965853

  8. Validating the Implementation Climate Scale (ICS) in child welfare organizations.

    PubMed

    Ehrhart, Mark G; Torres, Elisa M; Wright, Lisa A; Martinez, Sandra Y; Aarons, Gregory A

    2016-03-01

    There is increasing emphasis on the use of evidence-based practices (EBPs) in child welfare settings and growing recognition of the importance of the organizational environment, and the organization's climate in particular, for how employees perceive and support EBP implementation. Recently, Ehrhart, Aarons, and Farahnak (2014) reported on the development and validation of a measure of EBP implementation climate, the Implementation Climate Scale (ICS), in a sample of mental health clinicians. The ICS consists of 18 items and measures six critical dimensions of implementation climate: focus on EBP, educational support for EBP, recognition for EBP, rewards for EBP, selection or EBP, and selection for openness. The goal of the current study is to extend this work by providing evidence for the factor structure, reliability, and validity of the ICS in a sample of child welfare service providers. Survey data were collected from 215 child welfare providers across three states, 12 organizations, and 43 teams. Confirmatory factor analysis demonstrated good fit to the six-factor model and the alpha reliabilities for the overall measure and its subscales was acceptable. In addition, there was general support for the invariance of the factor structure across the child welfare and mental health sectors. In conclusion, this study provides evidence for the factor structure, reliability, and validity of the ICS measure for use in child welfare service organizations. PMID:26563643

  9. Understanding public perceptions of benefits and risks of childhood vaccinations in the United States.

    PubMed

    Song, Geoboo

    2014-03-01

    In the face of a growing public health concern accompanying the reemerging threat of preventable diseases, this research seeks mainly to explain variations in the perceived benefits and risks of vaccinations among the general public in the United States. As Mary Douglas and Aaron Wildavsky's grid-group cultural theory of risk perception claims, the analytical results based upon original data from a nationwide Internet survey of 1,213 American adults conducted in 2010 suggest that individuals' cultural predispositions contribute to the formation of their perceptions pertaining to vaccine benefits and risks at both societal and individual levels, in conjunction with other factors suggested by previous risk perception literature, such as perceived prevalence of diseases, trust, knowledge level, and demographic characteristics. Those with a strong hierarch orientation tend to envision greater benefits and lesser risks and conceive of a relatively high ratio of benefit to risk when compared to other cultural types. By contrast, those with a strong fatalist tendency are inclined to emphasize risks and downplay benefits while conceiving of a low vaccination benefit-risk ratio. Situated between hierarchs and fatalists, strong egalitarians are prone to perceive greater benefits, smaller risks, and a more positive benefit-risk ratio than strong individualists. PMID:24033739

  10. Global Warming: Claims, Science, and Consequences

    NASA Astrophysics Data System (ADS)

    Gould, Laurence I.

    2007-04-01

    Widespread (and seemingly dominant) claims about the dire consequences of anthropogenic global warming (AGW) have been propagated by both scientists and politicians and have been prominently featured by much of the mass media. This talk will examine some of those claims --- such as those made in the popular pro-AGW film, An Inconvenient Truth^1 --- from the perspectives of science^2 and scientific methodology^3. Some of the issues considered will be: What are the major ``greenhouse gases''? To what extent is global warming a result of human influences through an increase of ``greenhouse gases''? Is an increase in (1) global temperature and (2) carbon dioxide bad/good? What are some meanings that can be given to the term ``consensus'' in science? What are the estimated financial and other costs of governments implementing the Kyoto accords? Links to readings and videos will be given at the conclusion of the talk. ^1Gore, Al, An Inconvenient Truth: The Planetary Emergency of Global Warming and What We Can Do About It -- (Rodale Press, May, 2006). ^2Marlo Lewis, ``A Skeptic's Guide to An Inconvenient Truth'' http://www.cei.org/pages/aitresponse-book.cfm ^3Aaron Wildavsky, But Is It True? A Citizen's Guide to Environmental Health and Safety Issues (Harvard University Press, 1995), Intro. and Chap. 11. To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2007.NES07.C1.6

  11. Implementing a Measurement Feedback System in Community Mental Health Clinics: A Case Study of Multilevel Barriers and Facilitators.

    PubMed

    Gleacher, Alissa A; Olin, Serene S; Nadeem, Erum; Pollock, Michele; Ringle, Vanesa; Bickman, Leonard; Douglas, Susan; Hoagwood, Kimberly

    2016-05-01

    Measurement feedback systems (MFSs) have been proposed as a means of improving practice. The present study examined the implementation of a MFS, the Contextualized Feedback System (CFS), in two community-based clinic sites. Significant implementation differences across sites provided a basis for examining factors that influenced clinician uptake of CFS. Following the theoretical implementation framework of Aarons et al. (Adm Policy Mental Health Mental Health Serv Res 38(1):4-23, 2011), we coded qualitative data collected from eighteen clinicians (13 from Clinic U and 5 from Clinic R) who participated in semi-structured interviews about their experience with CFS implementation. Results suggest that clinicians at both clinics perceived more barriers than facilitators to CFS implementation. Interestingly, clinicians at the higher implementing clinic reported a higher proportion of barriers to facilitators (3:1 vs. 2:1); however, these clinicians also reported a significantly higher level of organizational and leadership supports for CFS implementation. Implications of these findings are discussed. PMID:25735619

  12. Van der Waals interactions in density functional theory

    NASA Astrophysics Data System (ADS)

    Langreth, David C.

    2009-03-01

    The van der Waals density functional which we introduced half a decade agoootnotetextM. Dion et al. Phys. Rev. Lett. 92, 246401 (2004). and its self-consistent generalizationootnotetextT. Thonhauser et al., Phys. Rev. B 76, 125112 (2007). will be briefly reviewed. There are many collaborators in the application review that will follow, not only those who worked in the physics department at Rutgers% ootnotetextMaxime Dion, Aaron Puzder, T. Thonhauser, Valentino R. Cooper, Shen Li, Eamonn Murray, Lingzhu Kong, and Kyuho Lee. and at Chalmers,% ootnotetextHenrik Rydberg, Svetla Chakarova-K"ack, Jesper Kleis, Elsebeth Schr"oder, Per Hyldgaard, and Bengt I. Lundqvist. but also at Denmarks Technical University,% ootnotetextAndrei Kelkkanen, Poul G. Moses, Jesper Kleis, and Bengt I. Lundqvist. the chemistry department at Rutgers,% ootnotetextKonhoa Li, Jing Li, Yves Chabal, and Wilma K. Olson. and most recently at the University of Texas at Dallas.% ootnotetextNour Nijem and Yves Chabal. I will expand on our recent review article,ootnotetextD. C. Langreth et al., J. Phys. Cond. Mat. (in press). which hopefully will be published before the present talk, and include applications by other groups not listed below. If possible, I will also review results from a more recent collaboration to study nucleosomal DNA and beyond.

  13. Modeling cell-matrix traction forces in Keratinocyte colonies

    NASA Astrophysics Data System (ADS)

    Banerjee, Shiladitya

    2013-03-01

    Crosstalk between cell-cell and cell-matrix adhesions plays an essential role in the mechanical function of tissues. The traction forces exerted by cohesive keratinocyte colonies with strong cell-cell adhesions are mostly concentrated at the colony periphery. In contrast, for weak cadherin-based intercellular adhesions, individual cells in a colony interact with their matrix independently, with a disorganized distribution of traction forces extending throughout the colony. In this talk I will present a minimal physical model of the colony as contractile elastic media linked by springs and coupled to an elastic substrate. The model captures the spatial distribution of traction forces seen in experiments. For cell colonies with strong cell-cell adhesions, the total traction force of the colony measured in experiments is found to scale with the colony's geometrical size. This scaling suggests the emergence of an effective surface tension of magnitude comparable to that measured for non-adherent, three-dimensional cell aggregates. The physical model supports the scaling and indicates that the surface tension may be controlled by acto-myosin contractility. Supported by the NSF through grant DMR-1004789. This work was done in collaboration with Aaron F. Mertz, Eric R. Dufresne and Valerie Horsley (Yale University) and M. Cristina Marchetti (Syracuse University).

  14. The Use of Size Distributions in Determining Growth Mechanisms: The Growth of Grain Boundary Precipitates in Cobalt-20 Iron

    NASA Astrophysics Data System (ADS)

    Northover (Née Payne), Shirley M.

    2015-01-01

    Accurate prediction of microstructural stability in an alloy depends not only on a sound knowledge of the thermodynamics of the system but also of the kinetics of the phase changes involved. Conventionally, precipitate growth mechanisms have been inferred from the variation with aging time of various single parameters such as the mean, mode or maximum of the precipitate size distribution, which has then been compared to theoretical models of growth of an individual precipitate. In the present study, the development, with aging time at 1003 K (730 °C), of the size and shape distributions of grain boundary precipitates in Co-20Fe has been examined to determine the rate-controlling processes, and the conclusions compared to those from conventional analysis. The growth of the precipitates was well described by the grain boundary-dependent collector plate mechanism of Brailsford and Aaron. As the precipitates grew, low-energy facets were formed, which could move only by the propagation of ledges, and thickening was inhibited. The precipitates' diffusion fields in the grain boundary overlapped and the size distributions of the longest aged specimens showed that local coarsening occurred under partial interface control.

  15. Adiabatic Quantum Computation with Neutral Atoms

    NASA Astrophysics Data System (ADS)

    Biedermann, Grant

    2013-03-01

    We are implementing a new platform for adiabatic quantum computation (AQC)[2] based on trapped neutral atoms whose coupling is mediated by the dipole-dipole interactions of Rydberg states. Ground state cesium atoms are dressed by laser fields in a manner conditional on the Rydberg blockade mechanism,[3,4] thereby providing the requisite entangling interactions. As a benchmark we study a Quadratic Unconstrained Binary Optimization (QUBO) problem whose solution is found in the ground state spin configuration of an Ising-like model. In collaboration with Lambert Parazzoli, Sandia National Laboratories; Aaron Hankin, Center for Quantum Information and Control (CQuIC), University of New Mexico; James Chin-Wen Chou, Yuan-Yu Jau, Peter Schwindt, Cort Johnson, and George Burns, Sandia National Laboratories; Tyler Keating, Krittika Goyal, and Ivan Deutsch, Center for Quantum Information and Control (CQuIC), University of New Mexico; and Andrew Landahl, Sandia National Laboratories. This work was supported by the Laboratory Directed Research and Development program at Sandia National Laboratories

  16. Introduction to Diffraction in Materials Science and Engineering

    NASA Astrophysics Data System (ADS)

    Krawitz, Aaron D.

    2001-04-01

    Fundamentals and practical applications of diffraction for researchers, engineers, and students Materials science relies heavily on diffraction for the analysis of materials. Introduction to Diffraction in Materials Science and Engineering is a survey of the practical aspects of this valuable tool. Though it contains basic discussion of the theory and physics of diffraction, this book emphasizes understanding and the practical application of diffraction in materials science-making it a valuable text and resource for students, professionals, and researchers. Designed as a teaching and self-study text, this resource begins with a treatment of the fundamentals of crystallography and crystal structure and its importance in diffraction before moving on to cover important aspects of diffraction applications. Numerous examples and problems at the end of each chapter, including critical thinking questions, make this an excellent tool for learning and understanding. The book includes treatments of: * Basics of crystallography * Geometrical representation of crystals and reciprocal space * X-rays and neutrons * Structure factors and intensity * Powder diffraction * Qualitative (Powder Diffraction File) and quantitative phase analysis * Use of the International Tables for more complex structures and the Reitveld method * Residual stress * Introductions to texture, small diffracting units, and long-range order Aaron Krawitz provides both a practical introduction to diffraction that suits the needs of students and a resource for professionals already at work in materials science or engineering who want to utilize the power of diffraction in the study of materials.

  17. Fingerprint enhancement revisited and the effects of blood enhancement chemicals on subsequent profiler Plus fluorescent short tandem repeat DNA analysis of fresh and aged bloody fingerprints.

    PubMed

    Frégeau, C J; Germain, O; Fourney, R M

    2000-03-01

    This study was aimed at determining the effect of seven blood enhancement reagents on the subsequent Profiler Plus fluorescent STR DNA analysis of fresh or aged bloody fingerprints deposited on various porous and nonporous surfaces. Amido Black, Crowle's Double Stain. 1,8-diazafluoren-9-one (DFO), Hungarian Red, leucomalachite green, luminol and ninhydrin were tested on linoleum, glass, metal, wood (pine, painted white), clothing (85% polyester/15% cotton, 65% polyester/35% cotton, and blue denim) and paper (Scott 2-ply and Xerox-grade). Preliminary experiments were designed to determine the optimal blood dilutions to use to ensure a DNA typing result following chemical enhancement. A 1:200 blood dilution deposited on linoleum and enhanced with Crowle's Double Stain generated enough DNA for one to two rounds of Profiler Plus PCR amplification. A comparative study of the DNA yields before and after treatment indicated that the quantity of DNA recovered from bloody fingerprints following enhancement was reduced by a factor of 2 to 12. Such a reduction in the DNA yields could potentially compromise DNA typing analysis in the case of small stains. The blood enhancement chemicals selected were also evaluated for their capability to reveal bloodmarks on the various porous and nonporous surfaces chosen in this study. Luminol. Amido Black and Crowle's Double Stain showed the highest sensitivity of all seven chemicals tested and revealed highly diluted (1:200) bloody fingerprints. Both luminol and Amido Black produced excellent results on both porous and nonporous surfaces, but Crowle's Double Stain failed to produce any results on porous substrates. Hungarian Red, DFO, leucomalachite green and ninhydrin showed lower sensitivities. Enhancement of bloodmarks using any of the chemicals selected, and short-term exposure to these same chemicals (i.e., less than 54 days), had no adverse effects on the PCR amplification of the nine STR systems surveyed (D3S 1358, HumvWA, Hum

  18. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells

    PubMed Central

    Ma, S; Henson, E S; Chen, Y; Gibson, S B

    2016-01-01

    Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor. PMID:27441659

  19. Dominant roles of Fenton reaction in sodium nitroprusside-induced chondrocyte apoptosis.

    PubMed

    Quan, Ying-Yao; Qin, Gui-Qi; Huang, Hao; Liu, Yu-Hong; Wang, Xiao-Ping; Chen, Tong-Sheng

    2016-05-01

    Sodium nitroprusside (SNP) has been widely used as an exogenous nitric oxide (NO) donor to explore the molecular mechanism of NO-mediated chondrocyte apoptosis during the latest two decades. We have recently found that NO-independent ROS play a key role in SNP-induced apoptosis in rabbit chondrocytes. This study aims to investigate what kind of ROS and how the reliable ROS mediators mediate the SNP-induced apoptosis. Data shows that SNP and NO-exhausted SNP (SNPex) induced ROS production or cytotoxicity to identically degree. SNP induced a marked increase in iron ions, superoxide anion (O2(•-)), hydrogen peroxide (H2O2) and hydroxyl radical ((•)OH) level. H2O2 scavenger (CAT) and (•)OH scavenger (DMSO) significantly inhibited SNP-induced chondrocyte apoptosis. Iron ions chelator (DFO) entirely prevented SNP-induced chondrocyte apoptosis. In contrast, O2(•-) scavenger (SOD) and glutathione depletion agent (BSO) promoted SNP-induced cytotoxicity. K3[Fe(CN)6] exhibited no cytotoxicity, and H2O2 alone up to 250µM or iron ions alone up to 90µM is non-cytotoxic to chondrocytes. Combination of 25µM FeSO4 and 100µM H2O2 in the presence of BSO induced chondrocyte death similar to SNP treatment. Fetal bovine serum (FBS) enhanced iron ions release from SNP and the cytotoxicity of SNP. Our data shows that the extracellular Fenton reaction between iron ions released from SNP and H2O2 induced by SNP plays a key role in SNP-induced chondrocyte apoptosis. Overall, our results indicate that the potential of SNP to increase iron ions and ROS should be especially considered for some biological functions and, possibly, also for clinical applications of this drug. PMID:26923801

  20. Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1.

    PubMed

    Watson, Ailsa; Lipina, Christopher; McArdle, Harry J; Taylor, Peter M; Hundal, Harinder S

    2016-05-01

    Iron is an indispensable micronutrient that regulates many aspects of cell function, including growth and proliferation. These processes are critically dependent upon signalling via the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Herein, we test whether iron depletion induced by cell incubation with the iron chelator, deferoxamine (DFO), mediates its effects on cell growth through mTORC1-directed signalling and protein synthesis. We have used Caco-2 cells, a well-established in vitro model of human intestinal epithelia. Iron depletion increased expression of iron-regulated proteins (TfR, transferrin receptor and DMT1, divalent metal transporter, as predicted, but it also promoted a marked reduction in growth and proliferation of Caco-2 cells. This was strongly associated with suppressed mTORC1 signalling, as judged by reduced phosphorylation of mTOR substrates, S6K1 and 4E-BP1, and diminished protein synthesis. The reduction in mTORC1 signalling was tightly coupled with increased expression and accumulation of REDD1 (regulated in DNA damage and development 1) and reduced phosphorylation of Akt and TSC2. The increase in REDD1 abundance was rapidly reversed upon iron repletion of cells but was also attenuated by inhibitors of gene transcription, protein phosphatase 2A (PP2A) and by REDD1 siRNA--strategies that also antagonised the loss in mTORC1 signalling associated with iron depletion. Our findings implicate REDD1 and PP2A as crucial regulators of mTORC1 activity in iron-depleted cells and indicate that their modulation may help mitigate atrophy of the intestinal mucosa that may occur in response to iron deficiency. PMID:26827808

  1. Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells.

    PubMed

    Lovejoy, David B; Richardson, Des R

    2002-07-15

    We previously demonstrated that 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and other aroylhydrazone chelators possess potent antineoplastic activity because of their ability to bind iron (Fe). From these studies, we identified structural components of the hydrazones that provide antineoplastic activity, namely the salicylaldehyde and 2-hydroxy-1-naphthylaldehyde moieties. A related group of chelators known as the thiosemicarbazones also show pronounced antitumor activity because of their ability to inhibit ribonucleotide reductase. Considering this, we designed a new series of "hybrid ligands" by condensation of the aldehydes described above with a range of thiosemicarbazides. The parent compound of these ligands is 2-hydroxy-1-naphthylaldehyde thiosemicarbazone (NT). Of 8 NT analogues, 3 chelators, namely NT, N4mT (2-hydroxy-1-naphthylaldehyde-4-methyl-3-thiosemicarbazone), and N44mT (2-hydroxy-1-naphthylaldehyde-4,4-dimethyl-3-thiosemicarbazone), showed high antiproliferative activity against SK-N-MC neuroepithelioma cells (50% inhibitory concentration [IC(50)] = 0.5-1.5 microM). Indeed, their activity was significantly (P <.0001) greater than that of desferrioxamine (DFO) (IC(50) = 22 microM). We demonstrate that 311, a 311 analogue (311m), and several NT-series chelators have significantly (P <.001) greater antiproliferative activity against tumor cells than against a range of normal cell types. For example, the IC(50) values of NT and N4mT in SK-N-MC neuroepithelioma cells were 0.5 microM, whereas for fibroblasts the IC(50) values were greater than 25 microM. Further, the effect of one of the most potent chelators (311m) on preventing the growth of bone marrow stem cell cultures was far less than that of doxorubicin and similar to that of cisplatin. These studies support the further development of these chelators as antiproliferative agents. PMID:12091363

  2. Surface buoyant plumes from melting icebergs in the Labrador Sea

    NASA Astrophysics Data System (ADS)

    Yankovsky, Alexander E.; Yashayaev, Igor

    2014-09-01

    Canada's Department of Fisheries and Oceans (DFO) conducts annual surveys in the Labrador Sea along the repeat hydrography line AR7W. The occupation of the AR7W line in May 2013 was followed by the experiment aimed at resolving the imprint of melting drifting icebergs on the upper layer thermohaline characteristics in the Labrador Sea. We present high-resolution observations around two icebergs conducted with the towed undulating platform Moving Vessel Profiler (MVP). The first iceberg drifted in relatively warm water of Atlantic origin (~2.5-3.1 °C) off Greenland, while the second iceberg was on the Labrador shelf in cold water below 0 °C. Both icebergs had a lengthscale of O(100 m). In both cases surface buoyant plumes fed by melt water and attached to the iceberg were observed. The plumes were evident in the anomalous thermohaline characteristics of the seawater. Their density anomalies were sufficiently strong to produce visible frontal structures, which imply a development of the intrinsic dynamics associated with a plume. The first plume formed over a time interval of ~10 h, while the second plume formed over several days and extended for more than 1 km (tenfold the iceberg's size). Strong vertical displacements of the pycnocline were observed near the second iceberg. They are interpreted as the internal wave wake. This interpretation is based on the temporal scale of these oscillations (local buoyancy frequency), as well as on the spatial orientation of these waves with respect to the iceberg drift relative to the pycnocline. The observed internal waves partially overlapped with the plume and affected its structure. The saline seawater splashing by swell contributed to the surface melting of the icebergs. Scaling analysis of the second plume suggests that it could be in the “rotational” dynamic regime with recirculating anticyclonic flow.

  3. Knowledge Data Base of extreme weather events in Europe

    NASA Astrophysics Data System (ADS)

    Friedrich, K.

    2012-04-01

    The knowledge data base is a collection of extreme weather events within the region of RA VI of WMO (Europe and Middle East) for the last 50 years. The focal point of the data base is the impact of weather extremes and damage. The input comes from different data collections as the International Disaster Database (EM-DAT), the Dartmouth Flood Observatory (DFO), the archive of extreme weather events of Karlsruhe Institute of Technology (KIT) and GLIDE Number Database. Different raster datasets were used to define the geographical extent of those events. The combination of information as disaster type, geometry, duration, damage, causes, measured extremes and anomalies with geographical information gives the possibility to visualize those events in GIS and to use a spatial search algorithm to detect events in a certain region. This database will be applied in a Climate Watch System, which has been suggested by the WMO. Climate Watch Systems are early warning systems, which use climate monitoring data and results from long-range forecasts to detect critical weather periods such as heatwave, coldwave, flood, drought, wildfire and others. If the monitoring gives an indication of outstanding weather events and the long-range forecast shows continuation of those events, the knowledge data base can provide information about impact of similar events, hazards and damage in the affected region. The knowledge data base was developed in the WMO RA VI Pilot Regional Climate Centre on Climate Monitoring (RCC-CM). RCCs are Centres of Excellence that assist National Hydrological and Meteorological Services (NHMS) in a given region to deliver better climate services and products including regional long-range forecasts, and to strengthen their capacity to meet national climate information needs. Access to visualization of the data base for NMHS will be provided by connection to the Web Mapping Service of a geo server.

  4. Hydrogen peroxide (H2O2) increases the steady-state mRNA levels of collagenase/MMP-1 in human dermal fibroblasts.

    PubMed

    Brenneisen, P; Briviba, K; Wlaschek, M; Wenk, J; Scharffetter-Kochanek, K

    1997-01-01

    Reactive oxygen species (ROS) have been shown to be important messenger molecules in the induction of several genes. In human dermal fibroblasts the herbicide paraquat (PQ2+) was used to induce intracellular oxidative stress that was modulated by the inhibition of copper, zinc superoxide dismutase (Cu,ZnSOD), glutathione peroxidase (GSHPx), catalase, and blocking of the Fenton reaction. Interstitial collagenase (MMP-1) mRNA increased time dependently for up to 72 h following paraquat treatment. A correlation with the translation of MMP-1 could, however, only be detected up to 24 h, indicating an uncoupling of transcription and translation. Interleukin-1 alpha and beta mRNA showed two peaks at 6 h and 72 h. The inhibition of catalase by aminotriazol (ATZ), inhibition of GSHPx by buthionine sulfoximine (BSO), and blocking the Fenton reaction by the iron chelator desferrioxamine (DFO) in concert led to an increase in steady-state MMP-1 mRNA levels, possibly dependent on intracellular H2O2 increase. This combined treatment potentiated MMP-1 mRNA induction up to 6.5-fold compared to paraquat treated controls. Furthermore, exogenously added H2O2 caused an increase in MMP-1 mRNA levels. In contrast, inhibition of Cu,ZnSOD by diethyldithiocarbamate (DDC), leading to diminished H2O2 production from O2.-, decreased MMP-1 mRNA induction. Collectively, our data provide evidence that H2O2 is an important intermediate in the downstream signalling pathway finally leading to the induction of increased steady state MMP-1 mRNA levels. The synthesis of MMPs may contribute to connective tissue damage in vivo related to photoaging, inflammatory diseases, and tumor invasion. PMID:8981044

  5. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    PubMed

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment. PMID:27059255

  6. A Graph-Based Recovery and Decomposition of Swanson’s Hypothesis using Semantic Predications

    PubMed Central

    Cameron, Delroy; Bodenreider, Olivier; Yalamanchili, Hima; Danh, Tu; Vallabhaneni, Sreeram; Thirunarayan, Krishnaprasad; Sheth, Amit P.; Rindflesch, Thomas C.

    2014-01-01

    Objectives This paper presents a methodology for recovering and decomposing Swanson’s Raynaud Syndrome–Fish Oil Hypothesis semi-automatically. The methodology leverages the semantics of assertions extracted from biomedical literature (called semantic predications) along with structured background knowledge and graph-based algorithms to semi-automatically capture the informative associations originally discovered manually by Swanson. Demonstrating that Swanson’s manually intensive techniques can be undertaken semi-automatically, paves the way for fully automatic semantics-based hypothesis generation from scientific literature. Methods Semantic predications obtained from biomedical literature allow the construction of labeled directed graphs which contain various associations among concepts from the literature. By aggregating such associations into informative subgraphs, some of the relevant details originally articulated by Swanson has been uncovered. However, by leveraging background knowledge to bridge important knowledge gaps in the literature, a methodology for semi-automatically capturing the detailed associations originally explicated in natural language by Swanson has been developed. Results Our methodology not only recovered the 3 associations commonly recognized as Swanson’s Hypothesis, but also decomposed them into an additional 16 detailed associations, formulated as chains of semantic predications. Altogether, 14 out of the 19 associations that can be attributed to Swanson were retrieved using our approach. To the best of our knowledge, such an in-depth recovery and decomposition of Swanson’s Hypothesis has never been attempted. Conclusion In this work therefore, we presented a methodology for semi- automatically recovering and decomposing Swanson’s RS-DFO Hypothesis using semantic representations and graph algorithms. Our methodology provides new insights into potential prerequisites for semantics-driven Literature-Based Discovery (LBD

  7. Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates

    SciTech Connect

    Larosche, Isabelle; Choumar, Amal; Fromenty, Bernard; Letteron, Philippe; Abbey-Toby, Adje; Van Remmen, Holly; Epstein, Charles J.; Richardson, Arlan; Feldmann, Gerard; Pessayre, Dominique; Mansouri, Abdellah

    2009-02-01

    Alcohol consumption increases reactive oxygen species formation and lipid peroxidation, whose products can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. A possible role of manganese superoxide dismutase (MnSOD) on these effects has not been investigated. To test whether MnSOD overexpression modulates alcohol-induced mitochondrial alterations, we added ethanol to the drinking water of transgenic MnSOD-overexpressing (TgMnSOD) mice and their wild type (WT) littermates for 7 weeks. In TgMnSOD mice, alcohol administration further increased the activity of MnSOD, but decreased cytosolic glutathione as well as cytosolic glutathione peroxidase activity and peroxisomal catalase activity. Whereas ethanol increased cytochrome P-450 2E1 and mitochondrial ROS generation in both WT and TgMnSOD mice, hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls were only increased in ethanol-treated TgMnSOD mice but not in WT mice. In ethanol-fed TgMnSOD mice, but not ethanol-fed WT mice, mtDNA was depleted, and mtDNA lesions blocked the progress of polymerases. The iron chelator, DFO prevented hepatic iron accumulation, lipid peroxidation, protein carbonyl formation and mtDNA depletion in alcohol-treated TgMnSOD mice. Alcohol markedly decreased the activities of complexes I, IV and V of the respiratory chain in TgMnSOD, with absent or lesser effects in WT mice. There was no inflammation, apoptosis or necrosis, and steatosis was similar in ethanol-treated WT and TgMnSOD mice. In conclusion, prolonged alcohol administration selectively triggers iron accumulation, lipid peroxidation, respiratory complex I protein carbonylation, mtDNA lesions blocking the progress of polymerases, mtDNA depletion and respiratory complex dysfunction in TgMnSOD mice but not in WT mice.

  8. Development and application of an assay for uranyl complexation by fungal metabolites, including siderophores.

    PubMed

    Renshaw, Joanna C; Halliday, Verity; Robson, Geoffrey D; Trinci, Anthony P J; Wiebe, Marilyn G; Livens, Francis R; Collison, David; Taylor, Robin J

    2003-06-01

    An assay to detect UO(2)(2+) complexation was developed based on the chrome azurol S (CAS) assay for siderophores (B. Schwyn and J. B. Neilands, Anal. Biochem. 160:47-56, 1987) and was used to investigate the ability of fungal metabolites to complex actinides. In this assay the discoloration of two dyed agars (one containing a CAS-Fe(3+) dye and the other containing a CAS-UO(2)(2+) dye) caused by ligands was quantified. The assay was tested by using the siderophore desferrioxamine B (DFO), and the results showed that there was a regular, reproducible relationship between discoloration and the amount of siderophore added. The ratio of the discoloration on the CAS-UO(2)(2+) agar to the discoloration on the CAS-Fe(3+) agar was independent of the amount of siderophore added. A total of 113 fungi and yeasts were isolated from three soil samples taken from the Peak District National Park. The fungi were screened for the production of UO(2)(2+) chelators by using the CAS-based assay and were also tested specifically for hydroxamate siderophore production by using the hydroxamate siderophore auxotroph Aureobacterium flavescens JG-9. This organism is highly sensitive to the presence of hydroxamate siderophores. However, the CAS-based assay was found to be less sensitive than the A. flavescens JG-9 assay. No significant difference between the results for each site for the two tests was found. Three isolates were selected for further study and were identified as two Pencillium species and a Mucor species. Our results show that the new assay can be effectively used to screen fungi for the production of UO(2)(2+) chelating ligands. We suggest that hydroxamate siderophores can be produced by mucoraceous fungi. PMID:12788768

  9. Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization.

    PubMed

    Vlachodimitropoulou Koumoutsea, Evangelia; Garbowski, Maciej; Porter, John

    2015-09-01

    Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half-maximum effect can be reduced by 3·8-fold when only 1 μmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator. PMID:26033030

  10. Towards the mechanism and comparative effect of diphenyl diselenide, diphenyl ditelluride and ebselen under various pathophysiological conditions in rat's kidney preparation.

    PubMed

    Hassan, Waseem; Ibrahim, Mohammad; Rocha, Joao Batista Teixeira

    2009-11-10

    As an extension of our previous work we not only evaluated the relationship between acidosis and lipid peroxidation in rat's kidney homogenate, but also determined for the first time the potential anti-oxidant activity of diphenyl diselenide, diphenyl ditelluride and ebselen at a range of pH values (7.4-5.4). Because of the pH dependency of iron redox cycling, pH and iron need to be well controlled and for the reason we tested a number of pH values (from 7.4 to 5.4) to get a closer idea about the role of iron under various pathological conditions. Acidosis increased rate of lipid peroxidation in the absence Fe (II) in kidney homogenates especially at pH 5.4. This higher extent of lipid peroxidation can be explained by; the mobilized iron which may come from reserves where it is weakly bound. Addition of iron (Fe) chelator desferoxamine (DFO) to reaction medium completely inhibited the peroxidation processes at all studied pH values including acidic values (5.8-5.4). In the presence of Fe (II) acidosis also enhanced detrimental effect of Fe (II) especially at pH (6.4-5.4). Diphenyl diselenide significantly protected lipid peroxidation at all studied pH values, while ebselen offered only a small statistically non-significant protection. The highest anti-oxidant potency was observed for diphenyl ditelluride. These differences in potencies were explained by the mode of action of these compounds using their catalytic anti-oxidant cycles. However, changing the pH of the reaction medium did not alter the anti-oxidant activity of the tested compounds. This study provides evidence for acidosis catalyzed oxidative stress in kidney homogenate and for the first time anti-oxidant potential of diphenyl diselenide and diphenyl ditelluride not only at physiological pH but also at a range of acidic values. PMID:19589335

  11. Operational coupled atmosphere - ocean - ice forecast system for the Gulf of St. Lawrence, Canada

    NASA Astrophysics Data System (ADS)

    Faucher, M.; Roy, F.; Desjardins, S.; Fogarty, C.; Pellerin, P.; Ritchie, H.; Denis, B.

    2009-09-01

    A fully interactive coupled atmosphere-ocean-ice forecasting system for the Gulf of St. Lawrence (GSL) has been running in experimental mode at the Canadian Meteorological Centre (CMC) for the last two winter seasons. The goal of this project is to provide more accurate weather and sea ice forecasts over the GSL and adjacent coastal areas by including atmosphere-oceanice interactions in the CMC operational forecast system using a formal coupling strategy between two independent modeling components. The atmospheric component is the Canadian operational GEM model (Côté et al. 1998) and the oceanic component is the ocean-ice model for the Gulf of St. Lawrence developed at the Maurice Lamontagne Institute (IML) (Saucier et al. 2003, 2004). The coupling between those two models is achieved by exchanging surface fluxes and variables through MPI communication. The re-gridding of the variables is done with a package developed at the Recherche en Prevision Numerique centre (RPN, Canada). Coupled atmosphere - ocean - ice forecasts are issued once a day based on 00GMT data. Results for the past two years have demonstrated that the coupled system produces improved forecasts in and around the GSL during all seasons, proving that atmosphere-ocean-ice interactions are indeed important even for short-term Canadian weather forecasts. This has important implications for other coupled modeling and data assimilation partnerships that are in progress involving EC, the Department of Fisheries and Oceans (DFO) and the National Defense (DND). Following this experimental phase, it is anticipated that this GSL system will be the first fully interactive coupled system to be implemented at CMC.

  12. Linking macrobenthic communities structure and zonation patterns on sandy shores: Mapping tool toward management and conservation perspectives in Northern France

    NASA Astrophysics Data System (ADS)

    Rolet, Céline; Spilmont, Nicolas; Dewarumez, Jean-Marie; Luczak, Christophe

    2015-05-01

    In a context of intensifying anthropogenic pressures on sandy shores, the mapping of benthic habitat appears as an essential first step and a fundamental baseline for marine spatial planning, ecosystem-based management and conservation efforts of soft-sediment intertidal areas. Mapping allows representing intertidal habitats that are basically characterised by abiotic (e.g sediments, exposure to waves…) and biotic factors such as macrobenthic communities. Macrobenthic communities are known to show zonation patterns across sandy beaches and many studies highlighted the existence of three biological zones. We tested this general model of a tripartite biological division of the shore at a geographical scale of policy, conservation and management decisions (i.e. Northern France coastline), using multivariate analyses combined with the Direct Field Observation (DFO) method. From the upper to the lower shores, the majority of the beaches exhibited three macrobenthic communities confirming the existence of the tripartite biological division of the shore. Nevertheless, in some cases, two or four zones were found: (1) two zones when the drying zone located on the upper shore was replaced by littoral rock or engineering constructions and (2) four zones on beaches and estuaries where a muddy-sand community occurred from the drift line to the mid shore. The correspondence between this zonation pattern of macrobenthic communities and the EUNIS habitat classification was investigated and the results were mapped to provide a reference state of intertidal soft-sediment beaches and estuaries. Our results showed evidence of the applicability of this EUNIS typology for the beaches and estuaries at a regional scale (Northern France coastline) with a macroecological approach. In order to fulfil the requirements of the European Directives (WFD and MFSD), this mapping appears as a practical tool for any functional study on these coastal ecosystems, for the monitoring of anthropogenic

  13. Molecular Imaging of Urogenital Diseases

    PubMed Central

    Cho, Steve Y.; Szabo, Zsolt; Morgan, Russell H.

    2013-01-01

    There is an expanding and exciting repertoire of PET imaging radiotracers for urogenital diseases, particularly in prostate cancer, renal cell cancer, and renal function. Prostate cancer is the most commonly diagnosed cancer in men. With growing therapeutics options for the treatment of metastatic and advanced prostate cancer, improved functional imaging of prostate cancer beyond the limitations of conventional computed tomography (CT) and bone scan (BS) is becoming increasingly important for both clinical management and drug development. PET radiotracers beyond 18F-Fluorodeoxyglucose (FDG) for prostate cancer include 18F-Sodium Fluoride, 11C-Choline and 18F-Fluorocholine and 11C-Acetate. Other emerging and promising PET radiotracers include a synthetic L-leucine amino acid analog (anti-18F-FACBC), dihydrotestosterone analog (18F-FDHT) and prostate specific membrane antigen (PSMA) based PET radiotracers (ex. 18F-DCFBC, 89Zr-DFO-J591, 68Ga(HBED-CC)). Larger prospective and comparison trials of these PET radiotracers are needed to establish the role of PET/CT in prostate cancer. Renal cell cancer imaging with FDG PET/CT although available can be limited, especially for detection of the primary tumor. Improved renal cell cancer detection with carbonic anhydrase IX (CAIX) based antibody (124I-girentuximab) and radioimmunotherapy targeting with 177Lu-cG250 appear promising. Evaluation of renal injury by imaging renal perfusion and function with novel PET radiotracers include p-18F-fluorohippurate (18F-PFH) and hippurate m-cyano-p-18F-fluorohippurate (18F-CNPFH) and Rubidium-82 chloride (typically used for myocardial perfusion imaging). Renal receptor imaging of the renal renin angiotensin system with a variety of selective PET radioligands are also becoming available for clinical translation. PMID:24484747

  14. A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.

    PubMed

    Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2016-09-22

    Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy. PMID:27403880

  15. IN VIVO BIODISTRIBUTION AND ACCUMULATION OF 89Zr IN MICE

    PubMed Central

    Abou, D.S.; Ku, T.; Smith-Jones, P.M.

    2015-01-01

    Introduction The present investigation focuses on the chemical and biological fate of 89Zr in mice. Electrophoreses of 89Zr solvated or chelated in different conditions are here presented. The biological fate of mice injected with [89Zr]Zr-oxalate, [89Zr]Zr-chloride, [89Zr]Zr-phosphate, [89Zr]Zr-desferrioxamine and [89Zr]Zr-citrate is studied with the biodistribution, the clearances and PET images. A special focus is also given regarding the quality of 89Zr bone accumulation. Methods Electrophoreses were carried out on chromatography paper and read by gamma counting. Then, the solutions were intravenously injected in mice, imaged at different time points and sacrificed. The bones, the epiphysis and the marrow substance were separated and evaluated with gamma counts. Results The clearances of [89Zr]Zr-chloride and [89Zr]Zr-oxalate reached 20% of ID after 6 days whereas [89Zr]Zr-phosphate was only 5% of ID. [89Zr]Zr-citrate and [89Zr]Zr-DFO were noticeably excreted after the first day p.i.. [89Zr]Zr-chloride and [89Zr]Zr-oxalate resulted in a respective bone uptake of ~15% ID/g and~20% ID/g at 8 h p.i. with minor losses after 6 days. [89Zr]Zr-citrate bone uptake was also observed, but [89Zr]Zr-phosphate was absorbed in high amounts in the liver and the spleen. The marrow cells were insignificantly radioactive in comparison to the calcified tissues. Conclusion Despite the complexity of Zr coordination, the electrophoretic analyses provided detailed evidences of Zr charges either as salts or as complexes. This study also shows that weakly chelated, 89Zr is a bone seeker and has a strong affinity for phosphate. PMID:21718943

  16. Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

    PubMed Central

    Watson, Ailsa; Lipina, Christopher; McArdle, Harry J.; Taylor, Peter M.; Hundal, Harinder S.

    2016-01-01

    Iron is an indispensable micronutrient that regulates many aspects of cell function, including growth and proliferation. These processes are critically dependent upon signalling via the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Herein, we test whether iron depletion induced by cell incubation with the iron chelator, deferoxamine (DFO), mediates its effects on cell growth through mTORC1-directed signalling and protein synthesis. We have used Caco-2 cells, a well-established in vitro model of human intestinal epithelia. Iron depletion increased expression of iron-regulated proteins (TfR, transferrin receptor and DMT1, divalent metal transporter, as predicted, but it also promoted a marked reduction in growth and proliferation of Caco-2 cells. This was strongly associated with suppressed mTORC1 signalling, as judged by reduced phosphorylation of mTOR substrates, S6K1 and 4E-BP1, and diminished protein synthesis. The reduction in mTORC1 signalling was tightly coupled with increased expression and accumulation of REDD1 (regulated in DNA damage and development 1) and reduced phosphorylation of Akt and TSC2. The increase in REDD1 abundance was rapidly reversed upon iron repletion of cells but was also attenuated by inhibitors of gene transcription, protein phosphatase 2A (PP2A) and by REDD1 siRNA — strategies that also antagonised the loss in mTORC1 signalling associated with iron depletion. Our findings implicate REDD1 and PP2A as crucial regulators of mTORC1 activity in iron-depleted cells and indicate that their modulation may help mitigate atrophy of the intestinal mucosa that may occur in response to iron deficiency. PMID:26827808

  17. Eclipse of epsilon Aurigae

    NASA Astrophysics Data System (ADS)

    Templeton, Matthew R.

    2009-07-01

    The bright, long-period, eclipsing binary star epsilon Aurigae is predicted to begin its next eclipse late July or early August of 2009. Epsilon Aurigae is now past solar conjunction and has reappeared as a morning object. All observers -- both visual and instrumental -- are encouraged to contribute observations of the eclipse during the next two years, beginning immediately for morning observers. Observations are urgently requested right now because it is less likely to be observed in the morning, and the eclipse will begin within the next month. The AAVSO is participating in a global campaign to record this eclipse as part of the International Year of Astronomy 2009 celebrations, organized by the Citizen Sky project (http://www.citizensky.org). For experienced visual observers, please observe this star on a weekly basis, using charts available via VSP from the AAVSO website. For novice visual observers, we recommend participating in this observing program by following the Citizen Sky 10-Star tutorial program, which provides a simple training experience in variable star observing. Photoelectric observers belonging to the AAVSO PEP-V program may submit data as usual via the WebObs feature of the AAVSO website Blue&Gold section. Photoelectric observers may also contribute reduced observations in all filters (including infrared J- and H-bands) directly to the AAVSO via WebObs. Observers using wide-field CCD and DSLR systems are also encouraged to participate; avoid saturating the star. For those with narrower-field systems (D < 2 degrees), we recommend taking a large number (10-100) of very short exposures and then stacking the resulting images. Observations should be submitted to the AAVSO International Database. Aaron Price is coordinating Citizen Sky for the AAVSO, and Dr. Robert Stencel and Jeffrey Hopkins are co-leading the precision photometry efforts.

  18. 50 years of fiber diffraction.

    PubMed

    Holmes, Kenneth C

    2010-05-01

    In 1955 Ken Holmes started working on tobacco mosaic virus (TMV) as a research student with Rosalind Franklin at Birkbeck College, London. Afterward he spent 18months as a post doc with Don Caspar and Carolyn Cohen at the Children's Hospital, Boston where he continued the work on TMV and also showed that the core of the thick filament of byssus retractor muscle from mussels is made of two-stranded alpha-helical coiled-coils. Returning to England he joined Aaron Klug's group at the newly founded Laboratory of Molecular Biology in Cambridge. Besides continuing the TMV studies, which were aimed at calculating the three-dimensional density map of the virus, he collaborated with Pringle's group in Oxford to show that two conformation of the myosin cross-bridge could be identified in insect flight muscle. In 1968 he opened the biophysics department at the Max Planck Institute for Medical Research in Heidelberg, Germany. With Gerd Rosenbaum he initiated the use of synchrotron radiation as a source for X-ray diffraction. In his lab the TMV structure was pushed to 4A resolution and showed how the RNA binds to the protein. With his co-workers he solved the structure of g-actin as a crystalline complex and then solved the structure of the f-actin filament by orientating the g-actin structure so as to give the f-actin fiber diffraction pattern. He was also able to solve the structure of the complex of actin with tropomyosin from fiber diffraction. PMID:20079849

  19. Clinical holistic medicine (mindful, short-term psychodynamic psychotherapy complemented with bodywork) in the treatment of experienced mental illness.

    PubMed

    Ventegodt, Søren; Thegler, Suzette; Andreasen, Tove; Struve, Flemming; Enevoldsen, Lars; Bassaine, Laila; Torp, Margrethe; Merrick, Joav

    2007-01-01

    Short-term psychodynamic psychotherapy (STPP) complemented with bodywork improved 31 of 54 patients (57.4%, 95% CI: 43.21-70.77%) who rated themselves mentally ill before treatment. Calculated from this we find 1.41 < NNT < 2.31; we estimate NNH > 500. Of the 54 patients, 40% had already had traditional treatment that did not help them. Bodywork helped the patients to confront repressed painful feelings from childhood and this seemingly accelerated and improved the therapy. The patients received in average 20 sessions over 14 months at a cost of 1600 EURO. For the treatment responders, all measured aspects of life (on a five point Likert Scale) improved significantly, simultaneously, and radically: somatic health (from 2.9 to 2.3), self-esteem/relationship to self (from 3.5 to 2.3), relationship to partner (from 4.7 to 2.9 [no partner was rated as "6"]), relationship to friends (from 2.5 to 2.0), ability to love (from 3.8 to 2.4), self-assessed sexual ability (from 3.5 to 2.4), self-assessed social ability (from 3.2 to 2.1), self-assessed working ability (from 3.3 to 2.4), and self-assessed quality of life (from 4.0 to 2.3. Quality of life as measured with QOL5 improved (from 3.6 to 2.3 on a scale from 1 to 5; p < 0.001). This general improvement strongly indicated that the patient had healed existentially, i.e., had experienced what Aaron Antonovsky (1923-1994) called "salutogenesis", defined as the process exactly the opposite of pathogenesis. For the treatment responders, the treatment provided lasting benefits, without the negative side effects of drugs. A lasting, positive effect might also prevent many different types of problems in the future. PMID:17334621

  20. Anne O'Tate: A tool to support user-driven summarization, drill-down and browsing of PubMed search results

    PubMed Central

    Smalheiser, Neil R; Zhou, Wei; Torvik, Vetle I

    2008-01-01

    Background PubMed is designed to provide rapid, comprehensive retrieval of papers that discuss a given topic. However, because PubMed does not organize the search output further, it is difficult for users to grasp an overview of the retrieved literature according to non-topical dimensions, to drill-down to find individual articles relevant to a particular individual's need, or to browse the collection. Results In this paper, we present Anne O'Tate, a web-based tool that processes articles retrieved from PubMed and displays multiple aspects of the articles to the user, according to pre-defined categories such as the "most important" words found in titles or abstracts; topics; journals; authors; publication years; and affiliations. Clicking on a given item opens a new window that displays all papers that contain that item. One can navigate by drilling down through the categories progressively, e.g., one can first restrict the articles according to author name and then restrict that subset by affiliation. Alternatively, one can expand small sets of articles to display the most closely related articles. We also implemented a novel cluster-by-topic method that generates a concise set of topics covering most of the retrieved articles. Conclusion Anne O'Tate is an integrated, generic tool for summarization, drill-down and browsing of PubMed search results that accommodates a wide range of biomedical users and needs. It can be accessed at [4]. Peer review and editorial matters for this article were handled by Aaron Cohen. PMID:18279519