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Multi-Sun EELS: Ultra-High Energy Resolution combined with High Spatial Resolution and High Beam Current
- N. Dellby, O.L. Krivanek, N.J. Bacon, G.J. Corbin, N. Johnson, R. Hayner, P. Hrncrik, B. Plotkin-Swing, D. Taylor, Z.S. Szilaygi, T.C. Lovejoy
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- Journal:
- Microscopy and Microanalysis / Volume 28 / Issue S1 / August 2022
- Published online by Cambridge University Press:
- 22 July 2022, pp. 2640-2642
- Print publication:
- August 2022
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Healthcare worker safety program in a coronavirus disease 2019 (COVID-19) alternate care site: The Javits New York Medical Station experience
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- Chad N. Thompson, Christopher Mugford, Joel R. Merriman, Mark A. Chen, Joseph D. Hutter, Thomas J. Maruna, Wanza R. Bacon, Richard W. Childs, Rituparna Pati, G. Travis Clifton, Renee M. Pazdan
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 44 / Issue 2 / February 2023
- Published online by Cambridge University Press:
- 18 April 2022, pp. 268-276
- Print publication:
- February 2023
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Objective:
In March 2020, New York City became the epicenter of the coronavirus disease 2019 (COVID-19) pandemic in the United States. Because healthcare facilities were overwhelmed with patients, the Jacob K. Javits Convention Center was transformed into the nation’s largest alternate care site: Javits New York Medical Station (hereafter termed Javits). Protecting healthcare workers (HCWs) during a global shortage of personal protective equipment (PPE) in a nontraditional healthcare setting posed unique challenges. We describe components of the HCW safety program implemented at Javits.
Setting:Javits, a large convention center transformed into a field hospital, with clinical staff from the US Public Health Service Commissioned Corps and the US Department of Defense.
Methods:Key strategies to ensure HCW safety included ensuring 1-way flow of traffic on and off the patient floor, developing a matrix detailing PPE required for each work activity and location, PPE extended use and reuse protocols, personnel training, and monitoring adherence to PPE donning/doffing protocols when entering or exiting the patient floor. Javits staff who reported COVID-19 symptoms were immediately isolated, monitored, and offered a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction (RT-PCR) test.
Conclusions:A well-designed and implemented HCW safety plan can minimize the risk of SARS-CoV-2 infection for HCWs. The lessons learned from operating the nation’s largest COVID-19 alternate care site can be adapted to other environments during public health emergencies.
Fundamental physics with the Square Kilometre Array
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- A. Weltman, P. Bull, S. Camera, K. Kelley, H. Padmanabhan, J. Pritchard, A. Raccanelli, S. Riemer-Sørensen, L. Shao, S. Andrianomena, E. Athanassoula, D. Bacon, R. Barkana, G. Bertone, C. Bœhm, C. Bonvin, A. Bosma, M. Brüggen, C. Burigana, F. Calore, J. A. R. Cembranos, C. Clarkson, R. M. T. Connors, Á. de la Cruz-Dombriz, P. K. S. Dunsby, J. Fonseca, N. Fornengo, D. Gaggero, I. Harrison, J. Larena, Y.-Z. Ma, R. Maartens, M. Méndez-Isla, S. D. Mohanty, S. Murray, D. Parkinson, A. Pourtsidou, P. J. Quinn, M. Regis, P. Saha, M. Sahlén, M. Sakellariadou, J. Silk, T. Trombetti, F. Vazza, T. Venumadhav, F. Vidotto, F. Villaescusa-Navarro, Y. Wang, C. Weniger, L. Wolz, F. Zhang, B. M. Gaensler
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 37 / 2020
- Published online by Cambridge University Press:
- 27 January 2020, e002
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The Square Kilometre Array (SKA) is a planned large radio interferometer designed to operate over a wide range of frequencies, and with an order of magnitude greater sensitivity and survey speed than any current radio telescope. The SKA will address many important topics in astronomy, ranging from planet formation to distant galaxies. However, in this work, we consider the perspective of the SKA as a facility for studying physics. We review four areas in which the SKA is expected to make major contributions to our understanding of fundamental physics: cosmic dawn and reionisation; gravity and gravitational radiation; cosmology and dark energy; and dark matter and astroparticle physics. These discussions demonstrate that the SKA will be a spectacular physics machine, which will provide many new breakthroughs and novel insights on matter, energy, and spacetime.
2468 CTSI 500 Stars Initiative (CTSI of SE-Wisconsin)
- Doriel D. Ward, Orsolya Garrison, Chamia Gary, Memory Bacon, Tim Sobotka
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- Journal:
- Journal of Clinical and Translational Science / Volume 2 / Issue S1 / June 2018
- Published online by Cambridge University Press:
- 21 November 2018, p. 53
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OBJECTIVES/SPECIFIC AIMS: Our Goal is to enroll 500 students over 10 years into the CTSI 500 Stars Initiative. Student family members and community members are essential to career achievement and success; as such, the program also engages student families, along with key community members, as part of an Advisory Group, throughout the entire student experience. Besides programmatic and planning activities, students, family, and community members participate in our CTSI Community Engagement Science Café monthly series, where students may also present on a number of research and health-related topics of interest. The Advisory Group meets every 3–4 months in ensuring continuous engagement and overall program success. METHODS/STUDY POPULATION: Our Initiative takes both direct and supportive roles in offering 2 educational and training pathways; namely, our Summer Internship Program (6–8 wk duration) and our Students Modeling a Research Topic (SMART) Year-round Education Program (usually offered in Fall and Spring academic semesters) for high school students only. In the SMART Teams program, we work with regional public and private school districts to train science teachers, and assist them in developing and/or enhancing their science curriculum, thus creating pathways towards careers in translational science settings. Our aim is that students who participate in the year-round program (along with additional students) subsequently participate in our summer program. Therefore, overall program engagement is continuous throughout the year. In Summer, 2017 we engaged with well-established regional partners and collaborators (CTSI affiliated numerous public school districts, and community-based organizations) to move the translational workforce along existing regional diversity education and training pipelines. A Kick-off event was held on June 15, 2107 and attended by students and family members. We offered 6–8 weeks of hands-on experiences working with faculty researcher mentors and their research teams conducting real-life studies, in addition to professional experiences in research “support” settings, as well as in the community. We also developed established a “Summer” SMART (Students Modeling a Research Topic) Teams Program and a Summer “Advanced” SMART Teams Program, where a number of students were placed at 2 CTSI partner and collaborator institutions. The primary goal of the SMART Teams experience is to introduce students to translational science by building upon laboratory research to better understand clinical and community impact of disease within a patient population. Overall, internship sites included research labs, protein modeling labs, numerous research support settings, clinical care settings, and community sites for those students who were interested in population health sciences. In addition, students were offered career enrichment and professional development lunch and learn sessions, career panel sessions presented by long term, expert professionals in various fields translational science, and confidence building and networking sessions. Students also participated in a community volunteer day activity, a trip to the Chicago Science Museum, and numerous CTSI engagement activities (Science Cafés, simulation lab tours, etc.). RESULTS/ANTICIPATED RESULTS: The 2018 year-round program will initiate in the Fall. Our 2017 Summer Internship Program received 192 students/trainees applications of whom 133 were underrepresented minorities (URMs). We enrolled 109 participants, including 83 URMs (84 high school students and 25 college students). A total of 53 Wisconsin high schools and 19 colleges and universities (local and out of state) participated. Students engaged in all activities as outlined in the Methods section. At the end of the summer program, students created and presented posters as part of the closing ceremony. Certificates of completion were given to the students by program leadership and the Al Hurvis/ADAMM leadership (program funding agency). Students wore white lab coats to create an atmosphere of cohesion and accomplishment. Parents and other family members attended the closing ceremony, demonstrating strong support for students and the program. Our anticipated results for CTSI 500 Stars Initiative is to increase diversity in the Translational Science Workforce via education and training of 500 high school and college students over 10 years. We will also remain engaged and track student’s various venues for at least 10 years to determine the outcome of their experiences towards careers in Translational Science settings. We will continue to engage community members and community-based organizations as collaborators and advisors to participate in every stage of our activities. Moreover, we plan to broaden our reach by establishing additional relationships with additional high schools and middle schools to further enhance the 500 Stars Initiative. In addition, we will develop metrics by which to measure the validity and success of our program. DISCUSSION/SIGNIFICANCE OF IMPACT: The aim of the CTSI 500 Stars Initiative is to provide real-life, practical experiences in translational science settings as a part of our efforts to train and cultivate the translational science workforce, while also engaging patients, families and community members in every phase of the translational process. Targeting under-represented minority students contributes towards increasing diversity in the workforce. It is also our hope that by increasing URMs in the workforce, there will be positive impact on communities of color, with respect to increasing participation in their health care decision making and in clinical/translational research; thus, ultimately leading to better health outcomes in the communities we live and serve. Our overall framework is to engage, educate, enrich, empower, elevate, enable students towards careers in clinical and translational settings.
Contributors
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- By Melisa Akan, Elisabeth Bacon, Rosemary Bradley, Alan S. Brown, Sarah Buchanan, Ana Buján, Anne M. Cleary, Katie Croft Caderao, Fernando Díaz, Anastasia Efklides, David Facal, Santiago Galdo-Álvarez, J. Richard Hanley, Trevor A. Harley, Marie Izaute, Fredrik U. Jönsson, Onésimo Juncos-Rabadán, Dilay Zeynep Karadoller, Kimberly R. Klein, Asher Koriat, Mónica Lindín, Siobhan B. G. MacAndrew, Janet Metcalfe, Chris J. A. Moulin, Ravit Nussinson, Justin D. Oh-Lee, Hajime Otani, Arturo X. Pereiro, Bennett L. Schwartz, Celine Souchay, Shelly R. Staley, Richard J. Stevenson
- Edited by Bennett L. Schwartz, Florida International University, Alan S. Brown, Southern Methodist University, Texas
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- Book:
- Tip-of-the-Tongue States and Related Phenomena
- Published online:
- 05 June 2014
- Print publication:
- 16 June 2014, pp vii-viii
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Radio Continuum Surveys with Square Kilometre Array Pathfinders
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- Ray P. Norris, J. Afonso, D. Bacon, Rainer Beck, Martin Bell, R. J. Beswick, Philip Best, Sanjay Bhatnagar, Annalisa Bonafede, Gianfranco Brunetti, Tamás Budavári, Rossella Cassano, J. J. Condon, Catherine Cress, Arwa Dabbech, I. Feain, Rob Fender, Chiara Ferrari, B. M. Gaensler, G. Giovannini, Marijke Haverkorn, George Heald, Kurt Van der Heyden, A. M. Hopkins, M. Jarvis, Melanie Johnston-Hollitt, Roland Kothes, Huib Van Langevelde, Joseph Lazio, Minnie Y. Mao, Alejo Martínez-Sansigre, David Mary, Kim Mcalpine, E. Middelberg, Eric Murphy, P. Padovani, Zsolt Paragi, I. Prandoni, A. Raccanelli, Emma Rigby, I. G. Roseboom, H. Röttgering, Jose Sabater, Mara Salvato, Anna M. M. Scaife, Richard Schilizzi, N. Seymour, Dan J. B. Smith, Grazia Umana, G.-B. Zhao, Peter-Christian Zinn
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 30 / 2013
- Published online by Cambridge University Press:
- 27 March 2013, e020
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In the lead-up to the Square Kilometre Array (SKA) project, several next-generation radio telescopes and upgrades are already being built around the world. These include APERTIF (The Netherlands), ASKAP (Australia), e-MERLIN (UK), VLA (USA), e-EVN (based in Europe), LOFAR (The Netherlands), MeerKAT (South Africa), and the Murchison Widefield Array. Each of these new instruments has different strengths, and coordination of surveys between them can help maximise the science from each of them. A radio continuum survey is being planned on each of them with the primary science objective of understanding the formation and evolution of galaxies over cosmic time, and the cosmological parameters and large-scale structures which drive it. In pursuit of this objective, the different teams are developing a variety of new techniques, and refining existing ones. To achieve these exciting scientific goals, many technical challenges must be addressed by the survey instruments. Given the limited resources of the global radio-astronomical community, it is essential that we pool our skills and knowledge. We do not have sufficient resources to enjoy the luxury of re-inventing wheels. We face significant challenges in calibration, imaging, source extraction and measurement, classification and cross-identification, redshift determination, stacking, and data-intensive research. As these instruments extend the observational parameters, we will face further unexpected challenges in calibration, imaging, and interpretation. If we are to realise the full scientific potential of these expensive instruments, it is essential that we devote enough resources and careful study to understanding the instrumental effects and how they will affect the data. We have established an SKA Radio Continuum Survey working group, whose prime role is to maximise science from these instruments by ensuring we share resources and expertise across the projects. Here we describe these projects, their science goals, and the technical challenges which are being addressed to maximise the science return.
EMU: Evolutionary Map of the Universe
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- Ray P. Norris, A. M. Hopkins, J. Afonso, S. Brown, J. J. Condon, L. Dunne, I. Feain, R. Hollow, M. Jarvis, M. Johnston-Hollitt, E. Lenc, E. Middelberg, P. Padovani, I. Prandoni, L. Rudnick, N. Seymour, G. Umana, H. Andernach, D. M. Alexander, P. N. Appleton, D. Bacon, J. Banfield, W. Becker, M. J. I. Brown, P. Ciliegi, C. Jackson, S. Eales, A. C. Edge, B. M. Gaensler, G. Giovannini, C. A. Hales, P. Hancock, M. T. Huynh, E. Ibar, R. J. Ivison, R. Kennicutt, Amy E. Kimball, A. M. Koekemoer, B. S. Koribalski, Á. R. López-Sánchez, M. Y. Mao, T. Murphy, H. Messias, K. A. Pimbblet, A. Raccanelli, K. E. Randall, T. H. Reiprich, I. G. Roseboom, H. Röttgering, D. J. Saikia, R. G. Sharp, O. B. Slee, Ian Smail, M. A. Thompson, J. S. Urquhart, J. V. Wall, G.-B. Zhao
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 28 / Issue 3 / 2011
- Published online by Cambridge University Press:
- 02 January 2013, pp. 215-248
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EMU is a wide-field radio continuum survey planned for the new Australian Square Kilometre Array Pathfinder (ASKAP) telescope. The primary goal of EMU is to make a deep (rms ∼ 10 μJy/beam) radio continuum survey of the entire Southern sky at 1.3 GHz, extending as far North as +30° declination, with a resolution of 10 arcsec. EMU is expected to detect and catalogue about 70 million galaxies, including typical star-forming galaxies up to z ∼ 1, powerful starbursts to even greater redshifts, and active galactic nuclei to the edge of the visible Universe. It will undoubtedly discover new classes of object. This paper defines the science goals and parameters of the survey, and describes the development of techniques necessary to maximise the science return from EMU.
Mesoscale dispersion of 85Kr in the vicinity of the AREVA La Hague reprocessing plant
- J. Barescut, D. Lariviere, T. Stocki, O. Connan, K. Smith, L. Solier, D. Maro, D. Hébert, G. Bacon
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- Journal:
- Radioprotection / Volume 46 / Issue 6 / 2011
- Published online by Cambridge University Press:
- 09 January 2012, pp. S423-S429
- Print publication:
- 2011
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The Institut de Radioprotection et de Sureté Nucléaire (IRSN) performed a series of air sampling campaigns at mesoscale distances (10–80 km) from the AREVA La Hague reprocessing plant (north west of France) between 2007 and 2009. These samples were collected in order to test and optimise a technique to measure low krypton-85 (85Kr) air concentrations, and to investigate the performance of three atmospheric dispersion models (RIMPUFF, HySplit, and ADMS). This paper presents 85Kr air concentrations measured at both land and sea locations. In addition, this paper compares the measured 85Kr air concentrations, which varied from 2 to 8000 Bq m−3, with the predictions from the atmospheric dispersion models. During stable wind conditions, the dispersion models make reasonable estimates of the 85Kr field measurements. In contrast, the models fail to accurately predict temporal peaks in concentration during periods of rapid and large changes in wind speed and/or wind direction.
The Fundamental Plane of Early-Type Galaxies
- M. Koleva, Ph. Prugniel, I. Vauglin, J. Falcón-Barroso, G. van de Ven, R. Bacon, M. Bureau, M. Cappellari, R.L. Davies, P.T. de Zeeuw, E. Emsellem, D. Krajnovic, H. Kuntschner, R.M. McDermid, R.F. Peletier, M. Sarzi, R.C.E. van den Bosch
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- Journal:
- European Astronomical Society Publications Series / Volume 48 / 2011
- Published online by Cambridge University Press:
- 11 July 2011, pp. 411-412
- Print publication:
- 2011
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We report recent results from the photometric follow-up study we are conducting in the context of the SAURON project. We use ground-based MDM V −band and Spitzer/IRAC 3.6 μm imaging to characterise our sample of E, S0 and Sa galaxies photometrically. Combined with SAURON integral-field spectroscopic observations, this information allows us to explore and understand the location of these galaxies on the Fundamental Plane relation, providing an important diagnostic tool to study their formation and evolution.
28 - Hereditary aceruloplasminemia
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 284-289
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Summary
Hereditary aceruloplasminemia (OMIM #604290) is a rare autosomal recessive disorder due to mutations of Cp, the gene that encodes the copper-binding protein ceruloplasmin (Cp). The first report of hereditary aceruloplasminemia was published in 1987 in Japan. The patient was a 52-year-old woman who had a movement disorder that resembled Parkinson's disease, blepharospasm, retinal degeneration, and diabetes mellitus. Her serum immunofixation test revealed that her serum Cp concentration was very low. Computed tomography scanning revealed increased amounts of iron in her basal ganglia and liver. Subsequent histologic evaluation confirmed that there was increased iron in her basal ganglia and substantia nigra and in her liver, without increased copper.
The frequency of homozygosity for deleterious Cp mutations in non-consanguineous marriages in Japan was estimated to be 1 per 2,000,000 population. Aceruloplasminemia has been reported in several countries including Japan, China, Ireland, Belgium, France, Italy, and the US. More Japanese patients have been reported than any other nationality. Altogether, about 60 patients with hereditary aceruloplasminemia have been described.
Ceruloplasmin (Cp) biochemistry
Cp is a plasma metalloprotein, an alpha-2 glycoprotein polypeptide of 1046 amino acids. A member of the multi-copper oxidase enzyme family, Cp is the principal copper transport protein in plasma. Cp is synthesized in hepatocytes where it binds copper, and is thereafter secreted into plasma. About 95% of circulating plasma copper is bound to Cp; the remainder is bound to albumin, precuprein, and complexes of copper and amino acids. Each Cp molecule can bind and transport six atoms of copper.
Plate section
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp -
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31 - Neuroferritinopathies
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 299-303
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Summary
Neuroferritinopathy (OMIM #606159), also known as adult-onset basal ganglia disease, is a progressive movement disorder caused by mutations in the coding region of the ferritin light chain gene (FTL, chromosome 19q13.3–q13.4). Persons with neuroferritinopathy have abnormal ferritin light chain polypeptide, decreased serum ferritin concentrations, and accumulation of iron in the basal ganglia. Curtis and colleagues first described this syndrome in an English kinship in 2001. They also coined the commonly used term “neuroferritinopathy.” Subsequent identification and study of other subjects have revealed additional observations on the genotypes, phenotypes, and epidemiology associated with neuroferritinopathy.
Other mutations of the FTL coding region segregate with a syndrome that comprises hyperferritinemia, absence of iron overload, and absence of ocular cataracts. Mutations of the iron-responsive element of FTL cause a different clinical syndrome characterized by elevated levels of otherwise normal ferritin, cataracts due to ferritin light-chain deposition in the ocular lens, and absence of neurological abnormalities (Chapter 17).
History
In 2001, Curtis and colleagues described late-onset autosomal dominant dystonia that segregated with FTL 460insA in an English kinship. In 2003, Chinnery, Curtis, and colleagues reported a French family in which some members had a similar clinical disorder and the same FTL mutation. In 2007, Chinnery and colleagues compiled observations in 41 patients with neuroferritinopathy and FTL 460insA. They presented between the ages of 38 and 58 years; some had chorea, others had focal dystonia, and others had an akinetic rigid Parkinsonian syndrome. Brain imaging showed basal ganglia cavitation that was confirmed at necropsy.
Contents
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp v-vi
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12 - Hemochromatosis associated with ferroportin gene (SLC40A1) mutations
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 171-180
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Summary
Mutations in the SLC40A1 (FPN1) gene that encodes ferroportin (OMIM *604653) cause an uncommon, heterogeneous group of iron overload disorders characterized by an autosomal dominant pattern of inheritance (OMIM #606069). Ferroportin hemochromatosis has been described worldwide in a variety of race/ethnicity groups. SLC40A1 mutations cause two major iron overload phenotype patterns, each depending on the particular mutation and its effect on the function of the transcribed ferroportin protein. In many ferroportin hemochromatosis kinships, serum iron measures and complications of iron overload typical of other types of hemochromatosis are relatively uncommon. The collective term “ferroportin disease” or “hemochromatosis type 4” is sometimes used to describe the clinical manifestations of ferroportin mutations.
History
In 1990, an autosomal dominant form of hemochromatosis was reported in a Melanesian pedigree from the Solomon Islands. All affected individuals had serum iron measures and a pattern of liver iron staining similar to those of HFE hemochromatosis, although linkage of this disorder to chromosome 6p was excluded. In 1999, Pietrangelo and colleagues reported a large Italian family that included persons with an iron overload condition that occurred in pattern consistent with autosomal dominant inheritance. Based on microsatellite marker analyses, this disorder was also not linked to chromosome 6p. In 2001, Njajou and colleagues identified the SLC40A1 mutation N144H associated with autosomal dominant hemochromatosis in a large multi-generation family from the Netherlands.
23 - Iron overload associated with pyruvate kinase deficiency
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 251-253
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Summary
Pyruvate kinase (PK) deficiency (OMIM #266200) is caused by mutations in the PKLR gene that encodes PK (chromosome 1q21). This disorder is the most common erythrocyte enzyme defect that causes hereditary non-spherocytic hemolytic anemia. It is transmitted as an autosomal recessive trait. On the basis of gene frequency, it was estimated that the prevalence of homozygous PK deficiency is 51 cases per million in the US white population. Based on data in a health registry, it was estimated that the prevalence of PK deficiency in northern England is 3.3 per million. PK deficiency has a worldwide distribution, but may be more common among individuals of northern European descent. Herein, the pathophysiology of PK deficiency is discussed. The clinical manifestations of this disorder are reviewed with emphasis on the complication of iron overload.
Etiology and pathogenesis
Mature erythrocytes depend on the glycolytic production of adenosine triphosphate (ATP) to meet metabolic requirements. Deficiencies in several glycolytic enzymes can result in hemolytic anemia. These types of hemolytic anemia are not associated with a distinctive morphologic abnormality of erythrocytes, and thus are known collectively as congenital non-spherocytic hemolytic anemias. Most of these disorders are rare and are transmitted as autosomal recessive disorders.
PK deficiency is the most common erythrocyte glycolytic enzymopathy. The predominant PK isoenzyme present in erythrocytes is the R form, encoded by PKLR. Multiple mutations can lead to PK deficiency, and the type of mutation may determine in part the severity of the clinical phenotype.
2 - Normal iron absorption and metabolism
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 10-27
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Summary
Iron is essential to life because it is the central oxygen ligand in the heme proteins hemoglobin and myoglobin. Accordingly, there are many interactions between iron homeostasis and oxygen regulation and delivery. Iron is also required for cytochrome P-450 enzyme oxidative metabolism and DNA synthesis. In health, body iron content is controlled by absorption that responds to iron losses and the rate of erythropoiesis. Multiple mechanisms provide functional feedback control of iron homeostasis, tissue oxygen sensing and delivery, and the tempo of red blood cell production. The physiologic capacity to excrete iron is very limited. Thus, body iron content is regulated almost entirely by controlled absorption. This chapter reviews the basic physiologic and molecular characteristics of iron metabolism and homeostasis, and their pertinence to iron overload disorders.
Iron physiology
Normal iron homeostasis is maintained by absorption of iron from the diet that precisely balances iron loss, and by controlled iron distribution in the body. Normal healthy adults have 4000–5000 mg of iron (Table 2.1). Daily iron loss occurs due to perspiration, desquamation from skin, and minor injuries, and from the gastrointestinal tract. The rate of this unavoidable iron loss is proportional to body iron stores. Women lose additional iron due to menstruation, pregnancy and childbirth, and lactation. Overall, daily iron losses in adult men and post-menopausal women are approximately 1.0 mg and in menstruating women approximately 1.5 mg. The median iron loss ascribable to pregnancy is 500 mg.
20 - Divalent metal transporter-1 (SLC11A2) iron overload
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 228-232
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Summary
Divalent metal transporter-1 (DMT1) is a member of the “natural-resistance-associated macrophage protein” (Nramp) family. DMT1 is upregulated by dietary iron deficiency, is expressed strongly on the microvillus membranes of duodenal enterocytes at the villus tips, and is a key mediator of iron absorption. DMT1 also mediates iron transfer from endosomes into the cytosol of developing erythroid cells. The SLC11A2 gene that encodes DMT1 is located on chromosome 12q13 (OMIM *604653).
In 1964, Shahidi and colleagues described a brother and sister of French-Canadian descent who had hypochromic, microcytic anemia. These siblings also had elevated serum iron concentrations, massive deposition of iron in hepatocytes, and absence of stainable iron in the bone marrow. These children apparently had no defect in transferrin or heme synthesis. Two of their siblings appeared to have normal iron phenotypes. In 2004 and 2005, Priwitzerova and colleagues described a Czech female in a consanguineous kinship who came to medical attention at age 3 months because she had a syndrome of abnormal iron metabolism characterized by severe hypochromic, microcytic anemia, erythroid hyperplasia, abnormal erythroid maturation, elevated serum iron concentration, normal to slightly increased serum ferritin level, and markedly increased serum transferrin receptor levels. In 2005, Mims and colleagues reported that this woman was homozygous for a mutation in SLC11A2.
Clinical description
Clinical observations in patients with two SLC11A2 mutations are limited. In one case, left ventricular hypertrophy was detected before birth, and birth weight was low. Pallor is presumed to have been present in all reported cases.
10 - Porphyria cutanea tarda
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 160-168
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Summary
Porphyrias are disorders caused by heritable or acquired deficiency of an enzyme that is required for the normal synthesis of heme. A ring structure, heme is formed by the insertion of an iron atom into protoporphyrin in the final step of the porphyrin synthesis pathway. The usual presenting symptoms and signs of porphyrias are either skin photosensitivity or neurovisceral symptoms and signs. Three types of porphyria are characterized by a predominance of photosensitivity (porphyria cutanea tarda (PCT), congenital erythropoietic porphyria, and erythropoietic protoporphyria). Two types of porphyria are characterized mainly by neurovisceral symptoms and signs (acute intermittent porphyria and aminolevulinate dehydratase deficiency). The two remaining types of porphyria are characterized by both photosensitivity and neurovisceral symptoms and signs (hereditary coproporphyria and variegate porphyria). The seven main types of porphyria, the associated enzyme deficiency, the mode of inheritance, and the major presenting symptoms and signs are displayed in Table 10.1. The only type of porphyria discussed here is PCT, the most common of all porphyrias.
Porphyria cutanea tarda (PCT)
PCT is estimated to occur in about 1 per 5000 to 25,000 individuals in the general population. PCT is caused by decreased specific activity of the uroporphyrinogen decarboxylase enzyme, the fifth enzyme in the heme synthesis pathway. Three types of PCT can be identified on the basis of decreased activity of the uroporphyrinogen decarboxylase enzyme (URO-D) in liver cells or in erythrocytes.
18 - Iron overload in Native Africans and African-Americans
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
-
- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 211-221
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Summary
African iron overload
African iron overload occurs in 14%–18% of Bantu-speaking Natives in at least 15 countries in sub-Saharan Africa. This type of non-transfusion iron overload is due primarily to the ingestion of large quantities of iron contained in traditional beer, although unconfirmed evidence suggests that there is an African iron overload gene (Table 18.1).
History
Iron overload in native sub-Saharan Africans was first described by Strachan in his 1929 thesis on tuberculosis. The disorder was originally attributed to infections, to poisoning due to copper, tin, or zinc, or to malnutrition. In 1953, it was hypothesized that the intake of excessive quantities of iron leached from iron vessels used for food preparation could account for “Bantu siderosis.” In 1992, the etiology of African iron overload as a purely dietary disorder was contested with the demonstration that heritable factors may influence the development of this condition.
Clinical description
Patients with early iron overload identified during family or other group testing have no symptoms or signs attributable to iron overload. Symptoms usually do not occur until iron overload is severe; they may develop by late adolescence. Iron overload is progressive in most patients. Weakness and fatigue, abdominal discomfort or pain, or low back or hip pain are common presenting complaints. Iron overload occurs with greater frequency and severity among men than in women. Physical examination in subjects with severe iron overload may reveal hyperpigmentation, hepatomegaly, kyphosis, or femoral neck fracture.
8 - Classical and atypical HFE hemochromatosis
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 127-148
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Summary
Hemochromatosis and HFE mutations
The “classical” type of familial hemochromatosis that is transmitted as an autosomal recessive disorder is usually due to homozygosity for the C282Y mutation of the HFE gene. It is expected that mutations of HFE cause the great majority of the cases of heritable iron overload in humans. There are at least 37 known mutations of the HFE gene (Table 8.1) (Chapter 4). Some individuals who are homozygous for any of the known mutations may develop heavy iron overload. At least six mutations are associated with mild iron accumulation; and at least six mutations were discovered in patients who did not have iron overload. There is insufficient reported information in the literature to determine if six of the mutations are sufficiently deleterious to result in iron overload. Approximately 1500 mutations of the cystic fibrosis gene (CF) are known, and the gene encodes a 1480 amino acid protein. In contrast, HFE is much smaller than CF, and encodes a protein of only 343 amino acids. Thus, it is expected that fewer mutations of HFE than mutations of CF will be eventually discovered.
Molecular genetics
Although the autosomal recessive inheritance pattern of “classical” hemochromatosis had long been recognized, identification of the responsible gene remained elusive for many years (Table 8.1). An important breakthrough in the search for the gene occurred in 1976 when hemochromatosis was found to be linked closely to the human leukocyte antigen (HLA)-A*03 region of the short arm of chromosome 6.