27 results
A comparison of the remote food photography method and the automated self-administered 24-h dietary assessment tool for measuring full-day dietary intake among school-age children
- Traci A. Bekelman, Corby K. Martin, Susan L. Johnson, Deborah H. Glueck, Katherine A. Sauder, Kylie K. Harrall, Rachel I. Steinberg, Daniel S. Hsia, Dana Dabelea
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- British Journal of Nutrition / Volume 127 / Issue 8 / 28 April 2022
- Published online by Cambridge University Press:
- 04 June 2021, pp. 1269-1278
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- 28 April 2022
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The limitations of self-report measures of dietary intake are well-known. Novel, technology-based measures of dietary intake may provide a more accurate, less burdensome alternative to existing tools. The first objective of this study was to compare participant burden for two technology-based measures of dietary intake among school-age children: the Automated-Self-Administered 24-hour Dietary Assessment Tool-2018 (ASA24-2018) and the Remote Food Photography Method (RFPM). The second objective was to compare reported energy intake for each method to the Estimated Energy Requirement for each child, as a benchmark for actual intake. Forty parent–child dyads participated in two, 3-d dietary assessments: a parent proxy-reported version of the ASA24 and the RFPM. A parent survey was subsequently administered to compare satisfaction, ease of use and burden with each method. A linear mixed model examined differences in total daily energy intake between assessments, and between each assessment method and the Estimated Energy Requirement (EER). Reported energy intake was 379 kcal higher with the ASA24 than the RFPM (P = 0·0002). Reported energy intake with the ASA24 was 231 kcal higher than the EER (P = 0·008). Reported energy intake with the RFPM did not differ significantly from the EER (difference in predicted means = −148 kcal, P = 0·09). Median satisfaction and ease of use scores were five out of six for both methods. A higher proportion of parents reported that the ASA24 was more time-consuming than the RFPM (74·4 % v. 25·6 %, P = 0·002). Utilisation of both methods is warranted given their high satisfaction among parents.
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- By Mitchell Aboulafia, Frederick Adams, Marilyn McCord Adams, Robert M. Adams, Laird Addis, James W. Allard, David Allison, William P. Alston, Karl Ameriks, C. Anthony Anderson, David Leech Anderson, Lanier Anderson, Roger Ariew, David Armstrong, Denis G. Arnold, E. J. Ashworth, Margaret Atherton, Robin Attfield, Bruce Aune, Edward Wilson Averill, Jody Azzouni, Kent Bach, Andrew Bailey, Lynne Rudder Baker, Thomas R. Baldwin, Jon Barwise, George Bealer, William Bechtel, Lawrence C. Becker, Mark A. Bedau, Ernst Behler, José A. Benardete, Ermanno Bencivenga, Jan Berg, Michael Bergmann, Robert L. Bernasconi, Sven Bernecker, Bernard Berofsky, Rod Bertolet, Charles J. Beyer, Christian Beyer, Joseph Bien, Joseph Bien, Peg Birmingham, Ivan Boh, James Bohman, Daniel Bonevac, Laurence BonJour, William J. Bouwsma, Raymond D. Bradley, Myles Brand, Richard B. Brandt, Michael E. Bratman, Stephen E. Braude, Daniel Breazeale, Angela Breitenbach, Jason Bridges, David O. Brink, Gordon G. Brittan, Justin Broackes, Dan W. Brock, Aaron Bronfman, Jeffrey E. Brower, Bartosz Brozek, Anthony Brueckner, Jeffrey Bub, Lara Buchak, Otavio Bueno, Ann E. Bumpus, Robert W. Burch, John Burgess, Arthur W. Burks, Panayot Butchvarov, Robert E. Butts, Marina Bykova, Patrick Byrne, David Carr, Noël Carroll, Edward S. Casey, Victor Caston, Victor Caston, Albert Casullo, Robert L. Causey, Alan K. L. Chan, Ruth Chang, Deen K. Chatterjee, Andrew Chignell, Roderick M. Chisholm, Kelly J. Clark, E. J. Coffman, Robin Collins, Brian P. Copenhaver, John Corcoran, John Cottingham, Roger Crisp, Frederick J. Crosson, Antonio S. Cua, Phillip D. Cummins, Martin Curd, Adam Cureton, Andrew Cutrofello, Stephen Darwall, Paul Sheldon Davies, Wayne A. Davis, Timothy Joseph Day, Claudio de Almeida, Mario De Caro, Mario De Caro, John Deigh, C. F. Delaney, Daniel C. Dennett, Michael R. DePaul, Michael Detlefsen, Daniel Trent Devereux, Philip E. Devine, John M. Dillon, Martin C. Dillon, Robert DiSalle, Mary Domski, Alan Donagan, Paul Draper, Fred Dretske, Mircea Dumitru, Wilhelm Dupré, Gerald Dworkin, John Earman, Ellery Eells, Catherine Z. Elgin, Berent Enç, Ronald P. Endicott, Edward Erwin, John Etchemendy, C. Stephen Evans, Susan L. Feagin, Solomon Feferman, Richard Feldman, Arthur Fine, Maurice A. Finocchiaro, William FitzPatrick, Richard E. Flathman, Gvozden Flego, Richard Foley, Graeme Forbes, Rainer Forst, Malcolm R. Forster, Daniel Fouke, Patrick Francken, Samuel Freeman, Elizabeth Fricker, Miranda Fricker, Michael Friedman, Michael Fuerstein, Richard A. Fumerton, Alan Gabbey, Pieranna Garavaso, Daniel Garber, Jorge L. A. Garcia, Robert K. Garcia, Don Garrett, Philip Gasper, Gerald Gaus, Berys Gaut, Bernard Gert, Roger F. Gibson, Cody Gilmore, Carl Ginet, Alan H. Goldman, Alvin I. Goldman, Alfonso Gömez-Lobo, Lenn E. Goodman, Robert M. Gordon, Stefan Gosepath, Jorge J. E. Gracia, Daniel W. Graham, George A. Graham, Peter J. Graham, Richard E. Grandy, I. Grattan-Guinness, John Greco, Philip T. Grier, Nicholas Griffin, Nicholas Griffin, David A. Griffiths, Paul J. Griffiths, Stephen R. Grimm, Charles L. Griswold, Charles B. Guignon, Pete A. Y. Gunter, Dimitri Gutas, Gary Gutting, Paul Guyer, Kwame Gyekye, Oscar A. Haac, Raul Hakli, Raul Hakli, Michael Hallett, Edward C. Halper, Jean Hampton, R. James Hankinson, K. R. Hanley, Russell Hardin, Robert M. Harnish, William Harper, David Harrah, Kevin Hart, Ali Hasan, William Hasker, John Haugeland, Roger Hausheer, William Heald, Peter Heath, Richard Heck, John F. Heil, Vincent F. Hendricks, Stephen Hetherington, Francis Heylighen, Kathleen Marie Higgins, Risto Hilpinen, Harold T. Hodes, Joshua Hoffman, Alan Holland, Robert L. Holmes, Richard Holton, Brad W. Hooker, Terence E. Horgan, Tamara Horowitz, Paul Horwich, Vittorio Hösle, Paul Hoβfeld, Daniel Howard-Snyder, Frances Howard-Snyder, Anne Hudson, Deal W. Hudson, Carl A. Huffman, David L. Hull, Patricia Huntington, Thomas Hurka, Paul Hurley, Rosalind Hursthouse, Guillermo Hurtado, Ronald E. Hustwit, Sarah Hutton, Jonathan Jenkins Ichikawa, Harry A. Ide, David Ingram, Philip J. Ivanhoe, Alfred L. Ivry, Frank Jackson, Dale Jacquette, Joseph Jedwab, Richard Jeffrey, David Alan Johnson, Edward Johnson, Mark D. Jordan, Richard Joyce, Hwa Yol Jung, Robert Hillary Kane, Tomis Kapitan, Jacquelyn Ann K. Kegley, James A. Keller, Ralph Kennedy, Sergei Khoruzhii, Jaegwon Kim, Yersu Kim, Nathan L. King, Patricia Kitcher, Peter D. Klein, E. D. Klemke, Virginia Klenk, George L. Kline, Christian Klotz, Simo Knuuttila, Joseph J. Kockelmans, Konstantin Kolenda, Sebastian Tomasz Kołodziejczyk, Isaac Kramnick, Richard Kraut, Fred Kroon, Manfred Kuehn, Steven T. Kuhn, Henry E. Kyburg, John Lachs, Jennifer Lackey, Stephen E. Lahey, Andrea Lavazza, Thomas H. Leahey, Joo Heung Lee, Keith Lehrer, Dorothy Leland, Noah M. Lemos, Ernest LePore, Sarah-Jane Leslie, Isaac Levi, Andrew Levine, Alan E. Lewis, Daniel E. Little, Shu-hsien Liu, Shu-hsien Liu, Alan K. L. Chan, Brian Loar, Lawrence B. Lombard, John Longeway, Dominic McIver Lopes, Michael J. Loux, E. J. Lowe, Steven Luper, Eugene C. Luschei, William G. Lycan, David Lyons, David Macarthur, Danielle Macbeth, Scott MacDonald, Jacob L. Mackey, Louis H. Mackey, Penelope Mackie, Edward H. Madden, Penelope Maddy, G. B. Madison, Bernd Magnus, Pekka Mäkelä, Rudolf A. Makkreel, David Manley, William E. Mann (W.E.M.), Vladimir Marchenkov, Peter Markie, Jean-Pierre Marquis, Ausonio Marras, Mike W. Martin, A. P. Martinich, William L. McBride, David McCabe, Storrs McCall, Hugh J. McCann, Robert N. McCauley, John J. McDermott, Sarah McGrath, Ralph McInerny, Daniel J. McKaughan, Thomas McKay, Michael McKinsey, Brian P. McLaughlin, Ernan McMullin, Anthonie Meijers, Jack W. Meiland, William Jason Melanson, Alfred R. Mele, Joseph R. 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Wolterstorff, Rega Wood, W. Jay Wood, Paul Woodruff, Alison Wylie, Gideon Yaffe, Takashi Yagisawa, Yutaka Yamamoto, Keith E. Yandell, Xiaomei Yang, Dean Zimmerman, Günter Zoller, Catherine Zuckert, Michael Zuckert, Jack A. Zupko (J.A.Z.)
- Edited by Robert Audi, University of Notre Dame, Indiana
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21 - Hemoglobin SC Disease and Hemoglobin C Disorders
- from SECTION FIVE - SICKLE CELL DISEASE
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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- Disorders of Hemoglobin
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Summary
INTRODUCTION
HbC (HBB glu6lys), along with HbS (HBB glu6val) and HbE (HBB glu26lys), is one of the three most common hemoglobin variants in humankind. Its positive charge that allows it to bind the erythrocyte membrane, and perhaps other unique features of this variant, lead to loss of cell K+ and water, thereby increasing erythrocyte density. HbC disease, defined as homozygosity for the HbC gene, causes mild hemolytic anemia; simple heterozygosity for HbC (HbC trait, HbAC) is innocuous. In HbSC disease, in which the erythrocyte concentration of HbS and HbC is nearly equal, the dehydrated, dense erythrocyte accentuates the deleterious properties of HbS by producing a milieu favoring HbS polymerization. HbSC disease causes vasoocclusive disease and hemolytic anemia, albeit on average both less severe than found in sickle cell anemia (homozygosity for HbS). Like sickle cell anemia, the hematological and clinical features of HbSC disease are heterogeneous, but all of the complications that make sickle cell anemia notorious can be present; some even appear more often in HbSC disease.
HbC and HbC Disease
Origins, Selection, and Distribution of HbC
HbC, the second hemoglobin variant discovered, was described in 1950, and the first homozygous case was reported in 1953. The βC-globin gene contains a GAG→AAG transition and codes for lysine instead of glutamic acid. Shortly after its description in African Americans, HbC was found to be common in Africa.
22 - Sickle Cell Trait
- from SECTION FIVE - SICKLE CELL DISEASE
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
Parents of children with sickle cell anemia seldom have the same disease as their offspring. In 1927, 17 years after the first clinical description of sickle cell anemia, it was discovered that almost 10% of African Americans had erythrocytes that sickled when deoxygenated. With the subsequent identification of HbS, and the observation that patients with sickle cell anemia had predominantly HbS in their hemolysates, whereas their parents' had both HbS and HbA, the genetics of sickle hemoglobinopathies was characterized and sickle cell trait (HbAS) was defined.
Almost 40 years ago, reports of sudden death in military recruits with HbAS triggered a push for mandatory screening for HbAS, denial of military service for some carriers, and insurance coverage cancellation for others. An astounding list of complications of HbAS appeared in the literature. The interpretation of these reports often disregarded the distinction between statistically significant associations and coincidence, and almost all lacked any control comparisons. This chapter reviews what is known, what is presumed, and what is erroneous about the pathogenicity, clinical features, and management of HbAS.
PATHOGENESIS
HbAS is usually implies simple heterozygosity for the HbS gene (HBB glu6val). Less than half the hemoglobin in the HbAS erythrocyte is HbS; the remainder is mainly HbA. The probability that the mixed hybrid tetramer, α2βSβA, will enter the polymer phase is only half that of the HbS tetramer, α2βS2 (Fig. 22.1A).
Introduction, by David J. Weatherall
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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Summary
A few years ago, an eminent British professor of medicine, while reviewing a new edition of a well-known textbook of medicine, suggested that works of this type were becoming valueless because they were already out of date by the time they were published. His derogatory comments went further: Having taken the trouble to weigh the book, he suggested that volumes of this type would suffer the same fate as dinosaurs and become extinct by collapsing under their excessive weight. Even allowing for this bizarre and completely erroneous view of the biological fate of the dinosaurs, does this argument carry any weight beyond its metaphorical context?
Undoubtedly, there is feeling rife among medical publishers that the day of the major monograph in the biological sciences may be coming to an end. They argue that there is so much information online that the need for works of this type is becoming increasingly limited. Is this really the case? Although it is impossible to deny that the long gestation of monographs of this type may lead to the omission of the occasional “breakthrough” in a field, it seems very important that in any rapidly moving area of the biomedical sciences there is a regular and broad critical review of where it has got to and how it has been modified by recent advances. Not uncommonly in medical research and practice, today's breakthrough is tomorrow's breakdown.
Is the hemoglobin field moving rapidly? This was another question that had to be considered by the editors of this new edition.
Index
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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24 - Unstable Hemoglobins, Hemoglobins with Altered Oxygen Affinity, Hemoglobin M, and Other Variants of Clinical and Biological Interest
- from SECTION SIX - OTHER CLINICALLY IMPORTANT DISORDERS OF HEMOGLOBIN
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
Mutations of hemoglobin can be polymorphic (>1% of a population), like HbS, HbE, HbC, and the thalassemias, or rare. Our first edition listed 750 unique hemoglobin variants; this number is now more than 1,000. In this chapter we address rare mutations. Some are associated with clinical disease; others are interesting solely for the biological principles they illustrate. A current listing of variant human hemoglobins is maintained in the HbVar database at http://globin.cse.psu.edu/, and the journal Hemoglobin (Taylor & Francis, Philadelphia) is a rich source for reports of new variants. Both are invaluable resources for clinicians and investigators with interests in unusual hemoglobin disorders.
Globin gene mutations, which include nearly every class of mutation so far described, except trinucleotide repeats and other nucleotide expansions associated with neuromuscular disorders, provided an early catalog of the mutations that can cause genetic disease. Clinically important but rare mutants affect hemoglobin stability causing premature red cell destruction; interfere with normal oxygen binding kinetics producing erythrocytosis; and permit heme iron oxidation, causing cyanosis. Most rare variants have no phenotype and are of biological and diagnostic interest only.
Comparatively few globin residues are critical for maintaining the structural integrity and functional performance of the molecule (Chapter 6). Hemoglobin gene mutations are, as a rule, not associated with hematological or clinical abnormalities and escape detection, especially when they are chromatographically silent.
Large-scale population screening programs have defined the worldwide prevalence of medically important hemoglobinopathies and thalassemias.
7 - Hemoglobins of the Embryo, Fetus, and Adult
- from SECTION ONE - THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
During development, humans express six different hemoglobin types, the products of eight different globin genes (Fig. 3.1, Chapter 3). Hb Gower I (ς2ε2), Gower II (α2ε2), and Portland (ς2γ2) are found in the embryo, fetal hemoglobin (HbF; α2γ2) is present mainly in the fetus but also in the embryo and adult, whereas HbA (α2β2) and HbA2 (α2δ2) are seen primarily in adults. All hemoglobins undergo posttranslational modifications forming minor hemoglobins. Globin genes are discussed in Chapter 3, hemoglobin switching in Chapter 5, and the structure and function of hemoglobin in Chapter 6 and. In this chapter we discuss the clinical and physiological attributes of HbF, HbA2, embryonic hemoglobins, and their posttranslational modifications.
HEMOGLOBIN F
The observation that hemoglobin in newborns' erythrocytes was resistant to alkaline denaturation provided the first suggestion that a hemoglobin existed that differed from normal HbA.
Structure of the γ-Globin Genes and γ-Globin
γ-Globin chains differ from β-globin chains in either 39 or 40 amino acid residues, depending on whether a glycine or alanine residue is present at γ136. γ-Globin is the product of two nearly identical γ-globin genes. A glycine codon is present in the 5′ or Gγ gene (HBG2) and an alanine codon characterizes the 3′, or Aγ gene (HBG1). Also, a common polymorphism is found in the Aγ gene, where threonine (AγT) replaces isoleucine (AγI) at codon γ75 (HbF-Sardinia). This striking similarity in protein sequence and structure of the γ-globin genes reflect their concerted evolution from gene duplication and gene conversion.
19 - Clinical and Pathophysiological Aspects of Sickle Cell Anemia
- from SECTION FIVE - SICKLE CELL DISEASE
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
Many authors have recounted the history of sickle cell disease in Africa and its first recognition in the United States Sickle-shaped red cells were first described in 1910 in the blood of a sick, anemic student from Grenada. Sickle hemoglobin (HbS) was identified in 1949 and the mechanism of inheritance of sickle cell anemia was established afterward. A single amino acid difference was found to distinguish the sickle β-globin chain from the normal one. The breadth of clinical and laboratory manifestations of sickle cell disease and its multitudinous complications still challenge the pediatrician, internist, general surgeon, obstetrician, orthopedist, ophthalmologist, psychiatrist, and subspecialists in each of these disciplines.
The features of sickle cell anemia change as life advances. Life's first decade, with declining fetal hemoglobin (HbF) levels, is typified by a risk of severe life-threatening infection, dactylitis, acute chest syndrome, splenic sequestration, and stroke; pain is often the torment of adolescence. If the worst of childhood and adolescent problems are survived or escaped, young adulthood can be a time of relative clinical quiescence, but sickle vasculopathy is likely to progress despite producing few symptoms. Chronic organ damage leading to pulmonary hypertension, deteriorating pulmonary function, renal failure, and late affects of previous cerebrovascular disease, including neurocognitive impairment, become paramount as years advance. Sickle cell anemia is noted for its clinical heterogeneity (Chapter 27). Any patient can have nearly all known disease complications; some have almost none, but die with a sudden acute problem.
Contents
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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27 - Genetic Modulation of Sickle Cell Disease and Thalassemia
- from SECTION SEVEN - SPECIAL TOPICS IN HEMOGLOBINOPATHIES
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
Sickle cell anemia is a typical mendelian, single gene disease. Nevertheless, because of its characteristic phenotypic heterogeneity it resembles a multigenic trait. That is, the mutation in HBB is necessary, but alone insufficient to account for the phenotypic differences among patients, and other genes and the environment are likely to modulate its phenotype. In β thalassemia, and even in HbH disease, genotype–phenotype correlations are also often difficult to establish. Modulation of the phenotypes of these disorders by epistatic and other modifying genes has been a subject of increasing interest. Although studies based on candidate-modulating genes – genes chosen for study on the basis of their possible affects on a phenotype – have started to suggest genes and pathways that might modulate the phenotype of sickle cell anemia, a complete picture of genetic modulators should emerge as genome-wide association studies mature.
It is likely that fetal hemoglobin (HbF) concentration, and its distribution among erythrocytes is the major genetic modulator of both sickle cell disease and the β thalassemias. The coincidence of α thalassemia with sickle cell anemia or β thalassemia is another powerful modulatory influence. Individually, other genetic modulators are likely to have small effects, yet together the interactions of modulatory genes (and environmental factors) might have an important influence on morbidity and mortality.
In this chapter we will first discuss HbF and the genetic elements and genes that might modulate its levels and then the effects of α thalassemia in sickle cell disease and β thalassemia.
Preface
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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Frontmatter
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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List of Contributors
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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13 - The Molecular Basis of α Thalassemia
- from SECTION THREE - α THALASSEMIA
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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INTRODUCTION
Before describing the various ways in which α-globin expression may be downregulated in patients with α thalassemia, it is worth briefly reviewing the normal structure of the human α-globin cluster and how the genes are expressed throughout erythroid differentiation and development.
The α-globin cluster is located in a gene dense region of the genome close to the telomere of chromosome 16 (16p13.3). The genes are arranged along the chromosome in the order, telomere-ς-ψς-αD-ψα1-α2-α1-θ-centromere (Fig. 13.1). Upstream of the α cluster there are four highly conserved, noncoding sequences multispecies conserved sequences called MCS-R1–R4 that are thought to be important in the regulation of the α-like globin genes. They correspond to previously identified erythroid-specific DNase l hypersensitive sites (DHS) referred to as HS-48, HS-40, HS-33, and HS-10, the coordinates referring to their positions (kb) with respect to the ς-globin mRNA cap site. Of these elements, only MCS-R2 (HS-40) has been shown to be essential for α globin expression (summarized in Higgs et al.). The role(s) of the other MCS sequences are as yet unclear.
It has been shown that as progenitors commit to the erythroid lineage and differentiate to form mature red cells, a subset of the key erythroid transcription factors and cofactors (Chapter 4) progressively bind the upstream elements and the promoters of the α-like globin genes. Finally, RNA polymerase II is recruited to both the upstream regions and the globin promoters as transcription starts in early and intermediate erythroblasts.
SECTION SIX - OTHER CLINICALLY IMPORTANT DISORDERS OF HEMOGLOBIN
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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- Disorders of Hemoglobin
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- 17 August 2009, pp 587-588
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Summary
Three chapters discuss rare inherited hemoglobinopathies including unstable hemoglobins, hemoglobins with altered oxygen affinity, hemoglobins easily oxidized, and a miscellaneous group of hemoglobin variants with interesting biological properties, some of which are clinically important. Acquired disorders of hemoglobin can arise from heme iron oxidation due to inherited abnormalities of hemoglobin-reducing enzymes or because of exposure to exogenous oxidizing agents.
Rare hemoglobinopathies have taught us much about the struc24-87519-function relationships of hemoglobin. Hemoglobin mutants have provided the most comprehensive list of mutations of any system in human biology, creating a map for understanding mutation in other genetic loci. Globin gene mutations – these include nearly every class of mutation so far described – provided an early catalog of the possible mechanisms of genetic disease.
An accounting of globin gene mutations in early 2008 listed 1,326 unique mutations (http://globin.cse.psu.edu/). Here, we discuss some rare hemoglobin mutations. As comparatively few globin residues are critical for maintaining the structural integrity and functional utility of the molecule, most hemoglobin mutations are not associated with hematological or clinical abnormalities and so escape detection. Some mutations, although not medically important, illustrate interesting biological and anthropological principles.
Abnormal hemoglobins with high or low oxygen affinity, variants that have their heme iron oxidized to the ferric form causing methemoglobinemia (HbM), or hemoglobin variants that are unstable are abnormalities seen rarely by the general physician and infrequently encountered in the practice of hematology.
SECTION FOUR - THE β THALASSEMIAS
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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- Disorders of Hemoglobin
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Over the years, study of the thalassemia syndromes has served as a paradigm for gaining insights into the factors that can regulate or disrupt normal gene expression. The thalassemias constitute a heterogeneous group of naturally occurring, inherited mutations characterized by abnormal globin gene expression resulting in total absence or quantitative reduction of α- or β-globin chain synthesis in human erythroid cells. α Thalassemia is associated with absent or decreased production of α-chains, whereas in the β thalassemias, there is absent or decreased production of β-chains. In those cases in which some of the affected globin chain is synthesized, early studies demonstrated no evidence of an amino acid substitution. In all cases in which genetic evidence was available, the thalassemia gene appeared to be allelic with the structural gene encoding α- or β-globin. The elucidation of the nature of the various molecular lesions in thalassemia has been a fascinating process, and full of surprises. Increase in our knowledge of the molecular basis of β thalassemia has closely followed and depended on progress and technical breakthroughs in the fields of biochemistry and molecular biology. In particular, recombinant DNA and polymerase chain reaction–based technologies have contributed to a virtual explosion of new information on the precise molecular basis of most forms of thalassemia. The accrual of this knowledge has, to a great degree, paralleled the acquisition of new, detailed information on the structure, organization, and function of the normal human globin genes, as described in the preceding chapters.
SECTION FIVE - SICKLE CELL DISEASE
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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Summary
PATHOPHYSIOLOGY
A β-hemoglobin gene mutation results in the synthesis of the sickle β-globin chain. Sickle hemoglobin (HbS) polymerizes when deoxygenated, and polymer-associated injury to the sickle erythrocyte is the proximate cause of sickle cell disease. The principal pathophysiological features of this disease are shown in the figure and can be grouped as vasoocclusive/blood viscosity related and hemolysis/vasculopathy related. This complex pathophysiology involves diverse molecular and cellular defects that include abnormal erythrocyte volume regulation, impaired nitric oxide bioavailability, reperfusion injury and inflammation, altered hemostasis, defects of intercellular interactions, endothelial cell damage, leukocyte and platelet activation, and in all probability, other perturbations of normal physiology.
DIAGNOSIS
Sickle cell disease is a constellation of similar but not identical disorders, all of which have at least 50% HbS in the blood. The phenotype of sickle cell disease is caused by several common and some less common genotypes; homozygotes for the HbS gene are said to have sickle cell anemia; common compound heterozygous forms of disease include HbSC disease and HbS-β thalassemia. The cornerstone of the clinical laboratory diagnosis is the detection and quantification of HbS. Depending on the context of the diagnostic situation, direct detection of the HbS and other globin gene mutations can be warranted. Sickle cell trait is clinically benign and not considered a form of sickle cell disease.
CLINICAL FEATURES
The complications of sickle cell disease can occur acutely, producing dramatic clinical findings, or they can be chronic, disabling, and cause premature death.
SECTION ONE - THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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- Disorders of Hemoglobin
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Over the past 30 years we have become familiar with the way in which different types of hemoglobin are expressed at different stages of development. In the human embryo the main hemoglobins include Hb Portland (ζ2γ2), Hb Gower I (ζ2ε2), and Gower II (α2ε2). In the fetus, HbF (α2γ2) predominates and in the adult, HbA (α2β2) makes up the majority of hemoglobin in red cells. These simple facts belie the complexity of the cellular and molecular processes that bring about these beautifully coordinated changes in the patterns of globin gene expression throughout development.
To understand these phenomena we have to consider the individual components including 1) the origins of erythroid cells in development, 2) the processes by which erythroid cells differentiate to mature red cells at each developmental stage, and 3) the molecular events that produce the patterns of gene expression we observe.
Two different types of erythroid cells are observed during development. The first erythroid cells to be seen in the developing embryo are located in the blood islands of the yolk sac. These primitive erythroid cells are morphologically different from the definitive erythroid cells made in the fetal liver and bone marrow and contain predominantly embryonic hemoglobins. Somewhat later during embryonic development, definitive erythroid and other hematopoietic cells originate from multipotent cells identified in a part of the embryo that lies near the dorsal aorta, in the region close to where the kidneys first develop: the so-called aorta-gonads-mesonephros (AGM) region.
28 - Laboratory Methods for Diagnosis and Evaluation of Hemoglobin Disorders
- from SECTION SEVEN - SPECIAL TOPICS IN HEMOGLOBINOPATHIES
- Martin H. Steinberg, Boston University, Bernard G. Forget, Yale University, Connecticut, Douglas R. Higgs, David J. Weatherall, Albert Einstein College of Medicine, New York
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- Disorders of Hemoglobin
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INTRODUCTION
Hemoglobinopathy detection is often a part of the evaluation of anemia, hemolysis, microcytosis, cyanosis, or erythrocytosis. For this purpose, protein (hemoglobin)-, cellular-, and DNA-based approaches to the detection of variant hemoglobins and thalassemias are available. Diagnostic details can be found in each disease-specific chapter, whereas in the following pages we focus on the available methods and their strengths and weaknesses.
Characterization of mutant hemoglobins and thalassemias described throughout this book takes place in different contexts: large newborn screening laboratories that need to identify positively the most common mutants; general hematology laboratories that most often encounter common hemoglobinopathies and thalassemias; and reference or research laboratories that can detect rare mutant globin genes. Approaches that are necessary in one setting might not be practical in others.
Normal adult blood contains predominantly HbA (α2β2) and small amounts of HbF (α2γ2) and HbA2 (α2δ2). After synthesis, monomeric globin chains form α/non-α dimers that do not dissociate under physiological conditions. In the presence of oxygen, hemoglobin tetramers rapidly dissociate into very low concentrations of dimers that can then form new tetramers. This implies that when more than one α- or non-α-chain is present, the predominant form in the red cell will be the heterotetramer (for example, in red cells of HbSC disease, the dominant species will be α2βSβC, and α2βSγ heterotetramers form when HbS is present with high levels of HbF (Fig. 28.1).