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1. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes

Author

Thomas Donner, P. Rezaeian, John I. Malone, Sharon B. Schwartz, Xiaoyu Gao, Szilard Kiss, Matthew J. Budoff, David R. Sell, A. Dwoskin, Ronald J. Prineas, C. Pittman, M. Reid, C. McDonald, S. Caulder, M. Szpiech, Oscar B. Crofford, Rachel G. Miller, Louis A. Lobes, M. Patronas, C. Canny, M. E. Lackaye, Sandra R. Montezuma, Richard M. Bergenstal, Patricia Gatcomb, Julie A. Stoner, H. Pan, James L. Kinyoun, J. Mortenson, Osama Hamdy, Connie Fountain, David D. Moore, Kusiel Perlman, R. Trail, David A. Lee, J. Sheindlin, Samuel Dagogo-Jack, Jeffrey L. Mahon, Jill P. Crandall, L. Gill, T. Thompson, Lee M. Jampol, K. Koushan, David S. Schade, J. Brown-Friday, M. Basco, S. Dunnigan, J. Bylsma, R. Birk, L. H. Ketai, J. Hotaling, Stephen W. Scherer, W. Mestrezat, Stephan Villavicencio, R. Lyon, M. Carney, John Kramer, Sunder Mudaliar, David M. Nathan, M. Moran, F. Leandre, James W. Albers, L. Survant, Joseph F. Polak, Manjot K. Gill, Anton Orlin, M. Prince, Pamela A. Silver, Amy K. Saenger, John D. Brunzell, Kathleen E. Bainbridge, L. Babbione, Amisha Wallia, J. Vaccaro-Kish, Bradley D. Jones, M. Hebdon, L. McKenzie, Richard M. Hoffman, S. Chang, C. Siebert, George S. Sharuk, D. Counts, A. Lucas, P. Ramos, N. Burkhart, N. Bakshi, N. Flaherty, D. Kenny, M. Driscoll, Harjit Chahal, Ronald K. Mayfield, S. Hensley, E. Weimann, M. Franz, Martin J. Stevens, N. S. Gregory, Christopher J. O'Donnell, J. Laechelt, Pamela Ossorio, Jerry P. Palmer, Rama Natarajan, G. Ziegler, K. Martin, R. Beaser, C. Beck, L. Zhang, T. J. Declue, David M. Kendall, H. Solc, A. Vella, H. Martinez, Cormac T. Taylor, S. Neill, Douglas A. Greene, P. Lee, D. Norman, Andrew J. Barkmeier, Dean P. Hainsworth, Alka Jain, Sapna Gangaputra, N. Thangthaeng, Lorraine Thomas, Michael H. Brent, M. Bracey, Philip Raskin, Q. Clemens, Barbara H. Braffett, Mark S. Mandelcorn, Lloyd Paul Aiello, John E. Godine, T. Speigelberg, R. Chan, R. Hanna, Shelley B. Bull, William I. Sivitz, R. Sussman, C. Kwong, S. Cercone, P. Hollander, N. Leloudes, Joseph M. Terry, J. Wesche, E. A. Tanaka, D. Rosenberg, Wanjie Sun, L. Sun, Tom Clark, Deborah K. Schlossman, Louis M. Luttrell, R. Dunn, A. Farr, K. McVary, Gayle M. Lorenzi, A. Joseph, Catherine C. Cowie, M. Barr, D. Zimbler, S. Mendley, S. Schussler, N. Grove, Matthew D. Davis, Jong Mu Sun, Sophie Rogers, John P. Bantle, Brandy N. Rutledge, Senda Ajroud-Driss, Vincent M. Monnier, Cladd E. Stevens, Y. G. He, M. Phillips, C. Williams, J. MacIndoe, Kaleigh Farrell, Helen Lambeth, Ayad A. Jaffa, J. Quin, Morey W. Haymond, R. Kirby, D. Steinberg, William H. Herman, M. Mech, Arup Das, Robert Detrano, J. Brown, D. McMillan, Linda Snetselaar, Mark W. Johnson, R. Zeitler, T. Taylor, Peter R. Pavan, Michael H. Goldbaum, Bruce A. Perkins, R. G. Campbell, David A. Nicolle, R. J. van der Geest, Irene Hramiak, D. Freking, Lucy A. Levandoski, S. Colson, Charles Campbell, Victoria R. Trapani, Lawrence J. Singerman, D. Meyer, W. Tang, J. Soule, Anita Harrington, Julie A. Nelson, John A. Colwell, Naji Younes, P. Salemi, K. Hansen, Trevor J. Orchard, S. Huddleston, L. Steranchak, C. Sommer, G. Castle, J. Ginsberg, Paula McGee, V. Gama, John Dupre, Z. Strugula, M. Swenson, N. Wong, David A. Bluemke, M. Nutaitis, Anita Agarwal, M. Lin, K. Nickander, Elsayed Z. Soliman, Joao A. Lima, M. L. Schluter, Fred W. Whitehouse, Lisa Diminick, C. Cornish, M. Spencer, Daniel T. Lackland, Ionut Bebu, Hunter Wessells, S. Yacoub-Wasef, A. Determan, L. Van Ottingham, Howard Wolpert, R. Ehrlich, A. Blevins, L. Jovanovic, D. Finegold, Davida F. Kruger, Jye-Yu C. Backlund, K. Chan, Timothy J. Murtha, R. K. Mayfield, Robert W. Cavicchi, Maria F. Lopes-Virella, Thomas A. Weingeist, K. Lee, Mary E. Larkin, B. Blodi, J. Gott, Timothy J. Lyons, J. Selby, Chris Ryan, J. Harth, P. Pugsley, L. Keasler, John D. Maynard, Paul G. Arrigg, Amy B. Karger, P. Colby, J. Farquhar, Mark H. Schutta, Murk-Hein Heinemann, Kathie L. Hermayer, B. Bosco, C. Lovell, A. Bhan, A. Galprin, M. Cayford, M. Schumer, John E. Chapin, D. Rubinstein, F. Miao, V. Asuquo, Catherine L. Martin, Rodney A. Lorenz, Samuel S. Engel, L. Funk, Cyndi F. Liu, Barbara J. Maschak-Carey, Stephen S. Feman, P. Lindsey, M. Giotta, Philip A. Low, S. Kwon, R. Fahlstrom, A. Iannacone, B. French, H. Remtema, L. Cimino, S. Barron, J. McConnell, Jane L. Lynch, L. Kim, T. Williams, A. Degillio, Blanche M. Chavers, M. Novak, Julio V. Santiago, Ronald P. Danis, P. Gaston, Tae Sup Lee, T. Woodfill, R. Cuddihy, Scott M. Steidl, Alanna C. Morrison, E. Ryan, D. Lawrence, D. Cros, T. Adkins, D. Adelman, L. Dews, Patricia A. Cleary, J. Parker, L. Olmos De Koo, C. Kim, Mark R. Palmert, P. Astelford, Stefan Fritz, B. Olson, Kelvin C. Fong, Alan M. Jacobson, Stanley L. Hazen, D. Hornbeck, K. Folino, M. L. Bernal, Gabriel Virella, William V. Tamborlane, Neil H. White, Daniel L. McGee, Denis Daneman, H. Shamoon, William Dahms, S. Elsing, S. Brink, J. Ahern, Delnaz Roshandel, John M. Pach, N. W. Rodger, E. Cupelli, Dara D. Koozekanani, Abbas E. Kitabchi, K. Stoessel, B. Petty, Jamie R. Wood, J. Seegmiller, T. Strand, Y. Li, Eva L. Feldman, Larry Rand, Robert C. Colligan, T. Smith, A. Carlson, David J. Brillon, Margaret L. Bayless, M. Ong, S. Darabian, W. Hsu, Janet E. Olson, B. Rogness, N. Silvers, M. Pfiefer, B. Schaefer, E. Mendelson, S. Braunstein, Maren Nowicki, R. Reed, James S. Floyd, Z. M. Zhang, T. Sandford, R. B. Avery, A. Pratt, Paolo S. Silva, H. Bode, Alexander J. Brucker, Nikhil D. Patel, Alexander R. Lyon, M. Jenner, N. Wimmergren, L. Tuason, J. Rosenzwieg, D. J. Becker, C. Gauthier-Kelly, M. Richardson, Richard S. Crow, Andrew D. Paterson, Mark E. Molitch, Suzanne M. Strowig, S. Pendegast, M. Burger, Ramzi K. Hemady, J. Dingledine, I. H. de Boer, L. Mayer, F. Perdikaris, Om P. Ganda, F. Thoma, Karen J. Cruickshanks, Abraham Thomas, K. Klumpp, Jerry D. Cavallerano, D. Zheng, Annette Barnie, J. L. Canady, C. Wigley, David G. Miller, Sheila Smith-Brewer, D. Ostrowski, P. Crawford, K. Kelly, Robert G. Devenyi, B. Zimmerman, Susan M. Hitt, C. Johnson, L. Gurry, R. Jarboe, E. Angus, David E. Goldstein, A. Killeen, H. Schrott, Orville G. Kolterman, Mark R. Burge, Michael Rubin, J. Lipps Hagan, Alicia J. Jenkins, Hugh D. Wabers, R. Warhol, Edward Chaum, Karen L. Jones, L. Spillers, C. Miao, J. K. Jones, Angelo J. Canty, Rickey E. Carter, Evrim B. Turkbey, B. Burzuk, R. Woodwick, Evica Simjanoski, Michael W. Steffes, S. Crowell, Suresh D. Shah, H. Ricks, J. D. Carey, Paul A. Edwards, S. Holt, W. F. Schwenk, Ronald J. Oudiz, E. Brown, J. Heier, R. L. Ufret-Vincenty, L. M. Aiello, Robert A. Rizza, Karen L. Anderson, Valerie L. Arends, J. Giangiacomo, R. Liss, Aruna V. Sarma, B. Levy, Ellen J. Anderson, S. Catton, P. Callahan, Rodica Pop-Busui, S. Debrabandere, S. Moser, Bernard H. Doft, A. Malayeri, C. Johannes, R. Ramker, J. Rich, M. Fox, Rukhsana G. Mirza, Katherine A. Morgan, Thomas J. Songer, C. Shah, H. Engel, Saul M. Genuth, S. Ferguson, Anushka Patel, C. Haggan, P. Lou, J. Gordon, M. B. Murphy, D. Sandstrom, Dawn M. Ryan, Daniel H. O'Leary, B. Gloeb, Lois E. Schmidt, H. Zegarra, D. Dalton, W. Brown, Tom G. Sheidow, Margaret E. Stockman, Shyam M. Thomas, Charles McKitrick, Jyotika K. Fernandes, P. A. Bourne, L. Baker, G. Friedenberg, Allan Gordon, Allan L. Drash, S. Yoser, D. Wood, S. Johnsonbaugh, A. De Manbey, L. Kaminski, M. May, L. Bestourous, A. Kowarski, M. Geckle, M. Hartmuller, Michael Bryer-Ash, S. List, F. Goetz, V. Reppucci, D. Etzwiler, Rose A. Gubitosi-Klug, M. Brabham, E. Golden, A. Nayate, J. Hu, M. McLellan, Ronald Klein, N. Rude, B. Vittetoe, John M. Lachin, M. Christofi, Zhuo Chen, Isaac Boniuk, C. Strauch, K. Gunyou, L. Delahanty, W. T. Garvey, Andrew P. Boright, Larry D. Hubbard, D. Weiss, Igor Grant, Jonathan Q. Purnell, Jean M. Bucksa, N. Olson, and B. Zinman

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Diabetic neuropathy, Adolescent, 030209 endocrinology & metabolism, Gastroenterology, Nephropathy, Epigenesis, Genetic, Diabetic complications, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Diabetic Neuropathies, Internal medicine, Diabetes mellitus, Albumins, Genetics, Medicine, Humans, Molecular Biology, Genetics (clinical), Whole blood, Oligonucleotide Array Sequence Analysis, Type 1 diabetes, business.industry, Research, dNaM, DNA methylation age, DNA Methylation, medicine.disease, 030104 developmental biology, Blood pressure, Peripheral neuropathy, Diabetes Mellitus, Type 1, CpG Islands, Female, business, Developmental Biology, Genome-Wide Association Study
Abstract

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Published
2020

2. Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Author

M. Bracey, B. French, Brandy N. Rutledge, Sharon B. Schwartz, D. Steinberg, Peter R. Pavan, Xiaoyu Gao, Alan M. Jacobson, David A. Nicolle, C. Canny, Maria F. Lopes-Virella, A. Kitabchi, K. Hansen, M. E. Lackaye, Denis Daneman, Kandace A. Klumpp, David A. Lee, H. Engel, L. Survant, C. Haggan, K. Lee, G. Ziegler, Dawn M. Ryan, Lloyd Paul Aiello, Tom G. Sheidow, Allan Gordon, Allan L. Drash, S. Johnsonbaugh, L. Kaminski, S. Yoser, David J. Brillon, Osama Hamdy, Connie Fountain, N. Silvers, Kusiel Perlman, S. Caulder, M. Szpiech, D. Freking, Paula McGee, George S. Sharuk, D. Counts, H. Solc, David E. Goldstein, L. Bestourous, W. F. Schwenk, E. Brown, S. Cercone, M. Patronas, James L. Kinyoun, G. Castle, Mark H. Schutta, M. L. Schluter, Anton Orlin, E. Chaum, Daniel P. Joseph, F. Goetz, V. Reppucci, D. Etzwiler, E. Golden, A. Iannacone, R. Kirby, Lucy A. Levandoski, Lawrence J. Singerman, P. Salemi, A. Morrison, G. Vagstad, J. Laechelt, Pamela Ossorio, Tae Sup Lee, R. Cuddihy, S. Hitt, Fred W. Whitehouse, Michael H. Brent, Gayle M. Lorenzi, Anthony D. Morrison, B. Zinman, Szilard Kiss, D. Norman, N. Olson, Thomas Donner, John Dupre, M. Swenson, M. Spencer, Jerry P. Palmer, Scott M. Steidl, M. Franz, R. Beaser, H. Martinez, Samuel S. Engel, L. Diminick, J. Mortenson, David S. Schade, S. Yacoub-Wasef, Misty Good, John E. Chapin, Paolo S. Silva, J. Ginsberg, A. Dwoskin, John P. Bantle, J. D. Carey, D. McMillan, R. G. Campbell, Lisa Diminick, C. Cornish, Ramzi K. Hemady, P. Hollander, A. Farr, D. Zimbler, M. Mech, A. Lucas, Jye-Yu C. Backlund, K. Chan, Timothy J. Murtha, V. Asuquo, A. Bhan, A. Galprin, F. Perdikaris, Michael D. Larsen, L. Gill, Pamela A. Silver, S. Brink, Louis M. Luttrell, Sheila Smith-Brewer, D. Ostrowski, M. Bratkowksi, P. Crawford, M. Bryer-Ash, E. Angus, S. Braunstein, John I. Malone, R. Conwit, C. Pittman, Louis A. Lobes, Rodney A. Lorenz, J. Rosenzwieg, Neil H. White, William I. Sivitz, D. J. Becker, Stephen S. Feman, M. Zaucha, M. Reid, M. Jenner, L. Tuason, C. Gauthier-Kelly, C. McDonald, William H. Herman, John Kramer, Jeffrey L. Mahon, A. Campbell, J. L. Canady, A. Degillio, T. Adkins, P. W. Conrad, Senda Ajroud-Driss, L. Dews, Stephan Villavicencio, David G. Miller, Manjot K. Gill, D. Curtin, J. Brown-Friday, M. Basco, Elsayed Z. Soliman, J. Selby, Bradley D. Jones, M. Hebdon, B. Olson, John M. Pach, N. W. Rodger, K. Stoessel, N. Leloudes, J. Floyd, H. Lambeth, G. Lorenzi, Richard M. Hoffman, S. Chang, M. Guiliani, H. Zegarra, N. Bakshi, Dean P. Hainsworth, Murk-Hein Heinemann, S. Dagogo-Jack, Wanjie Sun, J. Warnicki, Dean B. Burgess, D. Kenny, L. McKenzie, B. Rogness, Martin J. Stevens, M. Nutaitis, William V. Tamborlane, L. Schmidt, Deborah K. Schlossman, J. Giangiacomo, C. Williams, R. Liss, Barbara J. Maschak-Carey, Barbara H. Braffett, Stefan Fritz, J. MacIndoe, Tom Clark, M. Novak, Michael H. Goldbaum, A. DeManbey, J. Ahern, L. Jovanovic, D. Finegold, Davida F. Kruger, Mary E. Larkin, M. Johnson, S. Shah, M. Ong, Catherine L. Martin, M. Giotta, R. Reed, B. Levy, Evica Simjanoski, L. Cimino, P. Callahan, S. Crowell, Rodica Pop-Busui, Howard Wolpert, Bernard H. Doft, J. Arch, C. Shipe, Mark R. Palmert, Philip Raskin, B. Schaefer, P. Astelford, Dara D. Koozekanani, R. B. Avery, Michael W. Steffes, Robert A. Rizza, Karen L. Anderson, Charles McKitrick, P. A. Bourne, L. Baker, G. Friedenberg, D. Wood, J. Wesche, M. Phillips, Gaurav K. Shah, John M. Lachin, M. Christofi, Kevin J. Blinder, R. Ehrlich, J. Rinkoff, Morey W. Haymond, Irene Hramiak, Z. Strugula, A. Blevins, R. Hyre, M. Richardson, Mark E. Molitch, I. H. de Boer, Annette Barnie, Mark R. Burge, M. Prince, P. Ramos, R. Chan, R. Hanna, Jong Mu Sun, Suzanne M. Strowig, C. Wigley, Om P. Ganda, R. Harris, Abraham Thomas, K. Klumpp, K. Kelly, David D. Moore, J. Sheindlin, T. J. Declue, Cormac T. Taylor, C. Kwong, Rose Gubitosi-Klug, T. Sandford, Isaac Boniuk, B. Zimmerman, R. Zeitler, S. Rogers, Joseph M. Terry, C. Johnson, Linda Snetselaar, Naji Younes, Ionut Bebu, N. Wimmergren, Rukhsana G. Mirza, K. Gunyou, Karl R. Olsen, H. Bode, J. Fruit, Michael Rubin, G. Grand, Trevor J. Orchard, Douglas A. Greene, J. Quin, R. Birk, W. Mestrezat, P. Pugsley, Anupam Agarwal, L. Mayer, C. Palmer, Timothy J. Lyons, C. Johannes, A. Determan, L. Van Ottingham, J. Gott, Jerry D. Cavallerano, D. Cros, J. Parker, M. May, Robert Bergren, A. Kowarski, L. Delahanty, Katherine A. Morgan, E. A. Tanaka, Robert W. Cavicchi, Thomas J. Songer, Robert G. Devenyi, J. Harth, Jill P. Crandall, T. Thompson, Lee M. Jampol, H. Schrott, Paul G. Arrigg, Orville G. Kolterman, R. Warhol, L. Thomas, S. Kwon, Jane L. Lynch, Arup Das, Theresa M. Williams, Thomas A. Weingeist, Patricia A. Cleary, Matthew A. Thomas, L. Babbione, Amisha Wallia, J. Lipps Hagan, D. Meyer, D. Rubinstein, P. Lindsey, Mark S. Mandelcorn, R. Fahlstrom, John E. Godine, Kathie L. Hermayer, B. Bosco, J. Rich, K. Folino, M. L. Bernal, S. Yalamanchi, S. Barron, J. McConnell, J. K. Jones, J. Vaccaro-Kish, R. Woodwick, P. Colby, Kelvin C. Fong, Ronald K. Mayfield, L. H. Ketai, Julio V. Santiago, M. B. Murphy, S. Schussler, N. Grove, Larry Rand, Robert C. Colligan, Ronald P. Danis, Valerie L. Arends, S. Ferguson, B. Petty, Christine Stevens, P. Ostrosaka, Margaret L. Bayless, S. Moser, Paul A. Edwards, R. Lyon, M. Carney, Katrina Jones, T. Strand, W. Hsu, Alexander J. Brucker, H. Shamoon, Alice T. Lyon, T. Smith, David M. Nathan, P. Lou, Bruce A. Perkins, Janet E. Olson, D. Rosenberg, H. Ricks, J. Gordon, D. Hornbeck, Nikhil D. Patel, Shelly Olson, Ellen J. Anderson, William Dahms, P. Paczan Rath, S. Elsing, L. Steranchak, L. M. Aiello, Saul Genuth, S. Catton, Sandra R. Montezuma, S. Pendegast, Richard M. Bergenstal, Patricia Gatcomb, Igor Grant, B. Braffett, W. Brown, Margaret E. Stockman, N. Burkhart, David M. Kendall, Jyotika K. Fernandes, S. List, J. Soule, Julie A. Nelson, John A. Colwell, M. McLellan, Silva A. Arslanian, N. Rude, B. Vittetoe, M. Driscoll, and E. Weimann

Subjects
Adult, Male, 030213 general clinical medicine, medicine.medical_specialty, Adolescent, Quality Assurance, Health Care, Psychological intervention, lcsh:Medicine, law.invention, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Health care, medicine, Humans, Medical physics, lcsh:Science, Multidisciplinary, Data collection, business.industry, lcsh:R, Quality control, 3. Good health, Surgery, Data quality, Cohort, 030221 ophthalmology & optometry, Female, lcsh:Q, business, Quality assurance, Follow-Up Studies, Research Article
Abstract

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Published
2015

3. Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci

Author

Mario Pirastu, G. E. Munn, L. H. Ketai, K. Taylor, Angela Döring, R. Chan, Jeffrey L. Mahon, Bradley D. Jones, M. Hebdon, Williams L. Dews, Douglas A. Greene, Michael D. Weiss, Sapna Gangaputra, E. A. Tanaka, J. Ginsberg, Ben A. Oostra, Alka Jain, D. Singer, M. Burger, Szilard Kiss, David A. Bluemke, Barbara H. Braffett, Jugnoo S Rahi, L. Sun, C. Clark, Richard M. Bergenstal, Patricia Gatcomb, Paul Mitchell, R. Trail, D. Ryan, Robert Bergren, D. D. Joseph, G. Grand, Blanche M. Chavers, J. M.Verhoeven Virginie, David S. Schade, C. Cowie, Sharon B. Schwartz, G. Ziegler, Lloyd Paul Aiello, Michael H. Brent, John I. Malone, C. Pittman, M. Reid, Stephen S. Feman, Maurizio Fossarello, Kathie L. Hermayer, J. Parker, M. N. Iyer, Hamid Mojibian, Rose Gubitosi-Klug, P. W. Conrad, Daniel T. Lackland, Michael Brändle, C. Canny, Alan F. Wright, M. E. Lackaye, David A. Lee, Rickey E. Carter, J. Brown-Friday, J. K. Jones, J. Distad, A. Thomas, Gordon C. Weir, S. Caulder, M. Szpiech, R. Gstalder, D. Rubinstein, Fred W. Whitehouse, T. Adkins, Gayle M. Lorenzi, L. Survant, Naji Younes, Robert Detrano, Lucy A. Levandoski, Charles Campbell, Lawrence J. Singerman, Johannes R. Vingerling, Joao A.C. Lima, D. Counts, V. Gama, D. M. Nathan, John Dupre, Cornelia M. van Duijn, N. Wong, Anita Harrington, Caroline Hayward, Shelley B. Bull, R. Hackel, William I. Sivitz, Enrico Cagliero, M. Spencer, Albert Hofman, Samuel S. Engel, John E. Hokanson, Julio V. Santiago, David M. Kendall, O. Crofford, T. Thompson, Lee M. Jampol, Kevin Morgan, R. Sussman, James W. Albers, Anita Agarwal, Kevin J. Blinder, Anthony D. Morrison, Nikhil D. Patel, R. Prusak, S. Hitt, Alexander R. Lyon, Saul Genuth, J. Sheindlin, J. Vaccaro-Kish, Goran Benčić, P. Titus, Lisa Diminick, N. Wimmergren, Shelly Olson, Z. Strugula, L. Goings, Lennart C. Karssen, A. Blevins, Harjit Chahal, Ronald K. Mayfield, S. Pendegast, T. J. Lyons, Ozren Polasek, Matthew A. Thomas, Annette Barnie, P. Lindsey, L. Funk, James L. Kinyoun, Neil H. White, L. Mayer, Rodney A. Lorenz, Susan G. Elner, R. L. Pate, E. Simjanoski, R. Beaser, J. Gothrup, Tien Yin Wong, Thomas Bettecken, Jae-Ho Lee, Elsayed Z. Soliman, Ronald P. Danis, Phillippa M. Cumberland, J. Selby, Pamela Rath, H. Martinez, S. Neill, D. Rosenberg, D. Zheng, R. Devenyi, Murk-Hein Heinemann, Albert V. Smith, Alicia J. Jenkins, Rukhsana G. Mirza, Konrad Oexle, Osama Hamdy, John D. Brunzell, Trevor J. Orchard, Daniel Cornfeld, K. Nickander, Igor Rudan, L. Kim, T. Williams, Christopher M. Ryan, William Dahms, P. Paczan Rath, S. Elsing, Matthew J. Budoff, Orville G. Kolterman, Seang-Mei Saw, Lisa A. Prosser, A. Determan, M. Espeland, L. Van Ottingham, B. Petty, A. Farr, Brandy N. Rutledge, Patricia A. Cleary, Margaret L. Bayless, E. Cupelli, Ronald J. Prineas, Jonathan Goldstein, Stefan Fritz, J. Harth, K. Stoessel, Jerry P. Palmer, J. Soule, John A. Colwell, Stephen W. Scherer, Cyndi F. Liu, M. Phillips, Alexander J. Brucker, B. Rogness, Caroline C W Klaver, Joan E. Bailey-Wilson, Claire L. Simpson, Gaurav K. Shah, Louis A. Lobes, S. Mohsen Hosseini, Veronique Vitart, Dwight Stambolian, Mark S. Mandelcorn, John E. Godine, Gabriel Virella, A. Cochrane, David A. Nicolle, Timothy J. Lyons, S. Schussler, Abbas E. Kitabchi, N. Grove, Matthew D. Davis, Andrew K. Vine, Joseph F. Polak, Helen Lambeth, Ayad A. Jaffa, S. Rogers, Samuel Dagogo-Jack, C. Siebert, K. Hansen, H. Shamoon, David J. Brillon, D. Schlossman, H. Ricks, Toby A. Gardner, Mary Frances Cotch, J. Quin, Om P. Ganda, Fernando Rivadeneira, F. Thoma, Brian Fleck, K. Klumpp, Manjot K. Gill, R. J. van der Geest, Hunter Wessells, P. Salemi, P. Gaston, Tae Sup Lee, T. Woodfill, Scott M. Steidl, Thomas Meitinger, Laura Portas, John E. Chapin, Robert Wojciechowski, Martin J. Stevens, Z. M. Zhang, John D. Maynard, Paul G. Arrigg, S. Yacoub-Wasef, Andrew D. Paterson, Barbara J. Maschak-Carey, Ramzi K. Hemady, J. Dingledine, Sheila Smith-Brewer, D. Ostrowski, D. Kenny, Leslie J. Raffel, R. Jarboe, E. Angus, G. Sharuk, Jie Jin Wang, Jye-Yu C. Backlund, K. Chan, R. K. Mayfield, M. Nutaitis, William V. Tamborlane, Emily Y. Chew, Michael H. Goldbaum, S. Kwon, Davida F. Kruger, Mary E. Larkin, Catherine L. Martin, M. Novak, David E. Goldstein, J. Rosenzwieg, D. J. Becker, A. E. Boulton, Jean M. Bucksa, Richard S. Crow, Thomas Donner, Philip A. Low, J. Fradkin, K. Folino, M. L. Bernal, Daniel L. McGee, R. D′Agostino, David G. Miller, Evrim B. Turkbey, Eva L. Feldman, Larry Rand, Harry Campbell, Mark R. Palmert, N. Silvers, M. Driscoll, M. Bracey, Mark E. Molitch, Boniuk Burgess, John P. Bantle, J. D. Carey, Edward Chaum, Philip Raskin, I. H. de Boer, Peter R. Pavan, C. Wigley, Maria F. Lopes-Virella, Pirro G. Hysi, C. Sommer, R. Eastman, B. Schaefer, Maren Nowicki, K. Lee, S. Braunstein, Hugh D. Wabers, A. F. Burrows, M. Johnson, B. Zinman, M. Ong, Samir S. Deeb, C. Gauthier-Kelly, S. Novella, C. Miao, S. Strowig, S. Crowell, Teri A. Manolio, S. Yalamanchi, Christian Gieger, D. Meyer, Louis M. Luttrell, Janie Lipps, William H. Herman, Michael W. Steffes, A. Galprin, A. Iannacone, Federico Murgia, E. Steuer, KyungMann Kim, James F. Wilson, S. Genuth, André G. Uitterlinden, Dean P. Hainsworth, J. Giangiacomo, Wanjie Sun, Aruna V. Sarma, R. Liss, S. Catton, Rodica Pop-Busui, S. Moser, Bernard H. Doft, A. Malayeri, B. Gloeb, W. T. Garvey, Andrew P. Boright, Alan M. Jacobson, Larry D. Hubbard, Barbara E.K. Klein, Shyam M. Thomas, Allan Gordon, Allan L. Drash, S. Yoser, S. Johnsonbaugh, L. Kaminski, G. Meekins, Jonathan Q. Purnell, B. Burzuk, John M. Lachin, M. Geckle, Ronald J. Oudiz, Isaac Boniuk, Xiaohui Li, V. Reppucci, H. Wolpert, D. Etzwiler, M. Brabham, Maria Schache, E. Golden, M. Fox, Jyotika K. Fernandes, Jerome I. Rotter, Paul N. Baird, Michael Bryer-Ash, M. Stern, H. Engel, M. Hawkins, Najaf Amin, C. O′Donnell, M. McLellan, G. Comer, Ronald Klein, D. Sandstrom, H. Zegarra, J. Gordon, M. B. Murphy, P. A. Bourne, L. Baker, Cristina Venturini, D. Wood, H.-Erich Wichmann, M. May, A. Kowarski, Timothy W. Olsen, Thomas J. Songer, Christopher J Hammond, P. Lou, Jill P. Crandall, Miao, Xiaoping, Ophthalmology, Obstetrics & Gynecology, Epidemiology, Clinical Genetics, and Internal Medicine

Subjects
Male, Linkage disequilibrium, Refractive error, genetic structures, Epidemiology, Genome-wide association study, Plant Science, Eye, Linkage Disequilibrium, ASSOCIATION SCANS, MULTIPLE, Medicine and Health Sciences, Myopia, 80 and over, 2.1 Biological and endogenous factors, Aetiology, Age of Onset, FAMILIAL AGGREGATION, Genetics, Aged, 80 and over, Multidisciplinary, AUSTRALIAN SCHOOL-CHILDREN, COMMON VARIANTS, Single Nucleotide, Middle Aged, RETINAL-PIGMENT EPITHELIUM, OUTDOOR ACTIVITY, Hyperopia, Phenotype, Genetic Epidemiology, Medicine, Female, Research Article, Genetic Markers, Adult, General Science & Technology, Science, DCCT/EDIC Research Group, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, and over, Biology, Disease Surveillance, Polymorphism, Single Nucleotide, White People, medicine, Genome-Wide Association Studies, Humans, Inherited Eye Disorders, Genetic Predisposition to Disease, Allele, Polymorphism, Eye Disease and Disorders of Vision, Alleles, Genetic Association Studies, Aged, Whites, Human Genome, Biology and Life Sciences, Computational Biology, Human Genetics, Heritability, Plant Pathology, medicine.disease, Genome Analysis, GENE, eye diseases, Ophthalmology, REFRACTIVE ERROR, Genetics of Disease, LINKAGE-DISEQUILIBRIUM, Age of onset
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014
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4. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial

Author

Timothy W. Olsen, S. Hitt, Thomas J. Songer, Alan M. Jacobson, A. Burwood, R. Beaser, M. Szpiech, H. Martinez, Gayle M. Lorenzi, Anthony D. Morrison, C. Hannon, A. Farr, M. Hebdon, R. Colligan, T. Manolio, C. Wilson, Kathie L. Hermayer, John I. Malone, B. Burzuk, Kathy Glander, N. Silvers, B. Jones, A. Galpirn, M. Reid, David E. Goldstein, L. Sun, J. Giangiacom, P. Lou, Dean P. Hainsworth, Shalamar D. Sibley, Ronald J. Prineas, Louis A. Lobes, H. Wolpert, Mark E. Molitch, J. Sheindlin, Senda Ajroud-Driss, L. Dews, Kate Edwards, John M. Pach, Wanjie Sun, E. Cupelli, K. Stoessel, Samuel Dagogo-Jack, K. Harvey, J. Gordon, M. B. Murphy, John P. Bantle, J. D. Carey, Inger Burnett-Zeigler, Andrew M. Paterson, Henry Ferreyra, Manjot K. Gill, Barbara H. Waberski, B. Rogness, Fred W. Whitehouse, R. Ufret, Gordon C. Weir, Daniel H. O'Leary, S. Thomas, Barbara E. K. Klein, G. Ziegler, C. Wigley, L. Kastorff, C. Siebert, M. Palmert, C. Clark, J. Brown-Friday, S. Braunstein, Martin J. Stevens, M. Nutaitis, S. Catton, Samir S. Deeb, William V. Tamborlane, J. Alappatt, Robert Bergren, R. Eastman, Samuel S. Engel, K. Gehres, John M. Lachin, Davida F. Kruger, Jill P. Crandall, P. Geithman, Blanche M. Chavers, Stephen S. Feman, Mary E. Larkin, Thomas C. Lee, Catherine L. Martin, J. Parker, C. West, A. Gordon, Hugh D. Wabers, Sharon B. Schwartz, B. Zinman, M. Espeland, Neil H. White, M. N. Iyer, Rose Gubitosi-Klug, C. Canny, Robert Detrano, S. MacLean, Alice T. Lyon, M. E. Lackaye, Oscar B. Crofford, David A. Lee, M. Brent, Mark S. Mandelcorn, D. Badal, Lucy A. Levandoski, Barbara J. Maschak-Carey, John E. Godine, M. Hawkins, R. Gstalder, L. Survant, Charles Campbell, Matthew D. Davis, Anupam Agarwal, Lawrence J. Singerman, Brandy N. Rutledge, Anita Harrington, M. Novak, David A. Nicolle, P. Gaston, Isaac Boniuk, William H. Herman, S. Park, D. Counts, J. Quin, Nancy L. Robinson, Enrico Cagliero, T. Adkins, T. Woodfill, Scott M. Steidl, John Dupre, P. A. Bourne, L. Baker, D. Sandstrom, K. Miner, L. Mayer, S. Schussler, N. Grove, N. Wong, A. Iannacone, D. Wood, Lisa Diminick, D. Meyer, Barbara Esser, T. Thompson, David M. Nathan, A. Edwards, Lee M. Jampol, David S. Schade, M. Croswell, Joseph F. Polak, M. Spencer, Helen Lambeth, Paul G. Arrigg, Janie Lipps, H. Zegarra, Rodney A. Lorenz, Ayad A. Jaffa, James W. Albers, P. Astlesford, Thomas A. Weingeist, J. Vaccaro-Kish, Alicia J. Jenkins, Ronald K. Mayfield, M. May, A. Kowarski, Michael W. Steffes, W. T. Garvey, Saul Genuth, D. Zheng, Andrew P. Boright, J. Ginsberg, M. L. Bernal, Daniel L. McGee, Eva L. Feldman, Larry Rand, P. Low, J. Rosenzweig, L. Funk, Larry D. Hubbard, Orville G. Kolterman, D. Blackburn, E. Steuer, D. Rosenberg, Rodica Pop-Busui, S. Moser, John E. Hokanson, Julio V. Santiago, Daniel T. Lackland, James L. Kinyoun, Kevin J. Blinder, K. Taylor, D. Hornbeck, C. O'Donnell, Bernard H. Doft, Susan G. Elner, Dean B. Burgess, D. Kenny, Jeffrey M. Joyce, John D. Brunzell, O. Hamdy, Jerry P. Palmer, Jonathan Q. Purnell, R. Zeither, Douglas A. Greene, E. A. Tanaka, Yu-Guang He, Ramzi K. Hemady, Arup Das, Michael Bryer-Ash, Sheila Smith-Brewer, D. Ostrowski, M. Stern, C. Williams, Andrew K. Vine, M. McLellan, Ronald Klein, Annette Barnie, Michael H. Goldbaum, E. Angus, S. Scherer, R. D'Agostino, Philip Raskin, Santica M. Marcovina, B. Schaefer, A. F. Burrows, K. Morgan, David J. Brillon, H. Ricks, S. Strowig, R. Oudiz, S. Yacoub-Wasef, Jye-Yu C. Backlund, K. Chan, B. Gloeb, M. Johnson, Stephen R. Russell, D. J. Becker, Richard S. Crow, J. L. Canady, David G. Miller, O. Stone, Allan L. Drash, S. Yoser, S. Johnsonbaugh, Edward Chaum, L. Kaminski, M. Fox, J. Kramer, M. Bracey, H. Engel, Peter R. Pavan, Maria F. Lopes-Virella, C. Sommer, Daniel P. Joseph, M. Geckle, V. Reppucci, D. Etzwiler, M. Brabham, J. Fradkin, K. Lee, Jean M. Bucksa, E. Golden, Thomas Donner, Edwin M. Stone, Shelley B. Bull, William I. Sivitz, J. Selby, Pamela Rath, Murk-Hein Heinemann, L. Kim, T. Williams, D. Noller, D. Singer, J. Long, G. Grand, R. Devenyi, J. M. Schluter, B. Petty, Margaret L. Bayless, Alexander J. Brucker, S. Fritz, C. Cowie, Om P. Ganda, F. Thoma, K. Klumpp, Z. Strugula, Timothy J. Lyons, Patricia A. Cleary, A. Blevins, H. Shamoon, J. Soule, John A. Colwell, M. Phillips, Gaurav K. Shah, C. Hurtenbach, S. Rogers, Richard M. Bergenstal, Patricia Gatcomb, R. Trail, H. Culver Boldt, J. Bayless, Jonathan Shankle, David M. Kendall, Matthew A. Thomas, P. G. Sharuk, P. Lindsey, Ronald P. Danis, Christopher M. Ryan, William Dahms, P. Paczan Rath, S. Elsing, Gabriel Virella, Abbas E. Kitabchi, D. Moore, S. Pendegras, Trevor J. Orchard, K. Nickander, A. Determan, L. Van Ottingham, J. Harth, Michael W. Neider, and Shelly Olson

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, endocrine system diseases, Adolescent, Article, law.invention, chemistry.chemical_compound, Young Adult, Randomized controlled trial, law, Risk Factors, Internal medicine, Diabetes mellitus, medicine, Prevalence, Humans, Hypoglycemic Agents, Insulin, Risk factor, Infusion Pumps, Glycated Hemoglobin, Type 1 diabetes, Diabetic Retinopathy, medicine.diagnostic_test, business.industry, Incidence, Fundus photography, Diabetic retinopathy, medicine.disease, Surgery, Ophthalmology, Diabetes Mellitus, Type 1, chemistry, Disease Progression, Female, Glycated hemoglobin, business, Retinopathy, Follow-Up Studies
Abstract

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Published
2008

5. Treatments and outcomes of nursing-home-acquired pneumonia

Author

R S, Thompson, N K, Hall, M, Szpiech, and L A, Reisenberg

Subjects
Aged, 80 and over, Male, Cross Infection, Likelihood Functions, Chi-Square Distribution, Incidence, New York, Administration, Oral, Comorbidity, Pneumonia, Anti-Bacterial Agents, Nursing Homes, Hospitalization, Treatment Outcome, Humans, Female, Survivors, Aged, Retrospective Studies
Abstract

Bronchopulmonary infections have been considered the leading cause of hospital admissions and death in the nearly 2 million nursing home residents in the United States. Very little is known about the treatments and outcomes of this entity. The purpose of our study was to document the incidence, treatments, and outcomes of nursing-home-acquired pneumonia in hospitalized and nonhospitalized patients.We conducted a retrospective chart review during a 24-month period of patients from two community nursing homes in upstate New York with a total average population of 330 residents. The main outcome measure was 6-week mortality.Pneumonia was diagnosed in 129 patients, whose overall 6-week mortality rate was 24.8 percent. Ninety-one patients were cared for in the nursing home, and 38 patients were hospitalized. Six-week mortality rate for the nonhospitalized group was 18.7 percent. The hospitalized group's 6-week mortality rate was significantly higher at 39.5 percent. There were no significant differences between the hospitalized and nonhospitalized groups before their diagnosis that predicted outcome.For many patients nursing-home-acquired pneumonia can be successfully treated in a nursing home with oral antibiotics at a considerable cost savings when compared with hospitalization.

Published
1997

6. Metabolism of l-bunolol

Author

Franz-Josef Leinweber, Joseph M. Szpiech, Ivan W. F. Davidson, and Frederick J. Di Carlo

Subjects
Pharmacology, Adult, Male, Chromatography, Dihydrobunolol, Chemistry, Blood Pressure, Absorption (skin), Urine, Metabolism, Excretion, Levobunolol, Humans, Pharmacology (medical), Glucuronide, Pulse, Active metabolite, Biotransformation, Half-Life
Abstract

The metabolism of l-bunolol, a new beta-blocking drug, was studied in man after single oral 3-mg doses of 3H-labeled compound. Absorption from the gut was rapid and virtually complete. Peak levels of bunolol and of dihydrobunolol, an active metabolite, were observed at 1 hr. Excretion of the administered radioactivity was mainly into the urine (78% in 4 days), with only 3% appearing in the feces. Bunolol, bunolol glucuronide, bunolol sulfate, dihydrobunolol, and dihydrobunolol glucuronide were identified and quantified in the plasma. These compounds represented 82% of the radioactivity in plasma at 30 min and 55% at 24 hr. Plasma half-lives (+/-S.D.) were estimated to be 6.1 +/- 0.3 hr for bunolol, 9.1 +/- 1.9 hr for bunolol glucuronide, 17.4 +/- 2.5 hr for bunolol sulfate, 7.1 +/- 0.5 hr for dihydrobunolol, and 7.7 +/- 0.8 hr for dihydrobunolol glucuronide.

Published
1977

7. Metabolism of 3-(hydroxymethyl)-8-methoxychromone in the rat. I. Absorption, tissue distribution and excretion

Author

Malcolm C. Crew, Frederick J. Di Carlo, and Joseph M. Szpiech

Subjects
Male, Health, Toxicology and Mutagenesis, Absorption (skin), Toxicology, Kidney, Biochemistry, Excretion, chemistry.chemical_compound, Feces, Oral administration, medicine, Animals, Hydroxymethyl, Tissue distribution, Pharmacology, Chromatography, Isotope, Chemistry, Respiration, General Medicine, Metabolism, Rats, Kinetics, medicine.anatomical_structure, Chromones, Organ Specificity
Abstract

1. Two 14C-labelled preparations of 3-(hydroxymethyl)-8-methoxychromone were used to study the absorption, tissue distribution and excretion of isotope after oral administration to rats (20 mg/kg).2. 14C, presumably from the labelled hydroxymethyl side-chain, was eliminated extensively as 14CC2. This excretion was triphasic; kinetic constants were calculated for each phase.3. The major excretion route was via the kidney although significant quantities of isotope were excreted with the faeces. Isotope did not accumulate in tissues.2. London: Academic Press.8. New York: J. Wiley & Sons, Inc.

Published
1976

8. l-Bunolol metabolism in rats: identification of urinary metabolites

Author

Joseph M. Szpiech, Franz-Josef Leinweber, and Frederick J. DiCarlo

Subjects
Male, Urinary system, Pharmaceutical Science, Urine, Metabolism, Pharmacology, Lactic acid, Rats, Acetic acid, chemistry.chemical_compound, chemistry, Antiadrenergic agent, Levobunolol, Animals, Sulfate, Glucuronide, Biotransformation
Abstract

Urine collected for 24 hr from rats given a single oral dose of 3H-l-bunolol (10 mg/kg) was found to contain only 25.8% of the dose and more than 30 labeled compounds. Nine compounds were identified and quantified as follows: bunolol (0.35% of urinary tritium), bunolol glucuronide (5.12%), bunolol sulfate (0.08%), dihydrobunolol (0.08%), dihydrobunolol glucuronide (0.74%), dihydrobunolol sulfate (0.12%), hydroxydihydrobunolol (0.58%), beta-(5-oxytetralonyl)lactic acid (0.74%), and (5-oxytetralonyl) acetic acid glucuronide (1.12%). The total quantity of identified labeled compounds was only 2.3% of the dose and 8.9% of the urinary radioactivity.

Published
1978

9. l-bunolol metabolites in human urine

Author

F J, Leinweber, J M, Szpiech, and F J, Di Carlo

Subjects
Adult, Male, Levobunolol, Sulfates, Lactates, Administration, Oral, Humans, Glucuronates, Chromatography, Thin Layer, Acetates, Chemical Fractionation, Biotransformation
Abstract

Nine radiolabeled compounds were identified in human urine after administering a single oral dose of 3H-l-bunolol (3 mg) to 5 male volunteers. These compounds represented 54.7% of the dose and 71.4% of the isotope excreted in 3 days. Intact bunolol accounted for 14.7% of the dose and its conjugates totaled an additional 5.0%. The major drug metabolite (28.2% of dose) was dihydrobunolol, a reduction product known to have the same pharmacological activity and potency as bunolol. Dihydrobunolol conjugates amounted to 3.9% of the dose. Two minor acidic metabolites were produced by oxidative cleavage of the bunolol side chain, and another minor metabolite (hydroxydihydrobunolol) resulted from both reductive and oxidative biotransformation. Bunolol metabolism in man showed qualitative and quantitative differences from patterns observed in the rat and dog.

Published
1978

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