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1. Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with type 2 diabetes

Author

Mark A. Espeland, Marjorie Howard, Wendy Bennett, Brian A. Robusto, Sevil Yasar, Christina E. Hugenschmidt, Jose A. Luchsinger, Judy Bahnson, Hussein Yassine, Karen C. Johnson, Delilah Cook, and Kathleen M. Hayden

Subjects
Male, Estradiol, Epidemiology, Endocrinology, Diabetes and Metabolism, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Endocrinology, Cognition, Developmental Neuroscience, Diabetes Mellitus, Type 2, Weight Loss, Internal Medicine, Humans, Female, Testosterone, Neurology (clinical), Geriatrics and Gerontology, Aged
Abstract

To assess associations that endogenous estradiol and testosterone levels have with cognitive function in older adults with Type 2 diabetes mellitus (T2DM).We use data from the Look AHEAD clinical trial of behavioral weight loss. Endogenous estradiol and total testosterone levels were determined using stored serum from 996 individuals, mean age 69 years, at two times (averaging 4 years apart) during years 8-18 of follow-up. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during this follow-up. Mixed effects models and multiple imputation were used to assess associations that estradiol and total testosterone levels had with body mass index and cognitive function.Estradiol levels were not associated with cognitive function in either sex. Total testosterone levels were not associated with cognitive function in women, but greater total testosterone levels were associated with better verbal fluency in men (p 0.001), most strongly among those carrying the APOE-e4 allele (interaction p = 0.02). The weight loss intervention left a legacy of relatively lower cognitive functioning among women, which was not mediated by current levels of sex hormones.Behavioral weight loss intervention does not affect cognitive functioning through mechanisms related to estradiol or testosterone.gov Identifier: NCT00017953.

Published
2022

2. Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Author

Mike Reidy, Christine Lee, Michael Brändle, Sherita Hill Golden, Samuel Dagogo-Jack, David Kessler, Elizabeth Barrett-Connor, Steve Jones, Ling Chen, Judith Wylie-Rosett, Ping Zhang, Paula Williamson, Carlos Lorenzo, Leigh Perreault, Dana Dabelea, Santica Marcovina, Rachel Williams, Marie Smith, Carmen Pal, Patricia Katz, William H. Herman, Sharon L Edelstein, Yong Ma, Vanita R Aroda, Costas A Christophi, Catherine Kim, Sherita H Golden, Edward Horton, Kieren J Mather, George A. Bray, Kishore Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St, Richard T. Tulley Amant, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Juliet Ojito, Patricia Rowe, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Olga Lara, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Beth Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Arlene Martinez, Tatiana Walker, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Sharon D. Jackson, Alan M. Jacobsen, Lori Lambert, Sarah Ledbury, Margaret Kocal, Lyn M. Kula, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Jessica Sansoucy, Dana Schweizer, Ellen W. Seely, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Kali D’Anna, Linda Delahanty, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, Sunder Mudaliar, William Polonsky, Jean Smith, Jennifer Torio-Hurley, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Susan Hagamen, Jose A. Luchsinger, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Renee Wiggins, Milvia Lagarda, Lilia Leon, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ysela Gonzales, Doris A. Hernandez-McGinnis, Carolyn King, Sofya Rubinchik, Willette Senter, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Bonny Rockette-Wagner, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Marjorie K. Mau, John S. Melish, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Charlotte Dodge, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Valerie Weinzierl, Jessica Harting, F. Alan Aldrich, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Morton B. Brown, David Altshuler, Liana K. Billings, Maegan Harden, Toni I. Pollin, Alan R. Shuldiner, Paul W. Franks, and Marie-France Hivert

Subjects
Male, Aging, Endocrinology, Diabetes and Metabolism, primary prevention, Overweight, Cardiovascular, Medical and Health Sciences, lcsh:Diseases of the endocrine glands. Clinical endocrinology, law.invention, Impaired glucose tolerance, 0302 clinical medicine, Sex hormone-binding globulin, Randomized controlled trial, law, Sex Hormone-Binding Globulin, polycyclic compounds, skin and connective tissue diseases, reproductive and urinary physiology, biology, DPP Research Group, Diabetes, Metformin, type 2, 030220 oncology & carcinogenesis, diabetes mellitus, Female, Clinical care/Education/Nutrition, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, Diabetes risk, hormone, Clinical Trials and Supportive Activities, Clinical Sciences, 030209 endocrinology & metabolism, Placebo, 03 medical and health sciences, Clinical Research, Internal medicine, Diabetes mellitus, Health Sciences, Glucose Intolerance, Diabetes Mellitus, medicine, Humans, Obesity, Life Style, Metabolic and endocrine, Nutrition, lcsh:RC648-665, business.industry, Prevention, life style, medicine.disease, Estrogen, Diabetes Mellitus, Type 2, biology.protein, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, sense organs, business
Abstract

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

Published
2020
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3. Diabetes, glycaemia, and cognition-a secondary analysis of the Finnish Diabetes Prevention Study

Author

Jenni, Lehtisalo, Jaana, Lindström, Tiia, Ngandu, Miia, Kivipelto, Satu, Ahtiluoto, Pirjo, Ilanne-Parikka, Sirkka, Keinänen-Kiukaanniemi, Johan G, Eriksson, Matti, Uusitupa, Jaakko, Tuomilehto, and Jose A, Luchsinger

Subjects
Adult, Male, Aging, Middle Aged, Overweight, Combined Modality Therapy, Body Mass Index, Cohort Studies, Prediabetic State, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Risk Factors, Early Termination of Clinical Trials, Disease Progression, Humans, Patient Compliance, Cognitive Dysfunction, Female, Life Style, Finland, Aged, Follow-Up Studies
Abstract

Type 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented.The Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n = 522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4 years) and follow-up (additional 9 years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes.Cognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA1C during the intervention period predicted better performance in the TMT (p = 0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p = 0.001) whereas those with long duration of diabetes did not (p = 0.844).Better glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9 years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration. Copyright © 2015 John WileySons, Ltd.

Published
2014

4. Insulin Dysfunction Induces In Vivo Tau Hyperphosphorylation through Distinct Mechanisms

Author

Emmanuel Planel, Mathieu Herman, Li Liu, Lili Wang, W. Haung Yu, Yoshitaka Tatebayashi, Jose A. Luchsinger, Karen Duff, Akihiko Takashima, Tomohiro Miyasaka, and Brian E. Wadzinski

Subjects
Male, medicine.medical_specialty, Neuropil, Time Factors, medicine.medical_treatment, Hyperphosphorylation, Neocortex, tau Proteins, Hypothermia, Hippocampus, Microtubules, Streptozocin, Body Temperature, Diabetes Mellitus, Experimental, Impaired glucose tolerance, Amyloid beta-Protein Precursor, Epitopes, Mice, Insulin resistance, GSK-3, Ca2+/calmodulin-dependent protein kinase, Internal medicine, mental disorders, medicine, Animals, Insulin, Protein Phosphatase 2, Phosphorylation, Amyloid beta-Peptides, Dose-Response Relationship, Drug, Chemistry, General Neuroscience, Protein phosphatase 2, Articles, medicine.disease, Streptozotocin, Axons, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Solubility, Female, medicine.drug, Protein Binding
Abstract

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in β-amyloid (Aβ) precursor protein (APP), APP C-terminal fragments, or Aβ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.

Published
2007

5. Alcohol intake and risk of dementia

Author

Jose A, Luchsinger, Ming-Xin, Tang, Maliha, Siddiqui, Steven, Shea, and Richard, Mayeux

Subjects
Aged, 80 and over, Male, Chi-Square Distribution, Alcohol Drinking, Urban Population, Incidence, Apolipoprotein E4, Beer, Wine, Diet Surveys, Stroke, Apolipoproteins E, Alzheimer Disease, Risk Factors, Population Surveillance, Surveys and Questionnaires, Multivariate Analysis, Humans, Dementia, Female, New York City, Aged, Follow-Up Studies, Proportional Hazards Models
Abstract

To examine the association between intake of alcoholic beverages and risk of Alzheimer's disease (AD) and dementia associated with stroke (DAS) in a cohort of elderly persons from New York City.Cohort study.The Washington Heights Inwood-Columbia Aging Project.Nine hundred eighty community-dwelling individuals aged 65 and older without dementia at baseline and with data on alcohol intake recruited between 1991 and 1996 and followed annually.Intake of alcohol was measured using a semiquantitative food frequency questionnaire at baseline. Subjects were followed annually, and incident dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria and classified as AD or DAS.After 4 years of follow-up, 260 individuals developed dementia (199 AD, 61 DAS). After adjusting for age, sex, apolipoprotein E (APOE)-epsilon 4 status, education, and other alcoholic beverages, only intake of up to three daily servings of wine was associated with a lower risk of AD (hazard ratio=0.55, 95% confidence interval=0.34-0.89). Intake of liquor, beer, and total alcohol was not associated with a lower risk of AD. Stratified analyses by the APOE-epsilon 4 allele revealed that the association between wine consumption and lower risk of AD was confined to individuals without the APOE-epsilon 4 allele.Consumption of up to three servings of wine daily is associated with a lower risk of AD in elderly individuals without the APOE epsilon-4 allele.

Published
2004

6. A Rare Presentation of Gastric Adenocarcinoma

Author

Fiona R. Pasternack, Jose A Luchsinger, Deepak Saluja, Kathleen O'Toole, Marc E. Grossman, David J Fusco, and Kimberley H.M. Ward

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Skin Neoplasms, Pleural effusion, Radiography, Adenocarcinoma, Diagnosis, Differential, Gastric adenocarcinoma, Stomach Neoplasms, Internal medicine, medicine, Humans, business.industry, Signet ring cell, Middle Aged, medicine.disease, Rash, Pleural Effusion, Malignant, Female, Presentation (obstetrics), medicine.symptom, business
Published
2009
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