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2. Risk Factors for Bile Aspiration and its Impact on Clinical Outcomes

Author

Rachel Rosen, Margot Lurie, Madeline Kane, Courtney DiFilippo, Alexandra Cohen, Dawn Freiberger, Debra Boyer, Gary Visner, Monica Narvaez-Rivas, Enju Liu, and Kenneth Setchell

Subjects
Risk Factors, Gastroenterology, Gastroesophageal Reflux, Bile, Humans, Esophagitis, Peptic, Lung Transplantation
Abstract

Bile reflux may cause for lung allograft rejection, yet there are no studies that determine (i) the relationship between gastric and lung bile concentrations, (ii) whether bile is present in lungs of nontransplant patients, (iii) the relationship between gastric dysmotility and lung bile, (iv) the impact of reflux therapies on lung bile, and (v) whether lung bile worsens outcomes in nontransplant patients. This study will address these gaps in the literature.We prospectively recruited lung transplant (LTX) patients and nontransplant patients with respiratory symptoms (RP) and collected paired gastric and lung samples. Bile concentration and composition of samples was assessed using liquid chromatography-mass spectrometry. Bile results were compared with clinical parameters, including the presence of esophagitis, gastric dysmotility, and/or pathologic gastroesophageal reflux.Seventy patients (48 RP and 22 LTX) were recruited. Overall, 100% of gastric and 98% of bronchoalveolar lavage samples contained bile. The mean gastric bile concentrations in RP and LTX patients were 280 ± 703 nmol/L and 1,004 ± 1721 nmol/L, respectively (P = 0.02). There was no difference in lung bile concentrations between RP (9 ± 30 nmol/L) and LTX (11 ± 15 nmol/L, P = 0.7). Patients with delayed gastric emptying had higher lung bile concentrations (15.5 ± 18.8 nmol/L) than patients with normal gastric emptying (4.8 ± 5.7 nmol/L, P = 0.05) independently of reflux burden. Proton pump inhibitor use increased the proportion of unconjugated gastric bile acids. High lung bile concentrations were associated with an increased risk of hospitalization and longer hospital stays in RP patients (P0.05).Lung bile is almost universally present in symptomatic patients, and higher concentrations are associated with poorer respiratory outcomes.

Published
2021

3. Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

Author

Maria Carolina, Florian, Hanna, Leins, Michael, Gobs, Yang, Han, Gina, Marka, Karin, Soller, Angelika, Vollmer, Vadim, Sakk, Kalpana J, Nattamai, Ahmad, Rayes, Xueheng, Zhao, Kenneth, Setchell, Medhanie, Mulaw, Wolfgang, Wagner, Yi, Zheng, and Hartmut, Geiger

Subjects
Zelle, Aging, Ratolins (Animals de laboratori), Cells, Longevity, Expression, macromolecular substances, Mice, Eukaryotic cells, DDC 570 / Life sciences, Envelliment, ddc:570, Animals, Drosophila Proteins, ddc:610, Cdc42, cdc42 GTP-Binding Protein, Interferon gamma, Inflammation, Gen, Cèl·lules eucariotes, Interleukin-18, Short Take, Altern, Mice, Inbred C57BL, Mice (Laboratory animals), Genes, Genexpression, Cytokines, Female, inflammaging, Epigenetics, Integrin alpha Chains, DDC 610 / Medicine & health, epigenetic clock, lifespan
Abstract

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain���of���activity mouse model presents with a premature aging���like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75���week���old) female C57BL/6 mice with a Cdc42 activity���specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN���treated animals displayed a youthful level of the aging���associated cytokines IL���1��, IL���1��, and INF�� in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan., publishedVersion

Published
2020
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5. Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study

Author

Vicky L. Ng, Lisa G. Sorensen, Estella M. Alonso, Emily M. Fredericks, Wen Ye, Jeff Moore, Saul J. Karpen, Benjamin L. Shneider, Jean P. Molleston, Jorge A. Bezerra, Karen F. Murray, Kathleen M. Loomes, Philip Rosenthal, Robert H. Squires, Kasper Wang, Ronen Arnon, Kathleen B. Schwarz, Yumirle P. Turmelle, Barbara H. Haber, Averell H. Sherker, John C. Magee, Ronald J. Sokol, Paula M. Hertel, Sanjiv Harpavat, Mary L. Brandt, Daniel H. Leung, Wikrom Karnsakul, Rebecca Torrance, Sherry Hall, Edward Doo, Jay H. Hoofnagle, Peter Whitington, Lee Bass, Alexander G. Miethke, James E. Heubi, Kenneth Setchell, Kevin E. Bove, Greg Tiao, Cara L. Mack, Michael R. Narkewicz, Amy G. Feldman, Shikha S. Sundaram, Frederick J. Suchy, Frederick M. Karrer, Mark Lovell, Johan L. Van Hove, Elizabeth B. Rand, James E. Squires, Veena L. Venkat, Rakesh Sindhi, Sarangarajan Ranganathan, Laura Bull, Jeffrey Teckman, Molly Bozic, Girish Subbarao, Simon Horslen, Evelyn Hsu, Laura Finn, Patrick Healey, Rohit Kohli, Danny Thomas, Nisreen Soufi, Sonia Michail, Matt Clifton, Nitika Gupta, Rene Romero, Miriam Vos, Shelley Caltharp, Binita M. Kamath, Simon C. Ling, Anna Gold, Annie Fecteau, Stephen L. Guthery, Kyle Jensen, Rebecka Meyers, Amy Lowichik, Linda Book, Robert M. Merion, Cathie Spino, and Karen Jones

Subjects
Male, Risk, Pediatrics, medicine.medical_specialty, Multivariate analysis, medicine.medical_treatment, Developmental Disabilities, Psychological intervention, Neuropsychological Tests, Chronic liver disease, Bayley Scales of Infant Development, Vulnerable Populations, Article, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Cognition, Biliary atresia, Biliary Atresia, 030225 pediatrics, medicine, Humans, Longitudinal Studies, Prospective Studies, Toddler, Randomized Controlled Trials as Topic, business.industry, Infant, medicine.disease, Hepatoportoenterostomy, Observational Studies as Topic, Treatment Outcome, Liver, Motor Skills, Child, Preschool, Pediatrics, Perinatology and Child Health, Multivariate Analysis, Regression Analysis, 030211 gastroenterology & hepatology, Female, business
Abstract

To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and85 for χThere were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age.Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Clinicaltrials.gov: NCT00061828 and NCT00294684.

Published
2017

6. Glucosylceramide induced complement activation triggers inflammation in Gaucher disease (CCR5P.212)

Author

Manoj Pandey, Stuart Tinch, Venette Inskeep, Wujuan Zhang, Kenneth Setchell, Jörg Köhl, and Gregory Grabowski

Subjects
Immunology, Immunology and Allergy
Abstract

Gaucher disease (GD) happens due to mutations in GBA1, which causes a deficiency of acid β-glucosidase critical for degradation of glucosylceramide (GC) into glucose and ceramide. Macrophages (Mɸs) were mainly having this defect and associated with eminent expression of cytokines, chemokines, and recruitment of activated immune cells in GD. The mechanism by which GC triggers such inflammation is still wanted. Excess of GC storage in dendritic and T cells has been reported to be the reason for their activation and production of inflammatory cytokines in Gba1 mouse model (D409V/null; 9V/null). Here, we have identified elevated expression of C5a and C5aR on 9V/null mice APCs. We therefore, hypothesized that GC induced C5a elicits immune inflammation in GD. To confirm this, conduritol B epoxide (CBE), induced chemical model of GD was developed in WT and C5aR-/- mice. We found that C5aR-/- mice were protected from CBE-induced GD development, which was associated with prolonged survival, marked reduction of GC, DCs and T cells positivity for CD40, CD80, CD86, CD40L, CD69, cytokines-chemokines secretion, immune cells recruitment, and decreased loss of red blood cells (RBCs) and platelets. Pharmacological blocking of C5aR in 9V/null mice showed marked reduction in several of these GD manifestations. Our data suggest that GC induced C5a contributes in disease development and targeting C5a signaling may have therapeutic potential for GD.

Published
2015
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7. CONTRIBUTORS

Author

Soraya Abbasi, Steven H. Abman, S. Lee Adamson, N. Scott Adzick, Kurt H. Albertine, Benjamin A. Alman, Steven M. Altschuler, Page A.W. Anderson, Russell V. Anthony, Elisabeth A. Aron, Ahmet R. Aslan, Jeanette M. Asselin, Richard L. Auten, Mary Ellen Avery, Ellis D. Avner, H. Scott Baldwin, Philip L. Ballard, Eduardo Bancalari, David J.P. Barker, Pierre M. Barker, Frederick C. Battaglia, Gary K. Beauchamp, Jacqueline Beesley, Corinne Benchimol, Laura Bennet, Robert A. Berg, Gerard T. Berry, Carol Lynn Berseth, Vinod K. Bhutani, Stan R. Blecher, Arlin B. Blood, David L. Bolender, Robert D.H. Boyd, Robert A. Brace, Eileen D. Brewer, Patrick D. Brophy, Delma L. Broussard, John C. Bucuvalas, Douglas G. Burrin, Bridgette M.P. Byrne, Anne Grete Byskov, Mitchell S. Cairo, Barbara Cannon, Michael S. Caplan, Neil Caplin, Susan E. Carlson, David P. Carlton, William J. Cashore, Tinnakorn Chaiworapongsa, Sylvain Chemtob, Robert L. Chevalier, Sadhana Chheda, Robert D. Christensen, David H. Chu, Robert Ryan Clancy, M. Thomas Clandinin, David A. Clark, Jane Cleary-Goldman, Ronald I. Clyman, Pinchas Cohen, Howard E. Corey, Robert B. Cotton, Beverly J. Cowart, Richard M. Cowett, Timothy M. Crombleholme, James E. Crowe, Leona Cuttler, Mary E. D'Alton, Enrico Danzer, Diva D. De León, Maria Delivoria-Papadopoulos, George A. Diaz, Chris J. Dickinson, John P. Dormans, David J. Durand, A. David Edwards, John F. Ennever, Robert P. Erickson, Bulent Erol, Mohamed A. Fahim, Leonard G. Feld, Miguel Feldman, Lucas G. Fernandez, Douglas G. Field, Delbert A. Fisher, William W. Fox, Hans-Georg Frank, Philippe S. Friedlich, Aaron L. Friedman, Joshua R. Friedman, Marianne Garland, Maria-Teresa Gervasi, James B. Gibson, P.D. Gluckman, Michael J. Goldberg, Armond S. Goldman, Gary W. Goldstein, R. Ariel Gomez, Bernard Gondos, Denis M. Grant, Lucy R. Green, Jay S. Greenspan, Adda Grimberg, Justin C. Grindley, Ian Gross, Jean-Pierre Guignard, Alistair J. Gunn, Gabriel G. Haddad, J. Nathan Hagstrom, Kathrin V. Halpern, K. Michael Hambidge, Margit Hamosh, Mark A. Hanson, Aviad Haramati, Richard Harding, Mary Catherine Harris, Musa A. Haxhiu, William W. Hay, Anthony R. Hayward, William C. Heird, Emilio Herrera, Harry R. Hill, A. Craig Hillemeier, Kurt Hirschhorn, Steven B. Hoath, David A. Horst, Tracy E. Hunley, Christian J. Hunter, Shahid M. Husain, Susan M. Hutson, Machiko Ikegami, Terrie E. Inder, Alan H. Jobe, Lois H. Johnson, Michael V. Johnston, Richard B. Johnston, Deborah P. Jones, Peter Lloyd Jones, Pedro A. Jose, Satish C. Kalhan, Suhas Kallapur, Stanley Kaplan, Saul J. Karpen, Sudha Kashyap, Frederick J. Kaskel, Lorraine E. Levitt Katz, Peter Kaufmann, Susan E. Keeney, Laurie Kilpatrick, John P. Kinsella, Margaret L. Kirby, Charles S. Kleinman, Barry A. Kogan, Otakar Koldovský, Valentina Kon, Ernest A. Kopecky, Helen M. Korchak, Gideon Koren, Nancy F. Krebs, Thomas J. Kulik, Jessica Katz Kutikov, Timothy R. La Pine, Miguel Angel Lasunción, John Laterra, P.C. Lee, Fred Levine, David B. Lewis, Chris A. Liacouras, Michael A. Linshaw, George Lister, Cynthia A. Loomis, John M. Lorenz, Steven Lobritto, Ralph A. Lugo, Akhil Maheshwari, Marilyn J. Manco-Johnson, Carlos B. Mantilla, M. Michele Mariscalco, László Maródi, Karel Maršál, Richard J. Martin, Dwight E. Matthews, Marcia McDuffie, Jane E. McGowan, James McManaman, Huseyin Mehmet, Julie A. Mennella, Andrew Metinko, Martha J. Miller, Paul Monagle, Jacopo P. Mortola, Glen E. Mott, M. Zulficar Mughal, Susan E. Mulroney, Upender K. Munshi, Leslie Myatt, Margaret A. Myers, Ran Namgung, Michael R. Narkewicz, Heinz Nau, Jan Nedergaard, Margaret C. Neville, Heber C. Nielsen, Lawrence M. Nogee, Shahab Noori, Errol R. Norwitz, Victoria F. Norwood, Edward S. Ogata, Robin K. Ohls, Thomas A. Olson, Taher I. Omari, James F. Padbury, Mark R. Palmert, Elvira Parravicini, Gilberto R. Pereira, Jeff M. Perlman, Anthony F. Philipps, Arthur S. Pickoff, C.S. Pinal, David Pleasure, Jeanette Pleasure, Sabine Luise Plonait, Richard A. Polin, Daniel H. Polk, Scott L. Pomeroy, Fred Possmayer, Martin Post, Gordon G. Power, Jorge A. Prada, Guy Putet, Theodore J. Pysher, Graham E. Quinn, Marlene Rabinovitch, Scott H. Randell, Timothy R.H. Regnault, Michael J. Rieder, Henrique Rigatto, Natalie E. Rintoul, Jean E. Robillard, Julian Robinson, Roberto Romero, Seamus A. Rooney, James C. Rose, Charles R. Rosenfeld, Arthur J. Ross, Colin D. Rudolph, Rakesh Sahni, Harvey B. Sarnat, Lisa M. Satlin, Ola Didrik Saugstad, Kurt R. Schibler, Karl Schulze, Jeffrey Schwartz, Gunnar Sedin, Jeffrey L. Segar, Istvan Seri, Kenneth Setchell, Thomas H. Shaffer, Philip W. Shaul, Jayant P. Shenai, Colin P. Sibley, Gary C. Sieck, Theresa M. Siler-Khodr, Faye S. Silverstein, Rebecca A. Simmons, Emidio M. Sivieri, Harold C. Slavkin, Evan Y. Snyder, Jeanne M. Snyder, Michael J. Solhaug, Kevin W. Southern, Adrian Spitzer, Alan R. Spitzer, Charles A. Stanley, F. Bruder Stapleton, Dennis Styne, William E. Sweeney, Norman S. Talner, Paul S. Thornton, William Edward Truog, Reginald C. Tsang, Alda Tufro, Nicole J. Ullrich, Socheata Un, John E. Van Aerde, Carmella van de Ven, Johannes B. van Goudoever, Robert C. Vannucci, Susan J. Vannucci, Minke van Tuyl, Joseph J. Volpe, Reidar Wallin, David Warburton, Robert M. Ward, Joern-Hendrik Weitkamp, Steven L. Werlin, Lynne A. Werner, Susan E. Wert, Lars Grabow Westergaard, Jeffrey A. Whitsett, Michaelann Wilke, John V. Williams, Dermot H. Williamson, Jerry A. Winkelstein, Jeremy S.D. Winter, Douglas A. Woelkers, Marla R. Wolfson, Robert P. Woroniecki, Walid K. Yassir, Stephen Yip, Mervin C. Yoder, Sharla Young, Stephen L. Young, and Dan Zhou

Published
2004
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9. Defects in Bile Acid Biosynthesis-Diagnosis and Treatment.

Author

Kenneth Setchell

Abstract

Bile acid synthetic defects represent a specific category of metabolic liver disease. This article highlights the history and summarizes our analytical approach to the diagnosis and treatment of genetic defects in bile acid synthesis. By the application of mass spectrometry as a screening tool, it is possible to perform rapid diagnosis of potential inborn errors in bile acid synthesis from urinary bile acid analysis. Molecular techniques then afford the identification of specific mutations in genes encoding the enzymes responsible for bile acid synthesis. Using this approach, 6 of the 7 known genetic defects that are causes of progressive cholestatic liver disease, syndromes of fat-soluble vitamin malabsorption, or neurological disease, have been characterized. Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis. [ABSTRACT FROM AUTHOR]

Published
2006
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