102 results on '"Mario Stylianou"'
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2. High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics
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Amisha V. Barochia, Elizabeth M. Gordon, Maryann Kaler, Rosemarie A. Cuento, Patricia Theard, Debbie M. Figueroa, Xianglan Yao, Nargues A. Weir, Maureen L. Sampson, Mario Stylianou, David F. Choy, Cecile T.J. Holweg, Alan T. Remaley, and Stewart J. Levine
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apolipoproteins ,immunology ,clinical studies ,lung ,inflammation ,eosinophils ,Biochemistry ,QD415-436 - Abstract
Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR. In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.
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- 2017
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3. Design of a multi-institutional neurocognitive discovery study in adult congenital heart disease (MINDS-ACHD)
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Scott Cohen, Michelle Gurvitz, Kristin M. Burns, Olivia Wheaton, Ashok Panigrahy, Laura Umfleet, Michelle Loman, Nicole Brown, Tim Cotts, Peter Ermis, Susan Fernandes, Stephanie Gaydos, Arvind Hoskoppal, Ian Lindsay, Larry W. Markham, Annique Nyman, Fred H. Rodriguez, Cynthia C. Smith, Mario Stylianou, Felicia Trachtenberg, and Ali N. Zaidi
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Cardiology and Cardiovascular Medicine - Published
- 2023
4. Microenvironment Regulators of Metastasis Favor Lymphangioleiomyomatosis Cell Growth and Disease Progression
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Gustavo Pacheco-Rodriguez, Wendy K. Steagall, Connie G. Glasgow, Rieko Onishi, Mario Stylianou, Jiro Kato, Shaowei Li, Leigh Samsel, J. Philip McCoy, Thomas N. Darling, and Joel Moss
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Pulmonary and Respiratory Medicine ,Clinical Biochemistry ,Cell Biology ,Molecular Biology - Published
- 2023
5. Supplementary Materials and Methods, Supplementary Figures 1 through 3 and Supplementary Tables 1 through 5 from Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation
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Souheil El-Chemaly, Joel Moss, Elizabeth P. Henske, Carmen Priolo, Ivan O. Rosas, Fernanda Golzarri, Benjamin Stump, Pranav Kidambi, Mario Stylianou, Gustavo Pacheco-Rodriguez, Anthony M. Lamattina, Wendy K. Steagall, and Ye Cui
- Abstract
Supplementary methods. Supplementary Figure S1. R406 and rapamycin induce G1 cell cycle arrest in TSC2- cells. Supplementary Figure S2. Densitometric analysis of phospho-Syk and Syk, related to Fig. 4D. Supplementary Figure S3. TSC2 deficiency leads to upregulation of MCP-1 gene expression in vitro. Supplementary Table S1. Characteristics of subjects who were part of the longitudinal studies, related to Fig.6B. Supplementary Table S2. Characteristics of healthy volunteers and LAM subjects whose PBMCs were studied, related to Fig.6C. Supplementary Table S3. siRNA sequences. Supplementary Table S4. Complete list of antibodies. Supplementary Table S5. Real-time PCR primer sequences.
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- 2023
6. Data from Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation
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Souheil El-Chemaly, Joel Moss, Elizabeth P. Henske, Carmen Priolo, Ivan O. Rosas, Fernanda Golzarri, Benjamin Stump, Pranav Kidambi, Mario Stylianou, Gustavo Pacheco-Rodriguez, Anthony M. Lamattina, Wendy K. Steagall, and Ye Cui
- Abstract
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.
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- 2023
7. Data from ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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Joel Moss, Connie G. Glasgow, Martin J. Lizak, Victoria Hoffmann, Mario Stylianou, Chengyu Liu, Jianfeng Zhu, and Jiro Kato
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Protein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP–ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose–protein bond. ARH1−/− cells or ARH1−/− cells overexpressing an inactive mutant ARH1 protein (ARH1−/−+dm) had higher proliferation rates than either wild-type ARH1+/+ cells or ARH1−/− cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1−/− and ARH1+/− mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1+/+ mice. In ARH1+/− mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression. Cancer Res; 71(15); 5327–35. ©2011 AACR.
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- 2023
8. Supplementary Methods from ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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Joel Moss, Connie G. Glasgow, Martin J. Lizak, Victoria Hoffmann, Mario Stylianou, Chengyu Liu, Jianfeng Zhu, and Jiro Kato
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Supplementary Methods from ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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- 2023
9. Supplementary Tables 1-4 from ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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Joel Moss, Connie G. Glasgow, Martin J. Lizak, Victoria Hoffmann, Mario Stylianou, Chengyu Liu, Jianfeng Zhu, and Jiro Kato
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Supplementary Tables 1-4 from ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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- 2023
10. Adapting pharmacological dose-finding designs for early phase behavioral intervention development research
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Mario Stylianou, Elizabeth K. Towner, Samiran Ghosh, Steven J. Ondersma, and April Idalski Carcone
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Pediatric Obesity ,Applied psychology ,Psychological intervention ,MEDLINE ,PsycINFO ,Telemedicine ,Psychiatry and Mental health ,Dose finding ,Drug development ,Behavior Therapy ,Intervention (counseling) ,Humans ,Child ,Early phase ,Psychology ,mHealth ,Applied Psychology - Abstract
The use of systematic dose-finding designs to develop behavioral health interventions is lacking. In contrast, drug development research consistently follows a prescribed, regulated, and iterative pathway that begins with empirically establishing optimal drug dose. Adapting dose-finding methodologies from the drug development literature offers several advantages to increasing the feasibility, efficiency, and rigor of this important intervention refining step for behavioral intervention development. This article discusses the current state of the science for dose finding within the behavioral intervention development literature. A detailed overview of one drug development dose-finding methodology (the Accelerated Biased Coin Up-and-Down design) is then presented, using our work to adapt the Prevention Plus Intervention for treatment of pediatric obesity for mHealth delivery as an example of how this design can be applied to empirically derive the dose for a behavioral intervention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
- Published
- 2021
11. Height Versus Body Surface Area to Normalize Cardiovascular Measurements in Children Using the Pediatric Heart Network Echocardiographic Z-Score Database
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Shahryar M. Chowdhury, Shubhika Srivastava, Aarti Bhat, James F. Cnota, Jami C. Levine, Mary E. van der Velde, Tiffanie R. Johnson, Jacqueline Marie Shuplock, Mario Stylianou, Karen Altmann, Leo Lopez, Christopher F. Spurney, Wyman W. Lai, Ricardo H. Pignatelli, Brian W. McCrindle, Peter C. Frommelt, David J. Goldberg, Ritu Sachdeva, Felicia L. Trachtenberg, Poonam P. Thankavel, Joseph Mahgerefteh, Dongngan Troung, Russel Gongwer, Steven D. Colan, and Joseph A. Camarda
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Male ,Normalization (statistics) ,Pediatric Obesity ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,Body Surface Area ,030204 cardiovascular system & hematology ,Overweight ,Standard score ,Pediatrics ,Article ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,Internal medicine ,medicine ,Humans ,Child ,Body surface area ,business.industry ,Heart ,Body Height ,Cardiac surgery ,030228 respiratory system ,Cardiovascular Diseases ,Echocardiography ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cardiology ,Population study ,Female ,medicine.symptom ,Underweight ,Cardiology and Cardiovascular Medicine ,business ,Body mass index - Abstract
Normalizing cardiovascular measurements for body size allows for comparison among children of different ages and for distinguishing pathologic changes from normal physiologic growth. Because of growing interest to use height for normalization, the aim of this study was to develop height-based normalization models and compare them to body surface area (BSA)-based normalization for aortic and left ventricular (LV) measurements. The study population consisted of healthy, non-obese children between 2 and 18 years of age enrolled in the Pediatric Heart Network Echo Z-Score Project. The echocardiographic study parameters included proximal aortic diameters at 3 locations, LV end-diastolic volume, and LV mass. Using the statistical methodology described in the original project, Z-scores based on height and BSA were determined for the study parameters and tested for any clinically significant relationships with age, sex, race, ethnicity, and body mass index (BMI). Normalization models based on height versus BSA were compared among underweight, normal weight, and overweight (but not obese) children in the study population. Z-scores based on height and BSA were calculated for the 5 study parameters and revealed no clinically significant relationships with age, sex, race, and ethnicity. Normalization based on height resulted in lower Z-scores in the underweight group compared to the overweight group, whereas normalization based on BSA resulted in higher Z-scores in the underweight group compared to the overweight group. In other words, increasing BMI had an opposite effect on height-based Z-scores compared to BSA-based Z-scores. Allometric normalization based on height and BSA for aortic and LV sizes is feasible. However, height-based normalization results in higher cardiovascular Z-scores in heavier children, and BSA-based normalization results in higher cardiovascular Z-scores in lighter children. Further studies are needed to assess the performance of these approaches in obese children with or without cardiac disease.
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- 2021
12. Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients
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Richard L. Nahin, Eldrin F. Lewis, Daniel B. Mark, Christine Goertz, Mario Stylianou, Kerry L. Lee, Francisco Ujueta, Rhonda Roberts, and Gervasio A. Lamas
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medicine.medical_specialty ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Lower risk ,Placebo ,Angina Pectoris ,Angina ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,030212 general & internal medicine ,Chelation therapy ,Myocardial infarction ,Stroke ,Edetic Acid ,Chelating Agents ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Chelation Therapy ,Treatment Outcome ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes. Methods Patients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables. Results Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47–0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77–1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p Conclusions Edetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit.
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- 2020
13. The trial to assess chelation therapy 2 (TACT2): Rationale and design
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Gervasio A. Lamas, Kevin J. Anstrom, Ana Navas-Acien, Robin Boineau, Hwasoon Kim, Yves Rosenberg, Mario Stylianou, Teresa L.Z. Jones, Bonnie R. Joubert, Regina M. Santella, Esteban Escolar, Y. Wady Aude, Vivian Fonseca, Thomas Elliott, Eldrin F. Lewis, Michael E. Farkouh, David M. Nathan, Ana C. Mon, Leigh Gosnell, Jonathan D. Newman, and Daniel B. Mark
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Double-Blind Method ,Diabetes Mellitus ,Myocardial Infarction ,Humans ,Vitamins ,Cardiology and Cardiovascular Medicine ,Chelation Therapy ,Edetic Acid ,Chelating Agents - Abstract
Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design.TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or NaResults are expected in 2024.TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.
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- 2022
14. Results of the FUEL Trial
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R. Mark Payne, Gail D. Pearson, Andrew S. Mackie, Stephen M. Paridon, Amanda J. Shillingford, Stacy Woyciechowski, Shabana Shahanavaz, Christopher K. Davis, James L. Yeager, David J. Goldberg, Arash Sabati, Bryan H. Goldstein, Shaji C. Menon, Victor Zak, Ruchira Garg, Benjamin P. Frischhertz, Matthew D. Files, Jeffrey P. Jacobs, Michael DiMaria, Jonathan Rhodes, Seong Ho Kim, Anji T. Yetman, Mario Stylianou, Michelle S Hamstra, Kevin D. Hill, Marc E. Richmond, Victoria L. Pemberton, Anitha S. John, Kathleen A. Rathge, Christopher J. Petit, Jonathan B Wagner, Salil Ginde, Brian W. McCrindle, Mark W. Russell, Michael G. McBride, Todd T. Nowlen, Kurt R. Schumacher, Elaine M. Urbina, Kimberly E. McHugh, Daniel J. Penny, Gi Beom Kim, and Peter C. Frommelt
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medicine.medical_specialty ,medicine.drug_mechanism_of_action ,business.industry ,medicine.medical_treatment ,Total cavopulmonary connection ,Fontan procedure ,medicine.anatomical_structure ,Physiology (medical) ,Internal medicine ,medicine ,Cardiology ,Vascular resistance ,Cardiology and Cardiovascular Medicine ,business ,Phosphodiesterase 5 inhibitor - Abstract
Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.
- Published
- 2020
15. Use of CT Imaging to Quantify Progression and Response to Treatment in Lymphangioleiomyomatosis
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Vissaagan Gopalakrishnan, Joel Moss, Nilo A. Avila, Wendy K. Steagall, Marcus Y. Chen, Jianhua Yao, Mario Stylianou, and Angelo M. Taveira-DaSilva
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Critical Care and Intensive Care Medicine ,Risk Assessment ,DLCO ,Multidetector Computed Tomography ,Parenchyma ,Humans ,Medicine ,Cyst ,Longitudinal Studies ,Lymphangioleiomyomatosis ,Sirolimus ,Lung ,Cysts ,business.industry ,Middle Aged ,respiratory system ,Prognosis ,medicine.disease ,Response to treatment ,Cross-Sectional Studies ,Treatment Outcome ,medicine.anatomical_structure ,Disease Progression ,Female ,Diffuse Lung Disease ,Ct imaging ,Cardiology and Cardiovascular Medicine ,business ,Nuclear medicine ,medicine.drug - Abstract
BACKGROUND: In lymphangioleiomyomatosis (LAM), infiltration of the lungs with smooth muscle-like LAM cells results in cystic destruction and decline in lung function, effects stabilized by sirolimus therapy. LAM lung disease is followed, in part, by high-resolution CT scans. To obtain further information from these scans, we quantified changes in lung parenchyma by analyzing image “texture.” METHODS: Twenty-six texture properties were quantified by analyzing the distribution and intensity of pixels with a computer-aided system. Both cross-sectional and longitudinal studies were performed to examine the relationships between texture properties, cyst score (percentage of lung occupied by cysts), FEV(1), and diffusion capacity for carbon monoxide (Dlco), and to determine the effect of sirolimus treatment. RESULTS: In the cross-sectional study, 18 texture properties showed significant positive correlations with cyst score. Cyst score and 13 of the 18 texture properties showed significant differences in rates of change after sirolimus treatment; 11 also significantly predicted FEV(1) and Dlco. CONCLUSIONS: Increased cyst score was associated with increased texture degradation near cysts. Sirolimus treatment improved lung texture surrounding cysts and stabilized cyst score. Eleven texture properties were associated with FEV(1), Dlco, cyst score, and response to sirolimus. Texture analysis may be valuable in evaluating LAM severity and treatment response.
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- 2019
16. Methacholine reactivity in lymphangioleiomyomatosis is inversely related to FEV
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Roberto, Cassandro, Davide, Elia, Antonella, Caminati, Gustavo, Pacheco-Rodriguez, Mario, Stylianou, Joel, Moss, and Sergio, Harari
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Forced Expiratory Volume ,Vascular Endothelial Growth Factor D ,Humans ,Lymphangioleiomyomatosis ,Bronchial Provocation Tests ,Methacholine Chloride - Published
- 2020
17. Pediatric Heart Network Echocardiographic Z Scores: Comparison with Other Published Models
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Andreea Dragulescu, L. LuAnn Minich, Leo Lopez, Carolyn L. Taylor, Ricardo H. Pignatelli, Christopher F. Spurney, Brian W. McCrindle, Luciana T. Young, Ritu Sachdeva, Justin T. Tretter, Lindsay R. Freud, Peter C. Frommelt, Jonathan H. Soslow, Ashwin Prakash, Russell Gongwer, Aarti Bhat, Michele A. Frommelt, Kristin M. Burns, Mario Stylianou, Felicia L. Trachtenberg, Thor Thorsson, Meryl S. Cohen, Joseph Mahgerefteh, Poonam P. Thankavel, Irene D. Lytrivi, and Steven D. Colan
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Body surface area ,business.industry ,Body Surface Area ,Racial Groups ,Heart ,030204 cardiovascular system & hematology ,Standard score ,urologic and male genital diseases ,CARDIOVASCULAR MEASUREMENTS ,Article ,030218 nuclear medicine & medical imaging ,Large sample ,Correlation ,03 medical and health sciences ,0302 clinical medicine ,Echocardiography ,Statistics ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Clinical care ,Cardiology and Cardiovascular Medicine ,business ,Child ,Boston - Abstract
Background Different methods have resulted in variable Z scores for echocardiographic measurements. Using the measurements from 3,215 healthy North American children in the Pediatric Heart Network (PHN) echocardiographic Z score database, the authors compared the PHN model with previously published Z score models. Methods Z scores were derived for cardiovascular measurements using four models (PHN, Boston, Italy, and Detroit). Model comparisons were performed by evaluating (1) overlaid graphs of measurement versus body surface area with curves at Z = −2, 0, and +2; (2) scatterplots of PHN versus other Z scores with correlation coefficients; (3) Bland-Altman plots of PHN versus other Z scores; and (4) comparison of median Z scores for each model. Results For most measurements, PHN Z score curves were similar to Boston and Italian curves but diverged from Detroit curves at high body surface areas. Correlation coefficients were high when comparing the PHN model with the others, highest with Boston (mean, 0.99) and lowest with Detroit (mean, 0.90). Scatterplots suggested systematic differences despite high correlations. Bland-Altman plots also revealed poor agreement at both extremes of size and a systematic bias for most when comparing PHN against Italian and Detroit Z scores. There were statistically significant differences when comparing median Z scores between the PHN and other models. Conclusions Z scores from the multicenter PHN model correlated well with previous single-center models, especially the Boston model, which also had a large sample size and similar methodology. The Detroit Z scores diverged from the PHN Z scores at high body surface area, possibly because there were more subjects in this category in the PHN database. Despite excellent correlation, significant differences in Z scores between the PHN model and others were seen for many measurements. This is important when comparing publications using different models and for clinical care, particularly when Z score thresholds are used to guide diagnosis and management.
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- 2020
18. Ultra-Small Lung Cysts Impair Diffusion Without Obstructing Air Flow in Lymphangioleiomyomatosis
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Shirley F. Rollison, B. Matthew, Angelo M. Taveira-DaSilva, Joel Moss, Nora M. Quade, A. Hasani, Marcus Y. Chen, Amanda M. Jones, Patricia Julien-Williams, Yun-Ching Chen, Mario Stylianou, Tania Machado, Han Wen, and Mehdi Pirooznia
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Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Critical Care and Intensive Care Medicine ,Pulmonary function testing ,rUHRCT, regional ultra-high resolution CT ,Diffusion ,03 medical and health sciences ,FEV1/FVC ratio ,LAM, lymphangioleiomyomatosis ,0302 clinical medicine ,DLCO ,Diffusing capacity ,parasitic diseases ,Medicine ,Humans ,Lung volumes ,Cyst ,030212 general & internal medicine ,Lymphangioleiomyomatosis ,Lung ,Lung cysts ,Work of Breathing ,business.industry ,Cysts ,respiratory system ,medicine.disease ,respiratory tract diseases ,Respiratory Function Tests ,PFT, pulmonary function test ,Airway Obstruction ,030228 respiratory system ,Printing, Three-Dimensional ,Diffuse Lung Disease: Original Research ,Artificial Organs ,Cardiology and Cardiovascular Medicine ,business ,Nuclear medicine ,Tomography, X-Ray Computed ,TSC, tuberous sclerosis complex ,circulatory and respiratory physiology ,Dlco, diffusing capacity of the lungs for carbon monoxide - Abstract
BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare lung disease found primarily in women of childbearing age, characterized by the formation of air-filled cysts, which may be associated with reductions in lung function. An experimental, regional ultra-high resolution CT scan identified an additional volume of cysts relative to standard chest CT imaging, which consisted primarily of ultra-small cysts. RESEARCH QUESTION What is the impact of these ultra-small cysts on the pulmonary function of patients with LAM? STUDY DESIGN AND METHODS A group of 103 patients with LAM received pulmonary function tests and a CT examination in the same visit. Cyst score, the percentage lung volume occupied by cysts, was measured by using commercial software approved by the US Food and Drug Administration. The association between cyst scores and pulmonary function tests of diffusing capacity of the lungs for carbon monoxide (Dlco) (% predicted), FEV1 (% predicted), and FEV1/FVC (% predicted) was assessed with statistical analysis adjusted for demographic variables. The distributions of average cyst size and ultra-small cyst fraction among the patients were evaluated. RESULTS The additional cyst volume identified by the experimental, higher resolution scan consisted of cysts of 2.2 ± 0.8 mm diameter on average and are thus labeled the "ultra-small cyst fraction." It accounted for 27.9 ± 19.0% of the total cyst volume among the patients. The resulting adjusted, whole-lung cyst scores better explained the variance of Dlco (P < .001 adjusted for multiple comparisons) but not FEV1 and FEV1/FVC (P = 1.00). The ultra-small cyst fraction contributed to the reduction in Dlco (P < .001) but not to FEV1 and FEV1/FVC (P = .760 and .575, respectively). The ultra-small cyst fraction and average cyst size were correlated with cyst burden, FEV1, and FEV1/FVC but less with Dlco. INTERPRETATION The ultra-small cysts primarily contributed to the reduction in Dlco, with minimal effects on FEV1 and FEV1/FVC. Patients with lower cyst burden and better FEV1 and FEV1/FVC tended to have smaller average cyst size and higher ultra-small cyst fraction. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT00001465; URL: www.clinicaltrials.gov.
- Published
- 2020
19. Effect of non-uniform cyst distribution in lymphangioleiomyomatosis on pulmonary function: a cross-sectional study
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Mehdi Pirooznia, B. Matthew, Joel Moss, Mahshid Goljamali, A. Hasani, Marcus Y. Chen, Yun-Ching Chen, Angelo M. Taveira-DaSilva, Mario Stylianou, and Han Wen
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lung Neoplasms ,Cross-sectional study ,business.industry ,Cysts ,respiratory system ,medicine.disease ,respiratory tract diseases ,Pulmonary function testing ,Cross-Sectional Studies ,DLCO ,hemic and lymphatic diseases ,parasitic diseases ,Lymphangioleiomyomatosis ,medicine ,Distribution (pharmacology) ,Humans ,Cyst ,Radiology ,business ,Lung - Abstract
Cysts in LAM patients tend to be more concentrated in the middle half of the lungs. FEV1 but not DLCO is influenced by cyst distribution.https://bit.ly/3p8z9CF
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- 2020
20. Non-Uniform of Cyst Distribution Influence Pulmonary Function in Lymphangioleiomyomatosis
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Joel Moss, N. Quade, H. Wen, Mehdi Pirooznia, Amanda M. Jones, B. Matthew, Tania Machado, Angelo M. Taveira-DaSilva, Shirley F. Rollison, A. Hasani, Yun-Ching Chen, Mario Stylianou, and Patricia Julien-Williams
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Pathology ,medicine.medical_specialty ,Distribution (number theory) ,Lymphangioleiomyomatosis ,medicine ,Cyst ,Biology ,medicine.disease ,Pulmonary function testing - Published
- 2020
21. Ultrahigh-Resolution, Short-Length CT Detects Small Cysts That Are Associated with a Decrease in DLCO but Not FEV1 in Patients with Lymphangioleiomyomatosis
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Patricia Julien-Williams, Shirley F. Rollison, Joel Moss, A. Hasani, H. Wen, N. Quade, B. Matthew, Angelo M. Taveira-DaSilva, Tania Machado, Yun-Ching Chen, Mehdi Pirooznia, Marcus Y. Chen, Amanda M. Jones, and Mario Stylianou
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Ultrahigh resolution ,business.industry ,DLCO ,Lymphangioleiomyomatosis ,Medicine ,In patient ,Short length ,business ,Nuclear medicine ,medicine.disease - Published
- 2020
22. Pregnancy in lymphangioleiomyomatosis: clinical and lung function outcomes in two national cohorts
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Simon R. Johnson, Joel Moss, Angelo M. Taveira-DaSilva, Patricia Julien-Williams, Mario Stylianou, and J.I. Johnson
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Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Lung Neoplasms ,Vital Capacity ,Article ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,DLCO ,Pregnancy ,Forced Expiratory Volume ,Advanced disease ,Medicine ,Humans ,Lymphangioleiomyomatosis ,Adverse effect ,Lung function ,030304 developmental biology ,0303 health sciences ,business.industry ,Obstetrics ,Pregnancy Outcome ,Pneumothorax ,medicine.disease ,030228 respiratory system ,Sirolimus ,Female ,business ,Pregnancy Complications, Neoplastic ,medicine.drug - Abstract
Pregnancy in women with lymphangioleiomyomatosis (LAM) has been associated with increased complications and worsening lung function although objective data to advise patients are not available. We assessed lung function and CT scans before and after pregnancy in 16 women with LAM. During the pregnancy, pneumothorax was frequent and mean forced expiratory volume in 1 s (FEV1) fell from 77%±19% prepregnancy to 64%±25% predicted and DLCO from 66±26 to 57±26 (both p1 decline were high and 10 patients required sirolimus. Women with LAM, especially with moderate or advanced disease should be counselled regarding adverse events and loss of lung function during the pregnancy.
- Published
- 2020
23. Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome
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Stephanie Burns Wechsler, Arvind Hoskoppal, Wyman W. Lai, Luciana Young, Reed E. Pyeritz, Ronald V. Lacro, Timothy J. Bradley, Kristin M. Burns, Jami C. Levine, Aimee Liou, Bruce D. Gelb, Julie De Backer, Felicia Trachtenberg, Angela M. Sharkey, Marie L. Gleason, Elif Seda Selamet Tierney, Lynn Mahony, Aaron K Olson, Jeanne James, Mario Stylianou, Shaji C. Menon, Amsterdam Neuroscience - Complex Trait Genetics, Paediatric Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and General Paediatrics
- Subjects
Adult ,Male ,Marfan syndrome ,medicine.medical_specialty ,Adolescent ,Referral ,Aortic Diseases ,030204 cardiovascular system & hematology ,Risk Assessment ,Article ,Losartan ,Marfan Syndrome ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine.artery ,Ascending aorta ,medicine ,Humans ,030212 general & internal medicine ,Child ,Referral and Consultation ,Antihypertensive Agents ,Aorta ,Receiver operating characteristic ,business.industry ,Sinotubular Junction ,Infant ,Repeated measures design ,Vascular surgery ,medicine.disease ,Dilatation ,Cardiac surgery ,Atenolol ,ROC Curve ,Echocardiography ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers ,Vascular Surgical Procedures - Abstract
Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.
- Published
- 2018
24. Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery
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Juan C. Ibla, Athena F. Zuppa, Hua Ni, Felicia L. Trachtenberg, Mario Stylianou, Nicole S. Wilder, Tera H Skeen, Erin A. Gottlieb, Susan C. Nicolson, Dean B. Andropoulos, and Kristin M. Burns
- Subjects
Heart Defects, Congenital ,Male ,medicine.medical_specialty ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Bolus (medicine) ,Pharmacokinetics ,030202 anesthesiology ,law ,Cardiopulmonary bypass ,medicine ,Humans ,Hypnotics and Sedatives ,Dosing ,Dexmedetomidine ,Cardiac Surgical Procedures ,Infusions, Intravenous ,Dose-Response Relationship, Drug ,business.industry ,Infant, Newborn ,Paediatric Anaesthesia ,Infant ,medicine.disease ,Confidence interval ,Cardiac surgery ,Anesthesiology and Pain Medicine ,Anesthesia ,Female ,business ,Junctional rhythm ,medicine.drug - Abstract
Background Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. Methods We included 122 neonates and infants (0–180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200–300 pg ml−1), medium (400–500 pg ml−1), and high (600–700 pg ml−1) DEX plasma concentrations. Results Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8–9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min−1 70 kg−1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th–95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml−1. Conclusions When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. Clinical trials registration NCT01915277.
- Published
- 2019
25. Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis
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Joel Moss, Wendy K. Steagall, Mario Stylianou, and Gustavo Pacheco-Rodriguez
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0301 basic medicine ,medicine.medical_specialty ,Angiotensin-Converting Enzyme Inhibitors ,Gastroenterology ,Pulmonary function testing ,03 medical and health sciences ,0302 clinical medicine ,DLCO ,Forced Expiratory Volume ,Internal medicine ,Diffusing capacity ,medicine ,Humans ,Lymphangioleiomyomatosis ,Lung ,Retrospective Studies ,Sirolimus ,Carbon Monoxide ,biology ,business.industry ,Standard treatment ,Angiotensin-converting enzyme ,General Medicine ,medicine.disease ,Respiratory Function Tests ,030104 developmental biology ,Enzyme inhibitor ,030220 oncology & carcinogenesis ,Disease Progression ,biology.protein ,Female ,Clinical Medicine ,business ,medicine.drug - Abstract
INTRODUCTION. A local renin-angiotensin system exists in the pulmonary nodules of lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected lymphangioleiomyomatosis disease progression. METHODS. Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. RESULTS. Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and sirolimus versus sirolimus alone. CONCLUSIONS. Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with lymphangioleiomyomatosis not treated with sirolimus. These inhibitors may be an option or adjunct in the treatment of lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. FUNDING. NIH.
- Published
- 2019
26. Challenges With Left Ventricular Functional Parameters: The Pediatric Heart Network Normal Echocardiogram Database
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Peter C. Frommelt, L. LuAnn Minich, Felicia L. Trachtenberg, Karen Altmann, Joseph Camarda, Meryl S. Cohen, Steven D. Colan, Andreea Dragulescu, Michele A. Frommelt, Tiffanie R. Johnson, John P. Kovalchin, Lina Lin, Joseph Mahgerefteh, Arni Nutting, David A. Parra, Gail D. Pearson, Ricardo Pignatelli, Ritu Sachdeva, Brian D. Soriano, Christopher Spurney, Shubhika Srivastava, Christopher J. Statile, Jessica Stelter, Mario Stylianou, Poonam P. Thankavel, E. Seda Tierney, Mary E. van der Velde, Leo Lopez, Kristin Burns, Jonathan Kaltman, Gail Pearson, Victoria Pemberton, Lynn Mahony, Shan Chen, Steven Colan, Dianne Gallagher, Eric Gerstenberger, Russell Gongwer, Suzanne Granger, Julia Keosaian, Susanne Langley, Tammi Mansolf, Stephanie Moine, Andrew Morrison, Katelyn Nelson, Brenda Ni, Janet Ortiz, David Pober, Michelle Pucillo, Paul Stark, Christiana Toomey, Felicia Trachtenberg, Barbara Winrich, Steven Schwartz, Fraser Golding, Brian McCrindle, Elizabeth Radojewski, Seema Mital, Patricia Walter, Cameron Slorach, Jane Newburger, John Triedman, Ashwin Prakash, Jami Levine, Stephen Paridon, Meryl Cohen, David Goldberg, Tonia Morrison, Andrew M. Atz, Eric Graham, Carolyn Taylor, Shahryar Chowdhury, Patricia Infinger, Richard V. Williams, Dongngan T. Truong, Linda M. Lambert, Marian E. Shearrow, Belva Stanton, Caren Goldberg, Richard Ohye, Suzanne Welch, James F. Cnota, Michelle Hamstra, Kathleen Ash, Joshua Sticka, Mark Payne, Timothy Cordes, Liz Swan, William Mahle, Heather S. Friedman, Laurie J. Clark, Daniel Penny, David Garuba, Carolynn Altman, Marc Richmond, Wyman Lai, Rosalind Korsin, Brett Anderson, Poonam Punjwani Thankavel, Hollie Carron, Salil Ginde, Michelle Otto, Michele Frommelt, Larry Markham, Jonathan H. Soslow, Luciana Young, Elise Duffy, Kathleen Van't Hof, Mark Lewin, Joel Lester, Aarti H. Bhat, Amy Payne, Irene Lytrivi, Helen Ko, Kelly Ann Balem, Craig Sable, Peter Frommelt, Hannah Hartsig, Michael Artman, Anu Rao, Ben Eidem, G. Paul Matherne, Timothy Feltes, Julie Johnson, Jeffrey P. Krischer, Patrick McBride, John Kugler, Frank Evans, David Driscoll, Mark Galantowicz, Sally Hunsberger, Thomas Knight, and Holly Taylor
- Subjects
Male ,Functional indices ,Adolescent ,Cardiac anatomy ,Systole ,030204 cardiovascular system & hematology ,computer.software_genre ,Ventricular Function, Left ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Wisconsin ,Reference Values ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Normal echocardiogram ,Child ,Reproducibility ,Core (anatomy) ,Ejection fraction ,Database ,business.industry ,Infant ,Reproducibility of Results ,Fractional shortening ,Clinical Practice ,Echocardiography ,Child, Preschool ,Female ,Cardiology and Cardiovascular Medicine ,business ,computer - Abstract
BACKGROUND: The reliability of LV systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of left ventricular (LV) size and systolic function in children with normal cardiac anatomy and qualitatively normal function. METHODS: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used 2-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers re-measured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices. RESULTS: Of 3215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF)
- Published
- 2019
27. Methacholine reactivity in lymphangioleiomyomatosis is inversely related to FEV1 and VEGF-D
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Sergio Harari, Mario Stylianou, Gustavo Pacheco-Rodriguez, Joel Moss, Antonella Caminati, Roberto Cassandro, and Davide Elia
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung ,business.industry ,medicine.disease ,Vascular endothelial growth factor ,Tuberous sclerosis ,chemistry.chemical_compound ,medicine.anatomical_structure ,Lymphatic system ,chemistry ,Sirolimus ,Internal medicine ,Lymphangioleiomyomatosis ,medicine ,TSC1 ,Differential diagnosis ,business ,medicine.drug - Abstract
Lymphangioleiomyomatosis (LAM) is a multisystem disease characterised by cystic lung destruction, leading to respiratory failure, and associated with kidney ( e.g. , angiomyolipomas (AML)) and lymphatic involvement ( e.g. , lymphangioleiomyomas, chylous effusions) [1, 2]. LAM occurs sporadically or in association with Tuberous Sclerosis Complex (TSC), an autosomal-dominant disorder characterised by mutations of the TSC1 or TSC2 genes. Lung destruction results from the proliferation of LAM cells, which possess neoplastic properties and are found in LAM lung nodules, in association with fibroblasts, mast cells, lymphocytes and lymphatic endothelial cells [3, 4]. LAM patients may show increases in serum levels of the lymphangiogenic factor, vascular endothelial growth factor-D (VEGF-D), a LAM biomarker used in differential diagnosis of cystic lung diseases and to identify LAM patients likely to respond to sirolimus treatment [5–7]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Dr. Cassandro has nothing to disclose. Conflict of Interest: Dr. Elia has nothing to disclose. Conflict of Interest: Dr. Caminati reports personal fees from Roche, personal fees from BI, outside the submitted work. Conflict of Interest: Dr. Pacheco has nothing to disclose. Conflict of Interest: Dr. Stylianou has nothing to disclose. Conflict of Interest: Dr. Moss has nothing to disclose. Conflict of Interest: Dr. Harari has nothing to disclose.
- Published
- 2021
28. Design and Rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial
- Author
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Kurt R. Schumacher, Matthew D. Files, Kimberly E. McHugh, Victoria L. Pemberton, Daniel J. Penny, Stephen M. Paridon, Peter C. Frommelt, Jonathan Rhodes, Brian W. McCrindle, Gail D. Pearson, Bryan H. Goldstein, Victor Zak, R. Mark Payne, James L. Yeager, Michelle S Hamstra, David J. Goldberg, Shaji C. Menon, Mario Stylianou, Felicia L. Trachtenberg, and Marc E. Richmond
- Subjects
Heart Defects, Congenital ,medicine.medical_specialty ,Cardiac output ,medicine.medical_treatment ,Population ,030204 cardiovascular system & hematology ,Fontan Procedure ,Article ,Fontan procedure ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,Longitudinal Studies ,Exercise physiology ,education ,Exercise ,Randomized Controlled Trials as Topic ,Postoperative Care ,education.field_of_study ,Udenafil ,Sulfonamides ,business.industry ,Central venous pressure ,Phosphodiesterase 5 Inhibitors ,Exercise Therapy ,Clinical trial ,Pyrimidines ,Tolerability ,Emergency medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short-term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double blind, placebo controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co., Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.
- Published
- 2018
29. Effect of beta-agonists on LAM progression and treatment
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Wendy K. Steagall, Thomas N. Darling, Martha Vaughan, Mario Stylianou, Joel Moss, Gustavo Pacheco-Rodriguez, and Kang Le
- Subjects
0301 basic medicine ,Adult ,Pharmacology ,Tuberous Sclerosis Complex 1 Protein ,03 medical and health sciences ,0302 clinical medicine ,Catalytic Domain ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Cyclic AMP ,Humans ,Lymphangioleiomyomatosis ,Phosphorylation ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Aged ,Cell Proliferation ,Retrospective Studies ,Skin ,Sirolimus ,Multidisciplinary ,biology ,Cell growth ,Chemistry ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,Isoproterenol ,Adrenergic beta-Agonists ,Fibroblasts ,Middle Aged ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Bronchodilator Agents ,Respiratory Function Tests ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,PNAS Plus ,Multivariate Analysis ,biology.protein ,Disease Progression ,Female ,TSC1 ,TSC2 ,medicine.drug ,Signal Transduction - Abstract
Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2+/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.
- Published
- 2018
30. The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned
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Roger D. Yusen, Gerard J. Criner, Alice L. Sternberg, David H. Au, Anne L. Fuhlbrigge, Richard K. Albert, Richard Casaburi, James K. Stoller, Kathleen F. Harrington, J. Allen D. Cooper, Philip Diaz, Steven Gay, Richard Kanner, Neil MacIntyre, Fernando J. Martinez, Steven Piantadosi, Frank Sciurba, David Shade, Thomas Stibolt, James Tonascia, Robert Wise, William C. Bailey, Ernestina Sampong, Karin Sloan, Ashley Wagner, Susan Anderson, Marilyn Moy, Osarenoma Okunbor, Scott Marlow, Yvonne Meli, Richard Rice, Loutfi S. Aboussouan, Robert Castele, Joseph Parambil, Sumita Khatri, Aman Pande, Joe Zein, Thomas Olbrych, Stephan Alkins, Christine Jocko, Franck Rahaghi, Jean Barton, Jennifer Underwood, Barry Make, John Davies, Richard Mularski, Allison Naleway, Sarah Vertrees, Janos Porszasz, Peggy Walker, Renee Indelicato, Lennard Specht, Kathleen Ellstrom, Jamie Portillo, David Horak, Brian Tiep, Mary Barnett, Janice Drake, Mahasti Rittinger, Rachael Compton, Scott Miller, Ralph J. Panos, Laura A. Lach, Gerard Criner, Carla Grabianowski, Francis Cordova, Parag Desai, Samuel Krachman, James Mamary, Nathaniel Marchetti, Aditi Satti, Eileen Mumm, Michelle Vega-Olivo, Jenny Hua, Vanna Tauch, Lii-Yoong Criner, Michael Jacobs, Peter Rising, Paul Simonelli, Michele Mitchell, Matthew Lammi, Connie Romaine, Howard Lee, Mary Ianacone, Steven Scharf, Wanda Bell-Farrell, M. Jeffery Mador, Ayesha Rahman, Mumtaz Zaman, Lisa Hill, Alec Platt, J. Allen Cooper, Kathleen Harrington, Mark Dransfield, Patti Smith, Donald Davis, Peruvemba Sriram, Katherine Herring, Fernando Martinez, Meilan Han, Kelly Rysso, Catherine Meldrum, K. P. Ravikrishnan, Daniel Keena, Jennifer DeRidder, Beth Kring, Antonio Anzueto, Alex Aguilera, Timothy Houlihan, Reda Girgis, Jennifer Cannestra, Benjamin Kelly, Mary Beth Scholand, G. Martin Villegas, Judy Carle, Edmunds Udris, Randall Curtis, David Au, Laura C. Feemster, Richard Goodman, Brianna Moss, Lynn Reinke, Moira Aitken, Bruce Culver, Mario Castro, Brigitte Mittler, Jeanne Heaghney, Myron Jacobs, Min Joo, Nina Bracken, Edward Diamond, Mary K. Joseph, Xavier Soler, Arianna Villa, Daniel Layish, Edwin Silverman, Roxanne Kelly, Daniel Cossette, Patricia Belt, Amanda Blackford, Betty Collison, John Dodge, Michele Donithan, Cathleen Ewing, Rosetta Jackson, K Patrick May, Jill Meinert, Girlie Reyes, Michael Smith, Mark Van Natta, Laura Wilson, Annette Wagoner, Katherine P. Yates, Rosemarie Hakim, Antonello Punturieri, Julie Bamdad, Thomas Croxton, Joanne Deshler, Pamela McCord-Reynolds, Mario Stylianou, Gail Weinmann, Gordon Bernard, James Anderson, Bernard Lo, Andrew Ries, Stuart Stoloff, Byron Thomashow, Barbara Tilley, and Kevin Weiss
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Randomization ,Time Factors ,medicine.medical_treatment ,Population ,law.invention ,Hypoxemia ,Treatment and control groups ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Patient Admission ,Randomized controlled trial ,law ,Oxygen therapy ,Medicine ,Humans ,Multicenter Studies as Topic ,030212 general & internal medicine ,education ,Aged ,Randomized Controlled Trials as Topic ,Clinical Study Design ,Aged, 80 and over ,education.field_of_study ,Geography ,business.industry ,Oxygen Inhalation Therapy ,Middle Aged ,Long-Term Care ,United States ,Clinical trial ,Oxygen ,030228 respiratory system ,Sample size determination ,Emergency medicine ,Physical therapy ,Quality of Life ,Female ,medicine.symptom ,business - Abstract
The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).
- Published
- 2018
31. Rates of change in FEV
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Angelo M, Taveira-DaSilva, Patricia, Julien-Williams, Amanda M, Jones, Mario, Stylianou, and Joel, Moss
- Subjects
Adult ,Sirolimus ,Carbon Monoxide ,Lung Neoplasms ,Adolescent ,TOR Serine-Threonine Kinases ,Middle Aged ,Article ,respiratory tract diseases ,Young Adult ,Treatment Outcome ,Premenopause ,Forced Expiratory Volume ,Disease Progression ,Humans ,Female ,Lymphangioleiomyomatosis ,Lung - Abstract
The value of rates of change in FEV(1) and DL(CO) to predict disease progression, and initiation of mTOR inhibitor therapy has not been evaluated. In 84 pre-menopausal LAM patients, individual rates of change in FEV(1) and DL(CO) and 95% confidence intervals (CI), were used to derive subsequent lowest values of FEV(1) and DL(CO) that would prompt initiation of sirolimus therapy. These treatment criteria were compared with one based on FEV(1) or DL(CO) ≤ 70 % predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated. Twenty-seven and 35 patients, respectively, who experienced rates of change in FEV(1) and DL(CO) greater than expected, would have been excluded from therapy based on an FEV(1) or DL(CO) > 70 % predicted. Twenty-five of the 84 patients were eventually treated but only when FEV(1) or DL(CO) were ≤ 70 %. Applying such treatment criteria to 12 patients undergoing sirolimus therapy, would have delayed treatment for many years. Pre-menopausal women in whom FEV(1) or DL(CO) are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV(1) or DL(CO) falls to ≤ 70 %.
- Published
- 2017
32. Relationship of Echocardiographic Z Scores Adjusted for Body Surface Area to Age, Sex, Race, and Ethnicity
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Brian D. Soriano, Michele A. Frommelt, Ritu Sachdeva, Mario Stylianou, Wyman W. Lai, Felicia Trachtenberg, Olukayode Garuba, Andreea Dragulescu, Carolyn L. Taylor, Jonathan H. Soslow, Peter C. Frommelt, James F. Cnota, Meryl Cohen, Ashwin Prakash, Steven D. Colan, L. LuAnn Minich, Shubhika Srivastava, Mary E. van der Velde, Suzanne Granger, Tiffanie R. Johnson, Joseph Mahgerefteh, Poonam P. Thankavel, Joseph Camarda, Ricardo H. Pignatelli, Gail D. Pearson, Christopher F. Spurney, and Leo Lopez
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,Body Surface Area ,Ethnic group ,030204 cardiovascular system & hematology ,Standard score ,Article ,03 medical and health sciences ,Race (biology) ,Sex Factors ,0302 clinical medicine ,Predictive Value of Tests ,Ethnicity ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Child ,Retrospective Studies ,Body surface area ,business.industry ,Racial Groups ,Age Factors ,Reproducibility of Results ,Heart ,Retrospective cohort study ,Nomogram ,Healthy Volunteers ,Nomograms ,Echocardiography ,Sample size determination ,Child, Preschool ,Sample Size ,Predictive value of tests ,North America ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background— Published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity. Variable methodologies have resulted in a wide range of Z scores for a single measurement. This multicenter study sought to determine Z scores for common measurements adjusted for body surface area (BSA) and stratified by age, sex, race, and ethnicity. Methods and Results— Data collected from healthy nonobese children ≤18 years of age at 19 centers with a normal echocardiogram included age, sex, race, ethnicity, height, weight, echocardiographic images, and measurements performed at the Core Laboratory. Z score models involved indexed parameters (X/BSA α ) that were normally distributed without residual dependence on BSA. The models were tested for the effects of age, sex, race, and ethnicity. Raw measurements from models with and without these effects were compared, and α ) were selected for each measurement. Multivariable regression revealed statistically significant effects by age, sex, race, and ethnicity for all outcomes, but all effects were clinically insignificant based on comparisons of models with and without the effects, resulting in Z scores independent of age, sex, race, and ethnicity for each measurement. Conclusions— Echocardiographic Z scores based on BSA were derived from a large, diverse, and healthy North American population. Age, sex, race, and ethnicity have small effects on the Z scores that are statistically significant but not clinically important.
- Published
- 2017
33. Effect of Fasting on the Size of Lymphangioleiomyomas in Patients With Lymphangioleiomyomatosis
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Patricia Julien-Williams, Mario Stylianou, Amanda M. Jones, Thomas H. Shawker, Angelo M. Taveira-DaSilva, Connie G. Glasgow, and Joel Moss
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Chyle ,Vascular Endothelial Growth Factor D ,Critical Care and Intensive Care Medicine ,Malignancy ,Severity of Illness Index ,Gastroenterology ,Interquartile range ,Diffusing capacity ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Ingestion ,Lymphangioleiomyomatosis ,Neoplasm Staging ,Original Research ,Lung ,business.industry ,Fasting ,medicine.disease ,medicine.anatomical_structure ,Lymphatic system ,Abdominal Neoplasms ,Female ,Tomography, X-Ray Computed ,Cardiology and Cardiovascular Medicine ,business ,Lymphangiomyoma ,Follow-Up Studies - Abstract
Lymphangioleiomyomas occur in 38% of patients with sporadic lymphangioleiomyomatosis (LAM) and may cause pain and increased abdominal girth, mimicking the presence of a malignancy. Lymphatic involvement in LAM is closely associated with elevated serum levels of vascular endothelium growth factor-D (VEGF-D). Because lymphangioleiomyomas undergo diurnal variation in volume, we hypothesized that daytime ingestion of food, by increasing chyle formation and lymphatic flow, is the cause of an increase in lymphangioleiomyoma volume.Subjects had abdominopelvic sonograms and blood drawn for measurement of serum VEGF-D levels under nonfasting (day 1) and fasting (day 2) conditions. The size of the lymphangioleiomyomas was determined by a radiologist who was blinded to the subjects' status. The Wilcoxon signed rank test was used to determine whether the nonfasting tumor size was different from the fasting tumor size.Thirty-five women were studied (aged 45.2 ± 8.5 years; FEV1, 82% ± 25%; diffusing capacity of the lung for carbon monoxide, 64% ± 25% predicted). Images suitable for volume measurements were obtained in 30 subjects. Fasting decreased the tumor size by 20.7 ± 39.3 cm3 (24% ± 40%, P.001). Fasting VEGF-D levels (10,650 ± 900 pg/mL) were not significantly different from nonfasting values (12,100 ± 800 pg/mL, P = .56).Lymphangioleiomyoma volume decreased during the fasting state. Conversely, a combination of food intake and decreased chyle flow through lymphatics partially obstructed by LAM cells may account for increases in lymphangioleiomyoma size. Imaging studies performed under fasting conditions may help in determining whether an abdominal tumor is a result of LAM or malignancy.
- Published
- 2015
34. High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics
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Patricia Theard, Cecile T.J. Holweg, Alan T. Remaley, Maryann Kaler, Xianglan Yao, David F. Choy, Amisha V. Barochia, Stewart J. Levine, Nargues Weir, Elizabeth M. Gordon, Debbie M. Figueroa, Maureen Sampson, Mario Stylianou, and Rosemarie A. Cuento
- Subjects
Adult ,Male ,medicine.medical_specialty ,Blood lipids ,Inflammation ,QD415-436 ,030204 cardiovascular system & hematology ,Periostin ,Biochemistry ,lung ,Atopy ,immunology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,clinical studies ,Asthma ,Lung ,business.industry ,Cell Biology ,medicine.disease ,Inflammatory biomarkers ,Eosinophils ,medicine.anatomical_structure ,030228 respiratory system ,Case-Control Studies ,lipids (amino acids, peptides, and proteins) ,Female ,medicine.symptom ,business ,Patient-Oriented and Epidemiological Research ,Lipoproteins, HDL ,apolipoproteins ,Cell Adhesion Molecules ,Biomarkers ,Lipoprotein - Abstract
Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR. In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.
- Published
- 2017
35. Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis
- Author
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Patricia Julien-Williams, Joel Moss, Mario Stylianou, Angelo M. Taveira-DaSilva, and Amanda M. Jones
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Pathology ,medicine.medical_specialty ,Angiomyolipoma ,Critical Care ,Urology ,Vascular Endothelial Growth Factor D ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,DLCO ,Forced Expiratory Volume ,medicine ,Humans ,In patient ,Lymphangioleiomyomatosis ,Age of Onset ,Lung function ,Sirolimus ,Carbon Monoxide ,business.industry ,respiratory system ,Middle Aged ,medicine.disease ,Long-Term Care ,Lymphatic disease ,030228 respiratory system ,Premenopause ,030220 oncology & carcinogenesis ,Female ,Menopause ,Cardiology and Cardiovascular Medicine ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Sirolimus reduces serum levels of vascular endothelial growth factor D (VEGF-D); the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas; and stabilizes lung function in patients with lymphangioleiomyomatosis (LAM). Methods To determine whether reductions in VEGF-D levels are sustained over time, as well as parallel changes in lung function and lymphatic disease, we evaluated 25 patients with LAM and measured VEGF-D levels, lung function, and extent of lymphatic disease before and during sirolimus therapy. Results Treatment with sirolimus stabilized FEV 1 and diffusion capacity for carbon monoxide (Dlco) over a period of 4.5 ± 1.6 years, caused resolution of lymphatic disease, and reduced the size of angiomyolipomas and VEGF-D levels (3,720 ± 3,020 pg/mL to 945 ± 591 pg/mL; P 1 % predicted and Dlco % predicted were reduced from –7.4% ± 1.4% to –0.3% ± 0.5% ( P P P 1 and Dlco during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, a greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy than did those without lymphatic disease. Conclusions Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated levels preceding therapy. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.
- Published
- 2017
36. CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis
- Author
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Patricia Julien-Williams, Connie G. Glasgow, Wendy K. Steagall, Mario Stylianou, Mary Haughey, Gustavo Pacheco-Rodriguez, Bernadette R. Gochuico, and Joel Moss
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Pathology ,medicine.medical_specialty ,Angiomyolipoma ,Pleural effusion ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,Young Adult ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Lymphangioleiomyomatosis ,Aged ,Aged, 80 and over ,Sirolimus ,Analysis of Variance ,Lung ,business.industry ,Mucins ,Middle Aged ,bacterial infections and mycoses ,medicine.disease ,Immunohistochemistry ,Respiratory Function Tests ,Pleural Effusion ,medicine.anatomical_structure ,030228 respiratory system ,030220 oncology & carcinogenesis ,CA-125 Antigen ,Disease Progression ,Biomarker (medicine) ,lipids (amino acids, peptides, and proteins) ,Female ,Diffuse Lung Disease ,Cardiology and Cardiovascular Medicine ,Ovarian cancer ,business ,Biomarkers ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic-like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, levels of cancer antigen 125 (CA-125), an ovarian cancer biomarker, can be elevated in patients with LAM. We hypothesized that elevated serum CA-125 levels seen in some patients with LAM were due to LAM, not other malignancies, and might respond to sirolimus treatment. Methods Serum CA-125 levels were measured for 241 patients at each visit. Medical records were reviewed for co-morbidities, disease progression, and response to sirolimus treatment. CA-125 expression in LAM cells was determined by using immunohistochemical analysis. Results Almost 25% of patients with LAM had at least one elevated serum CA-125 measurement. Higher serum CA-125 levels correlated with lower FEV 1 , premenopausal status, and pleural effusion in a multivariate model (each P P = .002). CA-125 and α-smooth muscle actin were co-expressed in LAM lung nodules. Conclusions Higher serum CA-125 levels were associated with pleural effusions and reduced pulmonary function and were decreased with sirolimus therapy. LAM cells express CA-125. Some elevated serum CA-125 levels may reflect serosal membrane involvement.
- Published
- 2017
37. A randomized, placebo-controlled, double-blinded, crossover trial of pioglitazone for severe asthma
- Author
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Mark J. Roth, Maryann Kaler, Amisha V. Barochia, Steven D. Nathan, Stewart J. Levine, Rosemarie A. Cuento, Ellen C. Vaughey, Nargues Weir, Armando C. Filie, and Mario Stylianou
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0301 basic medicine ,Agonist ,Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Severe asthma ,Immunology ,macromolecular substances ,Placebo ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Quality of life ,Double-Blind Method ,law ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Hypoglycemic Agents ,Asthma ,Cross-Over Studies ,Pioglitazone ,business.industry ,Middle Aged ,medicine.disease ,Crossover study ,respiratory tract diseases ,030104 developmental biology ,Endocrinology ,030228 respiratory system ,Female ,business ,medicine.drug - Abstract
The PPAR-γ agonist, pioglitazone, was associated with significant side effects and did not improve the primary outcome measure of the Juniper Asthma Quality of Life Questionnaire (AQLQ) score in severe asthmatics. We conclude that no further studies should be performed with pioglitazone for severe asthma.
- Published
- 2017
38. Sirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With Lymphangioleiomyomatosis
- Author
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Suowen Xu, J. Philip McCoy, Gustavo Pacheco-Rodriguez, Joel Moss, Mario Stylianou, Mary Haughey, Thomas N. Darling, Hai-Ping Wu, Xiong Cai, and Leigh Samsel
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Angiomyolipoma ,Loss of Heterozygosity ,Critical Care and Intensive Care Medicine ,Loss of heterozygosity ,Tuberous sclerosis ,hemic and lymphatic diseases ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Humans ,Lymphangioleiomyomatosis ,Original Research ,Sirolimus ,Antibiotics, Antineoplastic ,Lung ,biology ,business.industry ,Tumor Suppressor Proteins ,Middle Aged ,Neoplastic Cells, Circulating ,medicine.disease ,Lymphatic system ,medicine.anatomical_structure ,biology.protein ,Female ,Antibody ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2 , which leads to hyperactivation of the mammalian target of rapamycin. Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells. Methods Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation. Blood cells were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-phycoerythrin (PE) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH. Results LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy. Over a mean duration of 2.2 ± 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood ( P P = .003). Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients ( P = .025). Conclusions Patients receiving sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status.
- Published
- 2014
39. Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome
- Author
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Jill C. Handisides, Danielle Hollenbeck-Pringle, Karen Uzark, Felicia L. Trachtenberg, Victoria L. Pemberton, Teresa W. Atz, Timothy J. Bradley, Elizabeth Cappella, Sylvia De Nobele, Georgeann Keh-Teng Groh, Michelle S. Hamstra, Rosalind Korsin, Jami C. Levine, Bergen Lindauer, Aimee Liou, Meghan K. Mac Neal, Larry W. Markham, Tonia Morrison, Kathleen A. Mussatto, Aaron K. Olson, Mary Ella M. Pierpont, Reed E. Pyeritz, Elizabeth A. Radojewski, Mary J. Roman, Mingfen Xu, Ronald V. Lacro, Gail Pearson, Mario Stylianou, Lynn Mahony, Lynn Sleeper, Sharon Tennstedt, Steven Colan, Gloria Klein, Lin Guey, Lisa Wruck, Thomas Travison, Shan Chen, Eric Gerstenberger, Tanya Olesker, David F. Teitel, Jane Newburger, Martha King, Carolyn Dunbar-Masterson, Andrea Posa, Quincy Nang, Cara Hass, Daphne Hsu, Wyman Lai, William Hellenbrand, Beth Printz, Richard Devereux, Greysi Sherwood, Victoria Vetter, Stephen Paridon, Marie Gleason, Nicole Mirarchi, Sandra DiLullo, Agbenu Ejembi, Ruth Morgan, D. Woodrow Benson, William Border, James Cnota, Haleh Heydarian, Jeanne James, Kathryn Hogan, Lois Bogenschutz, Mary Pat Benham, Teresa Barnard, Page A.W. Anderson, Jennifer S. Li, Stephanie Burns Wechsler, Amanda Cook, Charles Sang, Wesley Covitz, Lori Jo Sutton, Kari Crawford, Summer Roberts, Deborah Palmer, J. Philip Saul, Andrew Atz, Geoffrey Forbus, Patricia Infinger, Aparna Choudhury, LuAnn Minich, Richard Williams, Angela Yetman, Marian Shearrow, Michelle Robinson, June Porter, Brian McCrindle, Jennifer Russell, Jack Colman, Svetlana Khaikin, Nancy Slater, Harry C. Dietz, William J. Ravekes, Mary Rykiel, Elisabeth Sparks, Gretchen MacCarrick, Jennifer Leadroot, Charles Canter, Angela Sharkey, Alan Braverman, Cheryl Rainey, John L. Jefferies, Timothy Slesnick, Hugo Martinez, Andres Menesses, Tunu Tenende, David Liang, Elisabeth Merkel, Bart Loeys, Julie De Backer, Jan Maarten Cobben, Thierry Sluysmans, Anne De Paepe, Bruce Gelb, Shubhika Srivastava, Tejani Mendiz-Ramdeen, Constance Weismann, Emily Lawrence, Stephanie Chin, Helen Ko, Jen Le Yau, Steven Webber, Stacey Drant, Jane Luce, Kevin Stiegler, Cheryl Kinnard, Cheri Stewart, Sue Sommers, Carol Madison, Luciana Young, Megan Domenico, Kathryn Waitzman, Carla Lozano, Charles Baker, Erin Zielinski, Heidi Vander Velden, Alison Overman, Mark Lewin, Amy Payne, David Rimoin, Mitchel Pariani, Robert Siegel, Asim Rafique, Paul Grossfeld, Arlene Smith, Terri McLees-Palinkas, Steven D. Colan, Elif Seda Selamet Tierney, Shari Trevey, Marga Rivera, Michael Artman, Erle Austin, H. Scott Baldwin, Daniel Bernstein, Timothy Feltes, Julie Johnson, Thomas Klitzner, Jeffrey Krischer, G. Paul Matherne, Kenneth G. Zahka, John Kugler, David J. Driscoll, Mark Galantowicz, Sally A. Hunsberger, Thomas J. Knight, Holly Taylor, Paediatric Genetics, and General Paediatrics
- Subjects
Marfan syndrome ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Severity of Illness Index ,Losartan ,Article ,Marfan Syndrome ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Neurodevelopmental disorder ,Quality of life ,030225 pediatrics ,Medicine ,Health Status Indicators ,Humans ,030212 general & internal medicine ,Patient Reported Outcome Measures ,Young adult ,Child ,Antihypertensive Agents ,Health related quality of life ,business.industry ,Chronic pain ,medicine.disease ,humanities ,Atenolol ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Quality of Life ,Female ,business ,Psychosocial - Abstract
Objective: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. Study design: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. Results: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤.003) and psychosocial (P
- Published
- 2019
40. Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation
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Elizabeth P. Henske, Joel Moss, Mario Stylianou, Wendy K. Steagall, Anthony M. Lamattina, Souheil El-Chemaly, Pranav Kidambi, Gustavo Pacheco-Rodriguez, Ivan O. Rosas, Carmen Priolo, Fernanda Golzarri, Ye Cui, and Benjamin Stump
- Subjects
0301 basic medicine ,Cancer Research ,Vascular Endothelial Growth Factor D ,Syk ,Apoptosis ,Mice, SCID ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,Tuberous sclerosis ,Mice ,0302 clinical medicine ,Germline mutation ,hemic and lymphatic diseases ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Syk Kinase ,Lymphangioleiomyomatosis ,Cells, Cultured ,Chemokine CCL2 ,Cell Proliferation ,Tumor Suppressor Proteins ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Cell Transformation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Immunology ,Mutation ,Cancer research ,Leukocytes, Mononuclear ,lipids (amino acids, peptides, and proteins) ,Female ,Signal transduction ,TSC2 ,Carcinogenesis ,Tyrosine kinase ,Follow-Up Studies ,Signal Transduction - Abstract
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.
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- 2016
41. Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation
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Shan Chen, Jonathan R. Kaltman, R. Mark Payne, Eileen Maunsell, Stephen M. Paridon, David J. Goldberg, James L. Yeager, Michelle S Hamstra, Mario Stylianou, Bryan H. Goldstein, Tina M. deVries, Elizabeth Radojewski, Seema Mital, Shaji C. Menon, Victor Zak, and Kurt R. Schumacher
- Subjects
Heart Defects, Congenital ,Male ,Pulmonary Circulation ,Time Factors ,Adolescent ,Heart Ventricles ,Cmax ,030204 cardiovascular system & hematology ,Fontan Procedure ,Drug Administration Schedule ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Medicine ,Humans ,030212 general & internal medicine ,Dosing ,Cardiac Output ,Postoperative Care ,Udenafil ,Sulfonamides ,Dose-Response Relationship, Drug ,business.industry ,Area under the curve ,Phosphodiesterase 5 Inhibitors ,Clinical trial ,Regimen ,Pyrimidines ,Treatment Outcome ,Echocardiography ,Anesthesia ,Cohort ,Female ,Vascular Resistance ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug ,Follow-Up Studies - Abstract
Background The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. Objectives This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. Methods A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. Results The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. Conclusions Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.
- Published
- 2016
42. Effects of tracheal orientation on development of ventilator-associated pneumonia: an experimental study
- Author
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Myra Epp, Viktoria Hoffmann, Massimo Cressoni, Alberto Zanella, Mario Stylianou, Theodor Kolobow, Zanella, A, Cressoni, M, Epp, M, Hoffmann, V, Stylianou, M, and Kolobow, T
- Subjects
medicine.medical_specialty ,Swine ,medicine.medical_treatment ,Intratracheal/adverse effects Respiratory tract infections/ prevention and control Aspiration/prevention and control ,Critical Care and Intensive Care Medicine ,Tracheal tube ,Enteral administration ,Patient Positioning ,Statistics, Nonparametric ,Mechanical ventilation ,Nosocomial infection ,Intubation, Intratracheal ,medicine ,Animals ,Intubation ,Hemodynamic ,Pig ,Animal ,business.industry ,Respiration ,Pneumonia Ventilator-associated pneumonia Semirecumbent position ,Hemodynamics ,Ventilator-associated pneumonia ,Pneumonia, Ventilator-Associated ,Pulmonary ,respiratory system ,medicine.disease ,Respiration, Artificial ,respiratory tract diseases ,Surgery ,Trachea ,Pneumonia ,Intubation Postural drainage ,Respiratory failure ,Anesthesia ,Swine, Miniature ,Female ,Artificial/adverse effect ,Postural drainage ,business - Abstract
Purpose: Orientation of the trachea and tracheal tube below horizontal may prevent aspiration of oropharyngeal secretions into the lungs, which is a pivotal pathway in the pathogenesis of ventilator-associated pneumonia (VAP). The incidence of VAP was evaluated in swine with orientation of trachea and tracheal tube above horizontal (model of semirecumbent position, currently recommended in patients) and below horizontal. Methods: Twenty-six mini-pigs were randomized into four groups: (A) eight mechanically ventilated with orientation of trachea 45above horizontal for 72 h. In the remaining groups (B, C, D) the trachea was oriented 10below horizontal, with (B) six mechanically ventilated for 72 h, (C) six mechanically ventilated for 72 h with enteral feeding, and (D) six mechanically ventilated for 168 h with enteral feeding. At the end of the study period, all pigs were sacrificed and the clinical diagnosis of VAP was microbiologically evaluated. No antibiotics were administered. Results: All eight pigs kept orientated with the trachea 45above horizontal developed VAP and respiratory failure (PaO2/ FiO2 = 132 ± 139 mmHg) with a median of 5.5 pulmonary lobes out of 6 colonized with average colonization of 9.3 9 107 CFU/g. None of the 18 pigs kept oriented with the trachea below horizontal developed VAP; 16 had sterile lungs, while 2, ventilated for 7 days, developed a low level of colonization. Conclusions: Orientation of the trachea above horizontal was uniformly associated with VAP and respiratory failure; positioning the trachea below horizontal consistently prevented development of VAP.© Copyright jointly held by Springer and ESICM 2012.
- Published
- 2012
43. Abstract 16911: Behind the Looking Glass: Comparing Time to First Event versus Multiple Events Analyses in a Post-myocardial Infarction Clinical Trial
- Author
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Kerry L Lee, Rhonda S Roberts, Daniel B Mark, Hussein R Al-Khalidi, Robin Boineau, Yves Rosenberg, Mario Stylianou, and Gervasio A Lamas
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Standard analysis of clinical trials with composite endpoints compare time-to-first event. Subsequent events are not counted and therefore not taken into account in treatment comparisons. We compared standard analyses to analyses that take into account all the events a patient may have experienced. Methods: The Trial to Assess Chelation Therapy (TACT) enrolled 1708 post-MI pts in a factorial trial comparing edetate disodium infusions versus placebo infusions and oral vitamins and minerals versus oral placebo. TACT had a composite primary endpoint: death, MI, stroke, coronary revascularization, and hospitalization for angina. Pre-specified primary analysis for TACT was based on the standard approach of considering time until the occurrence of the first event. Two different approaches for multiple events analyses were compared to the standard approach: 1] a generalization of the Cox model to handle recurrent events, developed by Andersen & Gill (AG), and 2] a marginal modeling approach developed by Wie, Lin, and Weissfeld (WLW). Each considers the correlation among multiple events occurring within a pt. Results: There were 743 events in TACT. 483/1708 (28%) of the patients had at least 1 event. Time-to-first-event analysis did not use information on 260 (35%) events. The standard analysis for edetate disodium vs placebo produced a hazard ratio (HR) 0.82, 95% confidence intervals 0.69,0.99, p=0.035. Both multiple events analyses demonstrated narrower confidence intervals and lower P values. AG: HR 0.80 (0.66,0.96), p=0.017; and WLW: HR 0.79 (0.66, 0.95), p=0.010. In the comparison of the active edetate + active MVM vs placebo edetate + placebo MVM, there were 247/858 (29%) pts with at least 1 event, but there were 371 events. Therefore, 124 (33%) were not used. Results of the standard analysis for edetate + MVM showed HR 0.74 (0.57,0.95), p=0.016; for AG HR 0.66 (0.51,0.85),p=0.002, and for WLW HR 0.38 (0.30,0.49), p Conclusion: In this post-MI trial, a standard time to first event analysis did not make use of over 1/3 of events. Multiple events analysis can improve the precision of the estimate of benefit by producing narrower confidence intervals. These methods could be considered to reduce sample size and budgets in future clinical trials.
- Published
- 2015
44. ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis
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Jiro Kato, Martin J. Lizak, Jianfeng Zhu, Victoria Hoffmann, Connie G. Glasgow, Mario Stylianou, Chengyu Liu, and Joel Moss
- Subjects
Cancer Research ,Genotype ,Mutant ,Loss of Heterozygosity ,Mice, Nude ,Biology ,medicine.disease_cause ,Article ,Loss of heterozygosity ,Mice ,Hydrolase ,medicine ,Animals ,Genetic Predisposition to Disease ,Neoplasm Metastasis ,N-Glycosyl Hydrolases ,Tumor Stem Cell Assay ,Mice, Knockout ,chemistry.chemical_classification ,Adenosine Diphosphate Ribose ,Mice, Inbred BALB C ,Mutation ,Cell growth ,Cancer ,Neoplasms, Experimental ,medicine.disease ,Molecular biology ,Neoplasm Proteins ,Mice, Inbred C57BL ,Cell Transformation, Neoplastic ,Enzyme ,Oncology ,chemistry ,Cancer research ,Female ,Carcinogenesis ,Protein Processing, Post-Translational ,Cell Division - Abstract
Protein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP–ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose–protein bond. ARH1−/− cells or ARH1−/− cells overexpressing an inactive mutant ARH1 protein (ARH1−/−+dm) had higher proliferation rates than either wild-type ARH1+/+ cells or ARH1−/− cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1−/− and ARH1+/− mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1+/+ mice. In ARH1+/− mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression. Cancer Res; 71(15); 5327–35. ©2011 AACR.
- Published
- 2011
45. Effects of Prolactin on TSC2-Null Eker Rat Cells and in Pulmonary Lymphangioleiomyomatosis
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Kinnosuke Yahiro, Ameae M. Walker, Joel Moss, Jilly F. Evans, Wendy K. Steagall, Yasuhiro Terasaki, Gustavo Pacheco-Rodriguez, and Mario Stylianou
- Subjects
Lung Diseases ,Pulmonary and Respiratory Medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Blotting, Western ,Biology ,Critical Care and Intensive Care Medicine ,Prolactin cell ,Tuberous sclerosis ,Forced Expiratory Volume ,Intensive care ,Internal medicine ,Tuberous Sclerosis Complex 2 Protein ,F. Interstitial Lung Disease ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Lymphangioleiomyomatosis ,Cell Proliferation ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Suppressor Proteins ,Pneumothorax ,Muscle, Smooth ,Rats, Inbred Strains ,medicine.disease ,Prolactin ,Rats ,Endocrinology ,medicine.anatomical_structure ,Female ,TSC1 ,TSC2 ,Signal Transduction ,Hormone - Abstract
Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues.To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis.Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro.Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo.Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.
- Published
- 2010
46. Cost-effectiveness of lower targets for blood pressure and low-density lipoprotein cholesterol in diabetes: The Stop Atherosclerosis in Native Diabetics Study (SANDS)
- Author
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Heather Huentelman, Barbara V. Howard, Marie Russell, Robert E. Ratner, Charlton Wilson, Mihriye Mete, Jerome L. Fleg, James M. Galloway, Elisa T. Lee, Fawn Yeh, Matthew R. Weir, Nawar Shara, Mario Stylianou, Angela Silverman, Jeffrey A. Henderson, Chun Chih Huang, Wm. James Howard, and Jason G. Umans
- Subjects
Adult ,Male ,medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,Endocrinology, Diabetes and Metabolism ,Blood Pressure ,Type 2 diabetes ,Article ,Diabetes Complications ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Antihypertensive Agents ,health care economics and organizations ,Aged ,Hypolipidemic Agents ,Nutrition and Dietetics ,business.industry ,Standard treatment ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,United States ,Quality-adjusted life year ,Clinical trial ,Blood pressure ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Indians, North American ,Physical therapy ,Female ,Quality-Adjusted Life Years ,Cardiology and Cardiovascular Medicine ,business ,Medicaid - Abstract
Background The Stop Atherosclerosis in Native Diabetics Study (SANDS) reported cardiovascular benefit of aggressive versus standard treatment targets for both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) in diabetic individuals. Objective In this analysis, we examined within trial cost-effectiveness of aggressive targets of LDL-C ≤70 mg/dL and systolic BP ≤115 mmHg versus standard targets of LDL-C ≤100 mg/dL and systolic BP ≤130 mmHg. Design Randomized, open label blinded-to-endpoint 3-year trial. Data Sources SANDS clinical trial database, Quality of Wellbeing survey, Centers for Medicare and Medicaid Services, Wholesale Drug Prices. Target Population American Indians ≥age 40 years with type 2 diabetes and no previous cardiovascular events. Time Horizon April 2003 to July 2007. Perspective Health payer. Interventions Participants were randomized to aggressive versus standard groups with treatment algorithms defined for both. Outcome Measures Incremental cost-effectiveness. Results of Base-Case Analysis Compared with the standard group, the aggressive group had slightly lower costs of medical services (−$116) but a 54% greater cost for BP medication ($1,242) and a 116% greater cost for lipid-lowering medication ($2,863), resulting in an increased cost of $3,988 over 3 years. Those in the aggressively treated group gained 0.0480 quality-adjusted life-years (QALY) over the standard group. When a 3% discount rate for costs and outcomes was used, the resulting cost per QALY was $82,589. Results of Sensitivity Analysis The use of a 25%, 50%, and 75% reduction in drug costs resulted in a cost per QALY of $61,329, $40,070, and $18,810, respectively. Limitations This study was limited by use of a single ethnic group and by its 3-year duration. Conclusions Within this 3-year study, treatment to lower BP and LDL-C below standard targets was not cost-effective because of the cost of the additional medications required to meet the lower targets. With the anticipated availability of generic versions of the BP and lipid-lowering drugs used in SANDS, the cost-effectiveness of this intervention should improve.
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- 2010
47. Rates of change in FEV1 and DLCO as potential indicators for mTOR inhibitor therapy in premenopausal lymphangioleiomyomatosis patients
- Author
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Patricia Julien-Williams, Angelo M. Taveira-DaSilva, Amanda M. Jones, Joel Moss, and Mario Stylianou
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Disease progression ,Urology ,Delayed treatment ,medicine.disease ,Discovery and development of mTOR inhibitors ,Confidence interval ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,DLCO ,Diffusing capacity ,Lymphangioleiomyomatosis ,Medicine ,030212 general & internal medicine ,Young adult ,business - Abstract
The value of rates of change in forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated.In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV1 and DLCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV1 and DLCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV1 or DLCO ≤70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.27 and 35 patients who experienced greater than expected rates of change in FEV1 and DLCO, respectively, would have been excluded from therapy based on an FEV1 or DLCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV1 or DLCO were ≤70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years.Premenopausal females in whom FEV1 or DLCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV1 or DLCO falls to ≤70% pred.
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- 2018
48. Reversible Airflow Obstruction in Lymphangioleiomyomatosis
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Wendy K. Steagall, Roberto Cassandro, Angelo M. Taveira-DaSilva, Joel Moss, Olanda Hathaway, Sergio Harari, Antoinette Rabel, and Mario Stylianou
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Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.drug_class ,Vital Capacity ,Critical Care and Intensive Care Medicine ,Cholinergic Antagonists ,White People ,Pulmonary function testing ,FEV1/FVC ratio ,immune system diseases ,Internal medicine ,Forced Expiratory Volume ,Diffusing capacity ,Bronchodilator ,Humans ,Medicine ,Albuterol ,Lymphangioleiomyomatosis ,Prospective cohort study ,Original Research ,Aged ,Retrospective Studies ,Asthma ,Aged, 80 and over ,Asian ,business.industry ,Ipratropium ,Hispanic or Latino ,Adrenergic beta-Agonists ,Middle Aged ,medicine.disease ,Bronchodilator Agents ,respiratory tract diseases ,Black or African American ,Treatment Outcome ,Anesthesia ,Cardiology ,Pulmonary Ventilation ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background We previously reported that approximately one-fourth of patients with lymphangioleiomyomatosis (LAM) may respond to therapy with bronchodilators. However, the validity of those observations has been questioned. The aims of the present study were to determine the prevalence of reversible airflow obstruction in patients with LAM and to identify associated clinical and physiologic parameters. Methods First, the clinical and physiologic characteristics of 235 patients were analyzed to determine the frequency of the response to albuterol during a total of 2,307 visits. Second, we prospectively evaluated the response to albuterol (2.5 mg) and ipratropium (500 μg) in 130 patients, and correlated their responses with their clinical and physiologic characteristics. Results In the retrospective study, 51% of the patients responded at least once to bronchodilators; of these, 12% responded ≥ 50% of the time. A higher frequency of positive bronchodilator responses was associated with greater rates of decline in FEV1 and diffusing capacity of the lung for carbon monoxide (D lco ). In the prospective study, 39 patients (30%) responded to bronchodilators, including 12 to ipratropium, 9 to albuterol, and 18 to both. The prevalence of asthma and smoking in the 39 responders was not different from that seen in the 91 nonresponders. Patients who responded to ipratropium, albuterol, or both had significantly (p lco, and a greater rate of FEV1 decline (p = 0.044) and D lco decline (p = 0.039) than patients who did not respond to these bronchodilators. After adjusting for FEV1/FVC ratio, D lco decline also was greater in responders than in nonresponders (p = 0.009). Conclusions Patients with LAM may have partially reversible airflow obstruction. A positive response to bronchodilators is associated with an accelerated rate of decline in pulmonary function.
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- 2009
49. Derivation of Exact Distributions Following an Up-and-Down Design
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Mario Stylianou
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Statistics and Probability ,Exact statistics ,Approximation theory ,Sequential analysis ,Sample size determination ,Phase (waves) ,Calculus ,Survey sampling ,Applied mathematics ,Probability distribution ,Confidence interval ,Mathematics - Abstract
Use of large sample theory in sequential designs, such as the up-and-down designs, to estimate parameters of interest may not be appropriate when the sample size is small, as is the case with many phase I clinical trials. In these situations, it may be desirable to derive the exact distribution of various statistics of interest. Having the exact distribution will enable us to calculate exact probabilities, moments or confidence intervals. We show how one can derive these exact distributions by enumerating all possible outcomes. We also derive a formula to obtain the total number of all possible treatment outcomes using the biased up-and-down design. These results will enable the experimenter to plan a phase I study with more confidence.
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- 2009
50. Cumulative effects and threshold levels in air pollution mortality: Data analysis of nine large US cities using the NMMAPS dataset
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Mario Stylianou and Mark J. Nicolich
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Pollution ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Air pollution ,Toxicology ,Urban area ,medicine.disease_cause ,Risk Assessment ,Environmental protection ,Air Pollution ,Statistics ,medicine ,Cities ,Mortality ,media_common ,Air Pollutants ,geography ,geography.geographical_feature_category ,Homogeneity (statistics) ,Cumulative effects ,General Medicine ,United States ,Risk Estimate ,Relative risk ,Epidemiological Monitoring ,Environmental science ,Risk assessment ,Environmental Monitoring - Abstract
We examined the existence of thresholds, cumulative effects and the homogeneity of five air pollutants on the relative risk of three mortality outcomes using data from nine major US cities using data from NMMAPS. Overall, PM 10 (usually 200-day accumulation) and ozone (3-day accumulation) were the two important predictors of outcome but their effect was not uniform across the nine cities. Many models exhibited thresholds (25–45 μm g/m 3 for PM 10 , and 10–45 ppb for O 3 ). Our preliminary exploratory analyses suggest that the use of a linear, no threshold, model for pollution studies is not consistent with the observed data. The heterogeneity in the risk estimates across the nine cities suggests combining the local risk estimates to obtain a national risk estimate may not be justifiable and the estimate is likely to be confounded.
- Published
- 2009
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