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2. Metabolomic Profiles Differentiate Scleroderma-PAH From Idiopathic PAH and Correspond With Worsened Functional Capacity

Author

Alotaibi, Mona, Shao, Junzhe, Pauciulo, Michael W, Nichols, William C, Hemnes, Anna R, Malhotra, Atul, Kim, Nick H, Yuan, Jason X-J, Fernandes, Timothy, Kerr, Kim M, Alshawabkeh, Laith, Desai, Ankit A, Bujor, Andreea M, Lafyatis, Robert, Watrous, Jeramie D, Long, Tao, Cheng, Susan, Chan, Stephen Y, and Jain, Mohit

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Women's Health, Scleroderma, Health Disparities, Orphan Drug, Rare Diseases, Lung, Autoimmune Disease, Clinical Research, Inflammatory and immune system, Humans, Familial Primary Pulmonary Hypertension, Hypertension, Pulmonary, Scleroderma, Systemic, Prognosis, Lipids, biomarkers, metabolomics, pulmonary hypertension, scleroderma, Clinical Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundThe prognosis and therapeutic responses are worse for pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) compared with idiopathic pulmonary arterial hypertension (IPAH). This discrepancy could be driven by divergence in underlying metabolic determinants of disease.Research questionAre circulating bioactive metabolites differentially altered in SSc-PAH vs IPAH, and can this alteration explain clinical disparity between these PAH subgroups?Study design and methodsPlasma biosamples from 400 patients with SSc-PAH and 1,082 patients with IPAH were included in the study. Another cohort of 100 patients with scleroderma with no PH and 44 patients with scleroderma with PH was included for external validation. More than 700 bioactive lipid metabolites, representing a range of vasoactive and immune-inflammatory pathways, were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography/high-resolution mass spectrometry-based approaches. Regression analyses were used to identify metabolites that exhibited differential levels between SSc-PAH and IPAH and associated with disease severity.ResultsFrom hundreds of circulating bioactive lipid molecules, five metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with markers of disease severity. Relative to IPAH, patients with SSc-PAH carried increased levels of fatty acid metabolites, including lignoceric acid and nervonic acid, as well as eicosanoids/oxylipins and sex hormone metabolites.InterpretationPatients with SSc-PAH are characterized by an unfavorable bioactive metabolic profile that may explain the poor and limited response to therapy. These data provide important metabolic insights into the molecular heterogeneity underlying differences between subgroups of PAH.

Published
2023

5. Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension

Author

Hong, Jason, Medzikovic, Lejla, Sun, Wasila, Wong, Brenda, Ruffenach, Grégoire, Rhodes, Christopher J., Brownstein, Adam, Liang, Lloyd L., Aryan, Laila, Li, Min, Vadgama, Arjun, Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A., Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A., Pauciulo, Michael W., Trembath, Richard C., Perros, Frédéric, Montani, David, Morrell, Nicholas W., Soubrier, Florent, Wilkins, Martin R., Nichols, William C., Aldred, Micheala A., Desai, Ankit A., Trégouët, David-Alexandre, Umar, Soban, Saggar, Rajan, Channick, Richard, Tuder, Rubin M., Geraci, Mark W., Stearman, Robert S., Yang, Xia, and Eghbali, Mansoureh

Published
2024
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6. Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension

Author

Tang, Haiyang, Gupta, Akash, Morrisroe, Seth A., Bao, Changlei, Schwantes-An, Tae-Hwi, Gupta, Geetanjali, Liang, Shuxin, Sun, Yanan, Chu, Aiai, Luo, Ang, Ramamoorthi Elangovan, Venkateswaran, Sangam, Shreya, Shi, Yinan, Naidu, Samisubbu R., Jheng, Jia-Rong, Ciftci-Yilmaz, Sultan, Warfel, Noel A., Hecker, Louise, Mitra, Sumegha, Coleman, Anna W., Lutz, Katie A., Pauciulo, Michael W., Lai, Yen-Chun, Javaheri, Ali, Dharmakumar, Rohan, Wu, Wen-Hui, Flaherty, Daniel P., Karnes, Jason H., Breuils-Bonnet, Sandra, Boucherat, Olivier, Bonnet, Sebastien, Yuan, Jason X.-J., Jacobson, Jeffrey R., Duarte, Julio D., Nichols, William C., Garcia, Joe G.N., and Desai, Ankit A.

Published
2024
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8. Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

Author

Callejo, Emily P., Day, Kristina M., Macaya, Daniela, Maldonado-Velez, Gabriel, Archer, Stephen L., Auckland, Kathryn, Austin, Eric D., Badagliacca, Roberto, Barberà, Joan-Albert, Belge, Catharina, Bogaard, Harm Jan, Bonnet, Sébastien, Boomars, Karin A., Boucherat, Olivier, Chakinala, Murali M., Condliffe, Robin, Damico, Rachel Lynn, Delcroix, Marion, Desai, Ankit A., Doboszynska, Anna, Elliott, C. Greg, Eyries, Melanie, Escribano Subías, Maria Pilar, Gall, Henning, Ghio, Stefano, Ghofrani, Ardeschir-Hossein, Grünig, Ekkehard, Hamid, Rizwan, Harbaum, Lars, Hassoun, Paul M., Hemnes, Anna R., Hinderhofer, Katrin, Howard, Luke S., Humbert, Marc, Kiely, David G., Langleben, David, Lawrie, Allan, Loyd, Jim E., Moledina, Shahin, Montani, David, Morrell, Nichols W., Nichols, William C., Olschewski, Andrea, Olschewski, Horst, Papa, Silvia, Pauciulo, Mike W., Provencher, Steve, Quarck, Rozenn, Rhodes, Christopher J., Scelsi, Laura, Seeger, Werner, Stewart, Duncan J., Sweatt, Andrew, Swietlik, Emilia M., Treacy, Carmen, Trembath, Richard C., Tura-Ceide, Olga, Vizza, Carmine Dario, Vonk Noordegraaf, Anton, Wilkins, Martin R., Zamanian, Roham T., Zateyshchikov, Dmitry, Welch, Carrie L., Aldred, Micheala A., Balachandar, Srimmitha, Dooijes, Dennis, Eichstaedt, Christina A., Gräf, Stefan, Houweling, Arjan C., Machado, Rajiv D., Pandya, Divya, Prapa, Matina, Shaukat, Memoona, Southgate, Laura, Tenorio-Castano, Jair, and Chung, Wendy K.

Published
2023
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9. Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension

Author

Karnes, Jason H, Wiener, Howard W, Schwantes-An, Tae-Hwi, Natarajan, Balaji, Sweatt, Andrew J, Chaturvedi, Abhishek, Arora, Amit, Batai, Ken, Nair, Vineet, Steiner, Heidi E, Giles, Jason B, Yu, Jeffrey, Hosseini, Maryam, Pauciulo, Michael W, Lutz, Katie A, Coleman, Anna W, Feldman, Jeremy, Vanderpool, Rebecca, Tang, Haiyang, Garcia, Joe GN, Yuan, Jason X-J, Kittles, Rick, de Jesus Perez, Vinicio, Zamanian, Roham T, Rischard, Franz, Tiwari, Hemant K, Nichols, William C, Benza, Raymond L, and Desai, Ankit A

Subjects
Lung, Good Health and Well Being, Adult, Black or African American, Aged, Female, Hispanic or Latino, Humans, Male, Middle Aged, Pulmonary Arterial Hypertension, Survival Rate, United States, White People, pulmonary arterial hypertension, Hispanic American, Native American, survival, health disparities, Medical and Health Sciences, Respiratory System
Abstract

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

Published
2020

10. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Author

Zhu, Na, Pauciulo, Michael W, Welch, Carrie L, Lutz, Katie A, Coleman, Anna W, Gonzaga-Jauregui, Claudia, Wang, Jiayao, Grimes, Joseph M, Martin, Lisa J, He, Hua, Shen, Yufeng, Chung, Wendy K, and Nichols, William C

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Lung, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Adult, Age of Onset, Aged, Biomarkers, Exome, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hemodynamics, Humans, Male, Middle Aged, Pulmonary Arterial Hypertension, Exome Sequencing, Pulmonary arterial hypertension, Exome sequencing, Case-control association testing, PAH Biobank Enrolling Centers’ Investigators, Clinical Sciences
Abstract

BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.MethodsTo identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.ResultsTissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.ConclusionsWe report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.

Published
2019

14. United States Pulmonary Hypertension Scientific Registry: Baseline Characteristics

Author

Simms, Robert, Fortin, Terry, Safdar, Zeenat, Burger, Charles D., Frantz, Robert P., Hill, Nicholas S., Airhart, Sophia, Elwing, Jean, Simon, Marc, White, R. James, Robbins, Ivan M., Chakinala, Murali M., Badlam, Jessica B., Badesch, David B., Austin, Eric D., Benza, Raymond L., Chung, Wendy K., Farber, Harrison W., Feldkircher, Kathy, Frost, Adaani E., Poms, Abby D., Lutz, Katie A., Pauciulo, Michael W., Yu, Chang, Nichols, William C., and Elliott, C. Gregory

Published
2021
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17. Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

Author

Harvey, Lloyd D, primary, Alotaibi, Mona, additional, Kim, Hee-Jung Janice, additional, Tai, Yi-Yin, additional, Tang, Ying, additional, Sun, Wei, additional, El Khoury, Wadih, additional, Woodcock, Chen-Shan C, additional, Aaraj, Yassmin Al, additional, St. Croix, Claudette M, additional, Stolz, Donna B, additional, Lee, Jiyoung, additional, Cheng, Mary Hongying, additional, Schwantes-An, Tae-Hwi, additional, Desai, Ankit A, additional, Pauciulo, Michael W, additional, Nichols, William C, additional, Webb, Amy, additional, Lafyatis, Robert, additional, Nouraie, Mehdi, additional, Wu, Haodi, additional, McDonald, Jeffrey G, additional, Chauvet, Caroline, additional, Cheng, Susan, additional, Bahar, Ivet, additional, Bertero, Thomas, additional, Benza, Raymond L, additional, Jain, Mohit, additional, and Chan, Stephen Y, additional

Published
2024
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18. Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival

Author

Griffiths, Megan, Yang, Jun, Nies, Melanie, Vaidya, Dhananjay, Brandal, Stephanie, Williams, Monica, Matsui, Elizabeth C., Grant, Torie, Damico, Rachel, Ivy, Dunbar, Austin, Eric D., Nichols, William C., Pauciulo, Michael W., Lutz, Katie, Rosenzweig, Erika B., Hirsch, Russel, Yung, Delphine, and Everett, Allen D.

Published
2020
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19. The relationship between obsessive‐compulsive symptoms and PARKIN genotype: The CORE‐PD study

Author

Sharp, Madeleine E, Caccappolo, Elise, Mejia‐Santana, Helen, Tang, Ming‐X, Rosado, Llency, Reilly, Martha Orbe, Ruiz, Diana, Louis, Elan D, Comella, Cynthia, Nance, Martha, Bressman, Susan, Scott, William K, Tanner, Caroline, Waters, Cheryl, Fahn, Stanley, Cote, Lucien, Ford, Blair, Rezak, Michael, Novak, Kevin, Friedman, Joseph H, Pfeiffer, Ronald, Payami, Haydeh, Molho, Eric, Factor, Stuart A, Nutt, John, Serrano, Carmen, Arroyo, Maritza, Pauciulo, Michael W, Nichols, William C, Clark, Lorraine N, Alcalay, Roy N, and Marder, Karen S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Disorders, Parkinson's Disease, Neurodegenerative, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Age of Onset, Aged, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Heterozygote, Humans, Male, Middle Aged, Mutation, Obsessive-Compulsive Disorder, Parkinson Disease, Ubiquitin-Protein Ligases, Parkinson's, neuropsychological, obsessive-compulsive, parkin, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundFew studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).MethodsThe Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.ResultsAmong patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).ConclusionsFirst, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Published
2015

20. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe G N, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Gräf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas W, and Wilkins, Martin R

Published
2019
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21. Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension

Author

Tai, Yi-Yin, primary, Yu, Qiujun, additional, Tang, Ying, additional, Sun, Wei, additional, Kelly, Neil J., additional, Okawa, Satoshi, additional, Zhao, Jingsi, additional, Schwantes-An, Tae-Hwi, additional, Lacoux, Caroline, additional, Torrino, Stephanie, additional, Al Aaraj, Yassmin, additional, El Khoury, Wadih, additional, Negi, Vinny, additional, Liu, Mingjun, additional, Corey, Catherine G., additional, Belmonte, Frances, additional, Vargas, Sara O., additional, Schwartz, Brian, additional, Bhat, Bal, additional, Chau, B. Nelson, additional, Karnes, Jason H., additional, Satoh, Taijyu, additional, Barndt, Robert J., additional, Wu, Haodi, additional, Parikh, Victoria N., additional, Wang, Jianrong, additional, Zhang, Yingze, additional, McNamara, Dennis, additional, Li, Gang, additional, Speyer, Gil, additional, Wang, Bing, additional, Shiva, Sruti, additional, Kaufman, Brett, additional, Kim, Seungchan, additional, Gomez, Delphine, additional, Mari, Bernard, additional, Cho, Michael H., additional, Boueiz, Adel, additional, Pauciulo, Michael W., additional, Southgate, Laura, additional, Trembath, Richard C., additional, Sitbon, Olivier, additional, Humbert, Marc, additional, Graf, Stefan, additional, Morrell, Nicholas W., additional, Rhodes, Christopher J., additional, Wilkins, Martin R., additional, Nouraie, Mehdi, additional, Nichols, William C., additional, Desai, Ankit A., additional, Bertero, Thomas, additional, and Chan, Stephen Y., additional

Published
2024
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23. Cognitive and Motor Function in Long-Duration PARKIN-Associated Parkinson Disease

Author

Alcalay, Roy N, Caccappolo, Elise, Mejia-Santana, Helen, Tang, Ming Xin, Rosado, Llency, Reilly, Martha Orbe, Ruiz, Diana, Louis, Elan D, Comella, Cynthia L, Nance, Martha A, Bressman, Susan B, Scott, William K, Tanner, Caroline M, Mickel, Susan F, Waters, Cheryl H, Fahn, Stanley, Cote, Lucien J, Frucht, Steven J, Ford, Blair, Rezak, Michael, Novak, Kevin E, Friedman, Joseph H, Pfeiffer, Ronald F, Marsh, Laura, Hiner, Bradley, Payami, Haydeh, Molho, Eric, Factor, Stewart A, Nutt, John G, Serrano, Carmen, Arroyo, Maritza, Ottman, Ruth, Pauciulo, Michael W, Nichols, William C, Clark, Lorraine N, and Marder, Karen S

Subjects
Acquired Cognitive Impairment, Brain Disorders, Neurosciences, Parkinson's Disease, Dementia, Clinical Research, Neurodegenerative, Aging, Mental Health, Genetics, Neurological, Age of Onset, Aged, Cognition Disorders, Cross-Sectional Studies, Disease Progression, Female, Heterozygote, Humans, Male, Middle Aged, Motor Skills Disorders, Parkinson Disease, Ubiquitin-Protein Ligases, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceData on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients.ObjectiveAmong patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers.Design, setting, and participantsCross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers.Main outcomes and measuresUnified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.ResultsCarriers had an earlier age at onset of PD (P

Published
2014

25. Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

Author

Potus, François, Pauciulo, Michael W., Cook, Elina K., Zhu, Na, Hsieh, Alexander, Welch, Carrie L., Shen, Yufeng, Tian, Lian, Lima, Patricia, Mewburn, Jeffrey, D’Arsigny, Christine L., Lutz, Katie A., Coleman, Anna W., Damico, Rachel, Snetsinger, Brooke, Martin, Ashley Y., Hassoun, Paul M., Nichols, William C., Chung, Wendy K., Rauh, Michael J., and Archer, Stephen L.

Published
2020
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29. SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics

Author

Sangam, Shreya, primary, Sun, Xutong, additional, Schwantes-An, Tae-Hwi, additional, Yegambaram, Manivannan, additional, Lu, Qing, additional, Shi, Yinan, additional, Cook, Todd, additional, Fisher, Amanda, additional, Frump, Andrea L., additional, Coleman, Anna, additional, Sun, Yanan, additional, Liang, Shuxin, additional, Crawford, Howard, additional, Lutz, Katie A., additional, Maun, Avinash D., additional, Pauciulo, Michael W., additional, Karnes, Jason H., additional, Chaudhary, Ketul R., additional, Stewart, Duncan J., additional, Langlais, Paul R., additional, Jain, Mohit, additional, Alotaibi, Mona, additional, Lahm, Tim, additional, Jin, Yan, additional, Gu, Haiwei, additional, Tang, Haiyang, additional, Nichols, William C., additional, Black, Stephen M., additional, and Desai, Ankit A., additional

Published
2023
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30. RASA3 is a Candidate Gene in Sickle Cell Disease‐Associated Pulmonary Hypertension and Pulmonary Arterial Hypertension

Author

Prohaska, Clare C., primary, Zhang, Xu, additional, Schwantes‐An, Tae‐Hwi L., additional, Stearman, Robert S., additional, Hooker, Stanley, additional, Kittles, Rick A., additional, Aldred, Micheala A., additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Nichols, William C., additional, Desai, Ankit A., additional, Gordeuk, Victor R., additional, and Machado, Roberto F., additional

Published
2023
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31. Insulin‐like growth factor binding Protein‐4: A novel indicator of pulmonary arterial hypertension severity and survival

Author

Torres, Guillermo, primary, Yang, Jun, additional, Griffiths, Megan, additional, Brandal, Stephanie, additional, Damico, Rachel, additional, Vaidya, Dhananjay, additional, Simpson, Catherine E., additional, Pauciulo, Michael W., additional, Nichols, William C., additional, Ivy, David D., additional, Austin, Eric D., additional, Hassoun, Paul M., additional, and Everett, Allen D., additional

Published
2023
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33. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, Wong, Brenda, Rhodes, Christopher J., Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A., Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A., Pauciulo, Michael W., Trembath, Richard C., Montani, David, Morrell, Nicholas W., Wilkins, Martin R., Nichols, William C., Trégouët, David-Alexandre, Aldred, Micheala A., Desai, Ankit A., Tuder, Rubin M., Geraci, Mark W., Eghbali, Mansoureh, Stearman, Robert S., and Yang, Xia

Subjects
Article
Abstract

Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.

Published
2023
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34. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, primary, Wong, Brenda, additional, Rhodes, Christopher J., additional, Kurt, Zeyneb, additional, Schwantes-An, Tae-Hwi, additional, Mickler, Elizabeth A., additional, Gräf, Stefan, additional, Eyries, Mélanie, additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Trembath, Richard C., additional, Montani, David, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Nichols, William C., additional, Trégouët, David-Alexandre, additional, Aldred, Micheala A., additional, Desai, Ankit A., additional, Tuder, Rubin M., additional, Geraci, Mark W., additional, Eghbali, Mansoureh, additional, Stearman, Robert S., additional, and Yang, Xia, additional

Published
2023
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36. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Author

Zhu, Na, Welch, Carrie L., Wang, Jiayao, Allen, Philip M., Gonzaga-Jauregui, Claudia, Ma, Lijiang, King, Alejandra K., Krishnan, Usha, Rosenzweig, Erika B., Ivy, D. Dunbar, Austin, Eric D., Hamid, Rizwan, Pauciulo, Michael W., Lutz, Katie A., Nichols, William C., Reid, Jeffrey G., Overton, John D., Baras, Aris, Dewey, Frederick E., Shen, Yufeng, and Chung, Wendy K.

Published
2018
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37. The Doctoral Education of Professional Marriage and Family Therapists

Author

Lee, Robert E., III and Nichols, William C.

Abstract

The professional practice of marriage and family therapy (MFT) scholarship is regulated at the master's level in the United States. Consequently, contemporary curricular issues have largely been focused on what is to be achieved within the master's degree, with an emphasis on clinical practice. We consider here what value may and should be added through the doctoral degree in marriage and family therapy. Doctoral programs are the developmental stage wherein we should seek to transmit the specialized knowledge and skills germane to MFT scholarship and practice in diverse settings, e.g., clinical and research intensive university, family law, health care, child development and education, child welfare, juvenile justice, faith based, and business. However, underlying this specialty education are three transcendental goals: sophistication of family systems scholarship, socialization into the profession of MFT, and cultivation of professional maturity.

Published
2010
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38. Low‐affinity insulin‐like growth factor binding protein 7 and its association with pulmonary arterial hypertension severity and survival.

Author

Torres, Guillermo, Lancaster, Andrew C., Yang, Jun, Griffiths, Megan, Brandal, Stephanie, Damico, Rachel, Vaidya, Dhananjay, Simpson, Catherine E., Martin, Lisa J., Pauciulo, Michael W., Nichols, William C., Ivy, David D., Austin, Eric D., Hassoun, Paul M., and Everett, Allen D.

Abstract

Insulin‐like growth factor (IGF) binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with pulmonary arterial hypertension (PAH) survival. IGF factor binding protein 7 (IGFBP7) is a unique low‐affinity IGFBP that, independent of IGF, stimulates prostacyclin production. This study proposed to establish associations between IGFBP7 and PAH severity and survival, using enrollment and longitudinal samples. Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjusting for age and sex, logarithmic increases in IGFBP7 were associated with a 20 m shorter six‐minute walk distance (6MWD; p < 0.001), a 2−3 mmHg higher mean right atrial pressure (p < 0.001 and 0.02), and a higher likelihood of a greater REVEAL 2.0 risk category placement (p < 0.001). Kaplan−Meier analysis demonstrated significantly decreased survival with IGFBP7 above the median and Cox multivariable analysis adjusted for age and sex, demonstrated higher serum IGFBP7 was an independent predictor of survival. Though the exact mechanism is still unknown, given IGFBP7's role as a prostacyclin stimulant, it has potential use as a therapeutic target for disease modulation. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Trends in Family Therapy Supervision: The Past 25 Years and into the Future

Author

Lee, Robert E., Nichols, David P., and Nichols, William C.

Abstract

This investigation repeats a survey of American Association for Marriage and Family Therapy (AAMFT) Approved Supervisors done in 1976 and 1986. Despite negative contemporary contextual influences, the AAMFT Approved Supervisor credential is still attractive to the same percentage of the AAMFT clinical membership as formerly and reflects in general the demographic characteristics of marriage and family therapists (MFTs) in clinical practice. Across the last quarter century there has been a steady increase in female AAMFT Approved Supervisors and those with terminal master's degrees. These and other trends are discussed with a view toward what supervision is becoming and what it needs to become.

Published
2004
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40. Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension

Author

Harbaum, Lars, primary, Rhodes, Christopher J., additional, Wharton, John, additional, Lawrie, Allan, additional, Karnes, Jason H., additional, Desai, Ankit A., additional, Nichols, William C., additional, Humbert, Marc, additional, Montani, David, additional, Girerd, Barbara, additional, Sitbon, Olivier, additional, Boehm, Mario, additional, Novoyatleva, Tatyana, additional, Schermuly, Ralph T., additional, Ghofrani, H. Ardeschir, additional, Toshner, Mark, additional, Kiely, David G., additional, Howard, Luke S., additional, Swietlik, Emilia M., additional, Gräf, Stefan, additional, Pietzner, Maik, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Southgate, L, additional, Machado, RD, additional, Martin, J, additional, Ouwehand, WH, additional, Pauciulo, MW, additional, Arora, A, additional, Lutz, K, additional, Ahmad, F, additional, Archer, SL, additional, Argula, R, additional, Austin, ED, additional, Badesch, D, additional, Bakshi, S, additional, Barnett, C, additional, Benza, R, additional, Bhatt, N, additional, Burger, CD, additional, Chakinala, M, additional, Elwing, J, additional, Fortin, T, additional, Frantz, RP, additional, Frost, A, additional, Garcia, JGN, additional, Harley, J, additional, He, H, additional, Hill, NS, additional, Hirsch, R, additional, Ivy, D, additional, Klinger, J, additional, Lahm, T, additional, Marsolo, K, additional, Martin, LJ, additional, Nathan, SD, additional, Oudiz, RJ, additional, Rehman, Z, additional, Robbins, I, additional, Roden, DM, additional, Rosenzweig, EB, additional, Saydain, G, additional, Schilz, R, additional, Simms, RW, additional, Simon, M, additional, Tang, H, additional, Tchourbanov, AY, additional, Thenappan, T, additional, Torres, F, additional, Walsworth, AK, additional, Walter, RE, additional, White, RJ, additional, Wilt, J, additional, Yung, D, additional, Kittles, R, additional, Aman, J, additional, Knight, J, additional, Hanscombe, KB, additional, Gall, H, additional, Ulrich, A, additional, Bogaard, HJ, additional, Church, C, additional, Coghlan, JG, additional, Condliffe, R, additional, Corris, PA, additional, Danesino, C, additional, Elliott, CG, additional, Franke, A, additional, Ghio, S, additional, Gibbs, JSR, additional, Houweling, AC, additional, Kovacs, G, additional, Laudes, M, additional, MacKenzie Ross, RV, additional, Moledina, S, additional, Newnham, M, additional, Olschewski, A, additional, Olschewski, H, additional, Peacock, AJ, additional, Pepke-Zaba, J, additional, Scelsi, L, additional, Seeger, W, additional, Shaffer, CM, additional, Sitbon, O, additional, Suntharalingam, J, additional, Treacy, C, additional, Vonk Noordegraaf, A, additional, Waisfisz, Q, additional, Wort, SJ, additional, Trembath, RC, additional, Germain, M, additional, Cebola, I, additional, Ferrer, J, additional, Amouyel, P, additional, Debette, S, additional, Eyries, M, additional, Soubrier, F, additional, and Trégouët, DA, additional

Published
2022
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41. Family Systems Therapy

Author

Nichols, William C., Roberts, Michael C., editor, Peterson, Lizette, editor, Russ, Sandra W., editor, and Ollendick, Thomas H., editor

Published
1999
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42. Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH

Author

Toshner, Mark, Church, Colin, Harbaum, Lars, Rhodes, Christopher, Villar Moreschi, Sofia S, Liley, James, Jones, Rowena, Arora, Amit, Batai, Ken, Desai, Ankit A, Coghlan, John G, Gibbs, J Simon R, Gor, Dee, Gräf, Stefan, Harlow, Louise, Hernandez-Sanchez, Jules, Howard, Luke S, Humbert, Marc, Karnes, Jason, Kiely, David G, Kittles, Rick, Knightbridge, Emily, Lam, Brian, Lutz, Katie A, Nichols, William C, Pauciulo, Michael W, Pepke-Zaba, Joanna, Suntharalingam, Jay, Soubrier, Florent, Trembath, Richard C, Schwantes-An, Tae-Hwi L, Wort, S John, Wilkins, Martin, Gaine, Sean, Morrell, Nicholas W, Corris, Paul A, Toshner, Mark [0000-0002-3969-6143], Villar, Sofia [0000-0001-7755-2637], Jones, Rowena [0000-0002-4551-2320], Graf, Stefan [0000-0002-1315-8873], Lam, Brian [0000-0002-3638-9025], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, and British Heart Foundation

Subjects
Adult, Male, Pulmonary Arterial Hypertension, Biomedical Research, Interleukin-6, Respiratory System, Uniphy Clinical Trials Network, Middle Aged, Treatment Outcome, Humans, Familial Primary Pulmonary Hypertension, Female, 11 Medical and Health Sciences, Aged
Abstract

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg-1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Published
2022
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43. Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

Author

Chartier-Harlin, Marie-Christine, Dachsel, Justus C., Vilariño-Güell, Carles, Lincoln, Sarah J., Leprêtre, Frédéric, Hulihan, Mary M., Kachergus, Jennifer, Milnerwood, Austen J., Tapia, Lucia, Song, Mee-Sook, Le Rhun, Emilie, Mutez, Eugénie, Larvor, Lydie, Duflot, Aurélie, Vanbesien-Mailliot, Christel, Kreisler, Alexandre, Ross, Owen A., Nishioka, Kenya, Soto-Ortolaza, Alexandra I., Cobb, Stephanie A., Melrose, Heather L., Behrouz, Bahareh, Keeling, Brett H., Bacon, Justin A., Hentati, Emna, Williams, Lindsey, Yanagiya, Akiko, Sonenberg, Nahum, Lockhart, Paul J., Zubair, Abba C., Uitti, Ryan J., Aasly, Jan O., Krygowska-Wajs, Anna, Opala, Grzegorz, Wszolek, Zbigniew K., Frigerio, Roberta, Maraganore, Demetrius M., Gosal, David, Lynch, Tim, Hutchinson, Michael, Bentivoglio, Anna Rita, Valente, Enza Maria, Nichols, William C., Pankratz, Nathan, Foroud, Tatiana, Gibson, Rachel A., Hentati, Faycal, Dickson, Dennis W., Destée, Alain, and Farrer, Matthew J.

Published
2011
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45. COL18A1 genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study

Author

Simpson, Catherine E., primary, Griffiths, Megan, additional, Yang, Jun, additional, Nies, Melanie K., additional, Vaidya, Dhananjay, additional, Brandal, Stephanie, additional, Martin, Lisa J., additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Coleman, Anna W., additional, Austin, Eric D., additional, Ivy, D. Dunbar, additional, Nichols, William C., additional, Everett, Allen D., additional, Hassoun, Paul M., additional, and Damico, Rachel L., additional

Published
2022
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46. Treating People in Families: An Integrative Framework.

Author

Nichols, William C. and Nichols, William C.

Abstract

Directed at practitioners and students of family therapy, this book presents a treatment framework that is compatible with a wide variety of therapeutic techniques. Focusing on the development over time of the family life cycles--from marriages in formation to the "postparental couple"--this book explores the unique challenges and opportunities that each stage of family life presents. Section one, "Personality, Context and Integration," offers a theoretical overview of family therapy, stressing the need to consider the force of the individual human personality in treatment. Chapters are: (1) Family Therapy: Revolution and Evolution; (2) An Integrative Approach to Family Therapy; and (3) The Family System and Development. The second section, "Evaluation and Treatment," demonstrates how to apply the integrative approach outlined in the first section to the various stages of the family's developmental life cycle. Chapters are: (4) Perspectives on Therapy; (5) Family Evaluation and Treatment; (6) Therapy with Families in Formation; (7) Therapy with Expanding Families; (8) Therapy with Contracting Families; (9) Therapy with Postparental Couples; (10) Therapy with Families in Transition: Divorce; and (11) Therapy with Families in Transition: Remarriage. Contains an index and over 400 references. (PKB)

Published
1996

47. Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects inGBAMutation Carriers

Author

Pal, Gian, primary, Mangone, Graziella, additional, Hill, Emily J., additional, Ouyang, Bichun, additional, Liu, Yuanqing, additional, Lythe, Vanessa, additional, Ehrlich, Debra, additional, Saunders‐Pullman, Rachel, additional, Shanker, Vicki, additional, Bressman, Susan, additional, Alcalay, Roy N., additional, Garcia, Priscilla, additional, Marder, Karen S., additional, Aasly, Jan, additional, Mouradian, M. Maral, additional, Link, Samantha, additional, Rosenbaum, Marc, additional, Anderson, Sharlet, additional, Bernard, Bryan, additional, Wilson, Robert, additional, Stebbins, Glenn, additional, Nichols, William C., additional, Welter, Marie‐Laure, additional, Sani, Sepehr, additional, Afshari, Mitra, additional, Verhagen, Leo, additional, Bie, Rob M.A., additional, Foltynie, Tom, additional, Hall, Deborah, additional, Corvol, Jean‐Christophe, additional, and Goetz, Christopher G., additional

Published
2022
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48. Hepatoma‐derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival

Author

Yang, Jun, primary, Ambade, Anjira S., additional, Nies, Melanie, additional, Griffiths, Megan, additional, Damico, Rachel, additional, Vaidya, Dhananjay, additional, Brandal, Stephanie, additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Coleman, Anna W., additional, Nichols, William C., additional, Austin, Eric D., additional, Ivy, Dunbar, additional, Hassoun, Paul M., additional, and Everett, Allen D., additional

Published
2022
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49. Abstract 12319: 16alpha-Hydroxyestrone Downregulates SOX17 During the Development of Pulmonary Arterial Hypertension

Author

Sangam, Shreya, primary, Schwantes-An, Tae-Hwi, additional, Zagorski, John, additional, Shi, Yinan, additional, Morrisroe, Seth, additional, Cook, Todd, additional, Fisher, Amanda, additional, Frump, Andrea, additional, Coleman, Anna, additional, Tang, Haiyang, additional, Crawford, Howard, additional, Lutz, Katie, additional, Pauciulo, Michael W, additional, Chaudhary, Ketul R, additional, Stewart, Duncan J, additional, Lahm, Tim, additional, Nichols, William C, additional, and Desai, Ankit A, additional

Published
2021
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