Jill P Buyon

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (245)1402.64 Total impact

  • Joan T. Merrill, Jill P. Buyon, Tammy Utset
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune connective tissuedisease, primarily affecting the skin, joints, kidneys, heart, lungs, nervous system, blood elements, and serosal membranes. SLE is characterized by cytokine dysregulation, polyclonal B-cell activation, autoantibody production, and increased immune complex formation due to aberrations involving hyperactive B cells, T cells, and cells of the monocytic lineage. The symptoms of SLE are often diverse and nonspecific, and timely identification of SLE and associated comorbidities in patients is critical as aggressive monitoring and therapy may be warranted especially in patients with poor prognoses. Based on the up-to-date understanding of the pathophysiology of SLE, the first targeted biological agent, belimumab, has been approved by the US Food and Drug Administration (FDA) in more than 50 years, and many targeted agents are being evaluated in late-stage clinical trials. There is a clear need to discuss how and when to incorporate the new and emerging biological agents in managing patients with SLE. Additionally, the potential for increased risk of infections is a factor that heavily influences the rheumatologist’s decision to use biological agents in managing patients with SLE. Hence, in this roundtable educational activity, expert faculty will review and discuss the strategies for timely diagnosis of SLE and associated comorbidities. They will also discuss the current understanding of the pathophysiology of SLE and how the new and emerging biological agents help address the underlying pathophysiological aberrations in patients with SLE. The faculty will also review strategies to minimize the risk of infections and other toxicities in patients with SLE.
    Seminars in Arthritis and Rheumatism 10/2014; · 3.63 Impact Factor
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    ABSTRACT: OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. RESULTS: Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8-4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7-5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2-5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9-6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5-5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3-4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8-38.4, p < 0.01). CONCLUSIONS: Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    Lupus 08/2014; · 2.48 Impact Factor
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    ABSTRACT: Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease including congenital heart block and cardiomyopathy, called cardiac Neonatal Lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third degree heart block in NL, although several treatments have shown some effectiveness in incomplete heart block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. β-agonists have been used to increase fetal heart rates in utero. The endurance of β-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.
    Cardiology in review. 07/2014;
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    ABSTRACT: To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
    Lupus science & medicine. 06/2014; 1(1):e000056.
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    ABSTRACT: Noninvasive carotid measurements have independent value in the estimation of future cardiovascular (CV) outcomes in systemic lupus erythematosus (SLE). Natural IgM-antibodies to phosphorylcholine (PC) epitopes can enhance apoptotic-cell clearance and induce anti-inflammatory pathways. Herein, we show that subclinical CV disease, as detected by carotid ultrasound, in a cross-sectional SLE cohort was associated with lower levels of IgM anti-PC, as well as lower levels of the ratio of IgM anti-PC/total IgM, compared to patients without plaque (p=0.004 and p=0.02, respectively).The IgM anti-PC/total IgM association remained significant after adjusting for age, cholesterol and hypertension. Adiponectin and sE-selectin were significantly elevated in patients with plaque, and statistical models showed that combining adiponectin, sE-selectin and IgM anti-PC/total IgM was better for predicting plaque than either test alone. These results support the hypothesis that IgM-natural autoantibodies may inhibit atherogenesis, and confirms the utility of IgM anti-PC levels as a biomarker for subclinical CV disease.
    Clinical Immunology 04/2014; · 3.77 Impact Factor
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    Lupus science & medicine. 04/2014; 1(1):e000033.
  • Article: Reply.
    Arthritis & rheumatology (Hoboken, N.J.). 02/2014; 66(2):480.
  • Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A257-A257. · 9.27 Impact Factor
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    Article: Editorial.
    Lupus science & medicine. 01/2014; 1(1):e000028.
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    ABSTRACT: Noninvasive carotid measurements have independent value in the estimation of future cardiovascular (CV) outcomes in systemic lupus erythematosus (SLE). Natural IgM-antibodies to phosphorylcholine (PC) epitopes can enhance apoptotic-cell clearance and induce anti-inflammatory pathways. Herein, we show that subclinical CV disease, as detected by carotid ultrasound, in a cross-sectional SLE cohort was associated with lower levels of IgM anti-PC, as well as lower levels of the ratio of IgM anti-PC/total IgM, compared to patients without plaque (p = 0.004 and p = 0.02, respectively).The IgM anti-PC/total IgM association remained significant after adjusting for age, cholesterol and hypertension. Adiponectin and sE-selectin were significantly elevated in patients with plaque, and statistical models showed that combining adiponectin, sE-selectin and IgM anti-PC/total IgM was better for predicting plaque than either test alone. These results support the hypothesis that IgM-natural autoantibodies may inhibit atherogenesis, and confirms the utility of IgM anti-PC levels as a biomarker for subclinical CV disease.
    Clinical Immunology. 01/2014;
  • Autoimmunity reviews 09/2013; · 6.37 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine the frequency and functionality of blood conventional dendritic cells (cDC) in relation to disease activity in Systemic Lupus Erythematosus. METHODS: Blood cDC were enumerated for 34 SLE patients, defined as "active" (SLEDAI≥4) or "inactive" (SLEDAI<4), 26 RA and 8 healthy subjects by FACS. cDC activation was measured by IL-12p40/70 staining following resiquimod stimulation. RESULTS: The frequency of blood cDC were significantly lower in active compared to inactive patients, however, with comparable cDC functionality. CONCLUSION: cDC frequency in active SLE is decreased with no perturbation in cDC function, possibly due to enhanced turnover and/or tissue-specific migration.
    Experimental and Molecular Pathology 06/2013; · 2.88 Impact Factor
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    ABSTRACT: Objective. Identify predictors of moderate-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase 3 belimumab trials and evaluate impact of standard therapies on preventing flares. Methods. Post-hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and without flare at treatment weeks 24/52. Severe flare: modified SLE Flare Index (SFI) and 1 new British Isles Lupus Assessment Group (BILAG) A. Severe and moderate flare: any new BILAG A/2 new B scores. Baseline characteristics associated with ≥10% absolute difference/≥50% increase in flare rates were considered predictive. Results. Frequencies of SFI, BILAG 1A, and BILAG 1A/2B flares over 52 weeks were 24%, 23%, and 32%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24/52: Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) ≥12, anti-dsDNA positivity and proteinuria (≥0.5 g/24h); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein, and B-lymphocyte stimulator (BLyS) ≥2 ng/mL. Independent predictors by multivariate analysis at week 52: SELENA-SLEDAI/BILAG renal involvement and anti-dsDNA ≥200 IU/mL (all 3 indices); SELENA-SLEDAI/BILAG neurologic and vasculitic involvement (BILAG A/2 B or 1A scores); BLyS ≥2 ng/mL (SFI and BILAG 1A/2B scores); and low complement 3 (C3; SFI). Baseline medications did not significantly decrease or increase moderate-severe SLE flare risk. Conclusion. Patients on standard SLE therapy with renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS, or low C3 had increased risk for clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive. © 2013 by the American College of Rheumatology.
    Arthritis & Rheumatology 06/2013; · 7.48 Impact Factor
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    ABSTRACT: Cardiac neonatal lupus (NL) is presumed to arise from maternal autoantibody targeting an intracellular ribonucleoprotein, Ro60, which binds noncoding Y RNA and only becomes accessible to autoantibodies during apoptosis. Despite the importance of Ro60 trafficking in the development of cardiac NL, the mechanism underlying cell surface exposure is unknown. To evaluate the influence of Y RNA on the subcellular location of Ro60 during apoptosis and activation of macrophages, stable Ro60 knockout murine fibroblasts expressing wild-type or mutated FLAG-Ro60 were assessed. FLAG3-Ro60(K170A R174A) binds Y RNA, whereas FLAG3-Ro60(H187S) does not bind Y RNA; fibroblasts expressing these constructs showed equivalent intracellular expression of Ro60. In contrast, apoptotic fibroblasts containing FLAG3-Ro60(K170A R174A) were bound by anti-Ro60, whereas FLAG3-Ro60(H187S) was not surface expressed. RNA interference of mY3 RNA in wild-type fibroblasts inhibited surface translocation of Ro60 during apoptosis, whereas depletion of mY1 RNA did not affect Ro60 exposure. Furthermore, Ro60 was not exposed following overexpression of mY1 in the mY3-depleted fibroblasts. In an in vitro model of anti-Ro60-mediated injury, Y RNA was shown to be an obligate factor for TLR-dependent activation of macrophages challenged with anti-Ro60-opsonized apoptotic fibroblasts. Murine Y3 RNA is a necessary factor to support the surface translocation of Ro60, which is pivotal to the formation of immune complexes on apoptotic cells and a TLR-dependent proinflammatory cascade. Accordingly, the Y3 RNA moiety of the Ro60 ribonucleoprotein imparts a critical role in the pathogenicity of maternal anti-Ro60 autoantibodies.
    The Journal of Immunology 05/2013; · 5.36 Impact Factor
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    ABSTRACT: Objective. Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined.Methods. Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies.Results. uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region.Conclusion. Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.
    Rheumatology (Oxford, England) 04/2013; · 4.44 Impact Factor
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    ABSTRACT: Toll-like receptor (TLR) signaling is an important component in the inflammatory response generated in diseases characterized by autoantibody reactivity to proteins such as SSA/Ro in complex with endogenous nucleic acids. Complement receptor 3 (CR3), a genetic variant of which has been identified as a risk factor in Systemic Lupus Erythematosus, has been shown to induce tolerogenic responses in dendritic cells and suppress TLR4 responses in a murine sepsis model. Accordingly, this study addressed the hypothesis that activation of CR3, influenced by genotype of CD11b, negatively regulates TLR7/8 dependent effector function. Allosteric activation of CD11b via pre-treatment with the small molecule, Leukadhedrin 1 (LA1), significantly attenuated TLR7/8 induced (hY3 RNA, R848) secretion of TNFα in THP-1 cells and human macrophages isolated from donors homozygous for the ancestral common ITGAM allele at rs1143679. This inhibition was accompanied by profound degradation of the adaptor protein MyD88, an effect not observed with direct inhibition of TLR ligation by an antagonist oligonucleotide. In contrast, the addition of LA1 after incubation with the TLR agonists did not result in MyD88 degradation and subsequent attenuation of TNFα secretion. In TLR 7/8 stimulated macrophages isolated from donors heterozygous for the CD11b variant, pre-treatment with LA1 did not downregulate TNFα release. These novel findings support a negative cross-talk between CR3 and TLR pathways likely to be induced by antibodies reactive with ribonucleoproteins and point to the development of CR3-specific agonists as potential therapeutics for diseases such as neonatal lupus.
    Journal of Biological Chemistry 02/2013; · 4.60 Impact Factor
  • Arthritis & Rheumatology 01/2013; · 7.48 Impact Factor
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    Arthritis & Rheumatology 10/2012; · 7.48 Impact Factor
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    ABSTRACT: OBJECTIVE: To establish the value of cell-bound complement activation products in combination with antinuclear (ANA), anti-double-stranded DNA (anti-dsDNA) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of systemic lupus erythematosus (SLE). METHODS: The study was multicentred, cross-sectional and enrolled 593 patients (210 SLE patients, 178 patients with other rheumatic diseases and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B-cells (BC4d) were determined using fluorescence-activated cell sorting. Serological markers were measured using enzyme-linked immunosorbent assays. Statistical analyses utilized area under receiver operating characteristic (ROC) curves, logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Several-fold higher EC4d, BC4d, PC4d and lower ECR1 were observed in SLE compared to other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (=20units), anti-MCV negativity (<70units) and elevation of both EC4d and BC4d (p<0.001) (ROC area=0.918). A positive Index score corresponding to the weighted sum of these four markers correctly categorized 72% of SLE patients. Specificity against other rheumatic diseases and normal healthy controls was >90%. Altogether, the combination of anti-dsDNA and the Index score positivity yielded 80% sensitivity for SLE, and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d and BC4d is sensitive and specific for the diagnosis of SLE. © 2012 American College of Rheumatology.
    Arthritis & Rheumatology 08/2012; · 7.48 Impact Factor
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    ABSTRACT: OBJECTIVE.: The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the ribonucleoproteins SSA/Ro and SSB/La enhanced by as yet unknown factors likely to involve the dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biological functions. METHODS.: Using data from our genome-wide association study (GWAS) in 116 cardiac-NL Caucasian children and 3,351 Caucasian controls, we tested for enrichment of SNP associations in genes with candidate biological functions related to fibrosis, immune, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll like receptors and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained. RESULTS.: A highly significant enrichment of P-values was observed in genes related to fibrosis (P=2.27×10(-9) ), apoptosis (P=7.67×10(-7) ), innate immune cell (P=2.53×10(-6) ), immune (P=5.01×10(-4) ), T cell (P=2.23×10(-4) ), and interferon functions (P=1.64×10(-3) ). The most significant non-HLA associations included the sialyltransferase ST8SIA2 (rs1487982, P=3.38×10(-5) , OR [95%CI]=2.20 [1.52-3.19]), the integrin ITGA1 (rs2432143, P=4.54×10(-5) , OR [95%CI]=2.31 [1.54-3.45]), and the complement regulator CSMD1 (rs7002001, P=6.33×10(-5) , OR [95%CI]=2.41 [1.57-3.72]). CONCLUSION.: This study identified novel candidate genes associated with cardiac-NL and highlights the value of this cohort in advancing our knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.
    Arthritis & Rheumatology 08/2012; · 7.48 Impact Factor

Publication Stats

8k Citations
1,402.64 Total Impact Points

Institutions

  • 2013
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
    • Sheba Medical Center
      Gan, Tel Aviv, Israel
  • 2012
    • Medical University of South Carolina
      • Division of Rheumatology and Immunology
      Charleston, SC, United States
  • 1996–2012
    • New York University
      • • Department of Pediatrics
      • • Department of Medicine
      • • Division of Rheumatology
      New York City, NY, United States
  • 1994–2012
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 1990–2012
    • CUNY Graduate Center
      New York City, New York, United States
  • 1988–2012
    • NYU Langone Medical Center
      • • Department of Medicine
      • • Division of Rheumatology
      New York City, NY, United States
  • 2011
    • Vanderbilt University
      • Department of Pediatrics
      Nashville, MI, United States
  • 2009–2010
    • New York Medical College
      • Department of Pediatrics
      New York City, New York, United States
    • Ospedali Riuniti di Bergamo
      Bérgamo, Lombardy, Italy
  • 2008
    • Saint Barnabas Medical Center
      Livingston, New Jersey, United States
  • 2007
    • University of Toronto
      • Centre For Prognosis Studies in the Rheumatic Diseases
      Toronto, Ontario, Canada
  • 2006
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2002–2006
    • Flinders University
      • • Department of Immunology, Allergy and Arthritis
      • • Flinders Medical Centre
      Adelaide, South Australia, Australia
    • Aurora St. Luke's Medical Center
      Milwaukee, Wisconsin, United States
  • 2005
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
    • King's College London
      • Department of Academic Rheumatology
      London, ENG, United Kingdom
  • 1997–2003
    • Azienda Ospedaliera Niguarda Ca' Granda
      Milano, Lombardy, Italy
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2001
    • Weill Cornell Medical College
      • Division of Rheumatology
      New York City, New York, United States
    • Children's National Medical Center
      • Division of Cardiology
      Washington, D. C., DC, United States
  • 1995–1999
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, CA, United States
  • 1998
    • State University of New York
      New York City, New York, United States
  • 1986–1996
    • State University of New York Downstate Medical Center
      • • Department of Medicine
      • • Department of Obstetrics and Gynecology
      Brooklyn, NY, United States
  • 1993
    • The European League Against Rheumatism (EULAR)
      Zürich, Zurich, Switzerland
  • 1992
    • Bellevue University
      Bellevue, Nebraska, United States
  • 1991
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 1989
    • The Rockefeller University
      New York City, New York, United States