Howard L Weiner

Beverly Hospital, Boston MA, BVY, Massachusetts, United States

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Publications (706)4798.03 Total impact

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    ABSTRACT: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers. In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells. Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.
    12/2015; 3(1):17. DOI:10.1186/s40478-015-0191-5
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    ABSTRACT: T helper cells producing IL-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study we characterized specific pathogenic features of Th17 cells in RA.Using nano-string technology we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23, and IL-21, and transcriptional regulators RORγt and JAK2, they produced high levels of IL-23R, CCL20, GM-CSF and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios producing, Foxp3 and IL2RA deficient cells indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and LIF. We observed that anti-TNF treatment had limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), pro-inflammatory cytokines (IL-17F, IL-23, IL-21 and TNF) and adaptor molecules (CXCR5 and CTLA-4), essential for efficient trans-differentiation and accumulation of Th17 cells.This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may trans-differentiate from Tregs and contribute to perpetuation of the disease.
    Molecular Medicine 06/2015; DOI:10.2119/molmed.2015.00057 · 4.82 Impact Factor
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    Murugaiyan Gopal, Lucien P. Garo, Howard L. Weiner
    Oncotarget 04/2015; 6(12):9644-9645. · 6.63 Impact Factor
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    ABSTRACT: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. We performed a genome-wide association study in IFNβ-treated MS patients followed by validation in three independent cohorts. The role of the validated variant was examined in several RNA datasets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. We found an association between rs9828519(G) and non-response to IFNβ (Pdiscovery =4.43x10(-8) ) and confirmed it in a meta-analysis across three replication datasets (Preplication =7.78x10(-4) ). Only one gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knock-down in T cells in vitro leads an increase of IFNγ expression, which is a pro-inflammatory molecule. This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNβ-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a pro-inflammatory fate and may have a broader role in MS disease activity, outside of IFNβ-treatment. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 04/2015; 78(1). DOI:10.1002/ana.24429 · 11.91 Impact Factor
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    ABSTRACT: A 4-year-old girl with a history of thoracic meningocele repair at the age of 3 months presented with progressive myelopathy. An intramedullary thoracic epidermoid was identified on MRI. The patient underwent excision of the epidermoid and subsequently returned to neurological baseline. This case illustrates the potential for delayed development of intraspinal epidermoid after initial repair of a simple meningocele.
    Journal of Neurosurgery Pediatrics 03/2015; 15(6):1-3. DOI:10.3171/2014.12.PEDS14270 · 1.37 Impact Factor
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    ABSTRACT: Accumulation of IL-17-producing Th17 cells is associated with the development of multiple autoimmune diseases; however, the contribution of microRNA (miRNA) pathways to the intrinsic control of Th17 development remains unclear. Here, we demonstrated that miR-21 expression is elevated in Th17 cells and that mice lacking miR-21 have a defect in Th17 differentiation and are resistant to experimental autoimmune encephalomyelitis (EAE). Furthermore, we determined that miR-21 promotes Th17 differentiation by targeting and depleting SMAD-7, a negative regulator of TGF-β signaling. Moreover, the decreases in Th17 differentiation in miR-21-deficient T cells were associated with defects in SMAD-2/3 activation and IL-2 suppression. Finally, we found that treatment of WT mice with an anti-miR-21 oligonucleotide reduced the clinical severity of EAE, which was associated with a decrease in Th17 cells. Thus, we have characterized a T cell-intrinsic miRNA pathway that enhances TGF-β signaling, limits the autocrine inhibitory effects of IL-2, and thereby promotes Th17 differentiation and autoimmunity.
    Journal of Clinical Investigation 02/2015; 125(3). DOI:10.1172/JCI74347 · 13.77 Impact Factor
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    ABSTRACT: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown. To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI). Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset). NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes. A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years. NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.
    JAMA Neurology 12/2014; 72(2). DOI:10.1001/jamaneurol.2014.3537 · 7.01 Impact Factor
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    Dataset: MovieS1
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    Dataset: MovieS1
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    Dataset: ana24304
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    ABSTRACT: Introduction: Magnetic Resonance Imaging (MRI) is an important part of diagnostic work-up and treatment monitoring of Multiple Sclerosis (MS) patients 1. MRI volumetric measurements are widely used as outcome measurements in clinical trials 2,3. Brain parenchyma fraction (BPF) or volume of brain normalized by intracranial cavity (ICC) represent MRI biomarker of brain atrophy. T2 weighted lesion volume (T2LV) represents MRI biomarker of inflammatory burden of MS disease. Their simultaneous unique combination and rate of change comprise quantitative MRI phenotype of the patient 4,5. To reveal natural pattern of quantitative MRI phenotypes in longitudinal MS population under CLIMB study observational retrospective analysis was performed. Conclusions: Our observations highlight distinct quantitative MRI phenotypes in longitudinal population of MS patients. It is unlikely that a single model could explain changes in the brain of MS population. Recent meta-analysis estimated annual rate for average MS patient receiving first generation disease modifying therapy drugs (DMT) or no DMT approximately 0.7% brain volume loss per year (0.1%-0.3% observed in normal aging) 12. Despite limitations of current analysis (linear modeling, interrater reliability estimation et ctr), trajectories of brain atrophy and MS lesions burden, establish normative reference of quantitative MRI biomarkers in MS population for monitoring effects of neuroprotective treatment. Quantitative MRI phenotypes can be applicable as surrogate end point in clinical trials including Progressive MS to increase sensitivity to detect changes as well as in defining no evidence disease activity (NEDA) patients. Further research is necessary to account for confounding factors (active lesions, gender) and integration of quantitative MRI phenotypes with clinical and biomarkers data.
    3rd Annual BWH Research Day, BWH, Boston, USA; 11/2014
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    ABSTRACT: For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Pediatric-onset MS provides an opportunity to study early disease processes.
    Neurology 11/2014; 83(24). DOI:10.1212/WNL.0000000000001066 · 8.30 Impact Factor
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    ABSTRACT: OBJECTIVE To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).METHODS Nanostring microRNA, microglia and immune gene profiles, protein mass spectrometry and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice.RESULTSIn SOD1 mice we found loss of the molecular signature that characterizes microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, Mafb and the upstream regulators Csf1r, Tgfb1 and Tgfbr1 which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51d in females and 27d in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes including Apoe in microglia. Treatment of adult microglia with APOE suppressed the M0-unique microglia signature and induced a M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1G93A/miR-155–/– mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes and peripheral anti-miR-155 treatment prolonged survival.INERPRETATIONWe found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 11/2014; 77(1). DOI:10.1002/ana.24304 · 11.91 Impact Factor
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    ABSTRACT: Background While disease categories (i.e. clinical phenotypes) of multiple sclerosis (MS) are established, there remains MRI heterogeneity among patients within those definitions. MRI-defined lesions and atrophy show only moderate inter-correlations, suggesting that they represent partly different processes in MS. We assessed the ability of MRI-based categorization of cerebral lesions and atrophy in individual patients to identify distinct phenotypes. Methods We studied 175 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, 124 (71%) women, Expanded Disability Status (EDSS) score 2.5 ± 2.3, n = 18 (10%) clinically isolated demyelinating syndrome (CIS), n = 115 (66%) relapsing-remitting (RR), and n = 42 (24%) secondary progressive (SP)]. Brain MRI measures included T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (to assess whole brain atrophy). Medians were used to create bins for each parameter, with patients assigned a low or high severity score. Results Four MRI phenotype categories emerged: Type I = low T2LV/mild atrophy [n = 67 (38%); CIS = 14, RR = 47, SP = 6]. Type II = high T2LV/mild atrophy [n = 21 (12%); RR = 19, SP = 2]; Type III = low T2LV/high atrophy [n = 21 (12%); CIS = 4, RR = 16, SP = 1]; Type IV = high T2LV/high atrophy [n = 66 (38%); RR = 33, SP = 33]. Type IV was the most disabled and was the only group showing a correlation between T2LV vs. BPF and MRI vs. EDSS score (all p < 0.05). Conclusions : We described MRI-categorization based on the relationship between lesions and atrophy in individual patients to identify four phenotypes in MS. Most patients have congruent extremes related to the degree of lesions and atrophy. However, many have a dissociation. Longitudinal studies will help define the stability of these patterns and their role in risk stratification.
    Journal of the Neurological Sciences 11/2014; 346(1-2). DOI:10.1016/j.jns.2014.08.047 · 2.26 Impact Factor
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    ABSTRACT: Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.
    Nature Medicine 09/2014; 20(10). DOI:10.1038/nm.3681 · 28.05 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) play a critical role in the maintenance of immunological tolerance. The best characterized Tregs are those expressing the transcription factor Foxp3 and in vivo modulation of Foxp3 Tregs has been employed to study their role in immune homeostasis. Latency associated peptide (LAP) is a membrane bound TGF-β complex that has also been shown to play a role in Treg function and oral tolerance. We developed a novel anti-mouse LAP monoclonal antibody that allowed us to investigate the effect of targeting LAP in vivo on immune function and on anti-CD3 induced oral tolerance. We found that in vivo anti-LAP monoclonal antibody administration led to a decrease in the number of CD4+LAP+ Tregs in spleen and lymph nodes without affecting CD4+Foxp3+ Tregs. Spleen cells from anti-LAP injected mice proliferated more in vitro and produced increased amounts of IL-2, IL-17 and IFN-γ. Moreover, injection of anti-LAP antibody abrogated the protective effect of oral anti-CD3 on EAE Finally, in vivo anti-LAP administration prior to MOG immunization resulted in severe EAE in the absence of pertussis toxin, which is used for EAE induction. Our findings demonstrate the importance of CD4+LAP+ T cells in the control of immune homeostasis and autoimmunity and provides a new tool for the in vivo investigation of murine LAP+ Tregs on immune function.
    International Immunology 09/2014; 27(2). DOI:10.1093/intimm/dxu083 · 3.18 Impact Factor
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    ABSTRACT: The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI-Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=-0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI-disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status.
    Neuroreport 08/2014; 25(14). DOI:10.1097/WNR.0000000000000244 · 1.64 Impact Factor
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    ABSTRACT: Objectives: Dendritic cells (DCs) serve a critical role both in promoting and inhibiting adaptive immunity. The goal of this study was to investigate the effect of natalizumab (NTZ) treatment on DC numbers, phenotype, and function in patients with multiple sclerosis (MS). Methods: Frequency and phenotype of myeloid and plasmacytoid DCs (MDCs and PDCs, respectively) were analyzed in blood from two separate cohorts of untreated, interferon-treated, or NTZ-treated MS patients. In addition, PDCs were stimulated with CpG-containing oligonucleotides or co-cultured with homologous T cells in the presence or absence of NTZ in vitro to determine functional effects of NTZ treatment. Results: We observed that NTZ treatment was associated with a 25-50% reduction in PDC frequency in peripheral blood as compared to untreated MS patients, while the frequency of MDCs was unchanged. PDCs in NTZ-treated patients displayed a mature, activated phenotype with increased expression of HLA-DR, TLR9, CCR7, IL-6 and IL-12. In contrast, in vitro treatment with NTZ did not increase markers of PDC activation or their ability to induce T cell differentiation. Conclusion: Our study shows that NTZ treatment is associated with a reduced frequency of PDCs in the peripheral circulation, but that PDCs in NTZ-treated individuals display an activated phenotype. Taken together the data suggests that transmigration of activated PDCs is preferentially affected by blockade of integrin alpha 4 leading to an increased frequency of activated PDCs in blood.
    PLoS ONE 07/2014; 9(7):e103716. DOI:10.1371/journal.pone.0103716 · 3.53 Impact Factor

Publication Stats

45k Citations
4,798.03 Total Impact Points

Institutions

  • 2006–2015
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
    • National Eye Institute
      베서스다, Maryland, United States
  • 1978–2015
    • Harvard Medical School
      • • Department of Neurology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1999–2014
    • NYU Langone Medical Center
      • • Division of Pediatric Surgery
      • • Department of Neurology
      New York, New York, United States
  • 1988–2014
    • Massachusetts General Hospital
      • • Biostatistics Center
      • • Partners Pediatric Multiple Sclerosis Center
      • • Department of Neurology
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 1983–2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1982–2014
    • Brigham and Women's Hospital
      • • Center for Neurologic Diseases
      • • Institute for the Neurosciences
      • • Center of Multiple Sclerosis
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2013
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 2000–2013
    • CUNY Graduate Center
      New York, New York, United States
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2008
    • McGill University
      Montréal, Quebec, Canada
  • 1994–2008
    • Hebrew University of Jerusalem
      • • Department of Statistics
      • • Department of Animal Sciences
      Yerushalayim, Jerusalem, Israel
  • 1999–2007
    • New York University
      • • Institute of Reconstructive Plastic Surgery
      • • School of Medicine NYU Langone Medical Center
      New York City, New York, United States
  • 2002
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 1990–1997
    • National Institutes of Health
      • Laboratory of Immunology
      베서스다, Maryland, United States
  • 1993
    • Beth Israel Medical Center
      • Department of Medicine
      New York, New York, United States
  • 1992
    • Alfred Hospital
      Melbourne, Victoria, Australia
  • 1991
    • Weizmann Institute of Science
      • Department of Immunology
      Israel
  • 1982–1984
    • Boston Children's Hospital
      • • Children's Hospital Primary Care Center
      • • Department of Neurology
      Boston, MA, United States
  • 1976–1978
    • University of Colorado Hospital
      • Department of Medicine
      Denver, Colorado, United States