Josef T Prchal

University of Utah, Salt Lake City, Utah, United States

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Publications (358)2768.13 Total impact

  • Leukemia and Lymphoma 09/2015; DOI:10.3109/10428194.2015.1091932 · 2.89 Impact Factor
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    ABSTRACT: Background: End-tidal breath carbon monoxide (ETCOc) levels correlate with catabolism of heme, but until recently, this measurement was not readily available for application to neonatology practice. Objectives: We performed a prospective, multihospital, test-of-concept study where ETCOc was measured during the birth hospitalization of neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram. This was done to test the feasibility and ease of use of this new device. Methods: Neonates with an elevated ETCOc (with a >95th percentile reference interval previously established) were labeled as having 'hemolytic jaundice'. We recommended a follow-up TB check <24 h after hospital discharge to these families. Results: One hundred and fifteen neonates were eligible for the study, the parents of 103 provided consent, and measurements were obtained for 100. Sixty-three had normal and 37 had elevated ETCOc values. By means of a direct antiglobulin test (DAT; Coombs), 11 of these 37 were found positive for ABO hemolytic disease; the remaining 26 had other etiologies. Thirty-six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home. None of the 100 were rehospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile (p = 0.079). Conclusion: ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to comply with instructions to bring the infant for a TB checkup <24 h after discharge home.
    Neonatology 09/2015; 109(1):1-5. DOI:10.1159/000438482 · 2.65 Impact Factor
  • S Swierczek · L T Lima · T Tashi · S J Kim · X T Gregg · J T Prchal
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2015; DOI:10.1038/leu.2015.249 · 10.43 Impact Factor
  • Josef T Prchal
    Proceedings of the National Academy of Sciences 08/2015; 112(33). DOI:10.1073/pnas.1512899112 · 9.67 Impact Factor
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    Mayo Clinic Proceedings 07/2015; 90(8). DOI:10.1016/j.mayocp.2015.06.001 · 6.26 Impact Factor
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    ABSTRACT: Interferon alpha (IFNα) is used clinically to restore polyclonal hematopoiesis in patients with the myeloproliferative neoplasms (MPN) polycythemia vera (PV) and essential thrombocythemia (ET), and to improve chemosensitivity in chronic myeloid leukemia patients. However, the mechanisms by which IFNα affects disease-initiating hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. While IFNα has been shown to transiently impair quiescence of murine hematopoietic stem cells, its effects on human HSPCs have not been studied in vivo. Here, we compared bone marrow serially obtained from MPN patients before and during pegylated IFNα (Peg-IFNα) treatment against marrow serially obtained from patients on hydroxyurea. The percentage of HSPCs actively undergoing cell cycle was increased after Peg-IFNα treatment in a majority of patients compared to hydroxyurea-treated controls, suggesting that IFNα promotes cell division. Furthermore, transcriptional profiling revealed that cell cycle-associated genes were induced, while genes involved in HSPC quiescence were repressed during IFNα treatment. Compared to hydroxyurea-treated controls, Peg-IFNα treated patients had similar HSPC numbers but increased numbers of hematopoietic progenitors as determined by colony formation assay, indicating an increase in myeloid proliferation/differentiation. These effects occurred regardless of JAK2 mutational status. Together, these data provide the first in vivo evidence that Peg-IFNα promotes cell division and differentiation of human HSPCs. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Experimental hematology 06/2015; DOI:10.1016/j.exphem.2015.05.013 · 2.48 Impact Factor
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    ABSTRACT: Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Three of these genes (EPAS1, EGLN1, and PPARA) are associated with decreased hemoglobin (Hb) levels compared to non-Tibetans living at altitude. Consistent with the phenotype, EGLN1 in Tibetans has a gain of function mutation that confers a higher affinity for oxygen, hence less sensitivity to hypoxia. Considering the demands imposed upon metabolism in meeting energy demands despite limitations on fuel oxidation, we hypothesized that other selected genes might alter metabolism to allow adaptation to altitude despite the desensitization of the upstream hypoxia sensing caused by the EGLN1 mutation that results in the failure to sense hypoxia. A shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would provide adaptation to decreased oxygen availability. Measurements of serum metabolites from Tibetans living at high altitude are consistent with this hypothesis: The EPAS1 haplotype is significantly associated with increased lactate levels (suggesting increased anaerobic metabolism), and the PPARA haplotype and serum free fatty acids are positively related (suggesting decreased fat oxidation). These data suggest that the high altitude adaptations may offer protection from diabetes at high altitude but increase diabetes risk at lower elevations and/or with adoption of a nontraditional diet. It should also be considered in future work in the field that because iron is a cofactor for EGLN1, there may be significant associations of phenotypes with the significant degrees of variation seen in tissue iron among human populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Experimental physiology 06/2015; DOI:10.1113/EP085292 · 2.67 Impact Factor
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    ABSTRACT: During prolonged hypoxia, hypoxia-inducible factors (HIFs) mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass and polycythemia. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. The molecular and biochemical mechanisms involved in neocytolysis are unknown. We developed a murine model of neocytolysis by exposing mice to 12 % oxygen for 10 days followed by return to normoxia. Upon return to normoxia, there was excessive accumulation of reactive oxygen species (ROS) in RBCs from an increased reticulocyte mitochondrial mass correlating with decreased Bnip3L transcripts (Bnip3L mediates reticulocyte mitophagy) and reduced catalase activity. During hypoxia, upregulated miR-21 resulted in low catalase activity in young RBCs. Furthermore, neocytolysis was attenuated by antioxidants and plasma catalase and blunted in mice that had constitutively high expression of HIFs. Among human neonates studied, we report data supporting the existence of neocytolysis during the first week of life. Together, these experiments indicate that the major mechanisms causing neocytolysis involve (1) production of young RBCs with low catalase during hypoxia and (2) lysis of the young RBCs after return to normoxia, mediated by ROS from an increased mitochondrial mass. We report a mouse model of neocytolysis. Neocytolysis is caused by excessive ROS formation mediated by HIF. ROS is generated from increased mitochondria in reticulocytes. Hypoxia-generated RBCs have low catalase and are preferentially destroyed. Reduced catalase is regulated by increased microRNA-21.
    Journal of Molecular Medicine 05/2015; 93(8). DOI:10.1007/s00109-015-1294-y · 5.11 Impact Factor
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    ABSTRACT: Activation of JAK2, frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia and myelofibrosis and is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2 selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F) - positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction - transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high dose group and were maintained well below the vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red blood cell parameters. After 42 days of treatment, the proportion of JAK2(V617F) - positive cells in hematopoietic tissues was identical or slightly increased compared to controls. Plasma concentrations of IL-6, IL-15, and TNFα were elevated in MPN mice and reduced in the high dose treatment group, while other cytokines were unchanged. Inhibitor activity after dosing was confirmed in a cell culture assay using the plasma of dosed mice and pSTAT5 flow cytometry. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2(V617F) - driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Experimental hematology 04/2015; 43(7). DOI:10.1016/j.exphem.2015.03.006 · 2.48 Impact Factor
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    ABSTRACT: The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 04/2015; 13(4):424-34. · 4.18 Impact Factor
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    ABSTRACT: At present, allo-SCT is the only curative treatment for patients with myelofibrosis (MF). Unfortunately, a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at the time of diagnosis. The approval of the first JAK inhibitor, ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support for assessing the drug's candidacy in the peritransplant period. The drug's precise impact on clinical outcome following allo-SCT is currently not known; nor are the drug's long-term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who undergo allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology Annual Meeting in New Orleans, USA on 6 December 2013, and the European Hematology Association's Annual Meeting in Milan, Italy on 13 June 2014. This document summarizes the results of these efforts.Bone Marrow Transplantation advance online publication, 9 February 2015; doi:10.1038/bmt.2014.323.
    Bone Marrow Transplantation 02/2015; 50(5). DOI:10.1038/bmt.2014.323 · 3.57 Impact Factor
  • Blood 01/2015; 125(2):414-5. DOI:10.1182/blood-2014-10-604660 · 10.45 Impact Factor
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    ABSTRACT: ABSTRACT We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. DLTs were observed in 3 patients overall, at the 100 mg (1) and 160 mg (2) twice daily dose levels. The MTD was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event.. Sixteen patients were evaluable for response at 12 weeks; 7 patients had clinical improvement by IWG-MRT criteria. Meaningful reductions in JAK2 V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of STAT5: doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed. [NCT00668421].
    Leukemia and Lymphoma 01/2015; DOI:10.3109/10428194.2014.1001986 · 2.89 Impact Factor
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    ABSTRACT: The causative genetic mutations of inherited giant platelet disorders (IGPD) encompass genes coding for the platelet glycoprotein Ib-IX complex (Bernard Soulier syndrome and its variants), myosin heavy chain 9 (MYH9 gene mutated in May-Hegglin anomaly and other IGPDs), GATA-01 (GATA-related thrombocytopenia), TUBB-1, ITGA2, ITGAB3, FLNA and some others. IGPDs are frequently associated with other disorders including renal disease, sensorineural deafness, and leukocyte inclusion bodies. Most are accompanied with variable degrees of bleeding diathesis, while others, like TUBB1 IGPD, do not have any bleeding manifestations. Harris platelet syndrome (HPS), previously called asymptomatic constitutional macrothrombocytopenia, is an autosomal dominant disorder characterized by low-normal to severe thrombocytopenia IGPD and absence of bleeding. HPS has also been observed in healthy blood donors from the northeastern part of India (Bengal) and some areas of Bangladesh, Bhutan and Nepal. We describe a high prevalence of an autosomal dominantly inherited form of IGPD with mild to severe thrombocytopenia in the Muslim population in Kashmir Valley in the northern Indian subcontinent. 830 voluntary, healthy, male blood donors from Kashmir Valley were included in the study. They were aged 15-55 years (median 31 years) and underwent ancillary screening as follows; CBC, peripheral smear, HBV, HCV, HIV, ANA and Anti-H pylori antibodies. 15% of the donors had thrombocytopenia (mean platelet count 109.6 compared to 189.9 in controls; p=<0.0001). No differences were noted in age between the 2 groups. The mean platelet volume (MPV) in thrombocytopenic subjects was higher (12.53 + 0.78 vs 9.52 + 1.03 fl). The red cell distribution width (RDW) in thrombocytopenic subjects was higher than in those with normal counts (15.6 + 1.61 Vs 13. 22 + 1.36, p=<0.001). Hematocrit and other red cell indices were not different in the 2 groups. None of the participants had a history of bleeding, renal disease, sensorineural deafness, or leukocyte inclusion bodies. Peripheral blood platelet morphology revealed large platelets in all subjects. In a pilot study of 7 families, Kashmiri thrombocytopenia was compatible with autosomal dominant inheritance affecting both genders. The congenital nature of Kashmiri thrombocytopenia was demonstrated by analyses of 34 consecutive neonates born in Sher-i-Kashmir Institute Hospital; among 20 girls and 19 boys, we found 18% (2 male and 5 female) to have low platelet count, the mean platelet count of the affected group when compared to unaffected group were 102.6 vs 234 (p=<0.001) respectively. We then searched for a causative mutation using the following approaches. We sequenced the MYH9 gene and no mutation was found. We then employed SNP array analyses using Shared Genome Segment (SGS) and Whole Genome Association Study (WGAS). We were able to exclude all previously reported IGPD-causing genes. SGS that overlapped with WGAS narrowed the target into 3 chromosome regions in Chr. 5 (rs6872531-rs100072476), Chr. 9 (rs11999541-rs12682912) and Chr. 10 (rs11013452-rs7083349). The performed SNP analyses included large genomic segments as candidates for a Kashmiri thrombocytopenia-causative gene. To further narrow down the cause of this disorder, we recruited 3 TRIO families (an affected parent and a child) for stronger linkage analysis and next-generation sequencing to continue the search for the cause of the Kashmiri thrombocytopenia.
    American Society of Hematology, San Francisco, California, USA; 12/2014
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    ABSTRACT: Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05 ± 55.48 m in the immediate intervention group and decreased a mean 11.45 ± 49.46 m in the wait list control group (p = 0.443). The hemoglobin increased a mean 0.39 ± 0.46 g/dL in the immediate intervention group and declined a mean 0.39 ± 0.85 g/dL in the wait list control group (p = 0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.
    Blood Cells Molecules and Diseases 12/2014; 53(4). DOI:10.1016/j.bcmd.2014.06.003 · 2.65 Impact Factor
  • R D Christensen · D K Lambert · E Henry · H M Yaish · J T Prchal
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    ABSTRACT: In the first days of life, low grade jaundice is essentially universal. The source of the elevated bilirubin level giving rise to "physiological jaundice of the newborn" is only partly known. We hypothesized that it is, at least in part, the result of active and specific hemolysis involving a physiological mechanism to lower the high fetal hematocrit, appropriate for the relatively low oxygen environment in utero, to a lower level appropriate for the state of oxygen abundance after birth. We tested this by quantifying end tidal carbon monoxide (ETCO) as a marker of the rate of heme metabolism to bilirubin. We found that ETCO values of 20 neonates and children with known hemolytic disorders were higher than 20 age-matched healthy controls (p<0.0001), indicating that this instrumentation recognizes hemolysis in neonates and children. We also found that ETCO reference intervals were indeed higher in healthy neonates during the first three days after birth (5th to 95th percentile reference range, 1.4 to 1.7ppm) than after 1month of age (all ≤1.0ppm, p<0.0001). These results suggest to us that hemolysis is physiological during the first days after birth. The cellular and molecular mechanisms responsible for transient hemolysis after birth are topics of current investigation. Copyright © 2014 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 11/2014; 54(3). DOI:10.1016/j.bcmd.2014.11.018 · 2.65 Impact Factor
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    ABSTRACT: von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHLR200W) and Croatian (VHLH191D) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHLD126N mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2014; 61(11). DOI:10.1002/pbc.25056 · 2.39 Impact Factor
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    ABSTRACT: Abstract Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis characterized by a high frequency of genetic alterations and include chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPNs. Herein we summarize recent advances and controversies in our understanding of the biology and therapy of these disorders, as discussed at the 8th post-American Society of Hematology CML-MPN workshop. The principal areas addressed include the breakthrough discovery of CALR mutations in JAK2/MPL wild type MPN patients, candidate therapies based on novel genetic findings in leukemic transformation and new therapeutic targets in MPNs, an appraisal of bone marrow histopathology in MPNs with a focus on the potential new clinical entity of 'masked' polycythemia vera, an update on clinical trials of JAK inhibitors is presented as well as current understanding regarding the definitions and mechanisms of resistance to JAK inhibitors and updated information on the safety and efficacy of discontinuation of tyrosine kinase inhibitors in CML patients.
    Leukemia and Lymphoma 10/2014; 56(7):1-19. DOI:10.3109/10428194.2014.974594 · 2.89 Impact Factor
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    ABSTRACT: We evaluated a neonate with severe jaundice but a negative family history. Spherocytes were present and suspected hereditary spherocytosis was confirmed by osmotic fragility and eosin-5-maleimide erythrocyte staining. We found he was a compound heterozygote for two pathogenic mutations in the gene encoding α-spectrin: a previously reported α(LEPRA) inherited from his asymptomatic mother, and a novel α-spectrin mutation in intron 45 +1 disrupting the consensus splice site, from his asymptomatic father. © 2014 S. Karger AG, Basel.
    Neonatology 10/2014; 106(4):355-357. DOI:10.1159/000365586 · 2.65 Impact Factor

Publication Stats

10k Citations
2,768.13 Total Impact Points


  • 2006–2015
    • University of Utah
      • • Department of Internal Medicine
      • • Division of Hematology
      • • School of Medicine
      • • Division of Pediatric Hematology and Oncology
      Salt Lake City, Utah, United States
  • 2013
    • National Institutes of Health
      Maryland, United States
  • 2011
    • The Children's Hospital of Philadelphia
      • Center for Applied Genomics
      Philadelphia, PA, United States
  • 2005–2011
    • Howard University
      • • Department of Medicine
      • • Center for Sickle Cell Disease
      Washington, WV, United States
    • Palacký University of Olomouc
      • Department of Pediatrics
      Olmütz, Olomoucký, Czech Republic
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2006–2010
    • Charles University in Prague
      • • Department of Pathophysiology (2. LF)
      • • Institute of Pathological Physiology (Pilsen)
      Praha, Praha, Czech Republic
  • 2005–2010
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2009
    • Arup
      Londinium, England, United Kingdom
  • 2007
    • University of Illinois at Chicago
      • Department of Medicine (Chicago)
      Chicago, Illinois, United States
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
  • 2001–2007
    • Baylor College of Medicine
      • • Department of Medicine
      • • Section of Hematology/Oncology
      Houston, Texas, United States
  • 1979–2004
    • University of Alabama at Birmingham
      • • Division of Nephrology
      • • Division of Hematology / Oncology
      • • Department of Medicine
      • • Department of Microbiology
      • • Division of Laboratory Medicine
      Birmingham, AL, United States
  • 2003
    • Texas Children's Cancer and Hematology Centers
      Houston, Texas, United States
  • 2002
    • Rochester General Hospital
      Rochester, New York, United States
  • 1997
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
    • George Washington University
      • Department of Medicine
      Washington, Washington, D.C., United States
  • 1996
    • Cooper Hospital
      Green Bay, Wisconsin, United States
  • 1993
    • McGill University
      Montréal, Quebec, Canada
  • 1982–1991
    • St. Elizabeth Hospital
      Louisiana, United States
  • 1989
    • CUNY Graduate Center
      New York, New York, United States
  • 1988
    • The University of Calgary
      Calgary, Alberta, Canada
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States
    • City of Hope National Medical Center
      Дуарте, California, United States
  • 1981–1985
    • University of Alabama
      Tuscaloosa, Alabama, United States
    • College of Saint Elizabeth
      Boston, Massachusetts, United States