Josef T Prchal

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

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Publications (325)2387.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower Km value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ~8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.
    Nature Genetics 08/2014; · 35.21 Impact Factor
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    ABSTRACT: From 2007 to 2011, 66 patients with primary myelofibrosis (PMF) or MF preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase II clinical trial of reduced intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium -101 trial. The study included patients with sibling donors (n=32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n=34) receiving conditioning with FluMel+anti-thymocyte globulin (rATG). Patient characteristics in the two cohorts were similar. Engraftment occurred in 97% of siblings and 76% unrelated transplants, while secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival was 75% in the sibling (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% CI:3,25) (HR 3.9, 95% CI: 1.8,8.9) (p<0.001). Non-relapse-mortality was 22% in siblings and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age or JAK2(V617F)-status. In patients with myelofibrosis with sibling donors AHSCT is an effective therapeutic option while AHSCT from unrelated donors with FluMel+ATG conditioning led to high rate of graft failure and limited survival. This study was registered at clinicaltrials.gov, identifier: 00572897.
    Blood 06/2014; · 9.06 Impact Factor
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    ABSTRACT: A fraction of polycythemia vera (PV) and essential thrombocythemia (ET) cases will, in time, undergo myelofibrotic transformation. In such cases, fibrosis may mask the diagnostic histologic features of the original underlying myeloproliferative neoplasm. Thus, confidently differentiating postfibrotic PV/ET from primary myelofibrosis (PMF) histologically may not be possible. It is controversial whether post-PV/ET myelofibrosis (MF) differs clinicopathologically from PMF, or whether these entities are biologically, clinically, and prognostically indistinguishable. To answer this question, we compared multiple candidate biological, morphologic, and prognostic parameters between 19 postfibrotic ET/PV individuals and 18 PMF individuals. The postfibrotic ET/PV and PMF cases did not differ with regard to clinical outcome, cytogenetic abnormalities, serum lactate dehydrogenase level, peripheral blast count, bone marrow morphology, or grade of reticulin fibrosis. Only JAK2 allele burden, which was higher in the postfibrotic PV/ET population (P=0.011), differed between the 2 groups. Cardinal morphologic features of PMF (ie, marrow cellularity, intrasinusoidal hematopoiesis, osteosclerosis, etc.) were commonly observed in post-PV/ET MF marrow biopsies, and only a minority of post-PV/ET MF marrow biopsies the retained diagnostic features of the primary myeloproliferative neoplasm (panmyelosis in PV and megakaryocytic hyperplasia in ET). Our study indicates that PMF and post-PV/ET MF are clinically and biologically indistinguishable.
    06/2014;
  • Haematologica 06/2014; 99(6):945-949. · 5.94 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 04/2014; · 2.35 Impact Factor
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    ABSTRACT: We postulated that the hypoxic response in sickle cell disease (SCD) contributes to altered gene expression and pulmonary hypertension, a complication associated with early mortality. To identify genes regulated by the hypoxic response and not other effects of chronic anemia, we compared expression variation in peripheral blood mononuclear cells from 13 SCD subjects with hemoglobin SS genotype and 15 Chuvash polycythemia subjects (VHL(R200W) homozygotes with constitutive up-regulation of hypoxia inducible factors in the absence of anemia or hypoxia). At 5% false discovery rate, 1040 genes exhibited >1.15 fold change in both conditions; 297 were up-regulated and 743 down-regulated including MAPK8 encoding a mitogen-activated protein kinase important for apoptosis, T-cell differentiation and inflammatory responses. Association mapping with a focus on local regulatory polymorphisms in 61 SCD patients identified expression quantitative trait loci (eQTL) for 103 of these hypoxia response genes. In a University of Illinois SCD cohort the A allele of a MAPK8 eQTL, rs10857560, was associated with pre-capillary pulmonary hypertension defined as mean pulmonary artery pressure ≥25 and pulmonary capillary wedge pressure ≤15 mm Hg at right heart catheterization (allele frequency=0.66; OR=13.8, P=0.00036, n=238). This association was confirmed in an independent Walk-PHaSST cohort (allele frequency=0.65; OR=11.3, P=0.0025, n=519). The homozygous AA genotype of rs10857560 was associated with decreased MAPK8 expression and present in all 14 identified pre-capillary pulmonary hypertension cases among the combined 757 patients. Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 eQTL associated with pre-capillary pulmonary hypertension.
    Circulation 02/2014; · 15.20 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2014; · 10.16 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2014; · 10.16 Impact Factor
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    ABSTRACT: High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin–oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai–Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in the downregulation of the HIF pathway. In order to see if Tibetans also developed high hemoglobin–oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin–oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin–oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin–oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.
    Blood Cells Molecules and Diseases 01/2014; · 2.26 Impact Factor
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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 01/2014; · 2.26 Impact Factor
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    ABSTRACT: Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS) and AML. Here we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of mononuclear cytopenia (DCML deficiency) with elevated Flt3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger's syndrome, monoMAC, and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frame-shift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells and naïve T cells and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision making.
    Blood 12/2013; · 9.06 Impact Factor
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    ABSTRACT: Overexpression of transcription factors RUNX1 and NF-E2 was reported in granulocytes of patients with polycythemia vera and other myeloproliferative neoplasms (MPN). Further, a transgenic mouse overexpressing the NF-E2 transgene was reported to be a model of MPN. We hypothesized that increased transcripts of RUNX1 and NF-E2 might characterize other polycythemic states with primary polycythemic features, i.e., those with exaggerated erythropoiesis due to augmented erythropoietin (EPO) sensitivity. We tested the expression of RUNX1 and NF-E2 in polycythemic patients of diverse phenotypes and molecular causes. We report that RUNX1 and NF-E2 overexpression is not specific for MPN; these transcripts were also significantly elevated in polycythemias with augmented hypoxia-inducible factor activity whose erythroid progenitors were hypersensitive to EPO. RUNX1 and NF-E2 overexpression was not detected in patients with EPO receptor (EPOR) gain-of-function, suggesting distinct mechanisms by which erythroid progenitors in polycythemias with defects of hypoxia sensing and EPOR mutations exert their EPO-hypersensitivity.
    Blood 12/2013; · 9.06 Impact Factor
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    ABSTRACT: We cared for a term male infant born to Burmese immigrants. At about 24 hours a total serum bilirubin (TSB) was 9.3 mg/dL, and phototherapy was begun. It was stopped 48 hours later, with a TSB of 10.9 mg/dL, and he was discharged from the hospital with an appointment for a repeat TSB check 48 hours later. A few hours before the appointment he became listless and apneic, and his parents took him to the emergency department of the regional children's hospital, where sepsis was suspected. The TSB was 41 mg/dL. He died 4 hours later, despite intensive care efforts, with opisthotonus and refractory hypotension. Blood drawn before the exchange transfusion had low glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity, and sequencing of the G6PD gene revealed the G6PD Mahidol mutation (c.487G>A). Cultures and postmortem examination did not demonstrate an infectious process, but kernicterus was present. Acute kernicterus can mimic septic shock.
    PEDIATRICS 11/2013; · 4.47 Impact Factor
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    ABSTRACT: We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis. Analysis of the α-spectrin gene (SPTA1) in the proband revealed two previously reported low-frequency heterozygous polymorphisms of unknown clinical significance and the α(LELY) allele. In addition, a novel heterozygous mutation was identified in exon 2 of the β-spectrin gene SPTB. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2). © 2013 S. Karger AG, Basel.
    Neonatology 10/2013; 105(1):1-4. · 2.57 Impact Factor
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    ABSTRACT: Abstract β-Thalassemia (β-thal) is a public health problem in the Gaza Strip, Palestine, where about 320 patients are currently managed through blood transfusions and iron chelation. Within the restrictive environment of the Gaza Strip, no advanced molecular analysis [sequencing, real-time polymerase chain reaction (real-time PCR)] technology is currently available for developing a premarital screening protocol and providing couples at risk with prenatal diagnosis. Therefore, genetic identification of samples with indicators of β-thal is delayed for weeks before the samples can be sequenced outside the country. As nine causative mutations have been identified in the majority of β-thal cases in the Gaza Strip, a basic genetic screening strategy was designed to improve timeliness in mutation identification and reduce costs to the Palestinian health system. In the present study, we developed a reliable method for the detection of nine Mediterranean β-thal mutations common to the Palestinian population using a panel of restriction enzyme digests. This strategy utilizes standard instrumentation (thermocycler and agarose gel electrophoresis) that would be available in any basic molecular genetics or biochemical laboratory and provides a reliable method of genetic screening and counseling for patients at risk for β-thal.
    Hemoglobin 10/2013; · 0.89 Impact Factor
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    ABSTRACT: Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including two propositi with atypical non-microcytic hereditary pyropoikilocytosis, seven hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the α spectrin gene, SPTAR34P that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTAαLELY in the two propositi and five of seven hereditary elliptocytosis individuals indicating that SPTAαLELY is not the sole determinant of the variable clinical expression. α Spectrin mRNA was mildly decreased in all hereditary elliptocytosis subjects, whereas both hereditary pyropoikilocytosis propositi had a severe decrease to ~10% of normal. Genotyping identified a unique SPTA intragenic crossover and uniparental disomy in one hereditary elliptocytosis individual. Two additional crossover events demonstrated the susceptibility of SPTA gene to rearrangement and revealed a novel segregation of the two SPTAαLELY mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTAR34P mutation in combination with: 1) inheritance in trans of either SPTAαLELY or 2) the wild type SPTA; 3) a decrease of α spectrin mRNA and 4) SPTA intragenic crossover.
    Haematologica 09/2013; · 5.94 Impact Factor
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    ABSTRACT: Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel disease models and accelerate drug development using distinct tissue target cells generated from isogenic iPSC lines with and without disease-causing mutations. To realize the potential of iPSCs in modeling acquired diseases which are usually heterogeneous, we have generated multiple iPSC lines including two lines that are JAK2-wild type and four lines homozygous for JAK2-V617F somatic mutation from a single polycythemia vera patient blood. In vitro differentiation of the same patient-derived iPSC lines have demonstrated the differential contributions of their parental hematopoietic clones to the abnormal erythropoiesis including the formation of endogenous erythroid colonies. This iPSC approach thus may provide unique and valuable insights into the genetic events responsible for disease development. To examine the potential of iPSCs in drug testing, we generated isogenic hematopoietic progenitors and erythroblasts from the same iPSC lines derived from PV patients and normal donors. Their response to three clinical JAK inhibitors, INCB018424 (Ruxolitinib), TG101348 (SAR302503) and the more recent CYT387 was evaluated. All three drugs similarly inhibited erythropoiesis from normal and PV iPSC lines containing the wild-type JAK2 genotype, as well as those containing a homozygous or heterozygous JAK2-V617F activating mutation that showed increased erythropoiesis without a JAK inhibitor. However, the JAK inhibitors had less inhibitory effect on the self-renewal of CD34+ hematopoietic progenitors. The iPSC-mediated disease modeling thus underlies the ineffectiveness of the current JAK inhibitors, and provides a modeling system to develop better targeted therapies for the JAK2 mutated hematopoiesis. Stem Cells 2013.
    Stem Cells 09/2013; · 7.70 Impact Factor
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    ABSTRACT: In congenital Chuvash polycythemia (CP), VHL(R200W) homozygosity leads to elevated hypoxia inducible factor (HIF) levels at normoxia. CP is often treated by phlebotomy resulting in iron deficiency, permitting us to examine the separate and synergistic effects of iron deficiency and HIF signaling on gene expression. We compared peripheral blood mononuclear cell gene expression profiles of eight VHL(R200W) homozygotes with 17 wildtype individuals with normal iron status and found 812 up-regulated and 2120 down-regulated genes at false discovery rate of 0.05. Among differential genes we identified three major gene regulation modules involving induction of innate immune responses, alteration of carbohydrate and lipid metabolism, and down-regulation of cell proliferation, stress-induced apoptosis and T-cell activation. These observations suggest molecular mechanisms for previous observations in CP of lower blood sugar without increased insulin and low oncogenic potential. Studies including 16 additional VHL(R200W) homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHL(R200W) for 50 genes including hemoglobin synthesis loci but suppressed the effect for 107 genes enriched for HIF-2 targets. This pattern is consistent with potentiation of HIF-1α protein stability by iron deficiency but a trend for down-regulation of HIF-2α translation by iron deficiency overriding an increase in HIF-2α protein stability.
    Blood Cells Molecules and Diseases 08/2013; · 2.26 Impact Factor
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    ABSTRACT: Disorders linked to mutations in the X chromosomes typically affect males. The aim of the study is to decipher the mechanism of disease expression in a female patient with a heterozygous mutation on the X-chromosome. Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Genomic ribonucleic acid (DNA) and complementary DNA (cDNA) underwent Sanger sequencing. Protein analysis was performed by flow cytometry. X-inactivation patterns were analyzed by evaluating the DNA methylation status and cDNA clonal expression of several genes on the X-chromosome. SNP array was used for molecular karyotyping of the X-chromosome. A female with thrombocytopenia, eczema and mild T-lymphocyte abnormalities with extensive negative diagnostic testing, was suspected to have Wiskott-Aldrich syndrome (WAS)/X-linked thrombocytopenia. Although the girl had a mutation (c.397G > A, p.E133K) in only one allele, she was found to have an extremely skewed X-inactivation pattern and no expression of the WAS protein. Family studies using DNA methylation analysis and cDNA clonal expression of several genes on the X-chromosome demonstrated that the patient developed de-novo non-random inactivation of the X-chromosome that does not carry the mutation. Genome-wide high-density molecular karyotyping excluded deletions and amplifications as a cause for the non-random inactivation of one X-chromosome. Our study emphasizes the need to test selected female patients with complete or incomplete disease expression for X-linked disorders even in the absence of a family history.
    Journal of Clinical Immunology 08/2013; · 3.38 Impact Factor
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    ABSTRACT: We cared for a term female newborn, who at 108 hours of age, with a total serum bilirubin of 15.4 mg/dL, was discharged from the hospital on home phototherapy. At a return appointment 44 hours later, her total serum bilirubin was 41.7 mg/dL and signs of acute kernicterus were present. Maternal/fetal blood group O/B incompatibility was identified, with a negative direct antiglobulin test, which was positive on retesting. She had abundant spherocytes on blood smear, and these persisted at follow-up, but neither parent had spherocytes identified. A heterozygous SLC4A1(E508K) mutation (gene encoding erythrocyte membrane protein band 3) was found, and in silico predicted to result in damaged erythrocyte cytoskeletal protein function. No mutations were identified in other red cell cytoskeleton genes (ANK1, SPTA1, SPTB, EPB41, EPB42) and the UGT1A1 promoter region was normal. Neurologic follow-up at 2 and 4 months showed developmental delays consistent with mild kernicterus.
    PEDIATRICS 07/2013; · 4.47 Impact Factor

Publication Stats

7k Citations
2,387.86 Total Impact Points

Institutions

  • 2006–2014
    • University of Utah
      • • Division of Hematology
      • • School of Medicine
      • • Division of Pediatric Hematology and Oncology
      Salt Lake City, Utah, United States
    • Ospedali Riuniti di Bergamo
      • Department of Hematology
      Bergamo, Lombardy, Italy
  • 2013
    • National Institutes of Health
      Maryland, United States
  • 2005–2013
    • University of Illinois at Chicago
      • • Comprehensive Sickle Cell Center
      • • Section of Hematology and Oncology
      Chicago, IL, United States
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 2012
    • Children's National Medical Center
      • Division of Cardiology
      Washington, D. C., DC, United States
    • Al-Azhar University - Gaza
      Ghazzah, Gaza Strip, Palestinian Territory
  • 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
  • 2010
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2009–2010
    • Institute of Hematology and Blood Transfusion
      Praha, Praha, Czech Republic
    • Arup
      Londinium, England, United Kingdom
  • 1978–2009
    • University of Alabama at Birmingham
      • • Department of Medicine
      • • Division of Nephrology
      • • Division of Hematology / Oncology
      • • Department of Ophthalmology
      • • Division of Laboratory Medicine
      Birmingham, AL, United States
  • 2008
    • Russian Children's Clinical Hospital
      Moskva, Moscow, Russia
  • 2007
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
    • Charles University in Prague
      • Institute of Pathological Physiology (Pilsen)
      Praha, Praha, Czech Republic
  • 2001–2007
    • Baylor College of Medicine
      • • Department of Medicine
      • • Section of Hematology/Oncology
      Houston, Texas, United States
  • 2003
    • Texas Children's Cancer and Hematology Centers
      Houston, Texas, United States
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1997
    • Chuvash State University
      Cheboksar’, Chuvashia, Russia
  • 1988–1997
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States
    • City of Hope National Medical Center
      Duarte, California, United States
    • The University of Calgary
      Calgary, Alberta, Canada
  • 1994–1996
    • Cooper Hospital
      Green Bay, Wisconsin, United States
  • 1995
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1985
    • University of Alabama
      Tuscaloosa, Alabama, United States