43 results on '"Thiele, J."'
Search Results
2. Spin-Based Data Storage
- Author
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Ozatay, O., primary, Mather, P.G., additional, Thiele, J.-U., additional, Hauet, T., additional, and Braganca, P.M., additional
- Published
- 2011
- Full Text
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3. Characterization of atmospheric aerosols using SR-TXRF and Fe K-edge TXRF-XANES
- Author
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Fittschen, U. E. A., Meirer, F., Streli, C., Wobrauschek, P., Thiele, J., Falkenberg, G., and Pepponi, G.
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ddc:540 - Published
- 2008
4. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.
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Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Döhner H, and Tefferi A
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- Acute Disease, Consensus, Genomics, Humans, World Health Organization, Hematologic Neoplasms pathology, Leukemia diagnosis, Leukemia genetics, Leukemia pathology, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology
- Abstract
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
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- 2022
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5. Optimized procedures for generating an enhanced, near physiological 2D culture system from porcine intestinal organoids.
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van der Hee B, Loonen LMP, Taverne N, Taverne-Thiele JJ, Smidt H, and Wells JM
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- Animals, Cell Differentiation, Cell Lineage, Cells, Cultured, Electric Impedance, Intestines ultrastructure, Organoids ultrastructure, Paneth Cells cytology, Sus scrofa, Tight Junctions metabolism, Tight Junctions ultrastructure, Cell Culture Techniques methods, Intestines cytology, Organoids cytology
- Abstract
An important practical limitation of the three-dimensional geometry of stem-cell derived intestinal organoids is that it prevents easy access to the apical epithelium for testing food components, microorganisms, bioactive and toxic compounds. To this end, we here report on a new robust method for generating confluent intestinal cell monolayers from single-cell suspensions of enzymatically-dissociated porcine organoids using modified culture conditions. With this method, cell seeding densities can be standardised, overcoming problems with methods based on mechanical dissociation of organoids. Confluent monolayers formed tight junctions with high transepithelial electrical resistance in three days and could be used in experiments for up to two weeks. Multilineage differentiation of ileal stem cells was demonstrated by immunohistochemistry and RT-qPCR of cell-specific transcripts, also unequivocally confirming the controversial existence of Paneth-like cells in the porcine small intestine. The method described here is useful to standardize primary epithelial monolayer formation from intestinal organoids and allows rapid and robust studies of intestinal physiology., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2018
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6. The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances.
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Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, and Tefferi A
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- Disease Susceptibility, Humans, Myeloproliferative Disorders etiology, World Health Organization, Myeloproliferative Disorders diagnosis, Practice Guidelines as Topic
- Abstract
Clinical evidence supports the need of changing the diagnostic criteria of the 2008 updated WHO classification for polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). In JAK2-mutated patients who show characteristic bone marrow (BM) morphology, clinical studies demonstrated that a hemoglobin level of 16.5g/dL in men and 16.0g/dl for women or a hematocrit value of 49% in men and 48% in women are the optimal cut off levels for distinguishing JAK2-mutated ET from "masked/prodromal" PV. Therefore BM morphology was upgraded to a major diagnostic criterion. Regarding ET the key issue was to improve standardization of prominent BM features enhancing differentiation between "true" ET and prefibrotic/early primary myelofibrosis (prePMF). These two entities have shown a different epidemiology and clinical outcomes. Concerning prePMF a more explicit clinical characterization of minor criteria is mandated for an improved distinction from ET and overt PMF and accurate diagnosis and outcome prediction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
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- 2016
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7. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
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Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, and Vardiman JW
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- Cell Lineage, Down Syndrome complications, Eosinophilia complications, Genes, Neoplasm, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Mastocytosis complications, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Myeloid Cells pathology, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology, Oncogene Proteins, Fusion genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma classification, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, World Health Organization, Leukemia, Myeloid classification, Myelodysplastic Syndromes classification, Myeloproliferative Disorders classification
- Abstract
The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here., (© 2016 by The American Society of Hematology.)
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- 2016
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8. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
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Vannucchi AM, Barbui T, Cervantes F, Harrison C, Kiladjian JJ, Kröger N, Thiele J, and Buske C
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- Humans, Philadelphia Chromosome, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative diagnosis, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative pathology, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative therapy
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- 2015
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9. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.
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Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, Gangat N, Fjerza R, Belachew AA, Lasho TL, Ketterling RP, Hanson CA, Rambaldi A, Finazzi G, Thiele J, Barbui T, Pardanani A, and Vannucchi AM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Polycythemia Vera diagnosis, Primary Myelofibrosis diagnosis, Prognosis, Survival Analysis, Thrombocythemia, Essential diagnosis, Young Adult, Calreticulin genetics, Janus Kinase 2 genetics, Mutation, Polycythemia Vera genetics, Primary Myelofibrosis genetics, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential genetics
- Abstract
Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative., (© 2014 by The American Society of Hematology.)
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- 2014
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10. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report.
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Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, Gotlib J, Dupriez B, Pardanani A, Harrison C, Hoffman R, Gisslinger H, Kröger N, Thiele J, Barbui T, and Barosi G
- Subjects
- Bone Marrow Neoplasms diagnosis, Bone Marrow Neoplasms drug therapy, Chronic Disease drug therapy, Consensus, Disease Progression, Erythrocyte Transfusion methods, Europe, Humans, International Cooperation, Medical Oncology standards, Myeloproliferative Disorders therapy, Practice Guidelines as Topic, Remission Induction, Treatment Outcome, Medical Oncology methods, Primary Myelofibrosis diagnosis, Primary Myelofibrosis drug therapy
- Abstract
The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment.
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- 2013
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11. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial.
- Author
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Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, Kralovics R, and Petrides PE
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Maximum Tolerated Dose, Middle Aged, Prognosis, Prospective Studies, Retrospective Studies, Single-Blind Method, Thrombocythemia, Essential pathology, World Health Organization, Young Adult, Hydroxyurea therapeutic use, Nucleic Acid Synthesis Inhibitors therapeutic use, Platelet Aggregation Inhibitors therapeutic use, Quinazolines therapeutic use, Thrombocythemia, Essential drug therapy
- Abstract
High platelet counts in essential thrombocythemia (ET) can be effectively lowered by treatment with either anagrelide or hydroxyurea. In 259 previously untreated, high-risk patients with ET, diagnosed according to the World Health Organization classification system, the efficacy and tolerability of anagrelide compared with hydroxyurea were investigated in a prospective randomized noninferiority phase 3 study in an a priori-ordered hypothesis. Confirmatory proof of the noninferiority of anagrelide was achieved after 6 months using the primary end point criteria and was further confirmed after an observation time of 12 and 36 months for platelet counts, hemoglobin levels, leukocyte counts (P < .001), and ET-related events (HR, 1.19 [95% CI, 0.61-2.30], 1.03 [95% CI, 0.57-1.81], and 0.92 [95% CI, 0.57-1.46], respectively). During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and hydroxyurea group regarding incidences of major arterial (7 vs 8) and venous (2 vs 6) thrombosis, severe bleeding events (5 vs 2), minor arterial (24 vs 20) and venous (3 vs 3) thrombosis and minor bleeding events (18 vs 15), or rates of discontinuation (adverse events 12 vs 15 or lack of response 5 vs 2). Disease transformation into myelofibrosis or secondary leukemia was not reported. Anagrelide as a selective platelet-lowering agent is not inferior compared with hydroxyurea in the prevention of thrombotic complications in patients with ET diagnosed according to the World Health Organization system. This trial was registered at http://www.clinicaltrials.gov as #NCT01065038.
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- 2013
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12. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis).
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Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Vannucchi AM, and Tefferi A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, International Classification of Diseases, Male, Middle Aged, Prognosis, Research Design, Thrombocythemia, Essential pathology, Young Adult, Severity of Illness Index, Thrombocythemia, Essential classification, Thrombocythemia, Essential diagnosis, World Health Organization
- Abstract
Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.
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- 2012
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13. A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment.
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Passamonti F, Thiele J, Girodon F, Rumi E, Carobbio A, Gisslinger H, Kvasnicka HM, Ruggeri M, Randi ML, Gangat N, Vannucchi AM, Gianatti A, Gisslinger B, Müllauer L, Rodeghiero F, d'Amore ES, Bertozzi I, Hanson CA, Boveri E, Marino F, Maffioli M, Caramazza D, Antonioli E, Carrai V, Buxhofer-Ausch V, Pascutto C, Cazzola M, Barbui T, and Tefferi A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, International Cooperation, Male, Middle Aged, Models, Statistical, Multicenter Studies as Topic, Primary Myelofibrosis etiology, Prognosis, Survival Analysis, Thrombocythemia, Essential therapy, World Health Organization, Young Adult, Primary Myelofibrosis therapy, Thrombocythemia, Essential diagnosis, Thrombocythemia, Essential mortality
- Abstract
Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 10(9)/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 10(9)/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.
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- 2012
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14. Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis.
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Barbui T, Thiele J, Carobbio A, Passamonti F, Rumi E, Randi ML, Bertozzi I, Vannucchi AM, Gisslinger H, Gisslinger B, Finazzi G, Ruggeri M, Rodeghiero F, Rambaldi A, Gangat N, and Tefferi A
- Subjects
- Adolescent, Adult, Age of Onset, Disease Progression, Disease-Free Survival, Follow-Up Studies, Humans, Janus Kinase 2 genetics, Kaplan-Meier Estimate, Primary Myelofibrosis therapy, Proportional Hazards Models, Risk Factors, Thrombocythemia, Essential therapy, Young Adult, Databases, Factual statistics & numerical data, Primary Myelofibrosis mortality, Thrombocythemia, Essential mortality
- Abstract
In the present study, we investigated disease characteristics and clinical outcome in young patients (< 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) compared with early/prefibrotic primary myelofibrosis (PMF) with presenting thrombocythemia. We recruited 213 young patients (median age, 33.6 years), including 178 patients (84%) with WHO-defined ET and 35 patients (16%) showing early PMF. Median follow-up time was 7.5 years. A trend for more overall thrombotic complications, particularly arterial, was seen in early PMF compared with ET. Progression to overt myelofibrosis was 3% in ET and 9% in early PMF, but no transformation into acute leukemia was observed. Combining all adverse events (thrombosis, bleeding, and myelofibrosis), the rate was significantly different (1.29% vs 3.43% of patients/year, P = .01) in WHO-ET and early PMF, respectively. In multivariate analysis, early PMF and the JAK2V617F mutation emerged as independent factors predicting cumulative adverse events.
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- 2012
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15. Negative pressure wound therapy reduces the ischaemia/reperfusion-associated inflammatory response in free muscle flaps.
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Eisenhardt SU, Schmidt Y, Thiele JR, Iblher N, Penna V, Torio-Padron N, Stark GB, and Bannasch H
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- Adult, Aged, Aged, 80 and over, Apoptosis, Bandages, Biopsy, Edema metabolism, Edema therapy, Female, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Interleukin-1beta metabolism, Male, Middle Aged, Petrolatum, Real-Time Polymerase Chain Reaction, Reperfusion Injury metabolism, Treatment Outcome, Tumor Necrosis Factor-alpha metabolism, Muscle, Skeletal transplantation, Negative-Pressure Wound Therapy, Reperfusion Injury therapy, Skin Transplantation methods, Surgical Flaps
- Abstract
Background: We recently established negative pressure wound therapy (NPWT) as a safe postoperative care concept for free muscle flaps; however, the molecular effects of NPWT on free muscle flaps remain elusive. Here we investigated the effects of NPWT on pathological changes associated with ischaemia/reperfusion injury in free flap tissue., Methods: From July 2008 to September 2010, 30 patients receiving skin-grafted free muscle transfer for defect coverage were randomly assigned to two treatment groups: In one group the skin-grafted free flap was covered by a vacuum dressing (NPWT); in the second group, flaps were covered by conventional petroleum gauze dressings (conv). Biopsies were taken intra-operatively prior to clipping of the pedicle and on postoperative day 5. Samples were analysed by immunohistochemistry for infiltration of inflammatory cells, real-time polymerase chain reaction (RT-PCR) for the analysis of expression levels of interleukin-1β (IL-1β) and tumour necrosis factor (TNF)-alpha as markers of inflammation. Histological samples were also examined for interstitial oedema formation, and apoptosis was detected by a terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay., Results: NPWT leads to a significantly reduced tissue infiltration of CD68 + macrophages and reduced expression of the inflammatory cytokines IL-1β and TNFα. None of these parameters was significantly elevated in the pre-ischaemic biopsies. Furthermore, NPWT reduced the interstitial oedema formation and the number of apoptotic cells in free flap tissue., Conclusion: NPWT of skin-grafted free muscle flaps leads to a reduced inflammatory response following ischaemia/reperfusion, resulting in reduced oedema formation improving the microcirculation and ultimately reduced tissue damage. We thereby deliver new insight into the effects of NPWT., (Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)
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- 2012
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16. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome.
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Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Randi ML, Bertozzi I, Marino F, Vannucchi AM, Pieri L, Rotunno G, Gisslinger H, Gisslinger B, Müllauer L, Finazzi G, Carobbio A, Gianatti A, Ruggeri M, Nichele I, D'Amore E, Rambaldi A, and Tefferi A
- Subjects
- Bone Marrow metabolism, Disease Progression, Fibrosis, Follow-Up Studies, Humans, Janus Kinase 2 genetics, Leukemia complications, Mutation, Polycythemia Vera complications, Polycythemia Vera genetics, Primary Myelofibrosis complications, Prognosis, Reticulin metabolism, Survival Analysis, Thrombosis complications, Bone Marrow pathology, Polycythemia Vera pathology
- Abstract
We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization-defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient-years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera.
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- 2012
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17. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients.
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Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Vannucchi AM, Antonioli E, Gisslinger H, Buxhofer-Ausch V, Finazzi G, Gangat N, Tefferi A, and Barbui T
- Subjects
- Cardiovascular Diseases complications, Female, Follow-Up Studies, Humans, Hypertension complications, Incidence, International Agencies, Janus Kinase 2 genetics, Male, Middle Aged, Mutation genetics, Polycythemia Vera complications, Prognosis, Risk Factors, Survival Rate, Thrombocythemia, Essential therapy, Thrombosis pathology, Venous Thrombosis pathology, Arteries pathology, Thrombocythemia, Essential complications, Thrombosis etiology, Venous Thrombosis etiology
- Abstract
In an international collaborative study, a central histologic review identified 891 patients with essential thrombocythemia, strictly defined by World Health Organization criteria. After a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. In multivariable analysis, predictors of arterial thrombosis included age more than 60 years (P = .03; hazard ratio [HR] = 1.7), thrombosis history (P = .003; HR = 2.1), cardiovascular risk factors including tobacco use, hypertension, or diabetes mellitus (P = .007; HR = 1.9), leukocytosis (> 11 × 10(9)/L; P = .04; HR = 1.7), and presence of JAK2V617F (P = .009; HR = 2.6). In contrast, only male gender predicted venous thrombosis. Platelet count more than 1000 × 10(9)/L was associated with a lower risk of arterial thrombosis (P = .007; HR = 0.4). These associations, except the one with leukocytosis, remained significant (or near significant) when analysis was restricted to JAK2V617F-positive cases. The current study clarifies the contribution of specific disease and host characteristics to the risk of arterial versus venous thrombosis in essential thrombocythemia.
- Published
- 2011
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18. Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.
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Thiele J, Kvasnicka HM, Müllauer L, Buxhofer-Ausch V, Gisslinger B, and Gisslinger H
- Subjects
- Cohort Studies, Female, Humans, Male, Middle Aged, Primary Myelofibrosis pathology, Prognosis, Survival Rate, Thrombocythemia, Essential pathology, World Health Organization, Bone Marrow pathology, Primary Myelofibrosis classification, Thrombocythemia, Essential classification
- Abstract
Controversy persists regarding the role of histopathology in the distinction between essential thrombocythemia (ET) and early-prefibrotic primary myelofi-brosis (PMF) presenting with thrombocythemia. To investigate the impact and reproducibility of bone marrow (BM) morphology according to the World Health Organization classification, 295 patients with the presumptive clinical diagnosis of either ET or early PMF were studied. Data of this cohort (Vienna group) were compared with 732 corresponding patients (Cologne group). Evaluating blindly (only age and gender known) BM specimens, the 2 groups of pathologists achieved an overall consensus of 78% regarding the total series and 88% concerning the discrimination between ET versus PMF. In 126 ET and 81 early PMF patients without pretreatment and complete documentation, a 90% concordance with the independently established clinical diagnosis was found. In 12 patients, overlapping of histopathology and some clinical findings between ET and polycythemia vera occurred. Contrasting ET, early PMF showed significant differences of presenting hematologic data and an unfavorable prognosis (estimated mean survival, 14 vs 21 years). Comparison of clinical and survival data of the Vienna cohort with the historical Cologne series revealed an overall congruence. This study highlights the impact of BM morphology for the differentiation between true vs false ET.
- Published
- 2011
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19. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
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Kröger N, Holler E, Kobbe G, Bornhäuser M, Schwerdtfeger R, Baurmann H, Nagler A, Bethge W, Stelljes M, Uharek L, Wandt H, Burchert A, Corradini P, Schubert J, Kaufmann M, Dreger P, Wulf GG, Einsele H, Zabelina T, Kvasnicka HM, Thiele J, Brand R, Zander AR, Niederwieser D, and de Witte TM
- Subjects
- Adult, Aged, Busulfan therapeutic use, Disease-Free Survival, Female, Graft vs Host Disease epidemiology, Humans, Male, Middle Aged, Myeloablative Agonists therapeutic use, Primary Myelofibrosis mortality, Recurrence, Stem Cell Transplantation adverse effects, Transplantation, Homologous, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Primary Myelofibrosis surgery, Stem Cell Transplantation methods, Transplantation Conditioning methods
- Abstract
From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen-mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.
- Published
- 2009
- Full Text
- View/download PDF
20. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.
- Author
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Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, and Bloomfield CD
- Subjects
- Acute Disease, Bone Marrow Examination standards, Cell Count, Cell Lineage, Chromosome Aberrations, Eosinophilia classification, Hematologic Neoplasms classification, Humans, Leukemia diagnosis, Leukemia genetics, Leukemia pathology, Mastocytosis, Systemic classification, Mutation, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Myelodysplastic-Myeloproliferative Diseases classification, Myelodysplastic-Myeloproliferative Diseases diagnosis, Myelodysplastic-Myeloproliferative Diseases genetics, Myelodysplastic-Myeloproliferative Diseases pathology, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology, Neoplastic Stem Cells pathology, Preleukemia classification, Terminology as Topic, World Health Organization, Leukemia classification, Myelodysplastic Syndromes classification, Myeloproliferative Disorders classification
- Abstract
Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
- Published
- 2009
- Full Text
- View/download PDF
21. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel.
- Author
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Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, and Vardiman JW
- Subjects
- Humans, Mitogen-Activated Protein Kinase 9 genetics, Mutation, Polycythemia Vera diagnosis, Polycythemia Vera genetics, Primary Myelofibrosis diagnosis, Primary Myelofibrosis genetics, Primary Myelofibrosis pathology, Thrombocythemia, Essential diagnosis, Thrombocythemia, Essential genetics, World Health Organization
- Abstract
The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 x 10(9)/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.
- Published
- 2007
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22. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT).
- Author
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Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odenike O, Cortes J, Wadleigh M, Solberg LA Jr, Camoriano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Hoffman R, Cross NC, Gilliland DG, and Kantarjian H
- Subjects
- Disease Progression, Humans, Janus Kinase 2, Mutation, Primary Myelofibrosis genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Treatment Outcome, Primary Myelofibrosis complications, Primary Myelofibrosis therapy
- Abstract
Myelofibrosis with myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
- Published
- 2006
- Full Text
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23. Bone marrow histopathology in the diagnosis of chronic myeloproliferative disorders: a forgotten pearl.
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Thiele J, Kvasnicka HM, and Vardiman J
- Subjects
- Humans, Leukemia, Neutrophilic, Chronic pathology, Myeloproliferative Disorders diagnosis, Polycythemia Vera pathology, Primary Myelofibrosis pathology, Thrombocythemia, Essential pathology, Bone Marrow pathology, Myeloproliferative Disorders pathology
- Abstract
Histopathology of bone marrow (BM) biopsies plays a crucial role in the interdisciplinary approach to diagnosis and classification of chronic myeloproliferative disorders (CMPDs). Based on careful clinicopathologic studies, BM features are critical determinants that help to predict overall prognosis, to detect complications such as progression to myelofibrosis and blast crisis, and to assess therapy-related changes. A systematic evaluation of BM histopathology allows an objective identification of cases of (true) essential thrombocythemia (ET) and their separation from (false) ET, which often is the prodromal stage of chronic idiopathic myelofibrosis (CIMF). By follow-up examinations that include BM biopsies, the progression of the disease process is unveiled, which is especially important for patients with initial (early) polycythemia vera and prefibrotic CIMF that may require a different therapeutic approach than the full-blown stages. In conclusion, BM biopsy should be considered as major diagnostic tool for evaluation and follow-up of patients enrolled in prospective studies.
- Published
- 2006
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24. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET).
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Barosi G, Bordessoule D, Briere J, Cervantes F, Demory JL, Dupriez B, Gisslinger H, Griesshammer M, Hasselbalch H, Kusec R, Le Bousse-Kerdiles MC, Liberato NL, Marchetti M, Reilly JT, and Thiele J
- Subjects
- Adult, Aged, Bone Marrow pathology, Europe, Hematology methods, Hematology standards, Humans, Middle Aged, Primary Myelofibrosis complications, Primary Myelofibrosis pathology, Primary Myelofibrosis diagnosis, Primary Myelofibrosis therapy
- Abstract
The European Myelofibrosis Network (EUMNET), a European research network on myelofibrosis with myeloid metaplasia (MMM), has developed a definition of response for the disease by using clinicohematologic, histologic, and cytogenetic criteria. A core set of 5 clinicohematologic criteria was selected out of 9 candidates on the basis of their sensitivity to change measured in 196 patients treated either during clinical trials or routine clinical practice. A consensus panel of 16 international experts was convened and asked to score the level of response in 104 patient profiles as major, moderate, minor, or no response according to changes of the clinicohematologic criteria. Using the experts' consensus as the gold standard, the performance of 100 possible definitions of response was evaluated. Criteria for major or moderate clinicohematologic response were determined to be changes in hemoglobin (Hb) and spleen size and the presence of constitutional symptoms, while changes in platelet count and white blood cell (WBC) count served as complementary criteria and were of value for defining minor responses. A histologic response was defined by changes in bone marrow fibrosis and cellularity grades. The combined use of these response definitions should help standardize the design and reporting of future clinical studies in MMM.
- Published
- 2005
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25. Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy.
- Author
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Kvasnicka HM, Thiele J, Staib P, Schmitt-Graeff A, Griesshammer M, Klose J, Engels K, and Kriener S
- Subjects
- Adult, Antineoplastic Agents therapeutic use, Benzamides, Bone Marrow Examination, Drug Evaluation, Humans, Hydroxyurea therapeutic use, Imatinib Mesylate, Interferon alpha-2, Interferon-alpha therapeutic use, Microcirculation, Recombinant Proteins, Remission Induction, Retrospective Studies, Bone Marrow blood supply, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neovascularization, Pathologic drug therapy, Piperazines therapeutic use, Pyrimidines therapeutic use
- Abstract
The effect of imatinib mesylate (imatinib) therapy on angiogenesis and myelofibrosis was investigated and compared with interferon (IFN) and hydroxyurea (HU) in 98 patients with newly diagnosed Philadelphia chromosome-positive/BCR-ABL(+) (Ph(+)/BCR-ABL(+)) chronic myeloid leukemia in first chronic phase and no other pretreatment. By means of immunostaining (CD34) and morphometry, a relationship between microvessel frequency and fiber density was detectable in initial bone marrow (BM) biopsies and sequential examinations after at least 8 months of therapy. First-line monotherapy with imatinib induced a significant reduction (normalization in comparison with controls) of microvessels and reticulin fibers. In most patients, decrease in BM vascularity was associated with a complete cytogenetic response. A significant anti-angiogenic effect was also observed after HU treatment, contrasting with IFN administration or combination regimens (IFN plus HU). In conclusion, our data support the anti-angiogenic capacity of imatinib by normalization of vascularity. In contrast, hematologic response following IFN treatment is independent from BM angiogenesis.
- Published
- 2004
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26. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis.
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Hartmann K, Artuc M, Baldus SE, Zirbes TK, Hermes B, Thiele J, Mekori YA, and Henz BM
- Subjects
- Adult, Child, Preschool, Humans, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-kit metabolism, RNA, Messenger metabolism, bcl-X Protein, Bone Marrow metabolism, Mastocytosis, Cutaneous metabolism, Mastocytosis, Systemic metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
Mastocytosis is a rare disease characterized by accumulation of mast cells in tissues. To investigate whether an altered regulation of mast cell apoptosis might be involved in the pathogenesis of mastocytosis, expression of the apoptosis-preventing molecules bcl-2 and bcl-xL was studied by immunohistochemistry in skin and bone marrow lesions of mastocytosis patients. In addition, reverse transcription-polymerase chain reaction was used to investigate levels of bcl-2 and bcl-xL mRNA in cutaneous mastocytosis lesions. Since activating mutations of c-kit are known to be associated with some forms of mastocytosis, human mast cell cultures were also stimulated via c-kit and the expression of bcl-2 and bcl-xL was assessed by immunoblotting. In patients with mastocytosis, the expression of bcl-2 protein but not bcl-xL in cutaneous mast cells was significantly enhanced, compared to healthy controls. Evaluating different subgroups of adult and pediatric mastocytosis patients, all groups were found to express significantly increased levels of bcl-2 protein, and none of the patient groups was found to overexpress bcl-xL, with the exception of solitary mastocytomas that showed a tendency for up-regulated bcl-xL protein. Furthermore, the expression of bcl-2 mRNA was significantly enhanced in cutaneous lesions of adult and pediatric patients, while bcl-xL mRNA levels were only slightly increased in pediatric, but not in adult patients with mastocytosis. In contrast to the skin lesions, bone marrow infiltrates of patients with systemic mastocytosis showed only low or absent immunoreactivity for bcl-2, but marked expression of bcl-xL. In vitro, stimulation of two different mast cell culture systems by activation of c-kit resulted in up-regulation of bcl-2 and also in an increase of bcl-xL, although less pronounced. Thus, overexpression of bcl-2 and bcl-xL leading to prolonged survival of mast cells may contribute to the pathogenesis of mastocytosis. Our findings may help to develop new strategies for the treatment of this disease.
- Published
- 2003
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27. Clinicopathology and histochemistry on bone marrow biopsies in chronic myeloproliferative disorders--a clue to diagnosis and classification.
- Author
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Thiele J and Kvasnicka HM
- Subjects
- Aged, Bone Marrow chemistry, Bone Marrow Examination methods, Diagnosis, Differential, Female, Hematocrit, Hemoglobins analysis, Humans, Male, Megakaryocytes pathology, Middle Aged, Myeloproliferative Disorders classification, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders epidemiology, Myeloproliferative Disorders metabolism, Platelet Count, Polycythemia diagnosis, Polycythemia Vera diagnosis, Retrospective Studies, Smoking blood, Thrombocythemia, Essential diagnosis, Thrombocythemia, Essential epidemiology, Thrombocytosis diagnosis, Thrombocytosis epidemiology, Bone Marrow pathology, Myeloproliferative Disorders pathology
- Abstract
A clinicopathological study was carried out to address the currently still controversial issues of: 1) thrombocythaemias in chronic myeloproliferative disorders (MPDs); 2) Initial, prefibrotic idiopathic myelofibrosis (IMF); 3) discrimination of spurious polycythaemic states or polyglobuly (PG) from polycythaemia vera (PV); 4) unclassifiable MPDs. Based on a synoptical approach which implicates a comparative evaluation of laboratory data and histopathology of the bone marrow, the discriminating efficiency of both diagnostic tools has been emphasized. An elaborate evaluation of histotopography and cytological appearance of megakaryopoiesis is an invaluable aid to distinguish the different subtypes of MPDs which may eventually present with a significant elevation of the platelet count. Prefibrotic IMF is not only associated with a certain set of clinical symptoms (minimal to slight anaemia, splenomegaly, thrombocytosis), but should also be characterized by specific alterations of bone marrow morphology. Moreover, follow-up studies are in keeping with the finding that these patients evolve into typical IMF regarding laboratory parameters and ensuing myelofibrosis. Smokers polycythaemia--PG may be separated from early PV by the significant raise in the red cell mass and also by a few, easily determinable clinical parameters (i.e. EPO level, thrombocytosis, LAP). Both conditions can be distinguished by regarding bone marrow features (megakaryopoiesis, interstitial changes) which exert a distinctive impact. According to our experience the majority of patients categorized as unclassifiable MPDs include cases in which clinical or morphological data are inadequate to permit a more precise diagnosis. Only in a small proportion not a failing methodology, but initial stages of the disease process requires sequential examinations to reach a correct diagnosis.
- Published
- 2001
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28. Sebaceous gland secretion is a major physiologic route of vitamin E delivery to skin.
- Author
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Thiele JJ, Weber SU, and Packer L
- Subjects
- Adult, Epidermis chemistry, Female, Humans, Male, Vitamin E analysis, Epidermis metabolism, Sebaceous Glands metabolism, Vitamin E metabolism
- Abstract
Skin plays an important part in the protection against oxidative stressors, such as ultraviolet radiation, ozone, and chemicals. This study was based on the observation that upper facial stratum corneum contained significantly higher levels of the antioxidant alpha-tocopherol than corresponding layers of arm stratum corneum. We hypothesized that the underlying mechanism involves sebaceous gland secretion of vitamin E. To test this, we examined in eight human volunteers: (i) stratum corneum levels and distribution profiles of vitamin E in sites with a different sebaceous gland density (arm versus cheek); (ii) whether vitamin E is a significant constituent of human sebum; and (iii) if there is a correlation between levels of vitamin E and squalene, a marker of sebum secretion, in skin surface lipids. Using standardized techniques for stratum corneum tape stripping and sebum collection, followed by high-performance liquid chromatography analysis of tocopherols and squalene, we found that: (i) the ratio of cheek versus upper arm alpha-tocopherol levels was 20 : 1 for the upper stratum corneum and decreased gradually with stratum corneum depth; (ii) vitamin E (alpha- and gamma-tocopherol forms) is a significant constituent of human sebum and is continuously secreted at cheek and forehead sites during a test period of 135 min; and (iii) vitamin E correlates well with levels of cosecreted squalene (r2 = 0.86, p < 0.001). In conclusion, sebaceous gland secretion is a relevant physiologic pathway for the delivery of vitamin E to upper layers of facial skin. This mechanism may serve to protect skin surface lipids and the upper stratum corneum from harmful oxidation.
- Published
- 1999
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29. Vitamin C, uric acid, and glutathione gradients in murine stratum corneum and their susceptibility to ozone exposure.
- Author
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Weber SU, Thiele JJ, Cross CE, and Packer L
- Subjects
- Animals, Epidermis chemistry, Female, Mice, Mice, Hairless, Antioxidants analysis, Ascorbic Acid analysis, Epidermis drug effects, Glutathione analysis, Ozone toxicity, Uric Acid analysis
- Abstract
The stratum corneum has been recognized as the main cutaneous oxidation target of atmospheric ozone (O3), a major part of photochemical smog. This study reports the presence and distribution of vitamin C, glutathione, and uric acid in murine stratum corneum, and evaluates their susceptibility to acute environmental exposure to O3. Based on tape stripping and a modified extraction method with high performance liquid chromatography electrochemical analysis, we detected vitamin C (208.0 +/- 82.5 pmol per 10 consecutive pooled tapes), glutathione (283.7 +/-96.3), and uric acid (286.4 +/-47.1) in murine stratum corneum as compared with only 16.5 +/- 1.4 pmol alpha-tocopherol. Vitamin C, glutathione (both p < 00.001), and urate (p < 0.01) were found to exhibit a gradient with the lowest concentrations in the outer layers and a steep increase in the deeper layers. To investigate the effect of O3 exposure on hydrophilic antioxidants, we exposed SKH-1 hairless mice to O3 concentrations of 0, 0.8, 1, and 10 p.p.m., and stratum corneum was analyzed before and after exposure. Whereas mock exposure with 0 p.p. m. for 2 h had no significant effect, O3 doses of 1 p.p.m. for 2 h and above showed depletion of all three antioxidants. Vitamin C was decreased to 80% +/- 15% of its pretreatment content (p < 0.05), GSH to 41% +/- 24% (p < 0.01), and uric acid to 44% +/- 28% (p < 0.01). This report demonstrates the previously unrecognized role of hydrophilic antioxidants in the stratum corneum and provides further evidence that O3 induces oxidative stress in this outer skin layer.
- Published
- 1999
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- View/download PDF
30. Myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and chronic myeloproliferative disorder (CMPD) in cats.
- Author
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Breuer W, Hermanns W, and Thiele J
- Subjects
- Acute Disease, Animals, Antibodies, Viral analysis, Bone Marrow pathology, Bone Marrow ultrastructure, Bone Marrow virology, Cat Diseases virology, Cats, Chronic Disease, Enzyme-Linked Immunosorbent Assay, Female, Gammaretrovirus isolation & purification, Leukemia, Myeloid pathology, Leukemia, Myeloid virology, Liver pathology, Lymph Nodes pathology, Male, Megakaryocytes pathology, Megakaryocytes ultrastructure, Myelodysplastic Syndromes pathology, Myelodysplastic Syndromes virology, Myeloproliferative Disorders pathology, Myeloproliferative Disorders virology, Spleen pathology, Cat Diseases pathology, Leukemia, Myeloid veterinary, Myelodysplastic Syndromes veterinary, Myeloproliferative Disorders veterinary
- Abstract
Histological, enzyme histochemical and ultrastructural findings in three cases of feline bone marrow neoplasia are described. The following changes were observed: in myelodysplastic syndrome (MDS), a low medullary blast count, strongly atypical (micromegakaryocytic) proliferative megakaryocytopoiesis, hypoplastic erythrocytopoiesis with impairment of differentiation, multifocal extravasation and lymphoid aggregates; in acute myeloid leukaemia (AML), medullary proliferation of undifferentiated cell types; in chronic myeloIproliferative disorder (CMPD), trilinear medullary proliferation with complete cellular maturation, osteomyelosclerosis and extramedullary haemopoiesis. In two cases (MDS, AML), ultrastructural demonstration of C-type virus particles (feline leukaemia virus) suggested a viral aetiology., (Copyright 1999 Harcourt Publishers Ltd.)
- Published
- 1999
- Full Text
- View/download PDF
31. Protein oxidation in human stratum corneum: susceptibility of keratins to oxidation in vitro and presence of a keratin oxidation gradient in vivo.
- Author
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Thiele JJ, Hsieh SN, Briviba K, and Sies H
- Subjects
- Adult, Amino Acid Sequence, Humans, Keratins chemistry, Molecular Sequence Data, Oxidation-Reduction, Epidermis metabolism, Keratins metabolism
- Abstract
The stratum corneum is located at the interface between body and environment and thus is constantly exposed to a pro-oxidative environment. Previously, we have demonstrated that stratum corneum lipids are targets of oxidative stress induced by ozone and by ultraviolet A and B exposure. Here, we employed an immunoblotting technique to detect protein oxidation in human stratum corneum obtained by tape stripping. After lysis, protein carbonyl groups were measured by derivatization with dinitrophenylhydrazine, separation by sodium dodecylsulfate-polyacrylamide gel electrophoresis, and immunoblotting using antibodies against dinitrophenyl groups. Keratin 10, identified by use of specific antibodies and by microsequencing, was demonstrated in vitro to be oxidizable by ultraviolet A irradiation, hypochlorite, and benzoyl peroxide. In vivo, a keratin 10 oxidation gradient with low levels in the lower stratum corneum layers, and about 3-fold higher contents of carbonyl groups towards the outer layers was demonstrated in forehead stratum corneum of healthy volunteers (n = 6). As protein oxidation can be associated with an increased susceptibility to proteases, this finding may be important for better understanding the process of desquamation.
- Published
- 1999
- Full Text
- View/download PDF
32. Depletion of human stratum corneum vitamin E: an early and sensitive in vivo marker of UV induced photo-oxidation.
- Author
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Thiele JJ, Traber MG, and Packer L
- Subjects
- Animals, Dose-Response Relationship, Radiation, Female, Humans, Malondialdehyde metabolism, Mice, Mice, Hairless, Osmolar Concentration, Oxidation-Reduction, Vitamin E radiation effects, Skin metabolism, Skin radiation effects, Ultraviolet Rays, Vitamin E metabolism
- Abstract
As the outermost barrier of the body, the stratum corneum (SC) is frequently and directly exposed to a pro-oxidative environment, including ultraviolet solar radiation (UVR). Therefore, we hypothesized that the SC is susceptible to UVR induced depletion of vitamin E, the major lipophilic antioxidant. To test this, we investigated (i) the susceptibility of SC tocopherols to solar simulated UVR in hairless mice, (ii) the baseline levels and distribution patterns of tocopherols in human SC, and (iii) the impact of a suberythemogenic dose of solar simulated UVR on human SC tocopherols. SC tocopherol levels were measured by high performance liquid chromotography analysis of SC extracts from tape strippings. In murine SC, overall tocopherol concentrations were determined, whereas in human SC, 10 consecutive layers were analyzed for each individual. The results on SC tocopherols demonstrated (i) their concentration dependent depletion by solar simulated UVR in hairless mice; (ii) a gradient distribution within untreated human SC, with the lowest levels at the surface (alpha-tocopherol 6.5 +/- 1.4 pmol per mg, and gamma-tocopherol 2.2 +/- 1.3 pmol per mg) and the highest levels in the deepest layers (alpha-tocopherol 76 +/- 12 pmol per mg, and gamma-tocopherol 7.9 +/- 3.7 pmol per mg, n = 10; p < 0.0001); and (iii) the depletion of tocopherols in human SC by a single suberythemogenic dose of solar simulated UVR (alpha-tocopherol by 45%, and gamma-tocopherol by 35% as compared with controls; n = 6; both p < 0.01). These results demonstrate that the SC is a remarkably susceptible site for UVR induced depletion of vitamin E.
- Published
- 1998
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33. [Melorheostosis--a rare bone dysplasia].
- Author
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Thiele J, Schenk S, and Schmidt F
- Subjects
- Adult, Bone and Bones pathology, Humans, Male, Shoulder Joint pathology, Diagnostic Imaging, Melorheostosis diagnosis
- Published
- 1997
34. Ozone-exposure depletes vitamin E and induces lipid peroxidation in murine stratum corneum.
- Author
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Thiele JJ, Traber MG, Polefka TG, Cross CE, and Packer L
- Subjects
- Animals, Dose-Response Relationship, Drug, Malondialdehyde analysis, Mice, Mice, Hairless, Oxidative Stress drug effects, Skin chemistry, Air Pollutants adverse effects, Lipid Peroxidation drug effects, Oxidants, Photochemical adverse effects, Ozone adverse effects, Skin drug effects, Vitamin E metabolism
- Abstract
The presence of ozone (O(3)) in photochemical smog is an important health concern. We hypothesized that the stratum corneum (SC), as the outermost skin layer and the permeability barrier of the skin, represents a sensitive target for O(3)-induced oxidative stress. To test this hypothesis, SKH-1 hairless mice were anesthetized and exposed for 2 h to O(3) by using two strategies: (i) single exposures to 0 (n = 12), 1 (n = 4), 5 (n = 4), and 10 (n = 4) ppm; and (ii) repeated daily exposures to 0 ppm (controls; n = 4) and 1 ppm (n = 4) for six consecutive days. New techniques based on the removal of SC by tape stripping were used to analyze the biologic effects of O(3) with respect to vitamin E depletion and lipid peroxidation. SC tissue was extracted from the tape and immediately analyzed by HPLC for vitamin E and malondialdehyde (MDA) concentrations. After in vivo exposure to increasing O(3) doses, vitamin E was depleted and MDA formation was increased, both in a dose-dependent manner. Remarkably, repeated low-level O(3) exposures resulted in cumulative oxidative effects in the SC: As compared with O(3) exposures of 0 ppm (alpha-tocopherol, 8.95 +/- 1.3 pmol per mg; gamma-tocopherol, 3.00 +/- 0.3 pmol per mg; MDA, 3.69 +/- 0.3 pmol per mg), vitamin E was depleted (alpha-tocopherol, 2.90 +/- 0.6 pmol per mg, p < 0.001; gamma-tocopherol, 0.5 +/- 0.1 pmol per mg, p < 0.001) and MDA levels were increased (4.5 +/- 0.2; p < 0.01). This report demonstrates the unique susceptibility of the SC to oxidative damage upon exposure to O(3).
- Published
- 1997
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35. [Computerized tomography measurement of lung ventilation by inhalation of Isovist-300].
- Author
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Thiele J and Klöppel R
- Subjects
- Administration, Inhalation, Humans, Contrast Media, Tomography, X-Ray Computed methods, Triiodobenzoic Acids, Ventilation-Perfusion Ratio physiology
- Published
- 1995
36. Secretion of cytokines (interleukins-1 alpha, -3, and -6 and granulocyte-macrophage colony-stimulating factor) by normal human bone marrow megakaryocytes.
- Author
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Wickenhauser C, Lorenzen J, Thiele J, Hillienhof A, Jungheim K, Schmitz B, Hansmann ML, and Fischer R
- Subjects
- Base Sequence, Cytokines analysis, Cytokines pharmacology, DNA Primers, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Hemolytic Plaque Technique, Humans, Interleukin-1 biosynthesis, Interleukin-3 biosynthesis, Interleukin-6 biosynthesis, Megakaryocytes drug effects, Megakaryocytes metabolism, Molecular Sequence Data, Polymerase Chain Reaction, RNA, Messenger analysis, RNA, Messenger biosynthesis, Receptors, Interleukin biosynthesis, Receptors, Interleukin-6, Recombinant Proteins pharmacology, Sensitivity and Specificity, Bone Marrow physiology, Cytokines biosynthesis, Interleukins biosynthesis, Megakaryocytes immunology
- Abstract
The effects of cytokine stimulation [recombinant human interleukin (rhIL)-1 alpha, rhIL-3, rhIL-6, rhIL-11, and rh granulocyte-macrophage colony-stimulating factor (GM-CSF)] on the secretory activity of normal human megakaryocytes were studied by means of the reverse hemolytic plaque assay (RHPA) in enriched cell preparations. This test facilitates an extremely sensitive determination of cytokine secretion at the single-cell level, together with the clear-cut identification of each immunostained (CD61) secretory active megakaryocyte. Moreover, the reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the expression of IL-6, IL-6 receptor (IL-6R), IL-9, IL-10, IL-12, and IL-13 mRNA in highly concentrated megakaryocyte preparations. In comparison with the spontaneous secretion rate, stimulation with rhIL-1 alpha, rhIL-6, and rhGM-CSF failed to induce a significant increase in the release of cytokines by CD61+ cells. On the other hand, both rhIL-3 and, in a less pronounced way, rhIL-11 exerted a marked effect on IL-6 secretion. Additionally, after stimulation with rhIL-3, a significant enhancement of the secretion of IL-3 and GM-CSF, but not of IL-1 alpha, could be observed. Using the RT-PCR, a significant induction of IL-6 expression could be appreciated in the enriched megakaryocyte population (60% to 80%) stimulated with rhIL-3. The results of this study provide persuasive evidence that a number of cytokines are synthesized and secreted by human megakaryocytes and not only by hematopoietic stroma cells. These data suggest the existence of autocrine and paracrine mechanisms that may influence maturation and differentiation of megakaryocytes as well as act on various stroma cells to sustain an appropriate hematopoietic micro-environment.
- Published
- 1995
37. PG-M1: a new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule.
- Author
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Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B, Durkop H, Eitelbach F, Thiele J, Pacini R, and Cavaliere A
- Subjects
- Antibody Formation, Antigens, CD analysis, Antigens, Differentiation, Myelomonocytic analysis, Cell Line, DNA genetics, Drug Resistance, Hematologic Diseases immunology, Hematopoietic System, Humans, Inflammation immunology, Lymphatic Diseases immunology, Neoplasms immunology, Precipitin Tests, Reference Values, Transfection, Antibodies, Monoclonal immunology, Antigens, CD immunology, Antigens, Differentiation, Myelomonocytic immunology, Epitopes, Fixatives pharmacology, Macrophages immunology
- Abstract
A new anti-macrophage monoclonal antibody (PG-M1) was produced by immunizing BALB/c mice with fresh spleen cells from a patient with Gaucher's disease. PG-M1 reacts strongly with a fixative-resistant epitope of an intracytoplasmic molecule, selectively expressed by virtually all macrophages of the human body. Although attempts to immunoprecipitate the molecule recognized by PG-M1 have failed so far, the reactivity of the antibody with COS-1 and WOP cells transfected with a human complementary DNA clone encoding for the CD68 antigen suggests that PG-M1 is a new member of the CD68 cluster. However, unlike other CD68 antibodies (KP1, EBM11, etc.), which react with both macrophages and myeloid cells, PG-M1 detects a fixative-resistant epitope on the macrophage-restricted form of the CD68 antigen. In 957 routinely fixed, paraffin-embedded samples, PG-M1 showed a more restricted reactivity with elements of the monocyte/macrophage lineage than the previously described monoclonal antibodies MAC-387 (anti-calgranulins), KP1 (CD68) and Ki-M1P. Among hematological malignancies, PG-M1 only labels acute leukemias of M4 and M5 type and rare examples of malignant histiocytosis/true histiocytic sarcoma. In contrast, acute leukemias of the M1, M2, M3, M6, M7, and L1-L3 types, non-Hodgkin's lymphomas, and Hodgkin and Reed-Sternberg cells of Hodgkin's disease are consistently PG-M1-negative. In the daily diagnostic practice, PG-M1 seems to be particularly valuable for the diagnosis of myelomonocytic or monocytic leukemia and neoplasms of true histiocytic origin in routine paraffin sections.
- Published
- 1993
38. Asymptomatic pulmonary cyst in a college student.
- Author
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Burlew BP, Cook EW Jr, and Thiele JS
- Subjects
- Adult, Echinococcosis, Pulmonary pathology, Female, Humans, Lung pathology, Tomography, X-Ray Computed, Echinococcosis, Pulmonary diagnostic imaging
- Published
- 1990
- Full Text
- View/download PDF
39. The treatment of postperfusion bleeding using epsilon-aminocaproic acid, cryoprecipitate, fresh-frozen plasma, and protamine sulfate.
- Author
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Lambert CJ, Marengo-Rowe AJ, Leveson JE, Green RH, Thiele JP, Geisler GF, Adam M, and Mitchel BF
- Subjects
- Aminocaproic Acid administration & dosage, Erythrocytes, Fibrinolysis, Hemorrhage etiology, Humans, Plasma, Protamines administration & dosage, Aminocaproates therapeutic use, Aminocaproic Acid therapeutic use, Blood Transfusion, Cardiopulmonary Bypass adverse effects, Hemorrhage therapy, Postoperative Complications therapy, Protamines therapeutic use
- Abstract
The evaluation of excessive hemorrhage was carried out in 774 patients after cardiopulmonary bypass. Excessive hemorrhage was defined in any adult patient as chest tube drainage of more than 600 ml within the first eight hours after operation. Using the prothrombin time, partial thromboplastin time, fibrinogen level, and tri-F titer tests, it was possible to differentiate medical from surgical bleeding. Hyperfibrinolytic bleeding was the most frequently identifiable coagulation disorder and occurred in 159 patients (20%). All these patients were successfully treated with Amicar (epsilon-aminocaproic acid) alone, or with Amicar supplemented with cryoprecipitate or fresh-frozen plasma. Three patients (0.4%) were noted to have residual heparin and required additional protamine sulfate. Five patients (0.6%) had normal coagulation studies and required immediate reexploration. The overall blood consumption per patient was 2.1 units of packed cells. Whole blood and platelets were not used.
- Published
- 1979
- Full Text
- View/download PDF
40. Differential distribution of voltage-dependent calcium channels and guanylate cyclase in the excitable ciliary membrane from Paramecium tetraurelia.
- Author
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Thiele J, Klumpp S, Schultz JE, and Bardele CF
- Subjects
- Animals, Cell Fractionation, Centrifugation, Density Gradient, Cilia enzymology, Cilia ultrastructure, Membranes analysis, Membranes enzymology, Paramecium ultrastructure, Calcium metabolism, Cilia analysis, Guanylate Cyclase metabolism, Ion Channels analysis, Paramecium analysis
- Abstract
A novel method for isolation of cilia and ciliary membrane vesicles from Paramecium tetraurelia has been developed. Using a continuous Percoll gradient of low osmolarity after fragmentation of purified cilia by French Press treatment two membrane fractions with different buoyant densities were obtained. These fractions were further purified by conventional discontinuous sucrose density gradients and characterized biochemically and by electron microscopy. Guanylate cyclase, a membrane bound enzyme, was found almost exclusively in membrane vesicles of high buoyant density while the voltage-sensitive calcium-channel of the ciliary membrane was predominantly localized in low density vesicles. Examination of both fractions by SDS polyacrylamide gel electrophoresis revealed only minor differences in protein pattern in the 34 and 64 kilodaltons range. Morphologically both membrane vesicle fractions had a diameter of about 300 nm, however, the high density vesicle fraction contained a considerably larger amount of multilamellar structures with a multishell, onion-like appearance. Freeze-fracture analysis failed to detect differences in intramembrane particle content between low and high density vesicles. The possible biological relevance of the spatial separation of the calcium-sensor enzyme guanylate cyclase and the voltage-sensitive calcium-channels in the ciliary membrane is discussed in terms of a diffusion controlled mechanism for graded signal transmission.
- Published
- 1982
41. Incorporation of [18O]water into 4-hydroxybenzoic acid in the reaction of 4-chlorobenzoate dehalogenase from pseudomonas spec. CBS 3.
- Author
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Müller R, Thiele J, Klages U, and Lingens F
- Subjects
- Chromatography, Gas, Isotope Labeling methods, Kinetics, Mass Spectrometry, Oxygen Isotopes, Water metabolism, Hydrolases metabolism, Hydroxybenzoates metabolism, Parabens, Pseudomonas metabolism
- Abstract
4-Chlorobenzoate is dehalogenated by 4-chlorobenzoate dehalogenase from Pseudomonas spec. CBS 3 to form 4-hydroxybenzoate. In 18O enriched water the hydroxygroup of 4-hydroxybenzoate is quantitatively labelled with 18O. This result clearly shows, that 4-chlorobenzoate dehalogenase catalyzes the hydrolytic cleavage of the halogen-carbon bond, without the involvement of molecular oxygen, a reaction not yet described.
- Published
- 1984
- Full Text
- View/download PDF
42. Treatment of severe coronary artery disease with 5, 6, and 7 saphenous vein bypasses: review of 131 consecutive patients.
- Author
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Geisler GF, Adam M, Mitchel BF, Lambert CJ, and Thiele JP
- Subjects
- Adult, Aged, Angina Pectoris etiology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Postoperative Complications, Transplantation, Autologous, Coronary Artery Bypass, Coronary Disease surgery, Saphenous Vein transplantation
- Abstract
One hundred thirty-one consecutive patients who received 5, 6, and 7 bypass grafts are analyzed. Ages ranged from 31 to 74 years. The male-to-female ratio was 7:1. As an indication of severity of disease, 25% were classified as having impending myocardial infarction and 46.6% were classified in New York Heart Association Functional Class IV. Left ventricular function was impaired in 37.4%, and 30% of the patients had left main coronary obstruction. Nonfatal perioperative myocardial infarction occurred in 4.6%. The hospital mortality was 3%. One hundred percent follow-up (5 to 55 months) revealed 4 late deaths, 3 presumably of cardiac origin. Only 7 patients in the postoperative follow-up group have complained of angina; 1 has since undergone successful reoperation.
- Published
- 1977
- Full Text
- View/download PDF
43. The tri-F titer: a rapid test for estimation of plasma fibrinogen and detection of fibrinolysis, fibrin(ogen) split products, and heparin.
- Author
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Lambert CJ, Marengo-Rowe AJ, Leveson J, Alivizatos P, Geisler GF, Adam M, Mitchel BF Jr, and Thiele JP
- Subjects
- Aminocaproates, Extracorporeal Circulation adverse effects, Fibrinogen metabolism, Hemorrhage etiology, Humans, Methods, Protamines, Prothrombin Time, Sodium Chloride, Thromboplastin, Fibrinogen analysis, Fibrinolysis, Heparin blood
- Published
- 1974
- Full Text
- View/download PDF
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