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  • 1
    ISSN: 1433-2965
    Keywords: Estrogen replacement therapy ; Menopause ; Osteoporosis ; Velocity of ultrasound
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Determination of apparent velocity of ultrasound (AVU) in bone has been proposed as a valuable tool for discriminating between normal and osteoporotic women. We have studied the influence of age, menopause and estrogen replacement therapy (ERT) on AVU at the patella in a large sample of pre- and postmenopausal women. Three hundred and eighteen woman aged 40–60 year participated in the study (112 women were premenopausal, 21 were perimenopausal and 185 were postmenopausal of whom 110 had received ERT for a minimum of 1 year). AVU was determined as the mean of four measurements at each patella using a Signet instrument (Osteo-Technology, Framingham, MA). An age-dependent decline in AVU was observed only after menopause (r=−0.33,p=0.0055); in premenopausal women there was a slight but not significant decrease in AVU with age (r=−0.12,p〉0.05). AVU was significantly lower in postmenopausal women compared with premenopausal women (1882±84 m/s vs 1961±73 m/s,p〈0.05). ERT prevented the menopause-related fall in AVU. There was a significant positive correlation between the duration of ERT and AVU measurements. Our findings demonstrate a pronounced influence of estrogens on AVU at the patella, supporting the concept of a protective role of ERT in bone stability. AVU measurements therefore merit further investigation as an inexpensive method for predicting fracture risk that does not expose the subject to radiation.
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  • 2
    ISSN: 1432-2307
    Keywords: Key words Macrophages ; Pseudo-Gaucher cells ; Chronic myeloid leukaemia ; Bone marrow transplantation ; Bone marrow biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A morphometric and immunohistochemical study was performed on 354 bone marrow trephine biopsies derived from 126 patients with chronic myeloid leukaemia (CML) before and after allogeneic bone marrow transplantation (BMT). The purpose of this investigation was to evaluate the macrophage population, including several subsets and their dynamics in the posttransplant period. In addition to the total CD68+ resident (mature) macrophages the so-called activated fraction identified by its capacity to express α-d-galactosyl residues, the pseudo-Gaucher cells (PGCs) and the iron-laden histiocytic reticular cells were also considered. Following immuno- and lectin-histochemical staining morphometric analysis was carried out on sequential postgraft bone marrow specimens at standardized intervals. Compared to the normal bone marrow and calculated per haematopoiesis (cellularity) an overall decrease of about 40–50% in the quantity of CD68+ macrophages and the BSA-I+ subpopulation was detectable in the early posttransplant period (9–45 days after BMT). Noteworthy was the temporal recurrence of PGCs in the engrafted bone marrow, which was not associated with a clonally transformed cell population or leukaemic relapse. Reappearance of postgraft PGCs was most prominent in the first 2 months after BMT. This conspicuous feature was presumed to be functionally associated with a pronounced degradation of cell debris following pretransplant myelo-ablative therapy (scavenger macrophages). Evidence for an activation of the BSA-I+ macrophage subset was derived from the identical carbohydrate-binding capacity shown by the PGCs. In the regenerating haematopoiesis shortly after BMT a significant correlation between the number of BSA-I+ macrophages and erythroid precursor cells was determinable. This result implicates a close functional relationship between postgraft reconstitution of erythropoietic islets and centrally localized activated macrophages. In conclusion, findings emerging from this study included the reappearance of PCGs in the engrafted bone marrow independently of a leukaemic relapse and the significant association of the activated BSA-I+ macrophage subset with the recovery of erythropoiesis.
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  • 3
    ISSN: 1432-2307
    Keywords: Megakaryocytes ; Sinus wall ; Transmural migration ; 3D-reconstruction ; Double-immunostaining
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using sequential double-immunostaining and a newly-developed three-dimensional (3D-) reconstruction technique on serially cut sections from bone marrow trephines, we studied the transmural passage of megakaryocytes through the sinus wall. Biopsies derived from patients with primary (idiopathic) osteomyelofibrosis were exposed to monoclonal antibody against type IV collagen to delineate the sinus walls and also the frequently thickened basement membrane. Staining with the primary antibody was followed by Y2/51 (CD61) to identify all elements of megakaryopoiesis. In most instances serial sectioning and 3D-reconstruction revealed an amoeboid shape of megakaryocytes and a tandem-like arrangement in close spatial contact with the abluminal surface of the sinus wall. Preceded by formation of cytoplasmic processes, straight penetration of entire megakaryocytes through gaps in the sinus walls into the lumen was seen. Where collagen deposits apparently presented a barrier, a mole-like tunnelling through the basement membrane material (type IV collagen) was recognizable. Our findings are in keeping with the assumption that megakaryocyte locomotion is an essential requirement for normal thrombocytogenesis.
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  • 4
    ISSN: 1432-0584
    Keywords: CML ; Morphometry ; Immunostaining (CD61, PG-M1) ; Prognostic variables ; Cox models ; Life expectancy ; ROC analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To evaluate the prognostic significance of clinical as well as histological disease features at the time of diagnosis, an immunohistochemical and morphometric study was performed on bone marrow trephine biopsies in 130 patients with Ph1+-CML. For identification of all cell elements of the megakaryocytopoiesis we used the monoclonal antibody CD61 (Y2/51) and for the macrophages, the recently characterized antibody PG-M1. Density of argyrophilic fibers was determined per fat cell-free marrow area. Based on a multivariate analysis-derived risk model, the reproducibility of the prognostic score described by Sokal and co-workers was tested, particularly with regard to histological variables. Additionally, we calculated the disease-specific loss in life expectancy. Our prognostic model (Cox model) consisted of the variables: age, spleen size, peripheral erythro-normoblasts, pseudo-Gaucher cells, and fiber density. To assess the validity of this new CML score, a receiver-operating curve (ROC) of sensitivity and specificity was constructed. The improved prognostic efficiency of this newly developed risk model in predicting death within 3 years after diagnosis of CML was demonstrated in comparison with generally accepted staging systems. Immunohistochemistry revealed that not the total number of macrophages, but only the subfraction of pseudo-Gaucher cells exerted a significant impact on survival. Furthermore, it was feasible to calculate the number of atypical micromegakaryocytes and pro-and megakaryoblasts. This abnormal and immature cell population showed a significant correlation with fiber density and prognosis. Finally, the practical value of the Hannover classification was tested. This histological classification enabled a discrimination between two groups with different survival patterns, i.e., granulocyte and/or megakaryocyte-rich subtypes versus subtypes with increase in reticulin and collagen fibers.
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  • 5
    ISSN: 1432-0584
    Keywords: Key words Chronic myeloproliferative disorders ; Erythroid precursors ; Neutrophil granulopoiesis ; Megakaryocytes ; Macrophages ; Myelofibrosis ; Enzyme-immunohistochemistry ; Morphometry ; Bone marrow biopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this review is to evaluate morphological characteristics of the different subtypes of chronic myeloproliferative disorders (MPDs) derived by applying immunohistochemical and morphometric techniques to bone marrow biopsies and to combine these results with relevant clinical parameters. In comparison to control specimens, a significant decrease in erythroid precursors is determinable in chronic myeloid leukemia (CML), while this cell lineage is most prominent in polycythemia vera (PV) and moderately to markedly reduced in idiopathic myelofibrosis (IMF). On the other hand, neutrophilic granulopoiesis shows a predominance in CML and a relevant increase in PV, but no conspicuous changes are detectable in essential thrombocythemia (ET). CML is characterized by a prevalent growth of dwarflike micromegakaryocytes, occurring in particular in the so-called megakaryocyte-rich subtypes (about 30%). This finding differs significantly from the pleomorphous aspect, i.e., clusters of small to giant-sized megakaryocytes in PV and the grossly abnormal (dysplastic) appearance of this cell lineage in patients with IMF. Similar cytological abnormalities of megakaryopoiesis consistent with maturation defects are never encountered in ET. The incidence of mature (resident) macrophages (phagocytic reticular cells) is significantly enhanced in IMF in comparison to the other MPDs and controls. Moreover, there is a striking difference in the density of reticulin-collagen fibers, ranging from normal (ET) to extreme values (IMF). In IMF more than 80% of the patients present with some degree of myelofibrosis-osteosclerosis at diagnosis, while the rest show an initial prefibrotic, hypercellular stage. This feature deserves special attention since, when accompanied by thrombocythemia, it may simulate ET. Sequential bone marrow biopsies in patients with IMF disclose that evolution of myelofibrosis is progressive, but occurs at a variable and unpredictable speed. A synoptical approach regarding clinical diagnosis and histological subtyping of MPDs is explicitly recommended and demonstrated by sets of diagnostic criteria. This rationale requires equal consideration of laboratory data and morphology by clinicians to include well-defined subtypes of MPDs into prospective management studies. Furthermore, it may even warrant follow-up studies and repeated bone marrow examinations in initially unclassifiable cases.
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  • 6
    ISSN: 1432-0584
    Keywords: Key words Idiopathic myelofibrosis ; PCNA labeling ; Apoptosis ; Dynamic disease features ; Prognosis ; Proportion of life loss ; Bone marrow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A retrospective study of 120 patients with the clinically and histologically established diagnosis of idiopathic (primary) myelofibrosis (IMF) was performed to determine prognostic factors of predictive value, including parameters characterizing the dynamics of hematopoietic cell kinetics. In contrast to previous studies, our cohort comprised the full spectrum of the disease, from initial prefibrotic to advanced osteosclerotic stages. The in situ end-labeling (ISEL) technique was used to demonstrate apoptosis, in order to determine dynamic parameters of predictive value. Cell proliferation was evaluated by employing the monoclonal antibody PC10 directed against proliferating cell nuclear antigen (PCNA). Proliferative activity (PCNA index) and frequency of apoptosis showed significant differences between early and advanced fibrosclerotic stages of disease. Decrease in proliferation indicated a significantly shorter survival, whereas a higher frequency of apoptotic cells was associated with a better prognosis. It may be speculated that a normal or enhanced proliferation rate expressed by PCNA positivity (late G1- and S-phase of the cell cycle) that is accompanied by a higher incidence of apoptosis reflects the regenerative (turnover) capacity of hematopoiesis. This may apply especially to early hypercellular stages without relevant myelofibrosis. In consideration of a recently published multivariate risk model, a simplified synthesis score for stratification of a patient's prognosis was constructed. Age, degree of anemia, leukocytes, and platelet count were regarded as the most important parameters. A substantial improvement of prognostic efficiency was further achieved by including PCNA index and frequency of apoptosis. Our results are in keeping with the assumption that generalization, indicated by myeloid metaplasia, has a prodigious impact on prognosis in IMF. Furthermore, in this context dynamic features such as proliferative activity and frequency of apoptosis exert an additional predictive value.
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  • 7
    ISSN: 1432-0584
    Keywords: Key words CML ; Myelofibrosis ; Dynamics ; Megakaryocytes ; Morphometry ; Interferon ; Busulfan ; Sequential bone marrow biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph1+-CML, a clinicopathological study was performed on sequential trephine biopsies of the bone marrow following either interferon (IFN) or busulfan (BU) monotherapy. Using the monoclonal antibody CD61 for the identification of megakaryopoiesis and Gomori's silver impregnation method, number of megakaryocytes and density of argyrophilic (reticulin and collagen) fibers were determined by morphometry. We studied specimens from 26 patients with IFN-alpha 2b (including nine patients with additional IFN gamma) therapy and from 23 patients who had received BU. In both groups, repeated bone marrow biopsies (total 125) revealed a significant increase in the fiber content, as well as in the number of megakaryocytes during treatment. To assess the dynamics of myelofibrosis more precisely, computation of differences in the degree of fiber density between the first and last examination was carried out. Regarding the considerable variations in the biopsy intervals, a so-called myelofibrosis progression index (MPI) was calculated. Following this rationale, we were able to demonstrate that, in comparison to the BU-group, speed of progression of bone marrow fibrosis was significantly increased in CML patients treated with IFN. Preliminary statistical analysis indicated a relationship between myelofibrosis on admission, which was always associated with increased growth of megakaryocytes, and the MPI with survival. Even when these parameters were regarded, prognosis was significantly more favorable in the IFN-treated patients. The failure of IFN and BU to inhibit the evolution of myelofibrosis may be related to several conversely acting pathomechanisms. Among others, the inability of both therapeutic agents to reduce the number of megakaryocytes more effectively should be taken into consideration.
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  • 8
    ISSN: 1432-0584
    Keywords: Key words Apoptosis ; PCNA-labeling ; Idiopathic thrombocytopenia ; Polyglobuly ; Reactive thrombocytosis ; Primary thrombocythemia ; Polycythemia vera ; AML ; Hematopoietic turnover index ; Bone marrow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In order to determine the dynamics of hematopoietic cell turnover, proliferative activity and incidence of apoptosis (programmed cell death) were evaluated in bone marrow trephine biopsies. Selection of patients (20 in each group) included in addition to a control group, idiopathic thrombocytopenia (ITP), reactive thrombocytosis (TH), secondary polycythemia-smokers' polyglobuly (PG), primary (essential-hemorrhagic) thrombocythemia (PTH), polycythemia vera (PV), and finally acute myeloid leukemia (AML). Apoptosis was demonstrated by the in situ end-labeling technique (ISEL) and proliferative activity by applying the monoclonal antibody PC10 raised against proliferating cell nuclear antigen (PCNA). To assess dynamic features of hematopoiesis, an index was calculated consisting of the ratio between PCNA-positive nuclei and the apoptotic cell fraction. This factor was termed the hematopoietic turnover index (HTI). Morphometric analysis revealed that the HTI was significantly increased in AML and PV. According to cell culture studies both disorders are characterized by either a prevalent proliferation of the myeloid or erythroid cell mass. On the other hand, PG, PTH, and TH showed no relevant enhancement of this index in comparison to the control specimen. In vitro experiment results are in keeping with the finding that PG and PTH are not associated with a significant expansion of the erythroid lineage (CFU-E). Similar to ITP and TH, in PTH megakaryocyte proliferation (CFU-MEG) is the predominant feature of cell turnover. Differences between PTH and TH are in line with the reduced in vitro formation of CFU-MEG in the latter disorder. In conclusion, our in situ study on turnover rates of the bone marrow in various neoplastic and reactive lesions extends previous experimental data on hematopoietic cell kinetics.
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  • 9
    ISSN: 1432-0584
    Keywords: CML ; Myelofibrosis ; Dynamics ; Megakaryocytes ; Morphometry ; Interferon ; Busulfan ; Sequential bone marrow biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph1+-CML, a clinicopathological study was performed on sequential trephine biopsies of the bone marrow following either interferon (IFN) or busulfan (BU) monotherapy. Using the monoclonal antibody CD61 for the identification of megakaryopoiesis and Gomori's silver impregnation method, number of megakaryocytes and density of argyrophilic (reticulin and collagen) fibers were determined by morphometry. We studied specimens from 26 patients with IFN-alpha 2b (including nine patients with additional IFN gamma) therapy and from 23 patients who had received BU. In both groups, repeated bone marrow biopsies (total 125) revealed a significant increase in the fiber content, as well as in the number of megakaryocytes during treatment. To assess the dynamics of myelofibrosis more precisely, computation of differences in the degree of fiber density between the first and last examination was carried out. Regarding the considerable variations in the biopsy intervals, a so-called myelofibrosis progression index (MPI) was calculated. Following this rationale, we were able to demonstrate that, in comparison to the BU-group, speed of progression of bone marrow fibrosis was significantly increased in CML patients treated with IFN. Preliminary statistical analysis indicated a relationship between myelofibrosis on admission, which was always associated with increased growth of megakaryocytes, and the MPI with survival. Even when these parameters were regarded, prognosis was significantly more favorable in the IFN-treated patients. The failure of IFN and BU to inhibit the evolution of myelofibrosis may be related to several conversely acting pathomechanisms. Among others, the inability of both therapeutic agents to reduce the number of megakaryocytes more effectively should be taken into consideration.
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  • 10
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: AimsBone marrow histopathology reveals a striking heterogeneity at diagnosis of Philadelphia chromosome positive (Ph1+) chronic myelogenous leukaemia (CML). Based on semiquantitative evaluations of the number of megakaryocytes and the content of fibres, various histological subtypes have been postulated. However, little information exists on whether these groups represent stable categories of the different classification systems and whether therapeutic regimes exert any influence on the putative shift of histological patterns.Methods and resultsA retrospective clinicopathological study was performed on 396 bone marrow biopsies derived from 173 patients. There were at least two representative trephines taken at diagnosis and at median intervals of 16 months. Processing of the specimens involved immunostaining with CD61 (megakaryopoiesis) and Ret40f (erythropoiesis) and Gomori's silver impregnation technique. Based on morphometric analysis and in accordance with the general appearance of bone marrow histology three different histological subtypes were distinguished. These consisted of a granulocytic (51 patients), a predominantly megakaryocytic (73 patients) and a myelofibrotic pattern (49 patients). Follow-up biopsies revealed that a significant transition of histological groups occurred and that, independently of treatment modalities, the myelofibrotic category was associated with an unfavourable prognosis. Of the 124 patients without myelofibrosis at onset, 42% later transformed into the myelofibrotic subtype. However, these patients showed no prevalence of either a pre-existing granulocytic or megakaryocytic growth. Myelofibrotic changes were significantly associated with interferon (IFN) and busulfan (BU) therapy. On the other hand, a transition of a myelofibrotic into a nonfibrotic subtype was detectable in 17 of the 49 patients under study and related to hydroxyurea (HU) treatment.ConclusionsHistological classification systems of bone marrow features in CML do not represent stable patterns, but may be significantly altered by therapy, in particular IFN and HU.
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