Summary:idiopathic noninfectious pneumonia; (3) pulmonary edema (hydrostatic or noncardiogenic); (4) respiratory failure (pulmonary and extrapulmonary etiologies); (5) inflammaFiberoptic bronchoscopy (FOB) has been reported to have a high diagnostic yield and to be safe in BMT tory conditions (diffuse alveolar damage (DAD), bronchiolitis obliterans organizing pneumonia (BOOP), bronchiolitis patients with pulmonary infiltrates. At our institution, BMT patients with respiratory symptoms and/or pulobliterans (BO), and pulmonary graft-versus-host disease); (6) pulmonary hemorrhage; and (7) The use of FOB to evaluate pulmonary infiltrates in BMT patients was not previously standardized at our institution. (15%) occurred in 10 FOBs (five acute respiratory failure, three pneumothoraces, one nose bleed, one death).Although the medical literature indicates that FOB in BMT patients with pulmonary infiltrates is a safe and valuable Hospital and 6-month survival based on episodes of clinical pneumonia were 47 and 32%, respectively. diagnostic procedure, its impact on providing a diagnosis, guiding treatment, and patient outcome at our institution Patients who had a diagnostic FOB or a FOB that changed treatment did not have better hospital or 6-was unclear. A data base was established to collect existing clinical information to assess the yield, impact on treatmonth survival compared to patients who had FOBs that were nondiagnostic or did not change treatment.ment, safety and survival in BMT patients who had FOB to evaluate respiratory symptoms and/or pulmonary infiltrates. FOB in our BMT patient population, had a low diagnostic yield (31%), infrequently changed treatment (24%), a significant complication rate (15%) and was not associated with improved patient survival. The role of rouMaterials and methods tine diagnostic FOB in BMT patients with pulmonary infiltrates and/or respiratory symptoms should be rePatient population evaluated.
Population dynamics of Calanus finmarchicus have been modelled using very finely divided representation of the stock accord~ng to age-within-stage, in the manner of models developed by C. S. Davis, A. Sciandra, F. Carlotti and others. A key assumption of the model is that development rate is relatively insensitive to food-limitation, so that stage duration can be represented by a temperature function alone. We used the Belehradek function for this purpose, noting that better data are needed for fitting its parameters. The model closely simulates the timing of stage progression and relative stage abundances of C. finmarchicus in the Malangen fjord system (northern Norway) during the winter-spring generation. The model 1s sensitive to the resolution of the age-within-stage division, but it is fully stable at 0.5 h increments. Modifications of the model simulated several methods for field estimation of stage duration in Calanus (or other highly seasonal copepod populations). A method based on changes in stage proportions (the 'Heinle graph' method) is biased by confounding of the effects of developmental progress and mortality on stage proportions. However, the model shows that the bias is mild and the method gives useful estimates of stage duration. Simulation of a method based on molting rate deterrninations ('Kirnmerer experiments') showed its unsuitability for highly seasonal stocks In which stage composition is changing rapidly. Differences in C. finmarchicus survivorship schedules between constant and continuously increasing temperatures were simulated, showing that such differences in pattern are critical to annual survival and stock production. Simple methods for fitting mortality rates to data using the model were extremely sensitive to sampling noise. More complex methods may succeed but remain to be developed.
Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.
Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.
The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML). In the present study, multiple aspects of topo II-mediated drug action were examined in marrows from adult AML patients. Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA required to diminish leukemic colony formation by 90% (LD90) varied over a greater than 20-fold range between different pretreatment marrows. Measurement of nuclear DNR accumulation in the absence and presence of quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82 samples at diagnosis and 5 of 36 samples at first relapse, but the largest quinidine-induced increment in DNR accumulation (< 2-fold) was too small to explain the variations in drug sensitivity. Restriction enzyme-based assays and sequencing of partial topo II alpha and topo II beta cDNAs from the most highly resistant specimens failed to demonstrate topo II gene mutations that could account for resistance. Western blotting of marrow samples containing greater than 80% blasts revealed that the content of the two topo II isoenzymes varied over a greater than 20-fold range, but did not correlate with drug sensitivity in vitro or in vivo. In addition, levels of topo II alpha and topo II beta in 46 of 47 clinical samples were lower than in human AML cell lines. Immunoperoxidase staining showed that these low topo II levels were accompanied by marked cell-to- cell heterogeneity, with topo II alpha being abundant in some blasts and diminished or absent from others. There was a trend toward increasing percentages of topo II alpha-positive cells in pretreatment marrows that contained more S-phase cells. Consistent with this observation, treatment of patients with granulocyte-macrophage colony- stimulating factor for 3 days before chemotherapy resulted in increases in topo II alpha-positive cells concomitant with increases in the number of cells traversing the cell cycle. These observations have implications for the regulation of topo II in AML, for the use of topo II-directed chemotherapy, and for future attempts to relate drug sensitivity to topo II levels in clinical material.
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