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The molecular analysis of acute lymphoblastic leukemia (ALL) has provided exciting insights into the pathogenesis of this disease. This disease is heterogenous and can be subtyped based on chromosomal, immunophenotypic, and structural criteria. The varying prognostic implications of different ALL subtypes markedly influence the treatment decisions in adults. Many patients with T-cell ALL can be cured with chemotherapy alone. in contrast, patients with early B-lineage ALL with certain chromosomal abnormalities, especially the Philadelphia chromosome, do not have durable responses to chemotherapy and should receive a bone marrow transplantation if an HLA-matched donor is available. Recent reports have shown improved results for adults with B-cell ALL (Burkitt's) after intensive alternating cycles of chemotherapy containing high doses of methotrexate and cyclophosphamide. Future clinical and laboratory investigation should lead to the development of novel and possibly more effective treatments specifically tailored for different subsets of ALL., A large amount of information has recently accrued regarding both the biology and the treatment of acute lymphoblastic leukemia (ALL). The molecular analysis of lymphoblasts has provided exciting new information [...]

By Lee Levitt Old Mutual has launched Bright Capital, a fund of hedge funds manager, which claims to have an industry-beating risk-control mechanism. The asset management subsidiary is aimed at [...]

Some letters to the editor are presented in response to previous issues of "The New Republic." The letters respond to the articles "Boxed Office," "Overcharged," "Criminal Records," "Our Incompetent Government," "Women's Worlds," "Nice Disguise," and others.

Only 6% of personal-computer software sales are made directly by software companies to end users. The vast majority of those sales are only upgrades. That contrasts with the relatively high [...]

Presents letters to the editor referencing articles and topics discussed in previous issues. "Bad Move," which focused on the relationship between Israel and conservative Christians; "Judge Not," which focused on the reason of Jason Zengerle for not giving the nominees of U.S. President George W. Bush a judiciary hearing; "Flacks Americana," which asserted that Rendon Group is running the public relations war against terrorism.

The efficacy of four separate methods of human bone marrow T lymphocyte depletion was assessed, and the effect of T cells and monocytes on in vitro growth of marrow (CFU-GEMM, BFU-E, and CFU-GM) and peripheral blood (BFU-E) hematopoietic progenitors was determined. Extent of T cell depletion was assessed by multiparameter fluorescent cell sorter (FACS) analysis and by functional studies. Cells staining positively by FACS analysis for one or more of three separate fluorescent pan-T cell monoclonal antibodies (MCAbs) comprised 8.4% to 9.5% of control marrow mononuclear cells (MNCs). T cells constituted 3.2% to 5.1% of marrow following single, sequential, or combination treatment with two different pan-T cell MCAbs (Leu 1 and TM1 ) plus complement, 1.5% to 2.2% of marrow following solid-phase immunoabsorption (“panning”), 0.2% of marrow after sheep cell rosetting, and only 0.05% of marrow after FACS selective cell sorting and gated separation. T cells made up 59% to 73% of control peripheral blood MNCs and 0.8% to 2.8% of peripheral MNCs following sheep cell rosetting plus treatment with Leu 1 MCAb and complement. Mitogen (PHA, Con A) and allogeneic MLC-induced blastogenic responses (stimulation indices, experimental/control or E/C) revealed a concordant decrement in marrow T cell function after MCAb plus complement (E/C of 3.9 to 9.0), after panning (E/C of 1.6 to 3.5) and after sheep cell rosetting (E/C of 0.7 to 1.3), compared with control marrow (E/C of 5.3 to 15.7). After T cell depletion, marrow BFU-E growth was 95% to 120% of control, CFU-GM growth was 90% to 108% of control, and CFU-GEMM growth was 89% to 111 % of control. Marrow T cell and/or monocyte depletion did not alter erythropoietin-dependent BFU-E growth in the absence of Mo-conditioned medium (81% to 95% of control), and the addition of as many as 50 to 100 × 103purified marrow monocytes or T cells to 105autologous nonadherent T cell-depleted marrow target cells had a negligible (P> .1) effect on marrow BFU-E growth in vitro. Peripheral blood (PB) BFU-E/105T-depleted target cells were 106% ± 19% of expected; PB BFU-E growth was significantly diminished after monocyte depletion alone (7% ± 6% of expected) or after monocyte plus T cell depletion (8% ± 4% of expected). Addition of as many as 150 × 103T cells to 105autologous nonadherent T cell-depleted PB “null” cells produced only small (18% to 30% of expected) increments in BFU-E growth, whereas addition of autologous monocytes to “null” target cells restored PB BFU-E growth to 82% to 94% of expected. We conclude that (1) T lymphocyte depletion does not appreciably alter in vitro growth of human marrow (BFU-E and CFU-GM) or PB (BFU-E) hematopoietic progenitors; (2) that monocytes are a major source of burst-promoting activity for PB but not marrow BFU-E erythropoietin-dependent differentiation; and (3) that functional and immunologic marrow T-cell depletion is more effectively achieved with panning, sheep cell rosetting, or gated FACS separation, rather than by treatment with pan-T cell (Leu 1, TM1) MCAb plus complement.

Mitogen-stimulated murine spleen cells produce humoral substances capable of supporting murine hematopoiesis and pluripotent stem cell proliferation in vitro. Thus, we evaluated conditioned media generated by human spleen cells (SCM) in the presence or absence of mitogens for factors stimulatory for human pluripotent (CFU-GEMM), erythroid (BFU-E), and myeloid (CFU-GM) precursors. Two and one half percent to 10% SCM stimulated proliferation of all three types of precursor cells from nonadherent buoyant human marrow target cells. Mitogen-stimulated SCM augmented CFU-GM (175% to 225%), whereas CFU-GEMM and BFU-E growth was essentially unchanged. Cell separation procedures used to determine which cells provided these microenvironmental stimuli indicated that nonadherent mononuclear spleen cells provided the bulk of the CSF-GM, whereas adherent cells (95% nonspecific esterase + monocyte-macrophages) and nonadherent cells provided similar proportions of CSF-mix and erythroid burst-promoting activity (BPA). The nonadherent cells generating high levels of CSF-mix, BPA, and CSF-GM were predominantly Leu-1-negative, ie, non-T, cells. In the presence or absence of mitogens, SCM was a more potent source (1.3- to 3.8-fold) than peripheral leukocyte CM of the growth factors for the three progenitor cell types. Specific in situ cytochemical stains for analyzing morphology of myeloid colonies demonstrated that SCM stimulated the proliferation of the same types and proportions of colonies as human placental CM, suggesting that these CMs may contain similar CSF-GMs. These data show the contribution of spleen cell subsets to the generation of hematopoietic growth factors and the responsiveness of these cells to various mitogenic stimuli.

lnterleukin-2 (IL-2) induces differential secretion of lym-phokines by IL-2 receptor (IL-2R)-positive and IL-2R-negative T cells. We studied T cell IL-2R-specific modulation of adult bone marrow erythropoiesis by recombinant IL-2 (rlL-2). IL-2R were induced by CD3 T cell surface determinant-triggering and analyzed by cytofluorography. Bone marrow monocyte and T cell-depleted (NAB-T) target cells were assessed for early erythroid progenitor expression (BFU-E) in the presence of 0 to 103U/mL of rlL-2. rlL-2 had no significant effect on BFU-E expression in the absence of T cells or in the presence of IL-2R-negative T cells. rlL-2 caused a dose-dependent inhibition (75% to 90%) of BFU-E in the presence of autologous IL-2R-positive T cells. The addition of anti-IL2-receptor antibody to cultures containing rlL-2 plus IL-2R-positive T cells entirely abrogated rlL-2-mediated inhibition of BFU-E. In the pres- ence of rlL-2 (102 U/mL) production of interferon gamma (IF-gamma) by adult marrow CD3-triggered IL-2R-positive T cells was increased 37- to 125-fold compared to IL-2R-negative T cells. rIF-gamma caused a dose-dependent (88% ± 17% at 103 U/mL) inhibition of adult BFU-E in the presence of CD3-triggered autologous T cells, rIL2-mediated inhibition of adult BFU-E in the presence of IL-2R-positive T cells was partially abrogated (52% ± 16%) following addition of monospecific IF-gamma antibody. These results demonstrate (a) rlL-2 modulation of adult marrow erythropoiesis is selectively dependent upon both the presence or absence of autologous T cells and the IL-2R status of these T cells; and (b) rlL-2-induced inhibition of adult marrow erythropoiesis is mediated in part by release of IF-gamma from IL-2R-positive T cells.

CD31 (PECAM-1) is an immunoglobulin gene superfamily cell adhesion molecule found on vascular endothelium, platelets, and leukocytes. Lymphocyte expression of CD31 is most closely associated with the CD45RA+CD8+naive T phenotype. CD31 has recently been shown to play a role in leukocyte egress to inflammatory sites. The mechanism of CD31 adhesion remains under investigation. Several investigators have reported evidence for a heterotypic ligand. We have previously shown that CD31 is phosphorylated with cell activation, which suggests a possible role for CD31 in cell activation events. We therefore studied the effects of CD31 antibodies on in vitro assays of lymphocyte activation. One CD31 antibody, LYP21, inhibited the mixed lymphocyte reaction (MLR) in a specific and dose-dependent fashion. An LYP21 epitope was localized to the sixth Ig domain of CD31. This peptide and a scrambled control peptide were synthesized and used to study effects of this epitope on lymphocyte activation. The CD31 peptide strongly inhibited the MLR. Because CD31 is expressed on both stimulator and responder populations, stimulator peripheral blood leukocytes and responder lymphocyte populations were separately incubated with CD31 peptide or control peptide and then washed before mixing. The CD31 peptide inhibited the MLR equally when either stimulator or responder cells were pre-incubated with the CD31 peptide. We further sorted responder cells into CD31-high and CD31-low populations and separately incubated these subsets with peptides. The CD31 peptide strongly inhibited MLRs, regardless of level of re-sponder-cell CD31 expression. Examination of MLR reactions involving the CD31 peptide showed dispersed small aggregates of cells, rather than the single large aggregate observed in control MLRs. The CD31 peptide did not affect activation of lymphocytes by phorbol myristate acetate (PMA) and ionomycin. These results suggest that a surface CD31-ligand interaction may have a functional role in alloim-mune lymphocyte activation and identify a functionally important domain of CD31.

The interleukin-3 receptor (IL-3R) is composed of α and β subunits, members of the class I cytokine receptor family. Here we describe isolation and characterization of the chromosomal gene for the mouse IL-3R α subunit (mlL-3Rα). Whereas the human IL-3Rα gene is tightly linked with the granulocyte-macrophage colony-stimulating factor receptor α subunit (GM-CSFRα) gene in the pseudoautosomal region of the X and Y chromosomes, the mlL-3Rα gene (II3ra)is located in the proximal region of mouse chromosome 14, separated from the mouse GM-CSFRα gene, which is on chromosome 19. The mlL-3Rα gene spans about 10 kb and is divided into 12 exons. All the exon-intron boundaries possess the splicing junction consensus sequences (5'GT-AG3'), and the whole genomic structure is similar to those of the previously reported class I cytokine receptor genes. There are two major transcription initiation sites that are located at 215 and 188 nucleotides upstream of the initiator codon. The promoter region is GC-rich and contains potential binding sites for GATA, Ets, c-myb, Sp1, Ap-2, and G-C boxes, but not a typical TATA or CAAT sequence. A fusion gene containing 0.8 kb of the 5' noncoding sequence linked to the firefly luciferase gene directed the transcription in mouse mast cells but not in fibroblasts or T cells, suggesting that this promoter functions in a cell type-specific manner. Further sequential deletion of the 5' region suggests two potential regulatory regions for transcription of the mlL-3Rα gene.

Tissue and marrow (BM) in vivo 02tensions have been estimated at 23 to 40 mm Hg (3% to 5% 02). We have investigated cellular regulation of burst-forming units-erythroid (BFU-E) under 5% 02. BFU-E from BM mononuclear cells (MNC) were cultured in methylcellulose medium and erythropoietin (Ep) ± monocyte-conditioned medium (MoCM, a source of burst-promoting activity, BPA) in the presence or absence of autologous T cells (T) and/or monocytes (Mø) under either 5% or 21% 02after depletion of T (MNC-T), M⊘(nonadherent buoyant cells, NAB) or both T and depletion M⊘(NAB-T). MNC BFU-E growth under 5% 02was augmented over 0.1 to 1.5 U/mL of Ep. BFU-E augmentation under 5% 02was abolished by depletion of BM M⊘T, or both from MNC. The addition of MoCM affected neither a BFU-E increase under 5% 02nor the abrogation of that increase upon T or M⊘depletion. The addition of 5% to 20% M⊘or 10% to 20% T to NAB-T failed to restore the BFU-E increase under 5% 02. However, BFU-E augmentation under 5% 02was reestablished when 10% autologous Mø, 10% T, or 10% T plus 10% M⊘were added back to marrow NAB, MNC-T, or NAB-T. BM BFU-E was not augmented in the presence of varying concentrations of catalase, superoxide dismutase, or reduced glutathione at 21% O2; moreover, BFU-E augmentation was maintained at 5% 02 relative to 21% O2 in the presence of each of these antioxidants. CM prepared under 5% or 21% O2 from BM Mø, T, or M⊘plus T were assessed for BPA against BM NAB-T using a sensitive BPA assay incorporating delayed Ep addition to cultures. Only CM from mixtures of M⊘and T cells at 5% O2 demonstrated potent BPA; little or no BPA was detected with T or M⊘CM at 5% O2 and at 21% O2 or T and Myl CM at 21% O2. The sensitivity of NAB-T BFU-E to exogenous BPA was virtually identical at 21% and 5% 02. These results indicate that human BM BFU-E are augmented under 5% 02 and that T cells and M⊘together mediate that augmentation by collaborating to produce BPA-like activity in response to physiological 02 tensions. ®1987 by Grune & Stratton, Inc.

We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt’s leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% ± 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% ± 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% ± 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% ± 13% of patients achieving remission remaining disease-free compared with 31% ± 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

We designed a treatment program to improve the outcome for adults with acute lymphoblastic leukemia (ALL). Treatment included a remission-induction phase followed by intensive alternating cycles of non-cross-résistant chemotherapy and prolonged oral maintenance therapy. Eighty-one consecutive previously untreated patients were entered on this study. Ninety-four percent of patients entered complete remission. A Kaplan-Meier analysis pre dicts that 53% ± 9% (SEM) of patients in remission will remain free of disease at 3 years. Neither age, sex, WBC count, nor immunophenotype had a significant effect on remission duration. This program of intensive cyclical chemotherapy has improved the disease-free survival of patients with adult ALL.

We investigated the mechanism for isolated agranulocytosis and marrow pure white cell aplasia in an elderly man receiving 0.5 to 1.0 g per day of chlorpropamide (Chl) without other toxic drug exposure or overt systemic illness. Patient marrow revealed an absence of recognizable granulocytic precursors; megakaryocytes and erythroid precursors were normal. The WBC count was 1800/ mm3on admission with only 2% neutrophils; the absolute neutrophil count first exceeded 500/mm3on the 17th day following cessation of Chl. A serum Chl level on admission was 100µg/mL (acute phase, AP); no Chl was detected inserum (convalescent phase, CP) assessed on the 22nd hospital day. Antineutrophil antibodies were not detected, and T cell depletion failed to augment patient in vitro granulopoiesis. Patient AP serum produced potent comple-ment-mediated inhibition (87% ± 7%) of autologous granulocyte progenitors (CFU-GM) with minimal inhibition of erythroid (11% ± 5%) or multipotent (5% ± 4%) progenitor cells. Selective inhibition by patient AP serum of CFU-GM (74% ± 11%) was also seen against two allogeneic marrows. Patient CP serum no longer inhibited (6% ± 4%) autologous CFU-GM. Addition of Chi (5 to 120 µg/mL) to CP serum but not to control serum resulted in potent drug concentration-dependent complement-me-diated inhibition of autologous and allogeneic CFU-GM. Inhibition of CFU-GM in the presence of Chl was no longer demonstrable following immunoabsorbent removal of IgG from patient serum. Patient serum in the presence of Chil had limited activity against morphologically recognizable marrow granulocytic precursors in a microimmunofluo-rescence assay. These results are most consistent with the development of Chl-dependent, selective antibody-mediated immune inhibition of granulopoiesis. © 1987 by Grune & Stratton, Inc.

Several letters to the editor are presented in response to articles in previous issues including "More Mergers, Dumb Idea," in the February 15, 1999 issue, "Will Privatizing Fix Social Security," in the March 1, 1999 issue, and "Getting Real About Global," in the February 15, 1999 issue.

Presents letters to the editor referencing articles and topics discussed in previous issues. "The Truth About David Schippers," which profiled David Schippers, Chief Council to the U.S. House of Representative Managers for the Impeachment Trial of President Bill Clinton; "You Bet Your Life," which contend against the viatical settlement industry which buys out the life insurance of terminally ill policy holders for less than the policies' face values; "Court of Dreams," which argued against a permanent International Criminal Court.

Presents letters to the editor referencing articles and topics discussed in previous issues. "The Contract With K Street," which claimed that the growth of businesses and social issues lobbies has created an unprecedented concentration of power in Washington; "Trading Places," which characterized journalist Pat Buchanan as American, Anglo-Saxon, Christian, and heterosexual; Review of the book "Neoconservatism: History of an Idea," by Irving Kristol.

Presents letters to the editor. Treatment of African Americans in clubs in the U.S.; Discrimination against doctors in hospitals; views on the report of the Electric Consumers Conference in Washington.

The article discusses the basic features and available options for the liquid-to-liquid recirculating heat exchange system. It mentions that the liquid-to-liquid heat exchange systems isolates the facility water loops and process coolant fluid by a blazed-plate heat exchanger while offering a process fluid temperature control. It states that liquid-to-liquid heat exchange will precisely supply tempered coolant to the process equipment.