[Bone marrow transplantation.].

For the last few decades there has been a major increase in the number of allogeneic bone marrow transplantations and every year several thousand transplants are performed. In the early days of transplantation the treatment was performed only in terminally ill patients but now transplantation is carried out early in the course of the disease with greatly improved results. The most common indications for treatment today include acute and chronic leukemia, Non-Hodgkin s lymphoma, Hodgkin s disease, multiple myeloma and congenital immune deficiencies. Sibling donors are the most common source of stem cells for transplantation but in recent years international donor registries have played an increasing role. Degree of HLA disparity between donor and recipient is the main risk factor for Graft versus Host disease which is still the major cause of morbidity and mortality after transplantation. Graft rejection is very rare when there is complete HLA match between the donor and recipient. Overall survival is also dependent on several other factors including disease stage at time of transplantation, age and disease categories. For the last few years an average of four Icelandic patients have received bone marrow transplantation each year and indicatioons are similar to other European countries.

Effect of nitric oxide production and oxygen tension on progenitor preservation in ex vivo culture.

Many cell types are capable of expressing inducible nitric oxide synthase (iNOS) in response to cytokines or endotoxin. We detected iNOS mRNA by reverse transcriptase polymerase chain reaction in CD34+ human bone marrow cells after 48-hour incubation with interferon-gamma (IFN-gamma)/tumor necrosis factor alpha (TNF-alpha) and IFN-gamma/lipopolysaccharide. Based on this finding, we examined the effect of nitric oxide (NO) on hematopoiesis and particularly on proliferation and survival of CD34+ marrow cells in in vitro culture. When CD34+ cells were cultured in the presence of an NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a dose-dependent inhibition of cell proliferation was observed. Addition of the selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine hydrochloride (L-NIL) at a dose of 500 microM increased the cell counts by 23% (range 0-89%). The expansion of total CD34+ cell number was 4-fold with a hematopoietic cytokine cocktail compared to 5.2-fold with the addition of L-NIL to this combination. At days 7 and 14 of culture, SNAP induced apoptosis in CD34+ human bone marrow cells detected by an in situ terminal deoxynucleotidyl transferase assay. The apoptosis was partially inhibited with the addition of L-NIL. SNAP also inhibited cell cycling, as evidenced by a 56% decrease in the number of cells in S phase after 5 days of culture in the presence of SNAP. To investigate if NO production was dependent on oxygen tension, J774A mouse macrophage cells were induced with lipopolysaccharide/IFN-gamma, and nitrite production measured by the Griess reaction. Nitrite production was persistently less in 5% compared to 21% oxygen. CD34+ marrow cells from normal donors were also grown under variable oxygen tension, and the cell proliferation in 5% oxygen was significantly greater at both 7 and 14 days of culture. CFU-GM colony growth also was increased in the low oxygen setting. The concentration of various cytokines was measured in CD34+ progenitor culture supernatants, including interleukin (IL)-1 alpha, IL-1 beta and TNF-alpha. SNAP increased IL-1 alpha production by CD34+ cells as well as from light-density bone marrow cells, whereas the effect on IL-1 beta and TNF-alpha production was not significant. Manipulation of oxygen tension and the inhibition of production of reactive oxygen and nitrogen intermediates may have potential to optimize cell expansion and progenitor preservation in ex vivo culture systems.

Effect of stromal cell coculture on progenitor cell expansion and myeloid effector function in vitro.

Stimulation of CD34(+)-enriched marrow or light density marrow with various growth factor combinations can generate granulocyte progenitors and mature neutrophils in vitro. In this work, we have examined the influence of irradiated marrow stromal layers on growth factor-induced myeloid and early multipotential progenitor expansion from enriched marrow CD34+ progenitors. We have also explored whether the addition of early-acting growth factors known to enhance myelopoiesis in long-term culture, such as fibroblast growth factor (b-FGF), insulin growth factor (IGF-1), c-kit ligand or stem cell factor (SCF), and flk-2flt-3 ligand (FL), can lengthen survival of CD34+ progenitors in these cultures. Stromal cell coculture resulted in greater numbers of total cells and CFU-GM at day 7 and day 14, but with the addition of multiple growth factors, these effects of stromal cell coculture were diminished. At day 14, generally < 1% of the expanded cells over stromal coculture conditions were CD34+, with up to 90% demonstrating CD15 positivity. Culture of CD34+ cells in the presence of early-acting growth factors did not cause significant expansion of CD34+ cells over a 14-day life span, even in the presence of marrow stromal cells. These data suggest that although stromal cell coculture for a period up to 14 days can enhance expansion of total cell numbers and CFU-GMs, stromal cell presence does not lead to expansion of CD34+ cells in these cultures and may diminish the number of clonogenic cells present when growth factors with differentiating capacity are present. Mature neutrophils harvested from such cultures are capable of chemotaxis, actin polymerization, and migration, suggesting a replete functional status.

Cytarabine-induced pericarditis: a case report and review of the literature of the cardio-pulmonary complications of cytarabine therapy.

Pericarditis is a rare complication of chemotherapy. This report describes a patient who developed symptoms, signs, and electrocardiographic evidence of pericarditis following treatment with high dose cytarabine. The patient had no clinical or echocardiographic evidence of infection or leukemic involvement of the pericardium. Isolated pericarditis associated with high dose cytarabine has been rarely reported. This therapy is frequently used and, therefore, it seems prudent to alert physicians to this potential complication of cytarabine. The cardiopulmonary complications of cytarabine are also reviewed.

Methotrexate treatment of rheumatoid arthritis: effects on radiological progression.

Radiological progression was evaluated in 15 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Prior to MTX treatment, all the patients had failed on other slow-acting agents and all showed radiological deterioration. For each patient, three sets of radiographs of hands and wrists were evaluated: prior to MTX treatment while on other slow-acting agents, at the beginning of MTX treatment, and at the most recent evaluation on MTX. Two experienced radiologists evaluated the radiographs independently. The rate of radiological progression was calculated by dividing the change in radiological score by the number of months between sets of radiographs. The mean time from film set one to two (period one) was 29.4 months and from set two to three (period two) 32.5 months. The mean rate of radiological progression for period one was 0.576 and for period two, 0.381. Eight patients showed decline in radiological progression during MTX treatment.