Some Legal Aspects of Compensation in Heart Disease Cases

Cadmium injections during molar tooth development in the rat were strongly caries-promoting in female rats. Cadmium also partially negated the cariostatic effects of fluoridated drinking water in both male and female rats. The mechanism for the caries-promoting properties of cadmium is unknown, but may be related to cadmium uptake into enamel and dentin. Cadmium was taken up into molar enamel and dentin in proportion to the amount of cadmium administered, but cadmium did not influence uptake of fluoride onto erupted enamel. Calcium and ash concentrations in molar enamel were not altered by cadmium administration.     

Radioprotection of mice by recombinant rat stem cell factor.

Treatment with recombinant rat stem cell factor (rSCF) protects mice from the lethal effects of irradiation. Mice treated with a single dose of rSCF prior to irradiation of up to 1150 rads [given as a split dose (1 rad = 0.01 Gy)] resulted in > 80% long-term survival, whereas a single injection given after the last dose of irradiation was not radioprotective. The combination of pre- and posttreatment (-20 h, -2 h, and +4 h) with rSCF resulted in 100% survival of otherwise lethally irradiated mice. Using this optimum schedule of rSCF administration, a radioprotective factor of 1.3-1.35 was achieved. The major cause of death in the control animals was massive bacteremia consisting of enteric organisms. The rSCF-treated animals had a much lower frequency of septicemia, due primarily to a rapid hematopoietic recovery of bone marrow function not evident in control animals.     

Acute and subacute hematologic effects of multi-colony stimulating factor in combination with granulocyte colony-stimulating factor in vivo.

Multi-colony stimulating factor (Multi-CSF, interleukin-3, IL-3) and granulocyte-CSF (G-CSF) administered concurrently as an intravenous (IV) injection induce a peripheral neutrophilia that is approximately additive in comparison with the neutrophilia induced by IL-3 and G-CSF individually. The bone marrow (BM) at 12 hours is depleted of mature neutrophils and shows a left-shifted myeloid hyperplasia, consistent with the neutrophil-releasing and myeloproliferative activities of both IL-3 and G-CSF individually. The BM at 24 hours shows a replenished reserve of mature neutrophils and a synergistic left-shifted myeloid hyperplasia as compared with IL-3 and G-CSF alone. Daily IV injections of IL-3 plus G-CSF for 1 week also induce an approximately additive daily peripheral neutrophilia. The BM after a week's administration of IL-3 plus G-CSF shows a generalized myeloid hyperplasia with a synergistic increase in mature neutrophils as compared with IL-3 or G-CSF alone. Daily injection of IL-3 plus G-CSF induced a significant decrease in erythroid, lymphoid, and eosinophilic marrow precursors, possibly owing to a myelophthisic effect of the myeloid hyperplasia and despite the fact that IL-3 alone induced a significant erythroid hyperplasia.     

Effects of granulocyte colony-stimulating factor and stem cell factor, alone and in combination, on the mobilization of peripheral blood cells that engraft lethally irradiated dogs

The effects of recombinant canine granulocyte colony-stimulating factor (rcG-CSF) and recombinant canine stem cell factor (rcSCF), a c-kit ligand, on the circulation of hematopoietic progenitor and stem cells were studied in a canine model. Administration of rcG-CSF (10 micrograms/kg) for 7 days led to a 5.4-fold increase in CFU-GM/mL of blood, while 7 days of rcSCF (200 micrograms/kg) led to an 8.2-fold increase. Although treatment with low-dose rcSCF (25 micrograms/kg) had no effect on the level of peripheral blood progenitors, 7-day exposure to a combination of G-CSF plus low dose SCF led to a 21.6-fold increase (P = .03). To assess the ability of these factors to increase the circulation of cells capable of rescuing animals after lethal total body irradiation (TBI), 1 x 10(8) peripheral blood mononuclear cells (PBMC)/kg were collected and cryopreserved from animals after 7 days of treatment with G-CSF, SCF or a combination of the two. One month later, animals were exposed to 9.2 Gy TBI and transplanted with the previously collected cells. Control animals transplanted with 1 x 10(8) PBMC/kg collected without pretreatment died with marrow aplasia 11 to 29 days after TBI as did animals treated with only low-dose SCF before cell collection. In contrast, all animals given PBMC collected after G-CSF, high-dose SCF, or a combination of G-CSF plus low-dose SCF recovered granulocyte function. Recovery to 500 granulocytes/microL after transplant took 17, 18.8, and 13.6 days, respectively, (P = .056 for the difference between the combination G-CSF-SCF group and the other two groups). In both the G-CSF and SCF groups, 4 of 5 animals completely recovered while 1 of 5 in each group died with prolonged thrombocytopenia. In the combination group, all 5 animals became long- term survivors. These studies demonstrate that both G-CSF and SCF dramatically increase the level of peripheral blood hematopoietic progenitor and stem cells and support the view that these factors can act synergistically.     

Synergistic interactions between hematopoietic growth factors as detected by in vitro mouse bone marrow colony formation

We have investigated the proliferative effects of several combinations of hematopoietic growth factors in agar cultures of murine bone marrow cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) synergized with granulocyte colony-stimulating factor (G-CSF), while G-CSF also synergized with macrophage colony-stimulating factor (CSF-1) and interleukin 3 (IL3), resulting in colony numbers greater than the sum of the numbers of colonies formed with each factor alone. In addition, these combinations resulted in increased colony sizes, with the formation of day-14 colonies with diameters greater than 0.5 mm. The combination of GM-CSF plus IL3 showed an increase in numbers of colonies that approximated the sum of that seen with each factor alone, however, the size of the colonies was increased with a number of day-14 and day-21 colonies having diameters greater than 0.5 mm. These data add to the list of hematopoietic factors known to synergistically stimulate myeloid progenitors and suggest that some of these interactions may be on early progenitor cells with high proliferative potentials.     

Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential

Splenectomized mice treated for 7 days with pegylated recombinant rat stem cell factor (rrSCF-PEG) showed a dose-dependent increase in peripheral blood progenitor cells (PBPC) that have enhanced in vivo repopulating potential. A dose of rrSCF-PEG at 25 micrograms/kg/d for 7 days produced no significant increase in PBPC. However, when this dose of rrSCF-PEG was combined with an optimal dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 200 micrograms/kg/d), a synergistic increase in PBPC was observed. Compared with treatment with rhG-CSF alone, the combination of rrSCF-PEG plus rhG-CSF resulted in a synergistic increase in peripheral white blood cells, in the incidence and absolute numbers of PBPC, and in the incidence and absolute numbers of circulating cells with in vivo repopulating potential. These data suggest that low doses of SCF, which would have minimal, if any, effects in vivo, can synergize with optimal doses of rhG-CSF to enhance the mobilization of PBPC stimulated by rhG-CSF alone.