Iron overload in patients with myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis in one or more cell lines, resulting in insufficient bone marrow function. For most patients with MDS, supportive care by blood transfusions is still the mainstay of treatment. Especially in low-risk patients, anemia represents the major clinical problem, and many of these patients develop transfusional iron overload. This paper reviews the literature on transfusional iron overload in patients with MDS, looking at pathophysiology, evaluation, and treatment of the transfusional iron burden with desferrioxamine and oral chelators.

[Metabolic aspects of endotoxin as a model of septic shock--approached from oxidative stress].

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca2+, Zn2+, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca2+ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms.

Effects of colloidal resuscitation fluids on reticuloendothelial function and resistance to infection after hemorrhage.

The effects of three resuscitation fluids, hydroxyethyl starch (HES), Haemaccel, and fresh autologous blood, on reticuloendothelial system phagocytic and catabolic functions and resistance to infection after 40% hemorrhages in BALB/c mice were studied. The mice, anesthetized with isoflurane, were bled over a 10-min period, left hypovolemic for 30 min, and then resuscitated with their shed blood or the same volume of asanguineous fluid. Normothermia was maintained throughout the experiments. The uptake and catabolism of intravenously injected double-labelled sheep erythrocytes (51Cr-125I-SRBC) in liver and spleen were determined at 1 and 48 h after hemorrhage. No significant changes in the uptake or catabolism of SRBC in liver or spleen were found at 1 h after hemorrhage and resuscitation with any of the fluids. However, at 48 h a significant increase in liver uptake of SRBC was seen in animals resuscitated with either Haemaccel or HES compared to that in animals resuscitated with shed blood or in animals subjected to a sham operation. The increase in liver uptake was accompanied by a small decrease in spleen uptake in animals resuscitated with Haemaccel but not with HES. No great changes in catabolic activity were seen at 48 h, although activity levels tended to be higher in animals resuscitated with Haemaccel. Separate groups of animals were challenged by an intraperitoneal injection with live Escherichia coli at 1 or 48 h after hemorrhage and resuscitation. Sixty-four percent of the animals resuscitated with shed blood survived the challenge with E. coli at 1 h after hemorrhage, whereas only 10 and 0% survival was seen for animals resuscitated with Haemaccel and HES, respectively. At 48 h survival was 80% for shed-blood-resuscitated animals and 60 and 70% for Haemaccel- and HES-resuscitated animals, respectively.

Factors that modify the effects of prostaglandin on diet-induced acute pancreatitis in mice.

Considerable disagreement exists as to whether prostaglandins improve survival in animals with experimental pancreatitis. In prior studies we have demonstrated a beneficial effect of prostaglandin in the choline deficient, ethionine supplemented diet model of acute hemorrhagic pancreatitis. In the present study we have examined the effects of 1) delaying treatment with 16,-16-dimethyl prostaglandin E2 (PGE2) till 24 h after introduction of the diet and 2) exposing animals to the test diet for 3 days instead of 2. Following delayed treatment mortality in the saline control group (57%) was significantly higher on the fourth day compared to the PGE2 treatment group (3%). However, the overall mortality on day 7 was not significantly different from that seen in the control group (43% versus 60%). In the second series of experiments, PGE2 no longer had a beneficial effect if animals were fed the CDE diet for 3 days. We would conclude from this study and others that the ability to demonstrate a protective effect of PGE2 on the pancreas is dependent upon the experimental protocol employed. Thus, the ability to demonstrate this effect is dependent upon the dose and type of prostaglandins employed, the length of exposure to the test diet, and the time at which treatment is started relative to the induction of the pancreatitis.

Relationship between the functional status of the reticuloendothelial system and the outcome of experimentally induced pancreatitis in young mice.

Physiologically, the main function of alpha 2-macroglobulin is the binding of active endopeptidases rather than their inhibition. The interaction results in a conformational change in the alpha 2-macroglobulin that leads to its rapid elimination by the reticuloendothelial system. In this way, the reticuloendothelial system may help in the regulation of extracellular proteolytic activity resulting from the release of proteinases from injured pancreatic acinar cells in acute pancreatitis. To evaluate this concept, the effect of feeding a choline-deficient diet supplemented with 0.5% DL-ethionine was determined in 4 and 6-wk-old mice in which the reticuloendothelial system was normal, stimulated, or depressed. Stimulating the reticuloendothelial system in 4-wk-old mice significantly (a) decreased the mortality rate; (b) lessened the drop in the plasma content of both alpha 2-macroglobulin and alpha 1-antitrypsin; and (c) decreased the severity of pancreatitis noted microscopically. In contrast, reticuloendothelial suppression in this group of mice had no demonstrable effect. However, when similar studies were done in 6-wk-old mice, in which this diet induces a milder disease, reticuloendothelial suppression significantly increased the mortality rate as compared with normal mice, whereas reticuloendothelial stimulation significantly decreased it. The possible mechanism for the salutory effect of stimulating the reticuloendothelial system on the outcome of diet-induced pancreatitis in mice is discussed.

The effect of combination chemotherapy on the reticuloendothelial system in man.

The effect of adjuvant combination chemotherapy (vincristine, CCNU/MeCCNU, 5-fluorouracil) on the phagocytic and catabolic properties of the reticuloendothelial system (RES) was studied in 4 patients before and during the anticancer treatment. The results indicate a transient impairment of both these functions, more prolonged with regard to phagocytosis. No significant changes were noted in the mobile macrophage system. This suggests that chemotherapy induces a depression especially of the stationary macrophage populations in the liver, spleen and bone-marrow.

In vivo behavior of fibrinogen fragment D in experimental renal, hepatic and reticuloendothelial dysfunction.

Fibrinogen Fg-D, obtained by plasmin-induced cleavage of fibrinogen, was separated and purified by ion exchange chromatography. The in vivo behavior was studied by administering 2 mg of (125)I-labeled Fg-D intravenously into each of 3 normal, 3 partially hepatectomized, 3 reticuloendothelial system (RES) blockaded, 4 nephrectomized and 2 ureter ligated rabbits. The plasma clearance in normal rabbits showed two components: 66.0 +/- 6.0% was cleared with a t(1/2) of 0.9 +/- 0.2 hours and 32.3 +/- 5.3% cleared with a t(1/2) of 3.6 +/- 0.3 hours. In both the partially hepatectomized and RES-blockaded groups, the clearance patterns were similar to those observed in the normal animals. In contrast, in the nephrectomized group, while the t(1/2) of the first component was similar to that in the normal group, the second component had a longer t(1/2) (6.0 +/- 1.0 hours) than the other groups. In the animals with both ureters occluded, the t(1/2)'s were similar to the normal animals. Measurements of urinary radioactivity suggested that complete in vivo catabolism had occurred. In vivo subfragments of Fg-D could not be detected in the plasma. Neither Fg-D nor subfragments were found in the urine. These results indicate that Fg-D is rapidly cleared from the plasma, that in vivo subfragmentation does not occur, and that the kidneys are important in the catabolism of a portion of Fg-D.