Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2-nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane-induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.     

Thoracic electric impedance and fluid balance during aortic surgery

Indices of fluid balance were evaluated during and after aortic surgery in 16 consecutive patients. Thoracic electrical impedance (TI), heart rate (HR), central venous (CVP), pulmonary artery mean (PAMP), pulmonary wedge (PWP) and mean arterial (MAP) pressures as well as fourteen arterial and venous blood gas variables were followed. Consistent with a reduction of TI during the operation, fluid balance was in excess, and it remained elevated on the first postoperative morning. The HR, MAP and PWP remained stable, while CVP and PAMP decreased. Of the determined variables only TI revealed a meaningful correlation to fluid balance (rho = -0.41; p < 0.01). The results indicate that while central venous and pulmonary artery mean pressures gave the impression of a volume deficit, the positive fluid balance was mirrored by thoracic electrical impedance.     

Colosplenic fistula in a patient treated with interleukin-2 for malignant melanoma

Interleukin-2 (IL-2) therapy often causes gastrointestinal side effects and at least 8 cases of bowel perforation have been reported. The patient reported here developed a colosplenic fistula, diagnosed by CT, with no neoplastic involvement of these organs. Awareness of these complications of IL-2 can help lead to earlier diagnosis.     

Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines

Certain bacterial immunostimulatory (i.s.) DNA sequences containing unmethylated CpG motifs stimulate antigen-presenting cells (APC) to express a full complement of costimulatory molecules and to produce cytokines including interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. While IL-12 is key to their T helper cell (Th)1-promoting adjuvant activity, secretion of toxic levels of TNF-alpha is harmful in that it promotes toxic shock. Given the beneficial as well as harmful consequences of i.s. DNA, we investigated the possibility of identifying DNA sequences, i.e. CpG oligodeoxynucleotides (ODN) which differentially activate IL-12 versus TNF-alpha cytokine production in APC. Here, we describe an i.s. DNA sequence with these characteristics. While its potential to induce IL-12 is preserved, its ability to trigger TNF-alpha release is strongly curtailed both in vitro and in vivo. I.s. DNA could be segregated into lethal and non-lethal in a mouse toxic shock model. The non-toxic i.s. DNA was useful as an adjuvant, thus allowing cytotoxic T cell responses to the soluble protein ovalbumin and conferring a resistant Th 1 phenotype to BALB/c mice lethally infected with Leishmania major. This i.s. CpG motif may thus be prototypic for a useful immunostimulating DNA sequence that lacks harmful side effects.     

Mutagenic and antimutagenic activities of human whole blood, plasma and albumin

The seeds of Crepis capillaris were used to examine the mutagenic und antimutagenic properties of human whole blood, plasma, serum albumin and gamma-globulin by recording chromosomal and chromatid aberrations. The antimutagenic activity was determined by preliminary, simultaneous, and subsequent biosubstrate treatments of the seeds. The whole and twice-diluted blood, as well as plasma, induced aberrations exceeding the level of self-arbitrary mutagenesis by 3.7-5.3 and 2.6-3.1 times, respectively. When the blood was diluted to its 20% concentration, the antimutagenic efficiency of biological fluids was recorded. Human serum albumin and gamma-globulin were found to have an antimutagenic effect. In the dilutions having no antimutagenic effect, blood, plasma, and albumin showed their ability to be effectively decrease the level of induced aberrations.     

The effects of treatment with PIXY321 (GM-CSF/IL-3 fusion protein) on human polymorphonuclear leukocyte function

During a phase I trial of the genetically engineered hematopoietic growth factor PIXY321 (granulocyte-macrophage colony-stimulating factor/interleukin-3 [IL-3] fusion protein), we examined the effects of PIXY321 treatment on human polymorphonuclear leukocyte (PMN) locomotive, respiratory burst, and phagocytic responses. PIXY321 treatment was associated with transient suppression of both unstimulated locomotion and chemotaxis responses to multiple stimuli, as well as significant transient enhancement of formyl peptide-stimulated H2O2 production. No effects on opsonic phagocytosis of Staphylococcus aureus were observed. In vitro exposure of control PMN to PIXY321 resulted in suppression of unstimulated locomotion/chemotaxis and enhancement of formyl peptide-stimulated H2O2 production but had no effects on phagocytosis. When patient cells were exposed in vitro to PIXY321 during treatment, suppression of chemotaxis and enhancement of H2O2 production were observed before PIXY321 treatment, but these effects diminished during treatment. The in vivo and in vitro exposure effects of PIXY321 treatment on PMN function are similar to those of the parent molecule, granulocyte-macrophage colony-stimulating factor (GM-CSF).