Effect of Systemic Pretreatment With Betamethasone on the Bacterial Flora,Inflammatory Response,and Polyp Formation in Experimentally Infected Rabbit Maxillary Sinus Mucosa

To investigate possible effects of corticosteroids on polyp formation and local bacterial colonization, pneumococcal sinusitis was experimentally induced in rabbits pretreated with betamethasone or saline. After 7 days, macroscopic polyps were counted post-mortem and on histologic slides after serial sectioning. Histologic sections were also examined with light microscopy. Macroscopic polyps were significantly fewer in animals given betamethasone, while there was no difference regarding the number of microscopic polyps. Ingrowth of pathogenic microorganisms was found in five of eight rabbits given placebo but in none of the animals treated with corticosteroids (P < 0.05). The reduced number of pathogenic strains in these animals may be explained by a better-preserved local host defense. The lower number of macroscopic polyps in the same animals could be because of a delayed mucosal repair and subsequent polyp formation.     

Distribution of estramustine in the BT4C rat glioma model

 Estramustine (EaM), a carbamate ester of 17β-estradiol and nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites estromustine (EoM), estradiol, and estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in glioma tissue. Whole-body autoradiography after [¹⁴C]-EaM administration revealed a strong ¹⁴C label simultaneously in tumor and normal brain tissue at 0.5 h after drug administration. In tumor tissue, sustained high levels of ¹⁴C label were detected at 12 h after drug administration. In contrast to the tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the tumor. The tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after drug administration. High levels of ¹⁴C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in tumor tissue, with the mean tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat glioma tissue and is retained in the tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for tumor tissue, exhibiting a high tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a protein with EaM-binding characteristics. Received: 12 January 1997 / Accepted: 28 August 1997     

Inhalation of low concentrations of toluene induces persistent effects on a learning retention task, beam-walk performance, and cerebrocortical size in the rat

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.     

Radiosensitizing effect of estramustine in malignant gliomain vitro andin vivo

Summary Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cellsin vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG,in vitro, and in the rat glioma BT4Cin vitro andin vivo. In all cell-lines an additive effect of EMP and radiation was obtainedin vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2–3 to 5–10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.     

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.     

Evidence of increased platelet activation after thrombolysis in patients with acute myocardial infarction.

OBJECTIVE--To assess platelet activation after thrombolysis in patients with acute myocardial infarction. DESIGN--Platelet function was assessed by measurement of the in vivo synthesis of thromboxane by gas chromatography-mass spectrometry of thromboxane's major urinary metabolite, 2,3-dinor-thromboxane-B2. SETTING--Coronary care unit of Huddinge University Hospital. SUBJECTS--30 patients with acute myocardial infarction given either streptokinase 1.5 million units intravenously over one hour + 500 mg aspirin (n = 10), 500 mg aspirin (n = 10), or neither thrombolysis nor aspirin (n = 10). RESULTS--Patients treated by thrombolysis had a 20-fold increase in thromboxane formation during thrombolysis compared with control patients not treated by thrombolysis (p = 0.0001). Until two days after thrombolysis thromboxane production in patients treated with streptokinase did not decrease to a value comparable with patients treated with aspirin but not given thrombolysis. CONCLUSION--Thromboxane production increased considerably during thrombolysis, possibly reflecting greatly enhanced platelet activation. The slow decrease in thromboxane formation after treatment with aspirin suggests that the efficacy of thrombolysis might be improved by more efficient antiplatelet treatment.     

In vivo production of prostacyclin and thromboxane in patients with acute myocardial infarction.

The in vivo production of prostacyclin and thromboxane was monitored by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in ten patients with acute myocardial infarction, five on standard treatment and five receiving prostacyclin infusion. During acute myocardial infarction excretion of 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, measured by a gas chromatography-mass spectrometry method with deuterated internal standards, was significantly increased. This indicates that thromboxane and prostacyclin synthesis are increased during the development of acute myocardial infarction. The excretion data for 2,3-dinor-thromboxane B2 showed that after administration of aspirin there was less pronounced and more variable inhibition than expected. Prostacyclin infusion did not markedly affect the excretion of the thromboxane metabolite.