The effect of selective phosphodiesterase inhibitors, alone and in combination, on a murine model of allergic asthma

BACKGROUND: The anti-inflammatory effects of the selective phosphodiesterase (PDE) inhibitors cilostazol (PDE 3), RO 20-1724 (PDE 4) and sildenafil (PDE 5) were examined in a murine model of allergic asthma. These compounds were used alone and in combination to determine any potential synergism, with dexamethasone included as a positive control. METHODS: Control and ovalbumin sensitised Balb/C mice were administered orally with each of the possible combinations of drugs at a dose of 3 mg/Kg for 10 days. RESULTS: When used alone, RO 20-1724 significantly reduced eosinophil influx into lungs and lowered tumour necrosis factor-α, interleukin-4 and interleukin-5 levels in the bronchoalveolar lavage fluid when compared to untreated mice. Treatment with cilostazol or sildenafil did not significantly inhibit any markers of inflammation measured. Combining any of these PDE inhibitors produced no additive or synergistic effects. Indeed, the anti-inflammatory effects of RO 20-1724 were attenuated by co-administration of either cilostazol or sildenafil. CONCLUSIONS: These results suggest that concurrent treatment with a PDE 3 and/or PDE 5 inhibitor will reduce the anti-inflammatory effectiveness of a PDE 4 inhibitor

Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study

INTRODUCTION: Body mass index (BMI) during adulthood is inversely related to the incidence of premenopausal breast cancer, but the role of body fatness earlier in life is less clear. We examined prospectively the relation between body fatness during childhood and adolescence and the incidence of breast cancer in premenopausal women. METHODS: Participants were 109,267 premenopausal women in the Nurses' Health Study II who recalled their body fatness at ages 5, 10 and 20 years using a validated 9-level figure drawing. Over 12 years of follow up, 1318 incident cases of breast cancer were identified. Cox proportional hazards regression was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for body fatness at each age and for average childhood (ages 5–10 years) and adolescent (ages 10–20 years) fatness. RESULTS: Body fatness at each age was inversely associated with premenopausal breast cancer incidence; the multivariate RRs were 0.48 (95% CI 0.35–0.55) and 0.57 (95% CI 0.39–0.83) for the most overweight compared with the most lean in childhood and adolescence, respectively (P for trend < 0.0001). The association for childhood body fatness was only slightly attenuated after adjustment for later BMI, with a multivariate RR of 0.52 (95% CI 0.38–0.71) for the most overweight compared with the most lean (P for trend = 0.001). Adjustment for menstrual cycle characteristics had little impact on the association. CONCLUSION: Greater body fatness during childhood and adolescence is associated with reduced incidence of premenopausal breast cancer, independent of adult BMI and menstrual cycle characteristics

Effect of a perfluorocarbon emulsion (Fluosol-DA) on reticuloendothelial system clearance function

To study the effect of a perfluorocarbon oxygen transport emulsion (Fluosol‐DA) on reticuloendothelial system (RES) function, we measured the blood clearance of human erythrocytes transfused to rats. Compared with saline treatment, Fluosol‐DA at 30 ml/kg doses significantly increased both the percent 20‐hour blood recovery (mean 8.9% ± 2.7 SEM vs 1.3% ± 0.25 SEM) and 51Cr t1/2 survival (mean 14.0 hours ± 2.7 SEM vs 3.5 hours ± 0.33 SEM) of the human red cells. This suppression of RES clearance function was transient and no longer detectable seven days after single Fluosol‐DA doses. The Fluosol‐DA‐induced RES block was about three times greater than that obtainable with 4 g/kg of a soybean oil emulsion used for clinical hyperalimentation. On the other hand, the effect of ethyl palmitate (0.5 g/kg), a potent but toxic RES blocker, was 3.5 times greater than that of Fluosol‐DA in this test system. If Fluosol‐DA also induces RES block in humans, this emulsion could be explored as a therapeutic RES blocker in certain immune cytopenias. Copyright © 1984 Wiley‐Liss, Inc., A Wiley Compan

Fault controlled Carboniferous A-type magmatism in the proto-Andean foreland (Sierras Pampeanas, Argentina): Geochemical constraints and petrogenesis

The intrusion of granitoids into the Eastern Sierras Pampeanas in the Early Carboniferous took place after a long period of mainly compressional deformation that included the Famatinian (Ordovician) and Achalian (Devonian) orogenies. These granitoids occur as small scattered plutons emplaced in a dominant extensional setting, within older metamorphic and igneous rocks, and many of them are arranged along a reactivated large shear zone. A set of 46 samples from different granitic rocks: Huaco granitic complex, San Blas pluton, and the La Chinchilla stock from the Sierra de Velasco, Zapata granitic complex from Sierra de Zapata, and the Los Árboles pluton from Sierra de Fiambalá, display high and restricted SiO2 contents between 69.2 and 76.4 wt.%. On both FeO/(FeO+MgO) vs. SiO2 and [(Na2O+K2O)−CaO] vs. SiO2 plots the samples plot in the ferroan and alkaline-calcic to calco-alkaline fields (FeO/(FeO+MgO)=0.88–1.0%;[(Na2O+K2O)−CaO]= 6.3–8.3%), thus showing an A-type granitoid signature. The high concentrations for the High Field Strength Elements (HSFE), such as Y, Nb, Ga, Ta, U, Th, etc. and flat REE patterns showing significant negative Eu anomalies are also typical features of A-type granites. Our petrogenetic model supports progressive fractional crystallization with dominant fractionation of feldspar and a source mineral assemblage enriched in plagioclase. Biotites have distinctive compositions with high FeO/MgO ratios (7.8–61.5), F (360– 5610 ppm), and Cl (120–1050 ppm). The FeO/MgO ratios together with the F and Cl content of igneous biotites seem to reflect the nature of their parental host magmas and may be useful in identifying A-type granitoids. The isotopic data (Rb–Sr and Sm–Nd) confirm that the A-type granites represent variable mixtures of asthenospheric mantle and continental crust and different mixtures lead to different subtypes of A-type granite (illustrating the lack of consensus about A-type magma origin). We conclude that prominent shear zones play an important role in providing suitable conduits for ascending asthenospheric material and heat influx in the crust, a hypothesis that is in accord with other recent work on A-type granites