Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate

Summary Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono-or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES>DES-MPDES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.Dedicated to Professor Dietrich Schmähl on occasion of his 60th birthdaySupported by the Deutsche Forschungsgemeinschaft and by the Verband der Chemischen Industrie, Fonds der Chemischen Industrie. The authors thank Dr. Weigert, Asta-Werke AG, Degussa Pharma Gruppe, Bielefeld, FRG, for the analysis of DES-MP and DP     

Fulminant hepatic failure

Opinion statement The rare but potentially devastating clinical syndrome of fulminant hepatic failure has as its components severe encephalopathy and finally cerebral edema, hemodynamic instability, renal failure, coagulopathy, profound metabolic disturbances and a particular susceptibility to bacterial and fungal infection. Despite advances in medical management, fulminant hepatic failure in its most severe form carries a high mortality rate unless urgent orthotopic liver transplantation is carried out. However, availability of cadaveric donor organs is limited and, due to the rapidly progressive clinical course in many cases, a substantial proportion of patients will die or develop contraindications to transplantation before the procedure can be performed. Consequently, recent interest has centred on living donor transplantation and the possibility of providing temporary liver support, either through auxiliary partial organ transplantation, extracorporeal perfusion or transplantation of hepatocytes, to allow time for either a liver graft to become available or native liver regeneration, on which spontaneous survival ultimately depends, to occur.     

Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii

The aim of this study was to identify retrospectively trends in species distribution and susceptibility patterns of Candida species causing bloodstream infections in 99 medical centres (55 in Spain and 44 in Argentina) from 1996 to 1999. A total of 744 Candida isolates were sent to the mycology reference laboratories during the study period (514 to the Spanish laboratory and 230 to the Argentinian laboratory). Candida non-albicans strains caused more episodes of fungaemia than Candida albicans isolates in both Spain and Argentina. C. albicans was isolated in 30.2% (155/514) and 40.9% (94/230) of episodes in Spain and in Argentina, respectively. In addition, Candida parapsilosis was the second most commonly isolated pathogen (36.4%). Candida tropicalis caused 13.7% of infections and Candida glabrata 7.4%. The amphotericin B MIC was 相似文献   

Changes in activity of non-specific esterases in cadmium treated Lymantria dispar larvae

Many biochemical, physiological and histological criteria have been used as indicators of exposures and effects of the contaminants. These changes can indicate the response of an organism to a specific environmental stressor. In the present paper, the effect of the acute and chronic exposure to cadmium as well as recovery from two cadmium concentrations (10 and 30 μgCd/g dry food) on gypsy moth (Lymantria dispar) midgut esterases was investigated. The influence of cadmium on trait plasticity was also examined. Esterases showed great sensitivity to low metal concentrations during acute and chronic treatments. Their activities during short-term exposure and after recovery significantly depended on cadmium concentrations. The esterases had greater index of plasticity during chronic treatments with 10 and 30 μgCd/dry food. Five esterase isoforms between 64 and 250 kDa were detected. Isoforms of esterases exposed to any of the two cadmium effects differed among several egg-masses. Isozymes were distinguished in one egg-mass during different cadmium treatments. We conclude that these enzymes could be considered potential and sensitive non-selective biomarkers for the presence of cadmium in food.     

Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects

CSF-1, a key regulator of mononuclear phagocyte production, is highly expressed in the skeleton by osteoblasts/osteocytes and in a number of nonskeletal tissues such as uterus, kidney and brain. The spontaneous mutant op/op mouse has been the conventional model of CSF-1 deficiency and exhibits a pleiotropic phenotype characterized by osteopetrosis, and defects in hematopoiesis, fertility and neural function. Studies to further delineate the biologic effect of CSF-1 within various tissues have been hampered by the lack of suitable models. To address this issue, we generated CSF-1 floxed/floxed mice and demonstrate that Cre-mediated recombination using Meox2Cre, a Cre line expressed in epiblast during early embryogenesis, results in mice with ubiquitous CSF-1 deficiency (CSF-1KO). Homozygous CSF-1KO mice lacked CSF-1 in all tissues and displayed, in part, a similar phenotype to op/op mice that included: failure of tooth eruption, osteopetrosis, reduced macrophage densities in reproductive and other organs and altered hematopoiesis with decreased marrow cellularity, circulating monocytes and B cell lymphopoiesis. In contrast to op/op mice, CSF-1KO mice showed elevated circulating and splenic T cells. A striking feature in CSF-1KO mice was defective osteocyte maturation, bone mineralization and osteocyte-lacunar system that was associated with reduced dentin matrix protein 1 (DMP1) expression in osteocytes. CSF-1KO mice also showed a dramatic reduction in osteomacs along the endosteal surface that may have contributed to the hematopoietic and cortical bone defects. Thus, our findings show that ubiquitous CSF-1 gene deletion using a Cre-based system recapitulates the expected osteopetrotic phenotype. Moreover, results point to a novel link between CSF-1 and osteocyte survival/function that is essential for maintaining bone mass and strength during skeletal development.     

Resistance to prooxidant agent paraquat in the short- and long-lived lines of the seed beetle (Acanthoscelides obtectus)

In the present study we test whether variation in resistance to paraquat (PQ), a free radical generator, correlates with variation in longevity in two sets of seed beetles (Acanthoscelides obtectus) experimental lines that were selected either for early reproduction and short-life or late reproduction and long-life. Long-lived late reproduction lines (L) showed increased resistance to PQ, while opposite was true for short-lived early reproduction line (E). Striking outcome of the selection for early and late reproduction in A. obtectus is asymmetry of responses to alternate mating schedules. The intensity of response depended on selection regime, sex and PQ dose. Evolution of longevity and PQ resistance was faster in L than E selection regime, and in females than males. To understand how age-specific mortality rates are affected by PQ we decomposed post-stress mortality data (using Gompertz mortality model) into initial mortality rate, which reflects basal vulnerability to stresses and age-specific mortality rate, which concerns the rate of increase in stress vulnerability, i.e. the rate of senescence. By estimating the parameters of the Gompertz mortality model we have shown that longevity reduction caused by PQ was the consequence of the increased baseline mortality rather than a speed up of the rate of ageing.     

Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo.

Dentin matrix protein 1 (DMP1) was originally postulated to be dentin specific. Further analysis showed that DMP1 is also expressed in mature cartilage and bone. In bone tissue, DMP1 is expressed predominantly in late osteoblasts and osteocytes. DMP1 belongs to the SIBLING (Small Integrin Binding Ligand N-linked Glycoprotein) family of cellular matrix proteins that also includes osteopontin, bone sialoprotein, dentin sialophosphoprotein, and others. In this study, we examined the effect of mechanical loading on expression of DMP1 mRNA and DMP1 protein in alveolar bone in the mouse tooth movement model by in situ hybridization and immunocytochemistry. The expression of DMP1 mRNA was determined quantitatively in mechanically loaded and control sites of dento-alveolar tissue at several time points from 6 h to 7 days after loading. The tooth movement model allows simultaneous evaluation of bone resorption and bone formation sites. Expression of DMP1 mRNA in osteocytes increased 2-fold as early as 6 h after treatment in both the bone formation and bone resorption sites. After 4 days, DMP1 expression in osteocytes increased to a maximum of 3.7-fold in the bone formation sites and 3.5-fold in the resorption sites. Osteoblasts responded in the opposite manner and showed a transient 45% decrease of DMP1 mRNA in bone formation sites and a constant decrease of DMP1 mRNA during the entire course of treatment in the bone resorption sites, with a peak inhibition of 67% at day 2. By immunocytochemistry using a C-terminal region peptide antibody to DMP1, we found that there was a transient decrease in immunoreactivity at 3 days after treatment on both the formation side and the resorption side compared with the matched contralateral control tissue. However by 7 days of loading, there was a dramatic increase in DMP1 protein immunoreactivity on both the formation side and the resorption side. These results represent changes in epitope availability using this antibody or true changes in protein levels. The observations imply that the DMP1 protein is undergoing dynamic changes in either synthesis or other protein/matrix interaction after mechanical loading of alveolar bone. The findings indicate that DMP1 is involved in the responses of osteocytes and osteoblasts to mechanical loading of bone. These results support the hypothesis that osteocytes alter their matrix microenvironment in response to mechanical loading.     

Effectiveness of spiramycin in murine models of acute and chronic toxoplasmosis

The antitoxoplasmic activity of spiramycin (SPI) was evaluated in murine models of infection using a type-1 (RH) or type-2 (Me49) strain of Toxoplasma gondii. In mice infected with 10(2) tachyzoites of the RH strain, treatment with 100 and 200 mg SPI/kg/day had only a limited effect; despite some dose-dependent prolongation of survival, it was unable to protect mice against death. In contrast, in acute infection induced by peroral inoculation of 10, but not 20, cysts of the Me49 strain, a 3-week course of 100 mg SPI/kg/day and a 4-week course of 200 mg/kg/day significantly enhanced protection and markedly reduced brain cyst burdens at 6 months post infection (p.i.). In chronic infection established by inoculation of 10 cysts 3 months previously, a 3-week course of 200 mg SPI/kg/day resulted in significantly decreased brain cyst burdens compared with controls, both 2 weeks after treatment cessation and by 6 months p.i. Although a favourable effect on chronic infection may be specific for mice, these data merit investigation, since they may have clinical ramifications.