Relationship between exposure duration,tissue residues,growth, and mortality in rainbow trout (Oncorhynchus mykiss) juveniles sub-chronically exposed to copper

We conducted a 56-day sub-chronic test on the effects of Cu on rainbow trout (Oncorhynchus mykiss) fry at a nominal water hardness of 100 mg l(-1) (as CaCO(3)). Response measures were growth, whole body Cu concentrations, and mortality. Significant mortality was observed in fish exposed to 54.1 microg Cu l(-1) (47.8%) and 35.7 microg Cu l(-1) (11.7%). Growth was dose-dependent over the range of Cu treatments (0-54 microg Cu l(-1)), and was modeled as a function of Cu exposure concentration and exposure duration. Calculated inhibition concentrations (based on change in wet weight through a 56-day Cu exposure) were IC(50)=54.0 microg Cu l(-1), IC(20)=21.6 microg Cu l(-1), IC(10)=10.8 microg Cu l(-1), and IC(01)=1.1 microg Cu l(-1). Measured whole body Cu was also dose-dependent, and growth of trout fry was readily modeled as a function of tissue Cu and exposure duration. This model was virtually identical to a model previously developed for rainbow trout exposed to Cu at a hardness of 25 mg l(-1). Following the 56-day exposure period, we performed a 96-h acute challenge to Cu and Cd to evaluate the effects of Cu acclimation on acute Cu and Cd toxicity. Sensitivity to Cu was dependent on the 'acclimation dose'; trout previously held in control aquaria (i.e. not acclimated to Cu) suffered over 80% mortality, whereas trout previously exposed to 35.7 microg Cu l(-1) for 56 day suffered 20% mortality. These fish also showed somewhat reduced sensitivity to Cd, suggesting acclimation to Cu can enhance tolerance to other metals. Finally, the relationship between growth response and hardness (derived from several studies) appeared to have a different slope than the hardness relationship previously observed for lethality responses.     

Pharmacokinetic interaction between tacrolimus and diltiazem: dose-response relationship in kidney and liver transplant recipients

OBJECTIVE: To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in kidney and liver transplant recipients. DESIGN: Nonrandomised seven-period stepwise pharmacokinetic study. PATIENTS: Stable kidney (n = 2) and liver (n = 2) transplant recipients maintained on oral tacrolimus twice daily but not taking diltiazem. METHODS: Patients were treated with seven incremental dosages of diltiazem (0 to 180 mg/day) at > or = 2-weekly intervals. At the end of each interval, 13 blood samples were taken over a 24-hour period to allow determination of morning (AUC(12)), evening (AUC(12-24)) and 24-hour (AUC(24)) areas under the concentration-time curve for tacrolimus, as well as AUC(24) for diltiazem and three of its metabolites. RESULTS: There was considerable interpatient variability in tacrolimus-sparing effect. In the two kidney transplant recipients, an increase in tacrolimus AUC(24) occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maximum increase in tacrolimus AUC(24) occurred at the maximum diltiazem dosage used (180 mg/day), when the increase was 48 and 177%. In the two liver transplant recipients, an increase in tacrolimus AUC(24) did not occur until a higher diltiazem dosage (60 to 120 mg/day) was given. The increase at the maximum diltiazem dosages used (120 mg/day in one and 180 mg/day in the other) was also lower (18 and 22%) than that exhibited by the kidney transplant recipients. The increase in tacrolimus AUC(12) was similar to the increase in AUC(12-24) when diltiazem was given in the morning only (dosages < or = 60 mg/day). Hence, diltiazem affects blood tacrolimus concentrations for longer than would be predicted from the half-life of diltiazem in plasma. CONCLUSIONS: The mean tacrolimus-sparing effect of diltiazem was similar in magnitude to the cyclosporin-sparing effect previously reported. Whether the lesser tacrolimus-sparing effect with diltiazem seen in the liver transplant recipients was due to functional differences in the transplanted liver is not known, but it was not due to lower plasma diltiazem concentrations. Diltiazem makes a logical tacrolimus-sparing agent because of the potential financial savings and therapeutic benefits. Because of interpatient variability, the sparing effect should be demonstrated in each patient and not merely assumed.     

Effect of organic isothiocyanates on the P-glycoprotein- and MRP1-mediated transport of daunomycin and vinblastine

Purpose. Organic isothiocyanates (ITCs), or mustard oils, are non-nutrient components present in the diet, especially in cruciferous vegetables. The purpose of this investigation was to examine the effect of ITCs on P-glycoprotein (P-gp)- and multidrug resistance-associated Protein (MRP1)-mediated transport in multidrug resistant (MDR) human cancer cell lines. Methods. The direct effect of ITCs on the 2-h cellular accumulation of daunomycin (DNM) and vinblastine (VBL), substrates for both P-gp and MRP1, were measured in sensitive and resistant MCF-7 cells and in PANC-1 cells. Resistant MCF-7 cells (MCF-7/ADR) overexpress P-gp whereas PANC-1 cells overexpress MRP1. The following compounds were evaluated: allyl-, benzyl-(BITC), hexyl-, phenethyl-(PEITC), phenyl-, 1-naphthyl-(NITC), phenylhexyl-, phenylpropyl-, and phenylbutyl-ITC, sulforaphane, erucin, and erysolin. Results. NITC significantly increased the accumulation of DNM and VBL in both resistant cell lines, but had no effect on DNM accumulation in sensitive MCF-7 cells. VBL accumulation in resistant MCF-7 cells was increased 40-fold by NITC whereas that in PANC-1 cells was increased 5.5-fold. Significant effects on the accumulation of DNM and VBL in resistant MCF-7 cells were also observed with benzyl-isothiocyanate whereas PEITC, erysolin, phenylhexyl-ITC, and phenylbutyl-ITC increased the accumulation of DNM and/or VBL in PANC-1 cells. Overall, the inhibitory activities of these compounds in MCF-7 cells and PANC-1 cells were significantly correlated (r²= 0.77 and 0.86 for DNM and VBL, respectively). Significant effects on accumulation were generally observed with the ITCs at 50 M concentrations, but not at 10 M concentrations. Conclusions. One strategy to enhance the effectiveness of cancer chemotherapy is to reverse the MDR phenomena. Our results indicate that certain dietary ITCs inhibit the P-gp- and the MRP1-mediated efflux of DNM and VBL in MDR cancer cells and suggest the potential for diet-drug interactions.     

Women, menopause, and (Ms.)information: communication about the climacteric

This research utilizes a communication perspective to examine the dissemination of information about menopause in terms of women's attitudes, beliefs, and knowledge. Specifically, this study uses a grounded theory approach (Glaser & Strauss, 1967) to explore the communicative processes of misinformation concerning women's lived experiences in relation to the climacteric. Five emergent themes extracted from premenopausal, perimenopausal, and postmenopausal women's discourse are identified and described through qualitative data analysis. Findings suggest that due to a lack of consistent communication, women are generally either unknowledgeable or misinformed about menopause and its related issues. Inaccurate information concerning a health-related experience that all women undergo has negative implications for women, their practitioners, and society. Moreover, a clearer understanding of women's experiences concerning menopause may enhance communication in physician-patient interactions (PPIs).     

Temporal and spatial relations between age specific mortality and ambient air quality in the United States: regression results for counties, 1960-97

Objective: To investigate longitudinal and spatial relations between air pollution and age specific mortality for United States counties (except Alaska) from 1960 to the end of 1997.