Pharmacokinetic-pharmacodynamic modeling of the anticonvulsant and electroencephalogram effects of phenytoin in rats

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg . kg-1 phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination. Vmax and Km values were, respectively, 386 +/- 31 microg . min-1 and 15.4 +/- 2.2 microg . ml-1 for the anticonvulsant effect in the cortical stimulation model and 272 +/- 31 microg . min-1 and 5.9 +/- 0.7 microg . ml-1 for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean ke0 values of 0.108 and 0.077 min-1 for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid Emax model, but Emax values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E = E0 + Bn . Cn) derived from the sigmoid Emax model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that Emax values cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient (B) of 2.0 +/- 0.4 microA . ml . microg-1 and an exponent (n) of 2.7 +/- 0.9. The derived EC50 value of 12.5 +/- 1. 3 microg . ml-1 for the EEG effect coincides with the "therapeutic range" in humans.     

A temporal modal defeasible logic for formalizing social commitments in dialogue and argumentation models

In this paper, we extend a temporal defeasible logic with a modal operator Committed to formalize commitments that agents undertake as a consequence of communicative actions (speech acts) during dialogues. We represent commitments as modal sentences. The defeasible dual of the modal operator Committed is a modal operator called Exempted. The logical setting makes the social-commitment based semantics of speech acts verifiable and practical; it is possible to detect if, and when, a commitment is violated and/or complied with. One of the main advantages of the proposed system is that it allows for capturing the nonmonotonic behavior of the commitments induced by the relevant speech acts.     

Frozen Storage of Unwashed Cod (Gadus morhua) Frame Mince with and without Kidney Tissue

Removal of kidney material was essential for a higher quality cod frame mince. The removal of kidney tissue before deboning eliminated typical “chemical” and “petroleum” type flavors and resulted in a white, less red, and higher quality unwashed frame mince. Those samples without kidney tissue had good frozen storage stability, (particularly at -40°C) and could be used as an ingredient in apropriate meat products. The length of iced storage of frames or whole cod had little effect on frame mince quality during frozen storage.     

Modelling of hydrogen production in batch cultures of the photosynthetic bacterium Rhodobacter capsulatus

The photosynthetic bacterium, Rhodobacter capsulatus, produces hydrogen under nitrogen-limited, anaerobic, photosynthetic culture conditions, using various carbon substrates. In the present study, the relationship between light intensity and hydrogen production has been modelled in order to predict both the rate of hydrogen production and the amount of hydrogen produced at a given time during batch cultures of R. capsulatus. The experimental data were obtained by investigating the effect of different light intensities (6000–50,000 lux) on hydrogen-producing cultures of R. capsulatus grown in a batch photobioreactor, using lactate as carbon and hydrogen source. The rate of hydrogen production increased with increasing light intensity in a manner that was described by a static Baly model, modified to include the square of the light intensity. In agreement with previous studies, the kinetics of substrate utilization and growth of R. capsulatus was represented by the classical Monod or Michaelis–Menten model. When combined with a dynamic Leudekong–Piret model, the amount of hydrogen produced as a function of time was effectively predicted. These results will be useful for the automatization and control of bioprocesses for the photoproduction of hydrogen.     

Identification and characterization of Saccharomyces cerevisiae dihydrosphingosine-1-phosphate phosphatase

We have identified the yeast sphingosine resistance gene (YSR2) of Saccharomyces cerevisiae as encoding a protein that specifically dephosphorylates dihydrosphingosine 1-phosphate (DHS-1-P), and we refer to this protein as dihydrosphingosine-1-phosphate phosphatase. Overexpression of YSR2 conferred sphingosine resistance to the dihydrosphingosine-1-P lyase-defective mutant (JS16) of S. cerevisiae, which is hypersensitive to sphingosine. The ysr2Delta deletion mutant of S. cerevisiae accumulated DHS-1-P compared with its wild type strain upon labeling with D-erythro-[4, 5-3H]dihydrosphingosine, whereas overexpression of YSR2 increased dephosphorylation of DHS-1-P. An epitope-tagged fusion protein (YSR2-Flag) was partially purified and found to specifically dephosphorylate DHS-1-P to yield dihydrosphingosine. YSR2 failed to dephosphorylate ceramide 1-phosphate or phosphatidic acid. Functionally, the mutant bearing the ysr2Delta deletion decreased labeling of sphingolipids and increased labeling of glycerolipids dramatically following in vivo labeling with D-erythro-[3H]dihydrosphingosine, but it slightly affected labeling of sphingolipids with inositol. Taken together, these results identify YSR2 as dihydrosphingosine-1-phosphate phosphatase. They also raise the intriguing possibility that phosphorylation followed by dephosphorylation is required for incorporation of exogenous long chain sphingoid bases into sphingolipids.     

Fluorine-18-fluorodeoxyglucose assessment of glucose metabolism in bone tumors

In our study, we investigate the glucose metabolism of various types of bone lesions with 18F-fluorodeoxyglucose (FDG) PET. METHODS: Twenty-six patients showing clinical and radiographic symptoms of a malignant bone tumor were included. Histological examination after the PET study revealed 19 malignant and 7 benign tumors. PET images were corrected for attenuation. Arterial blood samples were taken to establish the input function. The metabolic rate of glucose consumption (MRglc) was calculated for the whole tumor, for the 10 pixels with maximum activity and for contralateral normal muscle tissue. RESULTS: All lesions were clearly visualized with 18F-FDG PET except for a small infarction of the humerus. All the other lesions had increased glucose metabolism compared to surrounding and contralateral muscle tissue. Both maximum and average MRglc for benign, as well as malignant, lesions were significantly higher than for contralateral normal tissue. The maximum and average MRglc were not higher for malignant as opposed to benign lesions. There was a large overlap between the MRglc of benign and malignant lesions. CONCLUSION: Fluorine-18-FDG PET appears suitable to visualize bone tumors. With the quantification of glucose metabolism, it is not possible to differentiate between benign and malignant bone tumors. There does not seem to be a clear correlation between the MRglc and the biologic aggressiveness of the neoplasms.