Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses

We recently demonstrated that pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.     

Preliminary results on a dedicated silicon diode detector for proton dosimetry

The present work reports preliminary measurements on the behaviour of a new p-type stereotactic silicon diode. Hi-pSi, produced by Scanditronix and dedicated to proton dosimetry. Diode response was investigated in low-energy proton beams (26.7 MeV and 12 MeV nominal energy), mainly with attention to stability, linearity, dose rate and energy dependence of the detector response. Three different Hi-pSi diodes of the same type were investigated. The diode response was linear with dose and the standard deviation of repeated readings was less than 2.5%. A marked dependence on dose rate was observed for one of the diodes (a response increase of 47% in the 0.7-11 Gy x min(-1) range). After the dose rate and water to silicon mass collision stopping power ratio correction of the diode response in the depth dose measurements, the difference, at the Bragg peak, with respect to the reference chamber was about 4%, ascribed to poor knowledge of the materials in front of the sensitive volume. The diode response was also nearly independent of linear energy transfer (LET) in the 9.6-21.5 MeV effective energy range.     

Movement disorders in the context of P.K. Anokhin's theory of functional systems

The authors' own findings and the data available in the literature as to movement diseases (MD) in animals and man were reviewed in the context of P. K. Anokhin's theory of functional systems. The functional system of the human body's gravity center is detailed. There is evidence for that disintegration processes underlying MD first occur in the mnestic sphere since due to genetic and/or ontogenetic causes, memory has no preserved no motor programme required to achieve the end net efficiency of performance of this functional system,--to maintain the definite position of the gravity center of the body and its related vegetative status upon stress-induced vestibular exposures. Based on the above concepts of the pathogenesis of MD, its preventive measures have been proposed and tested, which include drug (nootropic agents) and non-drug (a special complex of physical exercises for children aged 2 to 7 years, which will form permanent motor programs in memory in definite periods of their ontogenesis) measures.     

Uclacyanins, stellacyanins, and plantacyanins are distinct subfamilies of phytocyanins: plant-specific mononuclear blue copper proteins

The cDNAs encoding plantacyanin from spinach were isolated and characterized. In addition, four new cDNA sequences from Arabidopsis ESTs were identified that encode polypeptides resembling phytocyanins, plant-specific proteins constituting a distinct family of mononuclear blue copper proteins. One of them encodes plantacyanin from Arabidopsis, while three others, designated as uclacyanin 1, 2, and 3, encode protein precursors that are closely related to precursors of stellacyanins and a blue copper protein from pea pods. Comparative analyses with known phytocyanins allow further classification of these proteins into three distinct subfamilies designated as uclacyanins, stellacyanins, and plantacyanins. This specification is based on (1) their spectroscopic properties, (2) their glycosylation state, (3) the domain organization of their precursors, and (4) their copper-binding amino acids. The recombinant copper binding domain of Arabidopsis uclacyanin 1 was expressed, purified, and shown to bind a copper atom in a fashion known as "blue" or type 1. The mutant of cucumber stellacyanin in which the glutamine axial ligand was substituted by a methionine (Q99M) was purified and shown to possess spectroscopic properties similar to uclacyanin 1 rather than to plantacyanins. Its redox potential was determined by cyclic voltammetry to be +420 mV, a value that is significantly higher than that determined for the wild-type protein (+260 mV). The available structural data suggest that stellacyanins (and possibly other phytocyanins) might not be diffusible electron-transfer proteins participating in long-range electron-transfer processes. Conceivably, they are involved in redox reactions occurring during primary defense responses in plants and/or in lignin formation.     

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.