Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis

The aim of this study was to assess whether P-glycoprotein (Pgp) inhibitors altered the blood-brain barrier and enhanced vinblastine (VBL) distribution in brain, testis and other Pgp-expressing tissues. Trifluoperazine, cyclosporin A, amiodarone, quinidine, the nifedipine analog Bay K8644 and verapamil were selected among Pgp inhibitors and were administered intraperitoneally 1 hr before an intravenous dose of 10 mg/kg VBL. Trifluoperazine and cyclosporin A were also administered intraperitoneally for 7 days before VBL. VBL and its metabolite O4-deacetylvinblastine were measured in tissues by high-performance liquid chromatography assay. None of the reversing agents (RA) appreciably raised VBL concentrations in brain and testis, whereas all except quinidine significantly enhanced VBL distribution in liver and kidney; the most effective were trifluoroperazine and cyclosporin A. In mice treated with RA and VBL combined, O4-deacetylvinblastine levels in liver and kidney reached either the same or higher levels than in mice treated with VBL alone, indicating that the increase in VBL levels is not due to inhibition of its metabolism. The main conclusions are that (1) inhibitors of Pgp, even at high doses, do not increase the permeability of the blood-brain barrier in mice, suggesting caution in the clinical use of RA combined with antitumor agents for brain tumors; and (2) several RA achieve high enough concentrations to enhance the distribution of VBL in other normal tissues expressing Pgp, thus potentially increasing VBL toxicity.     

Identification environment and robust forecasting for nonlinear time series

In this paper, the methods of time series for nonlinearity are briefly surveyed, with particular attention paid to a new test design based on a neural network specification. The proposed integrated expert system contains two main components: an identification environment and a robust forecasting design. The identification environment can be viewed as a integrated dynamic design in which cognitive capabilities arise as a direct consequence of their self-organizational properties. The integrated framework used for discussing the similarities and differences in the nonlinear time series behavior is presented. Moreover, its performance in prediction proves to be superior than the former work. For the investigation of robust forecasting, we perform a simulation study to demonstrate the applicability and the forecasting performance.     

Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry

OBJECTIVE: To characterize changes of Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) that occur during the course of HIV infection by cytoplasmic cytokine staining on single cell level. DESIGN AND METHODS: Mitogen-stimulated PBMC from 16 healthy donors, 18 HIV-1-infected individuals without AIDS and 14 patients with AIDS were stained intracellularly with fluorescein-labelled MAb against interleukin (IL)-2, IL-4, IL-10 and interferon (IFN)-gamma. Additionally, co-staining of CD4+ T-cell, CD8+ T-cell, natural killer (NK) cell, B-cell and monocytic markers was performed. Fluorescence staining was analysed by three-colour flow-cytometry. RESULTS: A reduced percentage of IL-2 and IFN-gamma (Th1 type)-producing cells among CD4+ T cells from HIV-1-infected individuals could be demonstrated. There was a continuous decrease of IFN-gamma-producing CD4+ T cells in the course of HIV infection and a dramatic reduction of IL-2-expressing cells among CD4+ T cells in patients with AIDS. In contrast to Th1 cytokines, the frequency of Th2 cytokine expressing cells among CD4+ T cells increased in HIV-infected individuals. The maximum frequency of IL-4-expressing cells among CD4+ T cells was seen in HIV-infected individuals without AIDS, whereas the rate of IL-10-producing cells was highest in patients with AIDS. In HIV-infected individuals no significant proportion of Th0 cells expressing both Th1 and Th2 cytokines was detectable. In CD8+ T cells the percentage of IL-2 was expressing cells decreased continuously accompanied by a strong increase of the frequency of IFN-gamma-producing cells. CONCLUSION: The decreased percentage of cells expressing IL-2 and IFN-gamma in conjunction with an increased proportion of IL-4- and IL-10-producing cells among the CD4+ T cells in HIV-1-infected individuals demonstrate a Th1 to Th2 cytokine shift in the course of HIV infection on a single cell level. There was no evidence of a Th1 to Th0 cytokine shift. In addition to the loss of CD4+ T cells in HIV infection, the qualitative changes of Th1/Th2 cytokine expression may serve as a marker for progressive failure of cell-mediated immunity.     

Effect of a crack on strength of fibre-reinforced plastics

In unidirectionally reinforced composites with an elastic-plastic matrix, there is a plastic zone with lengthY ₀ proportional to the crack lengthC (Y ₀ C) at the tip of a crack. This results in a new logarithmic dependence of glass and aramid PABI fibre-reinforced plastics (FRP) on crack length and non-fulfilment of the Griffith criterion. In glass and PABI FRP without an artificial notch, defects already exist equivalent to a crack with a length depending on composite fabrication practice. In GFRP, the epoxy matrix shear yield stress grows 2.0 to 2.5 times, compared to the yield in thin films due to fibre constraint of matrix yielding. The stress distribution in front of a crack in a highly anisotropic composite with an elastic-plastic matrix is derived. The stress concentration at the tip of a crack grows with increasing matrix yield stress, resulting in a change of failure mode from accumulation of fibre breaks at low matrix strength, to brittle failure at high matrix strength. The following factors lead to composite embrittlement: (1) increase of matrix yield stress and composite shear strength; (2) decrease of temperature; (3) increase of Young's modulus of the fibre; (4) reduction of fibre strength. The dependence of aramid PPTA FRP strength on temperature exhibits a maximum. Epoxy matrix plastification leads to some increase of aramid PPTA FRP strength.     

EFFECT OF FINE GRINDING ACTIVATION ON LEACHING BEHAVIOUR OF SCHEELITE CONCENTRATE

The influence of mechanical activation on the leaching behaviour of scheelite was studied bymeans of fine grinding in an attritor and subsequently HCl leaching in presence of PO_4~(3-).Results showed that after fine grinding in the attritor,the reaction rate of scheelitewith HCl-Na_3PO_4 solution was remarkably increased,the extraction of W increased fromabout 8 to 99%.The IR spectra and X-ray diffraction analysis indicated that in addition toan enlargement of surface area the fine grinding action had made also changes of fine struc-ture and reactivity of solid surface,hence the leaching process of scheelite can be carried outunder mild leaching conditions.     

Intensification of Convective Heat Transfer

Theoretical Foundations of Chemical Engineering -     

The functional role of the motor area of the cortex in the formation of riddance reactions in dogs

A model of instrumental conditioning similar to the classical model (Pavlovian) is proposed. Flexion of the ipsilateral forelimb was elicited while EDS was applied to the hind limb by stimulation of the motor area of the cortex (M1); both stimuli ceased during the raising of the forelimb. Uniform combinations of this kind led to the development of forepaw flexion reactions in response to the EDS of the hind paw. Prolongation of EDS by 3 sec following cortical stimulation led to rapid extinction of the developed reactions. Thus, the possibility of the effective instrumentalization of movements induced by stimulation of the M1 is proven. This argues that the forming "instrumental" connection (drive-motor structures) is addressed directly to the M1.     

Casein kinase 2 down-regulation and activation by polybasic peptides are mediated by acidic residues in the 55-64 region of the beta-subunit. A study with calmodulin as phosphorylatable substrate

The noncatalytic beta-subunit is responsible for the latency of casein kinase 2 (CK2) activity toward calmodulin. Twenty-one mutants of the beta-subunit bearing either deletions or Ala substitutions for charged residues in the 5-6, 55-70, and 171-178 sequences have been assayed for their ability to substitute for wild-type beta-subunit as a suppressor of activity toward calmodulin. The only mutations that reduced the ability of the beta-subunit to suppress calmodulin phosphorylation activity, though being compatible with normal reconstitution of CK2 holoenzyme, were those affecting Asp55, Glu57 and the whole triplet Glu59-Asp-Glu61. The activity of CK2 holoenzyme, either native or reconstituted, toward calmodulin can be elicited by a variety of polybasic effectors, including polylysine, polyarginine, salmine, and histones H4, H3, and, to a lesser extent, H2a and H2b. Histone H1 and polyamines are conversely ineffective. The latent "calmodulin kinase" activity of CK2 can also be specifically unmasked by a peptide (alpha[66-86]) reproducing a basic insert of the catalytic subunit. This effect is reversed by equimolar addition of a peptide (beta[55-71]) including the 55-64 acidic stretch of the beta-subunit. Comparable polylysine stimulation was observed with the holoenzymes reconstituted with either beta wt or the beta mutants capable of assembling with the alpha-subunit, with the notable exception of those bearing Ala substitutions for acidic residues at positions 55, 57, and 59-61. These were nearly insensitive to 42 nM polylysine, which conversely promotes a more than 10-fold increase of calmodulin phosphorylation with wild-type beta.(ABSTRACT TRUNCATED AT 250 WORDS)