Intermittent exposure of medulloblastoma cells to topotecan produces growth inhibition equivalent to continuous exposure

Camptothecin analogues such as topotecan increase the number of covalent topoisomerase I-DNA complexes, which, in turn, have been proposed to initiate apoptosis. If induction of apoptosis by the camptothecins is, in fact, dependent on the formation of topoisomerase I-DNA complexes, then it would be of clinical relevance to identify schedules of exposure to the camptothecins that maximize the formation of these complexes but minimize the total amount of the drug administered. The time and dose dependence of topoisomerase I-DNA complex formation was determined by incubating Daoy pediatric medulloblastoma cells in vitro with topotecan at concentrations equivalent to those achievable in the plasma clinically (10, 50, or 200 nM) and measuring the number of complexes present in cells incubated for 15 min to 48 h with the drug. Regardless of the concentration of topotecan used, covalent topoisomerase I-DNA complexes were maximal within 15 min following addition of the lactone form of topotecan to the tissue culture medium. After 2 h of exposure to topotecan, complexes had decreased from maximum to approximately half of that value. Few, if any, complexes were detectable with topotecan incubations of 24-48 h. Growth inhibition studies showed that the IC50s of topotecan for the Daoy cell line (2.2 x 10(-9) M) and also for a second pediatric medulloblastoma cell line, SJ-Med3 (3.6 x 10(-9) M), exposed to topotecan 8 h daily for 5 days or continuous exposure were equivalent. The decrease in topoisomerase I-DNA complexes between 15 min and 1 h was consistent with a pH-dependent re-equilibration of topotecan to the less active hydroxyacid form of the drug. The decrease in complexes after a 2-48-h incubation with the drug was attributable neither to biological inactivation of topotecan as shown by sequential growth inhibition studies nor to a decrease in amount of topoisomerase I in the drug-treated cells. Indirect immunofluorescence labeling of topoisomerase I in Daoy cells incubated for 48 h with 10 nM topotecan showed a redistribution of nucleolar topoisomerase I. We are currently evaluating the antitumor effect of intermittent repetitive exposures to topotecan in mice bearing Daoy cells as a xenograft. The clinical utility of each effective schedule of exposure will depend on whether the therapeutic index of repetitive intermittent exposure to the drug is more or less favorable than the therapeutic index of continuous exposure.     

Role of nitric oxide in the pancreatic vascular and metabolic responses associated with activation of capsaicin-sensitive neurons

A significant decrease in mean number of CD5+, CD8(+)-lymphocytes in persons, who worked in 30-km zone of Chernobyl nuclear power station was revealed. A significant increase in percent of CD5+, CD4(+)-cell percents was observed in workers, who worked for 1,2-2,5 years in zone, but absolute number, were decreased comparing a control and data received in people, who have just arrived to work in 30-km zone. The positive correlation exists between the percent of lymphocytes and years of service in 30-km zone. The lower level of alpha 1-thymosine was revealed in serum of the persons, who worked in zone for 4.5-5 years than data received in people, who worked for 0.5 year. Increase level of serum autoantibodies reacting with thymic epithelial cell was detected in men, who worked in zone for 3-3.5 years. In persons, who worked more 5 years and have just arrived in zone identical data were received.     

MR findings in pontocerebellar hypoplasia

We present four cases with combined hypoplasia of the cerebellum and the ventral pons-pontocerebellar hypoplasia (PCH). PCH represents an autosomal recessive neurodegenerative disorder with fetal onset. The disease is rare, with less than 20 cases having been reported. The main findings of PCH and the inclusion criteria for our cases can be summarised as progressive microcephaly from birth, pontocerebellar hypoplasia documented by MRI and marked chorea, which may change, later in childhood, to more dystonic patterns. The cerebral cortex becomes progressively atrophic. Motor and mental development are delayed, and epilepsy, mainly tonic-clonic seizures, is frequent. The MRI features in all of our cases were: (1) Hypoplastic cerebellum situated close to the tentorium. The hypoplastic cerebellum has a reduced number of folia, in contrast to the normal number of thin folia in simple cerebellar atrophy. (2) The cerebellar hemispheres are reduced to bean-like or wing-like structures. The cerebellar hemispheres appear to 'float' in the posterior fossa. (3) Markedly hypoplastic ventral pons. (4) Slight atrophy of the supratentorial gyral pattern. (5) Dilated cerebromedullary cistern and fourth ventricle. (6) Delayed myelination of the white matter. (7) No significant disorganisation of brain architecture and no severe corpus callosum defect.     

Structure–Activity Relationship of Inhibition of Fish Feeding by Sponge-derived and Synthetic Pyrrole–Imidazole Alkaloids

We investigated the relationship between the structures of pyrrole-containing alkaloids from marine sponges of the genus Agelas and their capacity to deter feeding by the omnivorous Caribbean reef fish, Thalassoma bifasciatum. Seven natural products were assayed at volumetric concentrations of 1, 5, and 10 mg/ml: dispacamide A, keramadine, oroidin, midpacamide, 4,5-dibromopyrrole-2-carboxylic acid, 4,5-dibromopyrrole-2carboxamide, and racemic longamide A. We also assayed 14 structural analogs obtained mostly by chemical synthesis. Of the seven natural products, only rac-longamide A was not significantly deterrent at any of the assay concentrations. The pyrrole moiety was required for feeding inhibition activity, while the addition of the imidazole group enhanced this activity. Variously functionalized imidazoles lacking the pyrrole moiety were not deterrent. Combinations of the natural products appeared to have an additive effect on feeding inhibition; there was no evidence of synergy. Given their high concentrations in sponge tissue, dispacamide A and oroidin most probably serve as the primary chemical defenses of many Agelas sp., while minor compounds such as keramadine are not present in high enough concentrations to contribute much to chemical defense.     

Psychology and the global commons: Perspectives of international psychology.

In Part I of this article, the role of international cooperation and exchange is outlined in the interest of developing cross-national understanding and goodwill among psychologists of different nationality. Part 2 describes the structure and operation of international and regional organizations of psychology, whereas in Part 3 examples are given of international educational and research programs as a way to facilitate cross-national developments. Finally, in Part 4 it is suggested that future challenges from society will increasingly require behavioral science-based approaches to meet new conditions of life. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Flavor avoidance induced by LiCl and dexfenfluramine in rats and mice using nondeprivation protocols.

Using dexfenfluramine as unconditional stimulus (US), the authors confirmed that sham-operated and area postrema (AP)-lesioned rats form comparable conditioned flavor avoidances. When lithium chloride (LiCI) was used as the US, AP-lesioned rats did not learn to avoid a drug-paired flavor conditional stimulus (CS+). Sham-operated, but not AP-lesioned, rats had low intakes of the placebo-paired flavor (CS-), which suggests that the lesions disrupted generalization of avoidance. Generalized avoidance in intact rats was similar when either sweetened milk or Polycose was used as the caloric vehicle for the CSs. When flavored gels of Polycose were used as CSs, C57BL/6J mice developed flavor avoidance with either LiCl or dexfenfluramine as US. Compared with rats, mice required higher doses of these agents, avoidance was not complete after many pairings, and there was no generalization to the CS-. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors influencing the preferential orientations in zinc coatings electrodeposited from chloride baths

The influence of factors affecting the texture formation in zinc coatings electrodeposited from weakly acid zinc baths has been investigated, particularly those of cathodic current density, electrolyte additives and substrate texture type. Deposits showing no preferential orientations were obtained from a chloride bath with no primary inhibitors, with which the earlier theory on autoinhibition caused by colloidal zinc hydroxide in sulphate electrolytes was confirmed. The addition of synthetic inhibitors resulted in the production of various types of texture according to the electrolysis conditions and substrate texture type. Cone fibre texture coatings were obtained on cold worked copper cathodes and at lower cathode densities. A simple fibre texture was produced only at higherD _c values. The preferential orientation of electrodeposited zinc coatings on electrolytic nickel textured substrates depended on whether the electrochemical conditions or the textured substrate was the dominant factor. Various simple fibre textures were formed on electrodeposited amorphous Ni–P alloy substrates irrespective of the electrochemical conditions. Within a relatively short time after the completion of the electrodeposition of zinc coatings from chloride or sulphate baths, recrystallization processes were observed at room temperature.     

Charge carriers and charge‐transfer reactions in OLED devices studied by electron paramagnetic resonance*

Abstract— Electron paramagnetic resonance (EPR) was used as a quantitative method to measure charge carriers that are present in OLED devices under various bias conditions. Charge‐transfer reactions that occur at the cathode interface through the interaction of charge‐injection layers and charge‐transport layers were investigated.     

Advances in membrane emulsification. Part B: recent developments in modelling and scale‐up approaches

Membrane emulsification is a promising process for formulating emulsions and particulates. It offers many advantages over conventional ‘high‐shear’ processes with narrower size distribution products, higher batch repeatability and lower energy consumption commonly demonstrated at a small scale. Since the process was first introduced around 25 years ago, understanding of the underlying mechanisms involved during microstructure formation has advanced significantly leading to the development of modelling approaches that predict processing output; e.g. emulsion droplet size and throughput. The accuracy and ease of application of these models is important to allow for the development of design equations which can potentially facilitate scale‐up of the process and meet the manufacturer's specific requirements. Part B of this review considers the advantages and disadvantages of a variety of models developed to predict droplet size, flow behaviour and other phenomena (namely droplet–droplet interactions), with presentation of the appropriate formulae where necessary. Furthermore, the advancement of the process towards an industrial scale is also highlighted with additional recommendations by the authors for future work. © 2013 Society of Chemical Industry     

Effect of directionally solidified microstructures on the room-temperature fracture-toughness properties of Ni-33(at. pct)Al-33Cr-1Mo and Ni-33(at. pct)Al-31Cr-3Mo eutectic alloys grown at different solidification rates

Directionally solidified (DS) Ni-33(at. pct)Al-33Cr-1Mo and Ni-33(at. pct)Al-31Cr-3Mo eutectic alloys were grown at different rates varying from 7.6 to 508 mm h⁻¹. The microstructures consisted of eutectic colonies with parallel lamellar NiAl/(Cr,Mo) plates for solidification rates at and below 12.7 mm h⁻¹. Cellular eutectic microstructures were observed at higher solidification rates, where the plates exhibited a radial pattern. Room-temperature fracture-toughness tests were conducted using a modified ASTM E-399 technique. The average fracture-toughness values for specimens with planar eutectic and cellular microstructures were about 12 to 15 and 17 MPa , respectively, for both alloys. However, the Ni-33(at. pct)Al-33Cr-1Mo specimens grown at and above 254 mm h⁻¹ exhibited fracture toughness values of about 8 MPa due to the presence of short (Cr,Mo) plates. The fracture toughness values for the Ni-33(at. pct)Al-31Cr-3Mo alloy were also correlated with quantitative microstructural data in an attempt to identify the relevant elements of the microstructure determining resistance to fracture. A phenomenological fracture model is presented in an attempt to rationalize the present observations.