Prevention of bromobenzene toxicity by N-acetylmethionine: correlation between toxicity and the impairment in O- and S-methylation of bromothiocatechols

Bromobenzene (800 mg/kg, ip) caused severe liver necrosis with massive hemorrhage in the golden Syrian hamster within the first 24 hr. Kidney injury was also observed. Treatment with N-acetylmethionine (NAM) at an ip dose of 1200 mg/kg at 5 hr after bromobenzene administration significantly protected the liver and kidney against injuries. Plasma glutamate pyruvate transaminase and blood urea nitrogen levels were substantially decreased in the NAM-treated animals. Histological evaluations confirmed these results. When the urinary neutral and phenolic metabolites of bromobenzene from NAM-treated and untreated hamsters were isolated and compared by GC and GC/MS, a striking result was observed in terms of O- and S-methylated thiol-containing metabolite formation. The NAM-treated animals showed approximately a 8- to 14-fold increase in the excretion of the four isomeric O- and S-methylated bromothiocatechols. These thiocatechols, which are now known to be the 3,4-series metabolites of bromobenzene, can undergo methylation at either the thiol or the hydroxyl functional group. The excretion of 3-S- and 4-S-methylated bromodihydrobenzene thiolols was also increased significantly in the NAM-treated hamster, but other neutral and phenolic metabolites were relatively unchanged. These results suggest that bromobenzene toxicity in the Syrian hamster may be associated with impaired methylation capabilities, an impairment that could be due to methionine and glutathione depletion.     

The C-terminus of c-ABL is required for proliferation and viability signaling in a c-ABL/erythropoietin receptor fusion protein

Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (triangle upSH3), the SH2 domain was deleted (triangle upSH2), the C-terminal actin-binding domain was deleted (triangle upABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the triangle upSH3 mutant was equivalent, the triangle upSH2 mutant was moderately impaired, and the triangle upABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and triangle upSH3. However, time to death was prolonged by at least twofold for triangle upSH2 and greater than threefold for triangle upABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.     

Characterisation of sub-100 nm-MOS-transistors processed by optical lithography and a sidewall-etchback technique

This paper describes the fabrication of NMOS-transistors with a geometric gate length of down to 50 nm using conventional optical lithography and a modified sidewall-etchback process. Based on measurements the transistors are characterised and their device parameters are compared to simulations. Finally the procedures for further optimisation of the process will be explained.     

Laser turn-on delay and chirp noise effects in Gb/sintensity-modulated direct-detection systems

This paper describes a new IM/DD optical transmission system simulation which incorporates the impact of laser diode stochastic turn-on effects on system performance. Using this simulation, experimentally observed error rate floors, due to inappropriate laser diode biasing, can be theoretically modelled and predicted, for the first time     

A statistical analysis of the received signal from blood duringlaminar flow

In order to determine the limiting velocity resolution that can be achieved using ultrasound, and to provide a model which can be generalized for the analysis of disturbed flow, a theoretical and experimental evaluation of the statistics of the received signal from laminar flow following the transmission of a train of short pulses is presented. The authors derive the autocorrelation function and determine the length of the correlated signal for various flow rates, comparing experimental measurements to theoretical predictions. High resolution experimental RF M-mode images are used to verify the theoretical model. Using a fluid with a density, viscosity, volume concentration, particle size, and speed of sound which is similar to that of blood, the authors show that the signal remains correlated for a long interval under many conditions of clinical interest. Including a comparison with experimental data, the effect of the lateral transit time through the sample volume and the axial velocity spread within the sample volume on the correlation of the received signal is evaluated. When a significant range of velocity components is present within the sample volume, this range is the limiting factor in the length of the correlated signal interval. Therefore, the use of a wideband signal, which reduces the sample volume size, produces a returned signal that may be correlated for a larger number of pulses, or for a longer time     

Enhancement Effects in the Percutaneous Absorption of Alprazolam Through Human Skin in vitro

The enhancement effects of some chemicals on the percutaneous absorption of alprazolam through human skin was investigated in vitro. Linoleic acid, oleic acid, Comperlan F® (linoleic acid diethanolamide), Comperlan KD® (coconut fatty acid diethanolamide) and Ethomeen C12® (bis-(2-hydroxyethyl)cocamine) were evaluated for their enhancing effect either as neat solvents or combined with propylene glycol. The effects of skin pretreatment with the enhancers on the percutaneous absorption of alprazolam from a drug suspension in an aqueous gel were also investigated: skin pretreatment with some enhancers has shown potentially interesting aspects. The determination of alprazolam partitioning into untreated and pretreated horny layer supported the idea that, with oleic and linoleic acid, a contribution to the modification of the diffusional resistance of the skin was given by an increase of the drug solubility in the stratum coraeum.     

A numerical investigation on the geometry dependence of the crack growth resistance in CT specimens

The influence of the specimen thickness B and the ligament length b on the J _R -curves is numerically investigated for CT specimens. The thickness effect is taken into account with 2-D analyses by dividing a plain sided specimen into a plane stress part and a plane strain part. The fracture process is controlled by experimentally determined critical values of the crack tip opening displacement for crack growth initiation (CTOD_i) and the crack tip opening angle for stable crack growth (CTOA_C). It is shown that for the global behaviour of a plain sided specimen, the B/b ratio is essential. The difference between the geometry dependence of the initiation value of the J-integral and the geometry dependence of the slope of the J _R -curves is also shown.     

Nature of terpenoids of aTaxodioxylon gypsaceum from the fossil forest of Dunarobba (Italy)

A specimen fromt he fossil forest of Dunarobba (Central Italy) attributed toTaxodioxylon gypsaceum was chemically analyzed particularly for its terpene content. Main chemical constituents show variations related to ageing and carbonization process, while terpene content exhibits a drop of mono- and sesquiterpenes in favour of diterpenes and higher MW compounds. All components are exclusively hydrocarbons and represent alicyclic or partially aromatic structures. The identified families include abietane, phyllocladane, norabietane and norpimarane among diterpenes and traces of cadinane and selinane among sesquiterpenes.