Mismatch negativity indexes auditory temporal resolution: evidence from event-related potential (ERP) and event-related field (ERF) recordings.

This study examined auditory temporal resolution as indexed by gap detection using the mismatch negativity (MMN) component of the auditory event-related potential (ERP) and its magnetic counterpart (MMNm). ERPs were recorded in 10 subjects who were presented with auditory stimuli. These stimuli were presented in sequences of repetitive continuous 'standard' sinusoidal tones interspersed with infrequently occurring 'deviant' stimuli that differed from standards only in that they contained a silent gap midway in the stimulus. The gap size varied in separate stimulus blocks and was either 3, 5 or 7 ms. The stimuli were presented monaurally either to the left or the right ear. In a separate session, event-related magnetic fields (ERFs) were recorded from eight subjects using a similar paradigm but with gap sizes of 3, 7 or 11 ms and with binaural stimulation. Both ERP and ERF recordings showed that the smallest gap size (3 ms) did not elicit as large or reliable MMN or MMNm as did the larger ones. There were no differences in the laterality of the MMN as might be predicted on the basis of previous behavioural studies, but this result is likely a reflection of differences in task requirements. Nonetheless, the findings suggest that MMN and MMNm successfully index auditory temporal resolution thresholds, as measures that are independent of attention.

Isoenzyme selective irreversible inhibition of rat and human glutathione S-transferases by ethacrynic acid and two brominated derivatives.

In the present study it has been shown that ethacrynic acid can inhibit glutathione S-transferase (GST) of the pi-class irreversibly. [14C]Ethacrynic acid, 0.8 nmol/nmol human P1-1 and 0.8 nmol/nmol rat GST 7-7 could be incorporated, resulting in 65-93% inhibition of the activity towards 1-chloro-2,4-dinitrobenzene (CDNB). Isoenzymes of the alpha- and mu-class also bound [14C]ethacrynic acid, however without loss of catalytic activity. Incorporation ranged from 0.3 to 0.6 and 0.2 nmol/nmol enzyme for the mu- and alpha-class GST isoenzymes, respectively. For all isoenzymes, incorporation of [14C]ethacrynic acid could be prevented by preincubation with tetrachloro-1,4-benzoquinone, suggesting, that a cysteine residue is the target site. Protection of GST P1-1 against inhibition by ethacrynic acid by the substrate analog S-hexylglutathione, indicates an active site-directed modification. The monobromo and dibromo dihydro derivatives of ethacrynic acid were synthesized in an effort to produce more reactive compounds. The monobromo derivative did not exhibit enhanced irreversible inhibitory capacity. However, the dibromo dihydro derivative inhibited both human and rat GST isoenzymes of the pi-class very efficiently, resulting in 90-96% inhibition of the activity towards CDNB. Interestingly, this compound is also a powerful irreversible inhibitor of the mu-class GST isoenzymes, resulting in 52-70% inhibition. The two bromine atoms only marginally affect the strong (reversible) competitive inhibitory capacity of ethacrynic acid, with IC50 (microM) of 0.4-0.6 and 4.6-10 for the mu- and pi-class GST isoenzymes, respectively.