Differential impact of executive dysfunction on verbal list learning and story recall.

The California Verbal Learning Test (CVLT) and the Logical Memory (LM) subtest from the Wechsler Memory Scale-Revised (WMS-R) are generally thought to be interchangeable measures of verbal memory. However, little is known about the effects of executive dysfunction on these tasks. The present study involved 96 patients referred for neuropsychological evaluation who were classified as having either significant executive dysfunction (SED) or minimal executive dysfunction (MED) based on the number of impaired executive tasks. Results showed that the SED group performed significantly worse on CVLT total words learned and most of the recall conditions compared to the MED patients (p <.01). However, performance on both immediate and delayed LM did not significantly differentiate the groups. CVLT measures of semantic clustering, perseveration, intrusions, and false positive errors did not appear to account for the group differences. The current study strongly suggests that the CVLT and the LM subtest are differentially associated with executive dysfunction, and argues for the inclusion of both types of tasks in a comprehensive neuropsychological evaluation.

Mechanism of inhibition of cathepsin K by potent, selective 1, 5-diacylcarbohydrazides: a new class of mechanism-based inhibitors of thiol proteases.

The nature of the inhibition of thiol proteases by a new class of mechanism-based inhibitors, 1,5-diacylcarbohydrazides, is described. These potent, time-dependent, active-site spanning inhibitors include compounds that are selective for cathepsin K, a cysteine protease unique to osteoclasts. The 1,5-diacylcarbohydrazides are slow substrates for members of the papain superfamily with inhibition resulting from slow enzyme decarbamylation. Enzyme-catalyzed hydrolysis of 2,2'-N, N'-bis(benzyloxycarbonyl)-L- leucinylcarbohydrazide is accompanied by formation of a hydrazide-containing product and a carbamyl-enzyme intermediate that is sufficiently stable to be observed by mass spectrometry and NMR. Stopped-flow studies yield a saturation limited value of 43 s(-)(1) for the rate of cathepsin K acylation by 2,2'N, N'-bis(benzyloxycarbonyl)-L-leucinylcarbohydrazide. Inhibition potency varies among proteases tested as reflected by 2-3 orders of magnitude differences in K(i) and K(obs)/I, but all eventually form the same stable covalent intermediate. Reactivation rates are equivalent for all enzymes tested (1 x 10(-)(4) s(-)(1)), indicating hydrolysis of a common carbamyl-enzyme form. NMR spectroscopic studies with cathepsin K and 2,2'-N,N'-bis(benzyloxycarbonyl)-L-leucinylcarbohydrazide provide evidence of inhibitor cleavage to generate a covalent carbamyl-enzyme intermediate rather than a tetrahedral complex. The product Cbz-leu-hydrazide does not appear enzyme-bound after cleavage in the NMR spectra, suggesting that the stable inhibited form of the enzyme is the thioester complex. 1, 5-diacylcarbohydrazides represent a new class of unreactive cysteine protease inhibitors that share a common mechanism of action across members of the papain superfamily. Both S and S' subsite interactions are exploited in achieving high selectivity and potency.

Pregnancy-associated plasma protein B (PAPP-B) in normal and abnormal pregnancies at term.

At term, the pregnancy-associated plasma protein B (PAPP-B) level in normal pregnancy was correlated with placental and newborn weights, but not with nine other normal obstetric variables. It was lower in pregnancies complicated by diabetes or severe toxaemia, and higher in twin pregnancies.