1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism symptoms in man, has been examined as a substrate of recombinant human cytochrome P450 2D6. When cumene hydroperoxide is used as an oxygen and electron donor, a single product is formed, identified as 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) for formation of this product (130 microM) is in agreement with the dissociation constants for MPTP binding to the enzyme determined by optical and nuclear magnetic resonance (NMR) spectroscopy. When the reaction is carried out with nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and recombinant human NADPH-cytochrome P450 reductase, a second product, identified as 1-methyl-4-(4'-hydroxyphenyl)-1,2,3,6-tetrahydropyridine, is formed in addition to 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) values for formation of these two products are 19 microM and 120 microM, respectively. Paramagnetic relaxation experiments have been used to measure distances between the protons of bound MPTP and the heme iron, and these have been used to construct models for the position and orientation of MPTP in the active site. For the cytochrome alone, a single mode of binding was observed, with the N-methyl close to the heme iron in a position appropriate for the observed N-demethylation reaction. In the presence of the reductase, the data were not consistent with a single mode of binding but could be explained by the existence of two alternative orientations of MPTP in the active site. One of these, characterized by a dissociation constant of 150 microM, is essentially identical to that observed in the absence of the reductase. In the second, which has a K(d) of 25 microM, the MPTP is oriented so that the aromatic ring is close to the heme iron, in a position appropriate for p-hydroxylation leading to the formation of the product seen only in the presence of the reductase. In the case of codeine, another substrate for cytochrome P450 2D6, the addition of reductase had no effect on the nature of the product formed, the dissociation constant, or the orientation in the binding site. These observations show that NADPH-cytochrome P450 reductase has an allosteric effect on the active site of cytochrome P450 2D6 that affects the binding of some substrates but not others.     

Adaptive nonlinear cancellation for high-speed fiber-optic systems

The authors propose techniques for adaptive nonlinear cancellation of intersymbol interference (ISI) in the electrical signal at the receiver in Gb/s lightwave systems and describe several demonstrations of these techniques. Techniques for adjustable nonlinear cancellations are discussed and demonstrations of these techniques using commercially available integrated circuits (ICs) at data rates as high as 1.7 Gb/s are described. Techniques for automatic adjustment are discussed, and a demonstration of adaptive nonlinear cancellation at 450 Mb/s is described. The authors discuss how these techniques can be integrated onto the detector IC for operations at 2.5 Gb/s and higher data rates. These techniques allow a single IC detector with adaptive nonlinear cancellation to be used in long-haul and undersea lightwave systems to optimize the detector threshold and compensate for the ISI     

Reducing the effects of transmission impairments in digital fiberoptic systems

The major impairments in lightwave systems and the signal-processing techniques that can be used to reduce these impairments are discussed. Guidelines for the use of these techniques are presented. These guidelines are used to determine the techniques with the most potential for providing improved performance in long-haul systems, local-area networks, and local loop systems. Although many of the techniques have been previously considered for these applications, few have been implemented in commercial products. Some of the most promising techniques include dispersion-compensating fibers, polarization control, nonlinear cancellation (NLC), and coding for reducing the effect of distortion in long-haul single-frequency-laser direct-detection systems     

A comparative evaluation of two sensitive serum neutralization tests for bovine herpesvirus-1 antibodies

The need for frequent injections and monitoring, the possibility of multiple gestations, and the higher cost compared to clomiphene citrate, prevents many clinicians from using human menopausal gonadotrophin (HMG) for ovulation induction. A sequential medication regimen, in which HMG is taken after clomiphene, overcomes these problems. We retrospectively compared per cycle fecundity and birth rates in 119 cycles of clomiphene-HMG, 524 cycles of clomiphene alone, 57 cycles of HMG alone, and 79 cycles of concurrent HMG and clomiphene in patients receiving intra-uterine insemination (IUI), who were free of endometriosis or tubal disease. Per cycle fecundity for clomiphene-HMG was 22% [95% confidence interval (CI) 12-34%], double that of clomiphene alone (11%) (95% CI 8-14%) (P < 0.01), and equal to HMG alone (18%) (95% CI 7-29%) or HMG and clomiphene together (19%) (95% CI 10-28%). The multiple birth rate for clomiphene-HMG (7/21) equalled that for HMG alone (3/12) and HMG and clomiphene together (3/8). The average number of ampoules of HMG required [follicle stimulating hormone (FSH) 75 mIU, luteinizing hormone (LH) 75 mIU] was decreased by 65% from 24.5 +/- 1.0 for HMG or HMG and clomiphene together to 8.6 +/- 0.3 for clomiphene-HMG (P < 0.001). Per cycle fecundity was identical when one, two or three ampoules of HMG per day were administered after clomiphene. We conclude that ovulation induction with sequential clomiphene-HMG results in fecundity double that of clomiphene alone and equal to HMG alone or concurrent with clomiphene, thereby reducing the requirement for HMG.     

The gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2

Two forms of glutathione synthetase deficiency have been described. While one form is mild, causing hemolytic anemia, the other more severe form causes 5-oxo-prolinuria with secondary neurological involvement. Despite the existence of two deficiency phenotypes, Southern blots hybridized with a glutathione synthetase cDNA suggest that there is a single glutathione synthetase gene in the human genome. Analysis of somatic cell hybrids showed the human glutathione synthetase gene (GSS) to be located on chromosome 20, and this assignment has been refined to subband 20q11.2 using in situ hybridization.