Characteristics of warfarin hydroxylation catalyzed by human liver microsomes

The oxidative biotransformation of (R)- and (S)-warfarin was studied in human liver microsomes to determine whether an in vitro model could be established that would correspond to the in vivo profile that is generally observed. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin indicated the presence of two easily distinguishable subsets of human liver cytochrome P-450; a high affinity subset (Km 3-15 microM) and a low affinity subset of isozymes (Km greater than 200 microM). The high affinity subset is primarily responsible for the metabolic profile of the biologically more potent (S)-enantiomer in vivo, whereas the low affinity subset is largely responsible for metabolism of the (R)-enantiomer. Apparent Vmax values alone did not reflect the relative in vivo formation clearances of the phenolic metabolites from either antipode, because the low affinity-high capacity component masked the metabolic profile of the (S)-enantiomer. However, the rank order of intrinsic clearance, Vmax/Km, for each metabolite was in good agreement with regio- and stereoselective metabolism in vivo. This investigation highlights the need for rigorous kinetic characterization of an in vitro model before reasonable correlation can be expected with in vivo data.     

Crossed–uncrossed projections from primate retina are adapted to disparities of natural scenes

In mammals with frontal eyes, optic-nerve fibers from nasal retina project to the contralateral hemisphere of the brain, and fibers from temporal retina project ipsilaterally. The division between crossed and uncrossed projections occurs at or near the vertical meridian. If the division was precise, a problem would arise. Small objects near midline, but nearer or farther than current fixation, would produce signals that travel to opposite hemispheres, making the binocular disparity of those objects difficult to compute. However, in species that have been studied, the division is not precise. Rather, there are overlapping crossed and uncrossed projections such that some fibers from nasal retina project ipsilaterally as well as contralaterally and some from temporal retina project contralaterally as well as ipsilaterally. This increases the probability that signals from an object near vertical midline travel to the same hemisphere, thereby aiding disparity estimation. We investigated whether there is a deficit in binocular vision near the vertical meridian in humans and found no evidence for one. We also investigated the effectiveness of the observed decussation pattern, quantified from anatomical data in monkeys and humans. We used measurements of naturally occurring disparities in humans to determine disparity distributions across the visual field. We then used those distributions to calculate the probability of natural disparities transmitting to the same hemisphere, thereby aiding disparity computation. We found that the pattern of overlapping projections is quite effective. Thus, crossed and uncrossed projections from the retinas are well designed for aiding disparity estimation and stereopsis.

In most vertebrates, optic-nerve fibers leaving either eye cross to the contralateral side of brain via the optic chiasm (1). Complete decussation refers to cases in which all fibers cross to the other side (i.e., all fibers from the left eye terminate in the right hemisphere of the central nervous system, while all from the right eye terminate in the left hemisphere). Partial decussation occurs in most mammals: many fibers project contralaterally, but some from the temporal retinas do not cross to the other hemisphere. Interestingly, the proportion of fibers that project ipsilaterally depends on the relative orientation of the eyes. If the eyes are directed laterally (i.e., large angle between the optic axes), a small proportion projects ipsilaterally. If the eyes are frontal (i.e., small angle between optic axes), a large proportion projects ipsilaterally. This relationship is codified by the Newton–Müller–Gudden Law that states that the ratio of uncrossed to crossed fibers is proportional to the width of binocular visual field, which in turn, depends on eye laterality (1–3).Animals with large laterality (e.g., mouse, rat, rabbit, sheep, squirrel, chipmunk) have a narrow binocular field that is subserved by the temporal retinas of both eyes (4) (Fig. 1A). Animals with less laterality (e.g., cats, nonhuman primates, humans) have a wide binocular field (4) (Fig. 1B). In these animals, the proportion of ipsilaterally projecting fibers can be half of the total proportion. The boundary between ipsilateral and contralateral projections is near the vertical meridians of the eyes. The nasal retina of the left eye and temporal retina of the right eye represent the left visual field, which is, in turn, represented in the right visual cortex. The temporal retina of the left eye and nasal retina of the right eye are stimulated by the right visual field, which is represented in the left cortex.Open in a separate windowFig. 1.Projections to hemispheres in lateral- and frontal-eyed mammals. (A) Top view of lateral-eyed animal. Nasal retina and temporal retina in the left eye are represented by pink and green, respectively, and the opposite for the right eye. Pink regions in front of the animal represent points in the visual scene that produce signals that travel to the right hemisphere. Green regions represent points that produce signals to the left hemisphere. The blue region represents the binocular visual field where points stimulate both retinas. (B) Top view of a frontal-eyed mammal with no crossed–uncrossed nasotemporal (NT) overlap in the decussation pattern. The left and right halves of the retinas are represented by green and pink, respectively. Green and pink regions in front of the animal represent scene points that produce signals from both eyes to the left and right hemispheres, respectively. Gray regions represent scene points that would send signals from the two eyes to different hemispheres (i.e., regions for which there is no binocular integration through direct paths from the retinas to cortex). (C) Top view of frontal-eyed mammal with crossed–uncrossed overlap in the decussation pattern. Green and pink regions in the retina again represent regions for which both eyes project to one hemisphere. Yellow regions in the retinas represent the crossed–uncrossed overlap: the parts of the retinas that project to both hemispheres. Yellow regions in front represent scene points that produce signals to both hemispheres due to the overlapping projections. Light yellow represents regions where stimulation occurs in either the nasal retinas of both eyes or the temporal retinas of both eyes. Due to the crossed–uncrossed overlap, signals from both eyes would be sent to both hemispheres. Gray regions represent points in the scene that send signals from the two eyes to different hemispheres. They are much smaller than when there is no crossed–uncrossed overlap.The nasotemporal division is the boundary in the retina that separates crossing and noncrossing fibers. As we said, the division in frontal-eyed mammals occurs near the vertical meridians. A significant problem for the neural computation of binocular disparity would arise if the nasotemporal division occurred precisely such that all retinal points to the left of the vertical meridian projected to one side of the brain, while all points to the right of the meridian projected to the opposite side (Fig. 1B). Small objects that were nearer or farther than current fixation would end up producing signals that traveled to opposite halves of the brain. For example, an object above fixation with uncrossed disparity (farther than fixation) would be imaged in the lower retina of the left eye just nasalward (i.e., rightward) from the vertical meridian and in the lower retina of the right eye just nasalward (leftward) from the vertical meridian; hence, the left eye’s signal would be sent to the right hemisphere, and the right eye’s signal would be sent to the left hemisphere. Combining the signals to estimate disparity would then require using pathways that cross from one hemisphere to the other via one of the commissures such as the corpus callosum. This would necessitate longer neural paths involving more synapses, which would surely adversely affect the speed and accuracy of computations required to estimate binocular disparity and the perception of depth from disparity (5–7). A solution is to have overlapping projections near the vertical meridian (i.e., some fibers in nasal retina near the meridian would project ipsilaterally, while most nasal fibers would still project contralaterally) (Fig. 1C). There is clear evidence for just this arrangement in cats and nonhuman primates and some evidence for this in humans.In cats, there is a strip of retina encompassing the vertical meridian in which retinal ganglion cell axons project to both hemispheres in the central nervous system (5, 8–11). The strip is about 1.5○ wide.There are analogous overlapping projections in nonhuman primates. Stone et al. (12) sectioned one optic tract in rhesus monkeys (Macaca mulatta). They then examined the two retinas to determine which ganglion cells had survived the ensuing retrograde degeneration. If the right optic tract was sectioned, one might expect to observe no surviving ganglion cells in the nasal retina of the left eye and temporal retina of the right eye. However, Stone et al. (12) observed such surviving cells as far as 1○ from the vertical midline, which indicates an overlap in projections near the nasotemporal boundary. In long-tailed macaque monkeys (Macaca fascicularis), Bunt et al. (13) injected a retrograde labeler into the lateral geniculate nucleus (LGN) on one side of the brain and measured where the label appeared in the two retinas. They found a region near the vertical meridian where the label appeared in both retinas. The width of the overlapping region was 1○ to 2○. Fukuda et al. (7) obtained similar results in Japanese macaques (Macaca fuscata). They injected different retrograde labelers into the left and right LGNs and observed clear crossed–uncrossed overlap near the vertical midline. The width of the overlap was roughly proportional to the distance from the fovea. They also observed an asymmetry. In the upper retina (lower visual field), more retinal axons on the nasal side of the midline projected ipsilaterally than axons on the temporal side of midline that projected contralaterally (14). To verify their observations, Fukuda et al. (7) also examined crossed–uncrossed projections in fluorescent dye experiments with injections in the optic tract and in physiological experiments employing antidromic responses in retinal ganglion cells due to stimulation of the left or right LGN. The results confirmed the asymmetry and the increasing width of the overlap region with eccentricity.The effectiveness of the overlapping projections in nonhuman primates was demonstrated indirectly by Cowey and Wilkinson (15). They showed that severing the corpus callosum (thereby preventing binocular processing via interhemispheric communication) had no discernible effect on rhesus monkeys’ stereoacuity near the vertical midline. In contrast, sectioning the optic chiasm had a very deleterious effect on stereoacuity.There is evidence for overlapping crossed–uncrossed projections in humans as well. Some investigators tested split-brain patients (i.e., commissurotomized patients) in an attempt to ascertain the parts of the visual field where intrahemispheric processing can occur. They asked whether such patients can make reliable same–different judgments of stimuli presented on opposite sides of vertical midline. Intrahemispheric processing is needed to make such judgments, so doing the task reliably would suggest the presence of some crossed–uncrossed overlap in projections from the retinas. Some reported obvious deficits (16–18), suggesting no projection overlap. One more recent study employed more careful monitoring of eye position, presented targets closer to the vertical midline, and reported very reliable same–different judgments (19). Thus, studies of split-brain patients offer some support in humans for crossed–uncrossed overlap in projections similar to that observed in nonhuman primates.Other investigators tested patients with loss of a visual hemifield (homonymous hemianopia) due to loss of a cortical hemisphere. Consider a patient with no useable right cortical hemisphere. If the nasotemporal split in the retina was precise, their residual functional visual field should be the right hemifield with a precise boundary along the vertical meridian through the fovea. If instead, there was crossed–uncrossed overlap, the functional field should extend slightly leftward from the vertical meridian. In most of these perimetry experiments, the patient is told to maintain fixation on a point while small bright targets are presented at various positions on an otherwise dark background. The patient reports on each trial whether he/she saw the target. Of course, the target could be detected due to light scattered from the nominally tested location to another part of the retina. One must also be certain that the patient maintained accurate fixation. Reinhard and Trauzettel-Klosinski (20) solved both of these problems by presenting dark spots on a bright background and monitoring the stimulus position by using a scanning laser ophthalmoscope to view the stimuli directly on the retina. In nearly all of the eyes they tested, the border of the functional field was shifted slightly across the vertical meridian: clear evidence for crossed–uncrossed overlap in central projections. In most of the eyes, the border was shifted farther from the meridian at greater vertical eccentricities, which is consistent with the monkey data (7, 14). Wessinger et al. (21) obtained similar results in similar patients.Here, we investigate the effectiveness of the crossed–uncrossed overlap. We first examine whether deficits in human stereopsis occur along the vertical meridian. We find no evidence for deficits. We next quantify the overlap from anatomical data from nonhuman primates and data from functional Magnetic Resonance Imaging (fMRI) from humans. We then calculate the proportion of common naturally occurring disparities that would send signals directly to the same cortical hemisphere given different patterns of overlap. We find that the pattern observed in humans and nonhuman primates is quite effective.     

米非司酮终止早孕绒毛组织中一氧化氮合成酶活性及血清雌二醇、孕酮的测定

米非司酮终止早孕绒毛组织中一氧化氮合成酶活性及血清雌二醇、孕酮的测定杨晓葵李明冯淑芝杨菁管楚玉近年来的研究发现，一氧化氮（Ｎｉ－ｔｒｉｃｏｘｉｄｅ，ＮＯ）是一种具有多种生物学潜能的局部调节因子，参与调节胚胎的发育和生殖激素的合成与释放。为了探讨米非司...