Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.

OBJECTIVE: To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure. METHODS: Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study. RESULTS: Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05). CONCLUSIONS: While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.

Management of chronic heart failure: perceived needs of general practitioners in light of the new general medical services contract.

BACKGROUND: Despite the existence of several chronic heart failure (CHF) guidelines the treatment of patients with CHF is suboptimal. The new general medical services (GMS) contract in primary care has only three specific performance indicators for patients with left ventricular dysfunction. The aim of this current questionnaire survey was to assess the views of general practitioners (GPs) on CHF treatments and services in light of the new GMS contract. METHODS AND RESULTS: All local GPs (717) were sent a questionnaire. Fifty three per cent were returned. Forty five per cent of GPs had access to a community CHF nurse. Having read a national guideline (SIGN) and having the support of a CHF nurse did not seem to affect the knowledge of GPs in terms of perceived benefits of drug treatments. GPs with access to a specialist CHF nurse service attached more importance to it than those with no specialist nurse (p = 0.003). CONCLUSIONS: Most GPs were aware of the existence of a national guideline but many had not read it. There was little or no difference in the knowledge level for various evidence based treatments between GPs who had or had not read the guideline suggesting that reading guidelines may not be a key factor in determining knowledge. Support for a specialist CHF nurse was higher among GPs who already had this service, suggesting that this service is valued. The new GMS contract may improve identification and diagnosis of patients with CHF but there is a danger that it may fall short of ensuring optimal treatment for patients with CHF.

Physician opinions on the implementation of the SIGN guideline for heart failure.

BACKGROUND AND AIMS: To assess physician opinion of and attitudes to, the Scottish Intercollegiate Guideline Network (SIGN) guideline for chronic heart failure (CHF) due to left ventricular systolic dysfunction. METHODS AND RESULTS: A questionnaire examining physicians' attitudes and their use of the SIGN guideline for CHF was distributed to 158 physicians in two teaching hospitals within one NHS trust. 65% of recipients responded. More cardiologists had read the guideline compared to non-cardiologists (91 vs 56%, p < 0.05). The majority of cardiologists and non-cardiologists agreed that it was applicable to their patients (92 vs 79%, p > 0.1) and that implementation may reduce hospital admissions (65 vs 59%, p > 0.5). In general, compliance was thought to be a problem in only a minority of patients in both groups for angiotensin converting enzyme inhibitors (8 vs 19%), diuretics (12 vs 29%) and digoxin (17 vs 19%, all p > 0.1). Beta-blocker compliance was identified as a problem by both groups (50 vs 53%, P > 0.5) while fewer cardiologists reported compliance as a problem with spironolactone (4 vs 25%, p < 0.05). More cardiologists felt that there was a need for a community based CHF nurse specialist (100 vs 57%, p < 0.001), and that this strategy would reduce hospital admissions (92 vs 57%, p < 0.01). CONCLUSIONS: Differences exist between cardiologist and non-cardiologist physicians' awareness of the SIGN guideline for CHE. Furthermore, we have shown differences in reported implementation of the guideline and perceived difficulties with specific drug therapies. This is in spite of high levels of agreement in both groups with the treatment suggested by the guideline and the anticipated benefits resulting from its implementation.

Stimulus configuration determines the detectability of motion signals in noise.

We measured the detectability of moving signal dots in dynamic noise to determine whether local motion signals are preferentially combined along an axis parallel to the direction of motion. Observers were asked to detect a signal composed of three dots moving in a linear trajectory among dynamic noise dots. The signal dots were collinear and equally spaced in a configuration that was either parallel to or perpendicular to their trajectory. The probability of detecting the signal was measured as a function of noise density, over a range of signal dot spacings from 0.5 degrees to 5.0 degrees. At any given noise density, the signal in the parallel configuration was more detectable than that in the perpendicular configuration. Our four observers could tolerate 1.5-2.5 times more noise in the parallel configuration. This improvement is not due merely to temporal summation between consecutive dots in the parallel trajectory. Temporal summation functions measured on our observers indicate that the benefit from spatial coincidence of the dots lasts for no more than 50 ms, whereas the increased detectability of the parallel configuration is observed up to the largest temporal separations tested (210 ms). These results demonstrate that dots arranged parallel to the signal trajectory are more easily detected than those arranged perpendicularly. Moreover, this enhancement points to the existence of visual mechanisms that preferentially organize motion information parallel to the direction of motion.

The use of an implicit standard for measuring discrimination thresholds.

We measured thresholds for comparing the separation between lines, using either the method of constant stimuli (MCS) or the method of single stimuli (MSS). In the MCS an explicit standard is presented on each trial, whereas in the MSS the standard is the mean of the set. The thresholds for the MSS procedure were nearly identical to those with the MCS procedure, whether or not feedback was used. A statistical model is presented showing how the threshold error estimated by MSS varies according to the number of past stimuli used by the observer to calculate the mean of the set. If the model is an accurate representation of human processing, our observers were averaging over the last 10-20 trials to estimate the implicit standard. Our results show that the explicit standard in the MCS procedure is generally superfluous. Provided that the test range is small, and that the observer is given some practice trials, thresholds measured with MSS procedure are just as precise as those measured with the traditional MCS procedure.

Neural mechanisms underlying amblyopia.

The nature of the neural basis of amblyopia is a matter of some debate. Recent neurophysiological data show correlates of amblyopia in the spatial properties of neurons in primary visual cortex. These neuronal deficits are probably the initial manifestation of the visual loss, but there are almost certainly additional deficits at higher levels of the visual pathways.

Local motion detectors cannot account for the detectability of an extended trajectory in noise.

Previous work has shown that a single dot moving in a consistent direction is easily detected among noise dots in Brownian motion (Watamaniuk et al., Vis Res 1995;35:65-77). In this study we calculated the predictions of a commonly-used psychophysical motion model for a motion trajectory in noise. This model assumes local motion energy detectors optimally tuned to the signal, followed by a decision stage that implements the maximum rule. We first show that local motion detectors do indeed explain the detectability of brief trajectories (100 ms) that fall within a single unit, but that they severely underestimate the detectability of extended trajectories that span multiple units. For instance, a 200 ms trajectory is approximately three times more detectable than two isolated 100 ms trajectories presented together within an equivalent temporal interval. This result suggests a nonlinear interaction among local motion units. This interaction is not restricted to linear trajectories because circular trajectories with curvatures larger than 1 degree are almost as detectable as linear trajectories. Our data are consistent with a flexible network that feeds forward excitation among units tuned to similar directions of motion.

Bias and sensitivity of stereo judgements in the presence of a slanted reference plane.

The perceived depth of features is known to be affected by the presence of a slanted reference plane. Mitchison and Westheimer ((1984). Vision Research, 24, 1063-1070) reported that two lines appear to be at the same depth when they lie in a plane approximately parallel with the reference plane. We measured the perceived depth of two lines presented in front of a regular grid of dots that was either fronto-parallel or slanted about a vertical axis. The effect of the slanted grid on perceived depth diminished as the grid was moved further in disparity from the lines. We also found that the slanted grid affected the sensitivity to differences in disparity. The minimum threshold for detecting changes in disparity is normally lowest in the fixation plane and rises systematically with increasing pedestal disparity. In the presence of a slanted reference plane, the minimum threshold is at or close to the plane of equal perceived depth and rises with increasing disparity from this plane.

Constraints on long range interactions mediating contour detection.

Contour detection may be mediated by lateral interactions between neighboring cortical neurons whose receptive fields have collinear axes of preferred orientation. This hypothesis was tested in psychophysical experiments and computer simulations using a contour detection task in which observers searched for groups of Gabor patches that followed spatially extended contour paths embedded in noise consisting of several hundred Gabor patches with random positions and orientations. The orientation-selective units in the simulated neural network were linked by facilitatory interconnections whose strength depended on the geometry (distance, curvature, change in curvature) of smooth curves connecting the orientation axes of units in a pairwise fashion. Psychophysical detection performance was much higher for contour signal groups that followed closed rather than open-ended paths. However, just two sudden changes in orientation of neighboring Gabor patch elements in closed-path contours reduced detection performance to the same levels obtained with open-ended contours. These psychophysical data agreed with the results of the neural network simulations. Furthermore, the simulations also accounted for previous findings that removal of a single Gabor patch element from a closed-path contour group significantly degraded detection performance. We conclude that closure alone is not sufficient to enhance the visibility of a contour. However, if a closed contour meets certain geometric constraints, then lateral interactions based on these constraints can generate facilitation that reverberates around the closed path, thereby enhancing the contour's visibility.

Simultaneous encoding of direction at a local and global scale.

Human observers can simultaneously encode direction information at two different scales, one local (an individual dot) and one global (the coherent motion of a field of dots distributed over a 10 degrees-diameter display). We assessed whether encoding global motion would preclude the encoding of a local trajectory component and vice versa. In the present experiments, a large number (100-150) of dots were randomly assigned directions in each frame from a uniform distribution of directions spanning a range of 160 degrees to create global motion in a single direction (Williams & Sekuler, 1984). Amidst these background dots, 1 dot moved in a consistent direction (trajectory) for the duration of the display. The direction of this "trajectory dot" was similar to the mean direction of the distribution of directions determining the movement of the background dots. Direction discrimination for both the global motion and the trajectory was measured, using the method of constant stimuli, under precued and postcued partial report conditions. A low- or high-frequency 85-msec tone signaled which motion the subject was to judge. In the precue condition, the tone was presented 200 msec before the onset of the stimulus, whereas in the postcue condition, the tone was presented immediately after the offset of the stimulus. Direction discrimination thresholds for both global and local motion in the postcued condition were not significantly different from those obtained in the precued condition. These results suggest that direction information for both global and local motion is encoded simultaneously and that the observer has access to either motion signal after the presentation of a stimulus.

Visual search for motion-in-depth: stereomotion does not 'pop out' from disparity noise.

In a visual search task, targets defined by motion or binocular disparity stand out effortlessly from stationary distractors ('pop-out'), suggesting that target and distractors are processed by different neural mechanisms. We used pop-out to explore whether motion directly toward or away from the observer (z-motion) is detected using binocular motion cues. A target moving laterally (x-motion) popped out amid stationary distractors with binocular disparity, but z-motion did not pop out. However, a small x-motion added to the target's z-motion caused it to pop out. We therefore suggest that the visual system may not be specifically sensitive to binocular motion differences.

Motion interference: perturbing perceived direction.

The minimum stimulus necessary to define motion is a change in position from one location to another in time, but past studies have provided evidence that the human motion system integrates motion over more than two positions. In this study we demonstrate strong sequential interactions affecting perceived direction in apparent-motion sequences; a perturbing dot can bias the perceived direction of motion between two test dots to which it is relatively close in space (up to 100 min arc) and time (up to 300 msec). These sequential interactions suggest a motion mechanism sensitive to the spatial characteristics of motion trajectories; the interactions are greatest for evenly spaced targets positioned along a single axis. The implications for motion-detection models and models based on attention as a mechanism to create apparent motion are discussed.

Fine-scale processing in human binocular stereopsis.

Many studies have demonstrated that the human visual system is sensitive to very small differences in relative binocular disparity. It is not known over what monocular regions information is spatially integrated to mediate performance in such tasks. In this study we present psychophysical observations that define the smallest spatial scale involved in disparity processing, and we indicate the nature of the computations performed by the units mediating that disparity discrimination. We show that human observers can identify the sign of disparity of a single target dot when it is embedded in a row of identical dots, with these noise dots presented either in the fixation plane or with a proportion binocularly uncorrelated. In conjunction with the psychophysical data, we explore how a class of simple correlator models of stereopsis must be constrained in order to account for human performance for the same fine-scale tasks. Such models can perform the task only when the correlation is carried out over a very small region of the image, for a very small range of disparities. Our results demonstrate that there is a fine-scale input to the stereo system, mediated by foveal mechanisms that spatially integrate visual signals over a region as small as 4-6 arcmin in diameter.

Is stereopsis effective in breaking camouflage for moving targets?

It has been suggested that breaking camouflage is one of the major functions of stereopsis (Julesz, 1971). In this study, we found that stereopsis is less effective in breaking camouflage for moving targets than for static ones. Observers were asked to detect a single dot moving on a straight trajectory amidst identical noise dots in random motion. In the three-dimensional (3D) condition, the noise dots filled a cylindrical volume 5.7 cm in height and diameter; the trajectory signal dot moved on an oblique 3D trajectory through the center of the cylinder. In the two-dimensional (2D) control condition, observers viewed one half-image of the 3D cylinder binocularly. Surprisingly, trajectory detection in the 3D condition was only slightly better than in the 2D condition. Stereoscopic tuning for motion detection was also measured with a novel target configuration in which the random motion noise was presented in two depth planes that straddled the fixation plane where the trajectory target was presented. As the disparity between the noise planes and the fixation plane was increased, trajectory detection improved, reaching a peak between 6 and 12 arcmin, and then declining to the 2D level at larger disparities, where the noise became diplopic. Similar tuning measurements were made for detecting a static pattern, a string of five aligned dots presented in the fixation plane between two planes of static noise dots. Adding disparity to the noise planes produced a far greater improvement in static detection than in motion detection, for a comparable range of disparities (1.5-12 arcmin). We speculate that the temporal characteristics of the stereo system are not well suited for responding to moving targets, with the result that stereo does not greatly enhance motion detection in noise.

Prediction of early-onset esotropia from components of the infantile squint syndrome.

PURPOSE: To examine the association between components of the infantile squint syndrome (ISS) and age of onset of esotropia among subjects in the Cooperative Amblyopia Classification Study (CACS). METHODS: Fifty subjects were classified retrospectively as having early-onset esotropia (EOE) and 150 subjects were classified as having late-onset esotropia (EOE), depending on whether symptoms of (or treatment for) strabismus occurred before the first birthday or between the first and ninth birthdays, respectively. The authors compared the degree to which latent nystagmus (LN), dissociated vertical deviation (DVD), monocular asymmetry of optokinetic nystagmus (MOKN), monocular asymmetry of smooth pursuit (MSP), and perceived monocular speed bias (MSB) predicted EOE. RESULTS: Slow-phase velocity of MOKN and MSP were faster in response to nasal than to temporal target motion. In contrast, MSB revealed that targets of equal velocity were perceived as moving faster temporally than nasally. The authors evaluated MOKN, MSP, and MSB as dichotomous and as continuous predictors. Dichotomous analysis showed significant associations between DVD and asymmetries of MOKN in the preferred eye of subjects with EOE. Univariate logistic regression models, based on DVD and LN as well as on continuous measures of MOKN, MSP, and MSB, revealed predictive power for all ISS components except LN. In the preferred eye, MSP asymmetry was the strongest single predictor of EOE; multivariate analysis revealed that prediction of EOE improved with the inclusion of DVD. CONCLUSIONS: Multivariate analysis indicated that dichotomous measures of DVD and continuous measures of MSP were independent predictors of EOE in a population of 8- to 40-year-old subjects with strabismus. In the preferred eye, MOKN asymmetry was predictive of EOE in the absence of information about MSP. Predictive values of all ISS components depended heavily on the baseline prevalence of EOE in the target population.

Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.

Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.

Temporal coherence theory for the detection and measurement of visual motion.

A recent challenge to the completeness of some influential models of local-motion detection has come from experiments in which subjects had to detect a single dot moving along a trajectory amidst noise dots undergoing Brownian motion. We propose and test a new theory of the detection and measurement of visual motion, which can account for these signal-in-Brownian-noise experiments. The theory postulates that the signals from local-motion detectors are made coherent in space and time by a special purpose network, and that this coherence boosts signals of features moving along non-random trajectories over time. Two experiments were performed to estimate parameters and test the theory. These experiments showed that detection is impaired with increasing eccentricity, an effect that varies inversely with step size. They also showed that detection improves over durations extending to at least 600 msec. An implementation of the theory accounts for these psychophysical detection measurements.

Seeing motion behind occluders.

The visual system has no difficulty maintaining the identity of an object as it disappears and reappears behind stationary occluders. In the natural world, a moving object may differ from occluders by many characteristics (colour, depth, shape and so on). Scene segmentation based on these characteristics is thought to happen early in visual processing, and to influence how objects, including moving objects, are identified. What happens if the only characteristic distinguishing an object is its direction of motion? Experiments with random dot displays show that one dot moving in a constant trajectory is readily detected among identical dots in brownian motion. Detection declines sharply if the trajectory is intermittently broken, but improves if occluders obscure the breaks in the trajectory. It is not sufficient that these occluders be perceived as segmented from the rest of the display (such as by colour or depth). Rather, it is critical that the occluders do not contain motion that is similar in direction to that of the target trajectory. We conclude that detection of the trajectory is due to the integration of information within a network of low-level motion detectors and is not dependent on segmentation processes.