Biomedical subjects
Publications and source records attributed to P Whittle.
The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.
Previous measurements of contrast discrimination threshold, delta C, as a function of pedestal contrast, C, for sine-wave gratings have shown a power law relationship between delta C and C at suprathreshold levels of C. However, these studies have rarely used contrasts greater than 50%. Whittle (1986), using incremental and decremental patches, found that delta C increased with C only up to about 50%. At higher contrasts it decreased. Since a periodic stimulus can be considered to be composed of increments and decrements, we thought we might find such an inverse U-shaped function for gratings if we used contrasts up to 100%. We tested this for both sine-wave and square-wave stimuli at spatial frequencies from 0.0625 to 8.0 c/deg. We found that for frequencies up to 0.5 c/deg, delta C in nearly all cases 'dipped down' after about C = 50% contrast. At 4.0 and 8.0 c/deg, however, no dip-down occurred. Additional experiments showed that the dip-down was unlikely to be due to cortical long-term adaptation and most likely an effect of localized light adaptation to the dark bars. We argue that the absence of dip-down at high spatial frequencies was mainly due to the attenuation of contrast by the optics of the eye. As for the results of Whittle (1986), a Weber's Law in W = (Lmax-Lmin)/Lmin describes the inverse U-shaped contrast discrimination function well. Two other contrast expressions also linearize the data on log-log plots. We show how some familiar notions about the physiological operation of localized light adaptation can easily account for the form of the contrast discrimination function. Finally we estimate the number of discriminable steps in contrast from detection threshold to maximum contrast for the various spatial frequencies tested.
Causal beliefs regarding the onset of psychiatric disorder and treatment expectations for clients admitted to a psychiatric unit were examined from the points of view of the clients themselves, their relatives and staff. Results suggested that these beliefs were influenced by the admission itself. Those clients who had been admitted previously held significantly higher biological causal beliefs than those who had been admitted for the first time; as compared to staff who did not distinguish between the two groups in this way. The mean psychosocial views of relatives decreased significantly over the two-month period following an admission. Clients' and relatives' mean biological views were significantly greater than those of staff. Various correlations were found between causal beliefs and treatment expectations including one in the relative's' view between psychosocial causal beliefs and the importance assigned to family therapy. Indeed, there was a significant decrease in the family therapy rating over time given by relatives.
The antiviral activities of two substrate-based inhibitors of human immunodeficiency virus type 1 (HIV-1) protease, UK-88,947 and Ro 31-8959, were studied in acute infections. H9 and HeLaCD4-LTR/beta-gal cells were infected either with HIV-1IIIB or a replication-defective virus, HIV-gpt(HXB-2). Both inhibitors were capable of blocking early steps of HIV-1 replication if added to cells prior to infection. Partial inhibition was also obtained by addition of inhibitor at the time of or as late as 15 min after infection. The inhibitors were ineffective if added 30 min postinfection. The inhibitory effects were studied by cDNA analysis with PCR followed by Southern blot hybridization and by infectivity assays allowing quantitation of HIV-1 in a single cycle of replication. When UK-88,947-treated H9 cells were coinfected with HIV-1 and human T-cell leukemia virus type I only the replication of HIV-1 was inhibited, demonstrating viral specificity. Pretreating the infectious virus stocks with the inhibitors also prevented replication, indicating that the inhibitors block the action of the viral protease and not a cellular protease. A panel of primer sets was used to analyze cDNA from cell lysates by PCR amplification at 4 and 18 h postinfection. Four hours after infection, viral specific cDNA was detected with all of the four primer pairs used: R/U5, nef/U3, 5' gag, and long terminal repeat (LTR)/gag. However, after 18 h, only the R/U5 and nef/U3 primer pairs and not the 5' gag or LTR/gag primer pair were able to allow amplification of cDNA. The results suggest a crucial role of HIV-1 protease in the early phase of viral replication. Although it is not clear what early steps are affected by the protease, it is likely that the target is the NC protein, as referred from our previous reports of the in situ cleavage of the nucleocapsid (NC) protein by the viral protease inside lentiviral capsids. The results suggest that it is not the inhibition of initiation and progression of reverse transcription but the stability of full-size unintegrated cDNA which is affected in the presence of protease inhibitors. Alternatively, the cleavage of the NC protein may be required for the proper formation of preintegration complex and/or for its transport to the nucleus.
1. The factor by which increment threshold rises with increasing background intensity is less if the target is small than if it is large. The difference is usually attributed to a reduction in the area over which visual signals are integrated as the visual system light adapts. Recently, however, it has been argued that the difference in slope may instead be caused by an increase in the gain of the local response function with light adaptation. 2. To test this hypothesis in the rod-driven visual system, we compared monoptic, small and large target increment thresholds, and dichoptic, large target brightness matches, measured as a function of background intensity in a typical, complete achromat, who has no cone vision. 3. The dichoptic brightness matches were made using a large target of a similar intensity to the threshold intensity of the small target. If local intensity is important, the large target brightness matching curve should be more similar to the shallow, small target threshold curve. But, if changes in spatial integration are important, the brightness matching curve should be similar to the steeper, large target threshold curve. 4. The slope of the large (1.85 deg) target increment threshold functions measured with either 200 or 50 ms test flashes were steeper than those of the small (10 min of arc) target functions by 0.10 (on logarithmic co-ordinates) or about 15%. 5. The logarithmic slopes of the dichoptic brightness curves were also slightly steeper than the small target increment functions. This is contrary to the local response (only) hypothesis, which predicts that the brightness curve should have the same slope as the small target function because the luminance of the targets in the two cases is the same. 6. We conclude that there must be a change in spatial integration in the rod visual system during light adaptation, over and above that due to local gain changes.
A particular rate of quantal absorption by photoreceptors may result in a dim or an intense percept, depending on light stimulating other parts of the retina. The brightness of an object in a natural scene, therefore, depends on the amount of light reflected from the object in comparison to light from other parts of the scene. We show this phenomenon is mediated by two separate neural mechanisms at distinct levels of the visual system. The first mechanism depends on retinal image contrast between adjacent regions. The second mechanism depends on the binocularly fused "cyclopian" representation and is influenced by more remote, noncontiguous areas of the visual field.
Subjects adjusted the luminances, L, of 16 or 25 circles, all visible at the same time on a computer monitor, to make equal-interval brightness series. The background was black, white or grey. The luminance steps between adjacent circles behaved like the luminance discrimination thresholds of Whittle, P. [(1986) Vision Research, 26, 1677-1691)]. They showed a sharp minimum at the background luminance, Lb: the "Crispening Effect". They followed Weber's Law with respect to L when L was small, but with respect to delta L (= magnitude of L-Lb) near Lb. The Crispening Effect was abolished by a thin outline or a hue difference between circles and background.
Previously, the anti-human immunodeficiency virus type I (HIV-1) activities were reported of four sulfated polysaccharides: dextran sulfate, pentosane polysulfate, chondroitin sulfate, and heparin sulfate. In the present study, the anti-HIV-1 activities of several other sulfated polysaccharides, monosaccharides, neutral polysaccharides, and polypeptides were evaluated. Anti-HIV-1 activities of these various agents were measured by four different assays: (1) HIV-1-induced syncytia formation; (2) infectivity of cell-free HIV-1 after preincubation with the putative anti-HIV-1 agent; (3) protective ability of the agents for target CD4+ cells, and (4) anti-reverse transcriptase activity. In addition, potential toxicity of the putative anti-HIV-1 agents was measured by their effects on cellular proliferation, cytotoxic effects, and effects on coagulation processes. These data indicate that only sulfated polysaccharides and one sulfated monosaccharide, glucosamine 6-sulfate, have significant anti-HIV-1 activity. The therapeutic potentials of these agents are also discussed, with special reference to absorption of glucosamine 6-sulfate through the gastrointestinal tract.
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Photopic luminance discrimination thresholds were measured between two simultaneous spatially separate 1 degree squares presented for durations between 6 and 800 msec on an 11 degree background. For increments and weak decrements, threshold was proportional to the luminance difference, delta L, between square and background. Stronger decrements, except at the shortest durations, were more discriminable than increments with the same delta L, threshold being proportional to absolute luminance down to a 'black limit'. All the data for durations over 100 msec obey to a first approximation the rule delta W/W = constant, where W = delta L/Lmin, and Lmin is the smaller of the square and background luminances.
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The impulse discharge of single on-off neurons and a graded field potential, the proximal negative response (PNR), were simultaneously recorded with an extracellular microelectrode in the inner frog retina. Normalized amplitude-intensity functions for the on-response of the PNR and the neuron's post-stimulus time histogram (PSTH) were nearly coincident and typically showed a dynamic range spanning approximately 2 log units of intensity. Thus a nearly linear relation is found between the amplitude of the PNR and the neuron's PSTH. A neuron's PSTH amplitude and maximum instantaneous frequency of discharge were usually highly correlated, but occasional marked disparities indicate that temporal jitter of the first spike latency is an additional, relatively independent variable influencing PSTH amplitude. It typically changes by a factor of 20-30 over the intensity range. These and other findings have implications for the functional significance of the PNR and the PSTH, for a possible linear link between amacrine and on-off ganglion cells, and for a mechanism of intensity coding in which temporal jitter of latency exerts a major role.
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