Search PubMed⌕ Search

Biomedical subjects

N Graham

Publications and source records attributed to N Graham.

At least 37 records · Page 2Linked to original sources
PubMed2000

Normalization: contrast-gain control in simple (Fourier) and complex (non-Fourier) pathways of pattern vision.

Results from two types of texture-segregation experiments considered jointly demonstrate that the heavily-compressive intensive nonlinearity acting in static pattern vision is not a relatively early, local gain control like light adaptation in the retina or LGN. Nor can it be a late, within-channel contrast-gain control. All the results suggest that it is inhibition among channels as in a normalization network. The normalization pool affects the complex-channel (second-order, non-Fourier) pathway in the same manner in which it affects the simple-channel (first-order, Fourier) pathway, but it is not yet known whether complex channels' outputs are part of the normalization pool.

Form Perception↗
PubMed1999

4-hydroxy-5,6-dihydro-2H-pyran-2-ones.3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1' and S2' of the HIV-1 protease enzyme.

5,6-Dihydro-2H-pyran-2-ones are potent inhibitors of HIV-1 protease, which bind to the S1, S2, S1', and S2' pockets and have a unique binding mode with the catalytic aspartyl groups and the flap region of the enzyme. Efforts to explore 3-position heterocyclic scaffolds that bind to the S1' and S2' pockets have provided a number of selected analogs that display high HIV-1 protease inhibitory activity. reserved.

Binding Sites↗
PubMed1999

Texture segregation shows only a very small lower-hemifield advantage.

Possible hemifield differences in texture segregation were investigated for both simple (Fourier, linear) and complex (non-Fourier, second-order) texture channels. There was only a very small lower-field advantage for texture segregation, consistent with the notion that the major processing in texture segregation is quite low level, perhaps V1. Complex-channel tasks do not show larger hemifield asymmetries than do simple-channel tasks, which suggests that the processes in complex texture channels are not higher level than those in simple.

Adolescent↗
PubMed1999

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor.

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Cell Line↗
PubMed1998

Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count.

CONTEXT: Plasma human immunodeficiency virus type 1 (HIV-1) viral load and CD4+ cell count are used to predict prognosis of persons infected with HIV. However, whether combining these markers improves prognostic accuracy and whether they predict prognosis for injection drug users (IDUs) and nonwhite persons infected with HIV has not been extensively investigated. OBJECTIVE: To evaluate plasma viral load and CD4+ cell count as prognostic indicators for the acquired immunodeficiency syndrome (AIDS) and infectious disease deaths. DESIGN: Cohort study initiated in 1988 and 1989 with follow-up for up to 7.9 years. PARTICIPANTS: Injection drug users infected with HIV recruited from the community in Baltimore, Md. MAIN OUTCOME MEASURES: Plasma HIV-1 RNA and CD4+ cell count measured at baseline compared with time to first clinical AIDS diagnosis and death due to an infectious disease. RESULTS: Of 522 subjects, 96% were African American, 80% were male, 96% injected drugs within the past 6 months, and the median age was 33 years. A total of 146 cases of AIDS and 119 infectious disease deaths were seen during a median follow-up period of 6.4 years. Time-fixed baseline levels of viral load and CD4+ cell count were independent predictors of progression to AIDS and infectious disease deaths, but in proportional hazards models, viral load had better predictive value than CD4+ cell count. Kaplan-Meier analysis of time to AIDS and to infectious disease deaths by viral load (<500, 500-9999, 10000-29 999, > or =30000 copies/mL) at 3 levels of CD4+ cell count (<0.20, 0.20-0.49, and > or =0.50x10(9)/L [<200,200-499, and > or =500/microL]) was reduced to a 5-stage classification scheme using a backward stepwise regression procedure. The 5-year cumulative probabilities for AIDS and infectious disease deaths ranged from 0% and 0%, respectively, for group I (viral load, <500 copies/mL; CD4+ cell count, 0.50x10(9)/L) to 81.2% and 76.1% respectively, for group V (viral load, > or =10000 copies/mL; CD4+ cell count, 0.20x10(9)/L). CONCLUSIONS: In this study, plasma HIV-1 viral load independently and in combination with CD4+ cell count measurements provided powerful prognostic information for progression to AIDS and death caused by infectious disease in a population of predominantly African American IDUs. Combining categories of both markers provided a simple method for prognostically staging HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1998

Word reading in Alzheimer's disease: cross-sectional and longitudinal analyses of response time and accuracy data.

Using a list of high- and low-frequency regular and exception words, we measured the reading performance of three groups of subjects: patients with mild dementia of the Alzheimer's type (DAT) at presentation (Stage 1) and 2-3 years later (Stage 2); moderately severe DAT patients; and control subjects. In the longitudinally studied patients, there was a dramatic increase in response times (RTs) from Stage 1 to Stage 2, but little change in either error rate or pattern. By contrast, a comparison of the Stage 2 with the Moderate patients revealed similar RTs but a significant increase in error rate for the Moderate group, particularly on low-frequency exception words. These two results for word naming were almost exactly mirrored by effects in picture naming. We conclude that correct word reading, especially for less common words with atypical spelling-sound correspondences, is compromised in DAT only when the disease produces a significant deterioration of semantic memory. These results are relevant to current theories about normal and impaired reading processes.

Aged↗
PubMed1998

Spatial summation in simple (Fourier) and complex (non-Fourier) texture channels.

Complex (non-Fourier, second-order) channels have been proposed to explain aspects of texture-based region segregation and related perceptual tasks. Complex channels contain two stages of linear filtering with an intermediate pointwise nonlinearity. The intermediate nonlinearity is crucial. Without it, a complex channel is equivalent to a single linear filter (a simple channel). Here we asked whether the intermediate nonlinearity is piecewise-linear (an ordinary rectifier), or compressive, or expansive. We measured the perceptual segregation between element-arrangement textures where the contrast and area of the individual elements were systematically varied. For solid-square elements, the tradeoff between contrast and area was approximately linear, consistent with simple linear channels. For Gabor-patch elements, however, the tradeoff was highly nonlinear, consistent with complex channels in which the intermediate nonlinearity is expansive (with an exponent somewhat higher than 2). Also, substantial individual differences in certain details were explainable by differential intrusion from "off-frequency" complex channels. Lastly, the results reported here (in conjunction with those of other studies) suggest that the strongly compressive intensive nonlinearity previously known to act in texture segregation cannot be attributed to a compressive nonlinearity acting locally and relatively early (before the spatial-frequency and orientation-selective channels) but could result from inhibition among the channels (as in a normalization network).

Contrast Sensitivity↗
PubMed1997

4-hydroxy-5,6-dihydropyrones. 2. Potent non-peptide inhibitors of HIV protease.

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P2 and P2'. Parent dihydropyrone 1c (IC50 = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50 = 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio] -2H-pyran-2-yl)pentanoic acid and 12c, IC50 = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3- [(2-phenyl-ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1' and S2' afforded potent HIV protease inhibitor 49 [IC50 = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-dihydro-4 -hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (< 475) have one or no chiral centers and are readily synthesized.

Anti-HIV Agents↗
PubMed1997

Dysgraphia in mild dementia of Alzheimer's type.

We assessed writing abilities in a cohort of 31 patients with a diagnosis of DAT (in two subgroups, with minimal [MMSE 24-28] and mild [MMSE 16-23] levels of dementia), and 10 matched controls. Central aspects of writing were assessed by both written and oral spelling to dictation of 72 single words varying in frequency (high or low) and predictability of sound-to-spelling correspondences (predictable, unpredictable and irregular). All subjects achieved better scores on high, as compared to low, frequency words. The performance of both patient groups was significantly affected by degree of predictability, and was equivalent in the written and oral spelling conditions. Phonologically acceptable alternative spellings (e.g. 'wade'-->WAID) constituted the majority of errors. More peripheral processes in writing were assessed by copying and cross-case transcription of single letters. Subjects were more successful at copying within case than transcribing across case. Performance was also better--substantially so for the mild DAT group--when the target response in either task was an upper- rather than a lower-case letter. There was considerable heterogeneity in performance on the spelling and the letter tasks. Some patients (even in the more affected DAT group) were unimpaired on both tasks, suggesting that dysgraphia is not a constant feature in early DAT. When writing deficits do become apparent, in the earliest stages of the disease the pattern is most likely to be one of mild surface dysgraphia, a form of central dysgraphia; impairments in more peripheral aspects of writing tend to emerge once the disease has progressed beyond the minimal stage.

Aged↗
PubMed1997

Probed-sinewave paradigm: a test of models of light-adaptation dynamics.

Studies of light adaptation have, in general, employed either aperiodic or periodic stimuli. In earlier work, models originally developed to predict the results from one tradition failed to predict results from the other but the models from the two traditions could be merged to predict phenomena from both. To further test these merged models, a paradigm combining both types of stimuli was used. The threshold for a brief flash (the probe) was measured at various phases on a background that was varied sinusoidally in time. The probe threshold depends upon the phase at which it is presented for all background frequencies used, 0-16 Hz. These threshold variations are not well described by a sinewave; the peak threshold is > 180 deg out of phase with the trough threshold. Further, the positions of the peaks and troughs shift fairly abruptly at background modulations of 4-8 Hz. The difference between the peak and trough thresholds varies as a function of temporal frequency in a manner approximating the temporal contrast sensitivity function. The dc level (mean threshold) does not. The peak-trough difference dominates at low frequencies of background modulation, while the dc level dominates for higher frequencies. Existing models of light adaptation do not predict the key features of the data.

Adaptation, Ocular↗
PubMed1997

A test of magnitude: does the strength of predictors explain differences in drug use among adolescents?

Prior research has provided much needed information on the association between gender, race, predictive factors, and drug use. However, none have provided conclusive evidence regarding the extent to which gender and race differences, or their interaction, in adolescent drug use is accounted for by predictors. Using data on adolescents in four public schools, this study examined variations in the comparative strength of predictors of self-reported drug use. Data were collected as part of an ongoing longitudinal study of a federally funded multi-model program intervention for the prevention of alcohol and drug abuse among high risk youth. Analysis of variance was used to examine gender by race differences in predictors and drug use and logistic regression was used to assess the comparative strength of predictors of adolescent drug use and to explore the effect of gender by race on the decision to use drugs. Findings indicated, in general, whites, both male and female, had a significantly stronger positive association between predictors and drug use relative to blacks. Regarding the effect of gender by race on the decision to use drugs, these data indicate, with or without adjustments, white females were most likely to use gateway substances, followed by white males.

Adolescent↗
PubMed1997

Early versus deferred zidovudine monotherapy: impact on AIDS-free time and survival in the multicenter AIDS cohort study.

The objective of this study was to compare the time to AIDS and to death between men receiving zidovudine therapy before or not before the diagnosis of AIDS. For the time to AIDS comparison, 821 men receiving zidovudine therapy before the diagnosis of AIDS were pair matched with men who did not receive zidovudine therapy until after diagnosis on their CD4 cell count (+/- 75 cells/mm3), haemoglobin level (+/- 0.75 g/dl), number of clinical symptoms and study visit at the time of initiation of zidovudine therapy and were monitored for a median of 2.08 years. For the time to death comparison, 186 men who received zidovudine therapy prior to AIDS diagnosis were pair matched on the same variables to men who received zidovudine therapy only after the AIDS diagnosis, and were monitored for a median of 2.88 years. Only men with < 350 CD4 cells/mm3 who received zidovudine therapy prior to AIDS diagnosis remained AIDS free significantly longer than their pair match who did not (P < 0.0001). The median extension of time to AIDS was 0.61 years for men with < 200 CD4 cells/mm3 and 1.13 years for men with 200-349 CD4 cells/mm3. Cox regression analysis showed a significantly increased time to AIDS for the men with < 350 CD4 cells/mm3, both before and after adjustment for the use of prophylactic drugs against Pneumocystis carinii pneumonia. No difference was seen in the time to death between men receiving zidovudine therapy before or only after AIDS diagnosis. Zidovudine treatment of asymptomatic HIV-1-infected men provides significant benefit to men with < 350 CD4 cells/mm3 by extending AIDS-free time, but does not extend survival. The analytical technique used is applicable to other observational studies of treatment.

Acquired Immunodeficiency Syndrome↗