Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo.

Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood-tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site-specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM-1 (CD31) and ICAM-1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post-injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding-detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one-to-one protein conjugates. Bivalent mAb-TM was superior to monovalent scFv-TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end-to-end anti-ICAM mAb-TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.

The role of nanostructure in the wetting behavior of mixed-monolayer-protected metal nanoparticles.

Self-assembled monolayer-protected nanoparticles are promising candidates for applications, such as sensing and drug delivery, in which the molecular ligands' interactions with the surrounding environment play a crucial role. We recently showed that, when gold nanoparticles are coated with a binary mixture of immiscible ligands, ordered ribbon-like domains of alternating composition spontaneously form and that their width is comparable with the size of a single solvent molecule. It is usually assumed that nanoparticles' solubility depends solely on the core size and on the molecular composition of the ligand shell. Here, we show that this is not always the case. We find that the ligand shell morphology affects the solubility of these nanoparticles almost as much as the molecular composition. A possible explanation is offered through a molecular dynamics analysis of the surface energy of monolayers differing only in their domain structure. We find that the surface free energy of such model systems can vary significantly as a function of ordering, even at fixed composition. This combined experimental and theoretical study provides a unique insight into wetting phenomena at the nano- and subnanometer scale.

Treatment options for small cell lung cancer - do we have more choice?

Small cell lung cancer (SCLC) is a significant health problem worldwide because of its high propensity for relapse. This review discusses existing and future therapies for the treatment of SCLC.

Magnification in striate cortex and retinal ganglion cell layer of owl monkey: a quantitative comparison.

Magnification, the relative size of the neural representation of a portion of the visual field, decreases more rapidly with increasing visual field eccentricity in striate cortex than in the retinal ganglion cell layer of the owl monkey (Aotus trivirgatus); the proportion of the cells in striate cortex devoted to central vision is much larger than the comparable proportion of retinal ganglion cells. Magnification in striate cortex is a power function of magnification in the retinal ganglion cell layer. A formula for convergence (ganglion cells to cortical neurons) follows from this relationship.

A randomised study comparing the effectiveness of acupuncture or morphine versus the combination for the relief of dyspnoea in patients with advanced non-small cell lung cancer and mesothelioma.

BACKGROUND: Dyspnoea is one of the commonest symptoms of lung cancer. Opioids can reduce dyspnoea. This study investigates acupuncture for relief of breathlessness in lung cancer. METHODS: We performed a single-centre, randomised phase II study of 173 patients with non-small cell lung cancer or mesothelioma with dyspnoea score of ≥4 on visual analogue scale (VAS). Randomisation was to acupuncture alone (A), morphine alone (M) or both (AM). Acupuncture was administered at upper sternal, thoracic paravertebral, trapezius trigger points and LI4. Manubrial semi-permanent acupuncture studs were inserted and massaged when symptomatic. Arm A patients received rescue morphine. Primary end-point was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 h. Measurements continued to day 14 and included VAS relaxation, line analogue rating (Lar) anxiety, hospital anxiety and depression and European Organisation for Research and Treatment of Cancer quality-of-life scores. RESULTS: Dyspnoea VAS improved ≥1.5 in 74%, 60% and 66% of arms A, M and AM, respectively, and was maintained in 45% at 2 weeks. There was no statistically significant difference between arms. VAS relaxation improved in arms A (1.06 points) and AM (1.48 points) compared to arm M (-0.19 points, p<0.001). At 7 d, the Lar anxiety score improved in arm A (1.5 points), arm AM (1.2 points) and arm M (no change, p=0.003). Fewer patients received at least one morphine dose in arm A compared with arm M or AM (21% versus 87% versus 87%, respectively, p<0.001). CONCLUSIONS: A, M and AM were effective in relieving dyspnoea. Acupuncture relieved anxiety and was morphine sparing, providing an alternative to morphine.

Behavioral evidence for brain-based ability factors in visuospatial information processing.

The present study examined possible parallels between the structure of human visuospatial abilities and the organization of the neural systems. Forty-eight participants were tested on seven speeded visuospatial tasks. Three of these tasks were constructed so as to rely primarily on known ventral stream functions and four were constructed so as to rely primarily on known dorsal stream functions. Both sets of tasks spanned approximately the same range of difficulty as indexed by both the speed and accuracy of decision making. Factor analysis of response times on the seven tasks revealed only two significant factors. The putative ventral stream tasks all loaded heavily on one factor (mean loading=0.843) but only weakly on the other factor (mean loading=0.222); the putative dorsal stream tasks showed the opposite pattern in that they all loaded heavily on the second factor (mean loading=0.828) but only weakly on the first factor (mean loading=0.229). These findings are consistent with the hypothesis that human visuospatial abilities can be classified using categories based on the specializations of underlying neural structures and systems.

The information-loss model: a mathematical theory of age-related cognitive slowing.

A model of cognitive slowing is proposed with the following assumption: Information is lost during processing, processing occurs in discrete steps with step duration inversely related to the amount of information currently available, and the effect of aging is to increase the proportion of information lost per step. This model correctly predicts a positively accelerated relation between latencies of older and younger adults and provides a unified account of the effects of task complexity, practice, speed-accuracy tradeoffs, and fluctuations in individual performance. Strong support for the thesis that cognitive slowing is global, and not localized in specific age-sensitive components, is provided by the fact that the model accurately predicts the latencies of older adults on the basis of those of younger adults, without regard to the nature of the task, across a latency range of nearly 2 orders of magnitude.

How general is general slowing? Evidence from the lexical domain.

Three analyses are reported that are based on data from 19 studies using lexical tasks and a reduced version of the Hale, Myerson, and Wagstaff (1987) nonlexical data set. The results of Analysis 1 revealed that a linear function with a slope of approximately 1.5 described the relationship between the lexical decision latencies of older (65-75 years) and younger (19-29 years) adults. The results of Analysis 2, based on response latencies from 6 lexical tasks other than lexical decision, revealed a virtually identical linear relationship. In Analysis 3, it was found that performance on nonlexical tasks spanning the same range of task difficulty was described by a significantly steeper regression line with a slope of approximately 2.0. These findings suggest that although general cognitive slowing is observed in both domains, the degree of slowing is significantly greater in the nonlexical domain than in the lexical domain. In addition, these analyses demonstrate how the meta-analytic approach may be used to determine the limits to the external validity of experimental findings.

General cognitive slowing in the nonlexical domain: an experimental validation.

Older and younger adults were tested on 4 nonlexical tasks: choice reaction time, letter classification, mental rotation, and abstract matching. A positively accelerated relation was observed between older and younger adults' latencies. Consistent with general slowing, the relation observed with the same subjects in each condition was more than 3 times as precise as in a comparable meta-analysis. Further analyses compared the ability of various models to describe the present data and also to predict the data on the basis of parameters estimated from a previous meta-analysis. Compared with linear models, the information-loss and overhead models provided more accurate accounts of general cognitive slowing in the nonlexical domain.

Age, variability, and speed: between-subjects diversity.

Two independent data sets were selected to examine the interrelations among reaction time (RT), between-subject variability or diversity (SD), and age. In both data sets, a strong correlation between RT and SD was obtained. This strong correlation was not affected when age was controlled in a partial correlation analysis. On the other hand, a weaker but significant correlation was obtained between age and SD. This correlation was eliminated when RT was controlled in a partial correlation analysis. Our analyses of the two data sets also indicated that the relation between RT and SD is identical for both young and elderly groups. Thus, the greater diversity often observed in performances of older groups is a direct consequence of slowing, rather than an independent effect of advancing age.

General slowing in semantic priming and word recognition.

Analyses of lexical decision studies revealed that (a) older (O) adults' mean semantic priming effect was 1.44 times that of younger (Y) adults, (b) regression lines describing the relations between older and younger adults' latencies in related (O = 1.54 Y-112 and unrelated conditions (O = 1.50 Y-93) were not significantly different, and (c) that there was a proportional relation between older and younger adults' priming effects (O = 1.48 Y-2). Analyses of word-naming studies yielded similar results. Analyses of delayed pronunciation data (Balota & Duchek, 1988) revealed that word recognition was 1.47 times slower in older adults, whereas older adults' output processes were only 1.26 times slower. Overall, analyses of whole latencies and durations of component processes provide converging evidence for a general slowing factor of approximately 1.5 for lexical information processing.

Temporal discounting in choice between delayed rewards: the role of age and income.

This study examined the effects of age and income temporal discounting (i.e. the decrease in the subjective value of a reward as the delay to its receipt increases). The value of delayed hypothetical monetary rewards was discounted at similar rates by adults of different ages but similar income levels, but at different rates by adults of similar age but different income levels. Specifically, lower income older adults showed a greater degree of temporal discounting than did either upper income older adults or upper income younger adults, but there were no age differences in discounting between the upper income groups. Comparison of these findings with those of a previous study (Green, Fry, & Myerson, 1994) suggests that impulsivity in decision making declines rapidly in young adulthood, reaching stable levels in the 30s. Further, age and income appear to interact in determining the impulsivity of decision making by adults.

Converging evidence that visuospatial cognition is more age-sensitive than verbal cognition.

In 3 separate experiments, the same samples of young and older adults were tested on verbal and visuospatial processing speed tasks, verbal and visuospatial working memory tasks, and verbal and visuospatial paired-associates learning tasks. In Experiment 1, older adults were generally slower than young adults on all speeded tasks, but age-related slowing was much more pronounced on visuospatial tasks than on verbal tasks. In Experiment 2, older adults showed smaller memory spans than young adults in general, but memory for locations showed a greater age difference than memory for letters. In Experiment 3, older adults had greater difficulty learning novel information than young adults overall, but older adults showed greater deficits learning visuospatial than verbal information. Taken together, the differential deficits observed on both speeded and unspeeded tasks strongly suggest that visuospatial cognition is generally more affected by aging than verbal cognition.

Amount of reward has opposite effects on the discounting of delayed and probabilistic outcomes.

Previous research has shown that the value of large future rewards is discounted less steeply than is the value of small future rewards. These experiments extended this line of research to probabilistic rewards. Two experiments replicated the standard findings for delayed rewards but demonstrated that amount has an opposite effect on the discounting of probabilistic rewards. That is, large probabilistic amounts were discounted at the same or higher rates than small amounts. Although amount had opposite effects on the discounting of delayed and probabilistic rewards, nevertheless, the same form of mathematical function accurately described discounting of both types of reward. The findings suggest that fundamentally similar, but not identical, processes are involved in decision making regarding delayed and probabilistic rewards. The implications of these findings for impulsivity and self-control are discussed.

Temporal discounting and preference reversals in choice between delayed outcomes.

Subjects chose between pairs of hypothetical amounts of money available after different delays. When smaller, more immediate amounts were selected over larger, more delayed amounts, the addition of a constant delay to both outcomes resulted in reversals of preference, contrary to the standard discounted utility model of economics. The delays at which preference reversed were determined for three pairs of amounts ($20 vs. $50, $100 vs. $250, and $500 vs. $1,250). The relation between the delay to the larger amount and the delay to the smaller amount at preference reversal was well fit by both linear and quadratic functions. Intercepts increased with amount, strongly suggesting that rate of discounting decreases with amount. The presence of significant negative curvature in the data from the majority of individual subjects poses problems for exponential and hyperbolic models of temporal discounting in self-control, both of which predict a linear relation between the delays to the larger and smaller amounts.

Age and individual differences in visuospatial processing speed: testing the magnification hypothesis.

Forty young adults and 40 older adults performed seven visuospatial information processing tasks. Factor analyses of the response times (RTs) yielded a single principal component with a similar composition in both age samples. For both samples, regressing the mean RTs of fast and slow subgroups for the seven tasks (18 conditions) on the corresponding mean RTs for their age group accounted for 99% of the variance. Taken together, these findings suggest that individual differences in processing time were largely task independent. The magnification hypothesis, a simple mathematical model of the interaction between age and ability, is presented. This model correctly predicts the finding that in both the young and the older adult groups, individual differences increased systematically with task difficulty. The magnification hypothesis also explains the regression parameters describing individual differences among young adults and predicts correctly that equivalent parameters describe individual differences among older adults. According to the magnification hypothesis, the RTs of slower individuals are more affected by aging than those of faster individuals, and slower individuals may be more at risk with respect to other biological insults (e.g., changes in health status) as well.

Individual and developmental differences in working memory across the life span.

The effects of secondary tasks on verbal and spatial working memory were examined in multiple child, young adult, and older adult samples. Although memory span increased with age in the child samples and decreased with age in the adult samples, there was little evidence of systematic change in the magnitude of interference effects. Surprisingly, individuals who had larger memory spans when there was no secondary task showed greater interference effects than their age-mates. These findings are inconsistent with the hypothesis that age and individual differences in working memory are due to differences in the ability to inhibit irrelevant information, at least as this hypothesis is currently formulated. Moreover, our results suggest that different mechanisms underlie developmental and individual differences in susceptibility to interference across the life span. A model is proposed in which memory span and processing speed both increase with development but are relatively independent abilities within age groups.

Converging evidence for domain-specific slowing from multiple nonlexical tasks and multiple analytic methods.

Older and young adults were tested on eight nonlexical tasks that overlapped extensively in complexity: disjunctive choice reaction time, line-length discrimination, letter classification, shape classification, mental rotation, visual search, abstract matching, and mental paper-folding. Performance on the first seven tasks was associated with equivalently low error rates in both groups, making it possible to directly compare their response times (RTs) on these tasks. Consistent with domain-specific slowing, the relationship between the RTs of the older adults and the RTs of the young adults was well described by a task-independent mathematical (Brinley) function. Evidence from this analysis and from analyses based on task-specific information-processing models leads to similar conclusions and provides converging support for general cognitive slowing in the nonlexical domain.

General lexical slowing and the semantic priming effect: the roles of age and ability.

Older adults performed three lexical information-processing tasks approximately 1.3 times slower than young adults. Consistent with general lexical slowing, slopes of regressions based on individual subjects' RTs on two of the tasks (single lexical decision and category judgment) did not differ from slopes based on the third (double lexical decision) task. Moreover, slopes based on the single lexical decision and category judgment tasks accurately predicted the size of semantic priming effects on the third (double lexical decision) task. This was true for the older group as a whole, and also for subgroups of fast, medium and slow older adults, as well as for young adult subgroups. The size of the semantic priming effects for the fast old and slow young subgroups (who differed in age but not in processing speed) were approximately equal, consistent with the idea that the effect of age on priming is entirely attributable to slowing. Across all tasks, each old subgroup (fast, medium, or slow) showed the same degree of slowing relative to the corresponding young subgroup, so that the differences in RTs observed between subgroups in the young sample were magnified in the old sample. Taken together, the present findings suggest that ability-related differences in lexical processing speed may be functionally equivalent to age-related differences and that both factors interact to determine performance on speeded lexical tasks.

Selective interference with verbal and spatial working memory in young and older adults.

Young and older adults were administered digit and location memory span tasks with and without verbal and spatial secondary tasks. Age differences were greater in location span than in digit span; however, there were no age differences in either the magnitude or pattern of effects of secondary tasks. There were also no age differences in the effects of secondary tasks on a combined (digit and location) task. On the digit and location span tasks, both young and older adults showed only domain-specific interference: naming colors selectively interfered with memory for digits, leaving memory for locations unaffected; pointing to matching colors selectively interfered with memory for locations, leaving memory for digits unimpaired. The results of the present study suggest a greater age deficit in spatial working memory than in verbal working memory, but provide no evidence of an age deficit in susceptibility to interference by secondary tasks in either domain.