Auditory-cued sensorimotor task reveals disengagement deficits in rats exposed to the autism-associated teratogen valproic acid.

Autism Spectrum Disorder (ASD) is often found to co-exist with non-core behavioral manifestations that include difficulties in disengagement of attention to sensory cues. Here we examined whether this behavioral abnormality can be induced in rats prenatally exposed to valproic acid (VPA), a well-established teratogen associated with ASD animal models. We tested rats using an auditory-cued sensorimotor task (ACST) based on the premise that ACST will be more sensitive to developmental changes in temporal association cortex (TeA) of the posterior attention system. We show that VPA rats learned the ACST markedly faster than control animals, but they exhibited a profound preoccupation with cues associated with the expectancy at the reward location such that disengagement was disrupted. Control rats on the other hand were able to disengage and utilize auditory cues for re-engagement. However, both control and VPA-treated rats performed similarly when tested on novel object recognition (NOR) and novel context mismatch (NOCM) behavioral tasks that are known to be sensitive to normal perirhinal and prefrontal network functioning respectively. Consistent with disrupted posterior rather than frontal networks, we also report that VPA can selectively act on deep-layer TeA cortical neurons by showing that VPA increased dendritic density in isolated deep-layer TeA but not frontal neurons. These results describe a useful approach to examine the role of cue-dependent control of attention systems in rodent models of autism and suggest that disengagement impairments may arise from an inability to modify behavior through the appropriate use of sensory cue associations.

Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse.

Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD.

Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.

Spatial factors in visual attention: a reply to Crassini.

Distances between stimuli and, derivatively, compactness of stimulus subsets are pervasive determiners of discrimination and classification performance. Contrary to Crassini (1986), these factors are sufficient to account for the major patterns in the chronometric data of Podgorny and Shepard (1978, 1983). Other factors, such as the dichotomous one distinguishing what Crassini terms unitary and nonunitary subsets, may exert some additional influence. But a convincing demonstration would require formulation of a quantitative model capable of being pitted against the distance-based model of Podgorny and Shepard within the context of their entire body of data.

Distribution of visual attention over space.

Subjects viewed 3 X 3 grids in which different subsets of the nine squares were designated as "figure," either by physical shading of those squares or by a verbal instruction to imagine those squares as shaded. The time taken by participants to respond "on" or "off" the figure was measured for single or multiple probe dots, which all appeared on or off the figural subset together, and which had already been shown to be equally detectable against shaded or unshaded squares and in all nine locations within the grid. In contrast to the set-size effect generally found in experiments on memory scanning, reaction time did not necessarily increase with the number of squares in the figural subset. Instead, the critical variable, which in previous research may often have adventitiously covaried with set size, was the spatial compactness of the subsets (as indexed by square-root-area over perimeter): Probes of less compact figures required more time to classify correctly. Subjects were evidently more successful in confining their attention to sets of mutually proximal items. Reasons are given for believing that this principle may also apply in the more abstract representational or semantic spaces that determine reaction times and errors in various other cognitive tasks.

Functional representations common to visual perception and imagination.

Subjects determined whether probe dots appearing in component squares of a 5 X 5 grid fell on a figure that, depending on the condition, was (a) visually presented as a pattern of darkened squares, (b) only remembered from a preceding presentation of such a pattern, or (c) imaginally generated from a verbal code. The speed and accuracy of the responses to the probes as well as the functional dependencies of the reaction times on structural variables were essentially the same whether the figural pattern was imagined, remembered, or actually seen. Reaction times averaged between 400 and 500 msec and were consistently faster (a) for on-figure than for off-figure responses, (b) for simpler figures that had fewer squares, (c) for off-figure probes that were more distant from the figure, and (d) for on-figure probes that consisted either of more dots on the figure or of a dot at the intersection of a horizontal and a vertical bar. The reults were consistent with a model in which a subject's perceptual or imaginal representations of these forms contain barlike units that respond independently to the probes.