Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

Neurobiological model of visuo-spatial cognition in young Williams Syndrome children: measures of dorsal-stream and frontal function

We examine hypotheses for the neural basis of the profile of visual cognition in young children with Williams syndrome (WS). These are: (a) that it is a consequence of anomalies in sensory visual processing; (b) that it is a deficit of the dorsal relative to the ventral cortical stream; (c) that it reflects deficit of frontal function, in particular of fronto-parietal interaction; (d) that it is related to impaired function in the right hemisphere relative to the left. The tests reported here are particularly relevant to (b) and (c). They form part of a more extensive programme of investigating visual, visuospatial, and cognitive function in large group of children with WS children, aged 8 months to 15 years. To compare performance across tests, avoiding floor and ceiling effects, we have measured performance in children with WS in terms of the ‘age equivalence’ for typically developing children. In this paper the relation between dorsal and ventral function was tested by motion and form coherence thresholds respectively. We confirm the presence of a subgroup of children with WS who perform particularly poorly on the motion (dorsal) task. However, such performance is also characteristic of normally developingchildren up to 5 years: thus the WS performance may reflect an overall persisting immaturity of visuospatial processing which is particularly evident in the dorsal stream. Looking at the performance on the global coherence tasks of the entire WS group, we find that there is also a subgroup who have both high form and motion coherence thresholds, relative to the performance of children of the same chronological age and verbal age on the BPVS, suggesting a more general global processing deficit. Frontal function was tested by a counterpointing task, ability to retrieve a ball from a ‘detour box’, and the Stroop-like ‘day-night’ task, all of which require inhibition of a familiar response. When considered in relation to overall development as indexed by vocabulary, the day-night task shows little specific impairment, the detour box shows a significant delay relative to controls, and the counterpointing task shows a marked and persistent deficit in many children. We conclude that frontal control processes show most impairment in WS when they are associated with spatially directed responses, reflecting a deficit of fronto-parietal processing. However, children with WS may successfully reduce the effect of this impairment by verbally mediated strategies. On all these tasks we find a range of difficulties across individual children and a small subset of WS who show very good performance, equivalent to chronological age norms of typically developing children. Neurobiological models of visuo-spatial cognition in children with WS p.4 Overall, we conclude that children with WS have specific processing difficulties with tasks involving frontoparietal circuits within the spatial domain. However, some children with WS can achieve similar performance to typically developing children on some tasks involving the dorsal stream, although the strategies and processing may be different in the two groups.

Speed tuning of direction repulsion describes an inverted U-function

Direction repulsion describes the phenomenon in which observers typically overestimate the direction difference between two superimposed motions moving in different directions (Marshak & Sekuler, Science 205(1979) 1399). Previous research has found that, when a relatively narrow range of distractor speeds is considered, direction repulsion of a target motion increases monotonically with increasing speed of the distractor motion. We sought to obtain a more complete measurement of this speed-tuning function by considering a wider range of distractor speeds than has previously been used. Our results show that, contrary to previous reports, direction repulsion as a function of distractor speed describes an inverted U-function. For a target of 2.5deg/s, we demonstrate that the attenuation of repulsion magnitude with high-speed disractors can be largely explained in terms of the reduced apparent contrast of the distractor. However, when we reduce target motion speed, this no longer holds. When considered from the perspective of Edwards et al.s (Edwards, Badcock, & Smith, Vision Research 38 (1998) 1573) two global-motion channels, our results suggest that direction repulsion is speed dependent when the distractor and target motions are processed by different globalmotion channels, but is not speed dependent when both motions are processed by the same, high-speed channel. The implications of these results for models of direction repulsion are discussed.

Dynamics and Function of Langerhans Cells In Vivo: Dermal Dendritic Cells Colonize Lymph Node Areas Distinct from Slower Migrating Langerhans Cells

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.

Disruption of the langerin/CD207 Gene Abolishes Birbeck Granules without a Marked Loss of Langerhans Cell Function

Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.

Relationship between G894T polymorphism (Glu 298 Asp variant) in endothelial nitric oxide synthase and nitric oxide mediated endothelial function in human atherosclerosis.

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104). Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P