Which visual pathways cause fixation-related inhibition?

Visual stimuli can both inhibit and activate motor mechanisms. In one well-known example, the latency of saccadic eye movements is prolonged in the presence of a fixation stimulus, relative to the case in which the fixation stimulus disappears before the target appears. This automatic sensory-motor effect, known as the gap effect or fixation-offset effect, has been associated with inhibitory connections within the superior colliculus (SC). Visual information is provided to the SC and other oculomotor areas, such as the frontal eye fields (FEF), mainly by the magnocellular geniculostriate pathway, and also by the retinotectal pathway. We tested whether signals in these pathways are necessary to create fixation-related inhibition, by using stimuli invisible to them. We found that such stimuli, visible only to short-wave–sensitive cones (S cones), do produce fixation-related inhibition (including when warning effects were equated). We also demonstrate that this fixation-related inhibition cannot be explained by residual activation of luminance pathways and must be caused by a route separate from that of luminance fixation signals. Thus there are at least two routes that cause fixation-related inhibition, and direct sensory input to the SC or FEF by the magnocellular or retinotectal pathways is not required. We discuss the implications that there may be both cortical and collicular mechanisms

In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances

<div><p>It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC_0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70–0.92), the peak concentraton (<i>C</i>_max) ratio 0.51 (p<0.001, 0.42–0.62) and the time to peak concentration (<i>T</i>_max) ratio 2.2 (p<0.001, 1.87–2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63–0.87, fed inferior p<0.01), 0.95 (0.81–1.11, bioequivalent) and 1.15 (0.97–1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC_0-∞ and <i>C</i>_max, and prolonged the <i>T</i>_max of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances.</p></div

Curves of geometric mean concentrations for the whole group.

<p>(a) Total flucloxacillin concentrations, and (b) free flucloxacillin concentrations in the fed (■) and fasting state (●). Error bars are not shown since statistics were performed on paired differences.</p

Mean (95% CI) values for the pharmacokinetic parameters for total and free plasma flucloxacillin concentrations in the fed and fasting states, and ratios^{^a} of fed/fasting (n = 12) based on non-compartmental analysis.

<p>Mean (95% CI) values for the pharmacokinetic parameters for total and free plasma flucloxacillin concentrations in the fed and fasting states, and ratios^{^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199370#t001fn001" target="_blank">a</a>}} of fed/fasting (n = 12) based on non-compartmental analysis.</p

Population parameter values (95% CI) for free concentrations, modelled with Monolix using a one-compartment model with <i>T</i>_lag.

<p>Population parameter values (95% CI) for free concentrations, modelled with Monolix using a one-compartment model with <i>T</i>_lag.</p

CONSORT flow diagram describing volunteer enrolment, allocation to intervention, follow-up and analysis.

<p>CONSORT flow diagram describing volunteer enrolment, allocation to intervention, follow-up and analysis.</p