No abstract

The two major prerequisites for a functional circadian system are the generation of an internal day (circadian cycle) and adjusting its length-and phase-to that of the external day (zeitgeber cycle). The generation of circadian cycles can be observed in constant conditions where organisms show a self-sustained, free-running rhythm. Their expression depends on the nature of the constant conditions (e.g., constant darkness, DD, or constant light, LL). The mechanism that synchronizes the circadian cycle length (τ) to that of the zeitgeber (T) can be explored by many experimental procedures (e.g., single light pulses), but it can only be fully understood under entertainment proper. When a clock is stably entrained, τ(LD) is, on average, equal to T, but the phase relationship between the clock (φ) and the zeitgeber (Φ) (phase of entrainment, ψ = Φ-φ) depends on the relationship between τ in constant conditions (τ(DD) or τ( LL)) and T. Phase of entrainment has traditionally been predicted by the clock's phase response curve (PRC) for a given zeitgeber stimulus and τ(DD). But there is an additional quality of the natural environment-namely, photoperiod-which is not easily incorporated into this entrainment paradigm. The authors therefore investigated phase of entrainment for 162 combinations of T, τ, and photoperiod in Neurospora crassa, which lends itself to a high-throughput approach. They entrained different strains (with long, short, and wild-type free-running periods) to different cycle lengths of the zeitgeber (16-26 h) and photoperiods (16%-84% of each cycle). These combinations produce a circadian surface with highly systematic phases of entrainment. The results suggest that the traditional entrainment paradigms using the PRC and τ(DD) have to be reevaluated.

Considering its role as a major blood-brain barrier gatekeeper, the dynamic regulation of the efflux transporter P-glycoprotein is of considerable functional relevance. In particular, disease-associated alterations in transport function might affect central nervous system drug efficacy. Thus, targeting regulatory signaling cascades might render a basis for novel therapeutic approaches. Using capillaries freshly prepared from patient tissue resected during epilepsy surgery, we demonstrate dynamic regulation of P-glycoprotein in human brain capillaries. Glutamate proved to up-regulate P-glycoprotein efflux transport in a significant manner via endothelial NMDA receptors. Both inhibition of cyclooxygenase-2 and antagonism at the glycine-binding site of the NMDA receptor prevented the glutamate-mediated induction of P-glycoprotein transport function in human capillaries. In conclusion, the data argue against species differences in the signaling factors increasing endothelial P-glycoprotein transport function in response to glutamate exposure. Targeting of cyclooxygenase-2 and of the NMDA receptor glycine-binding site was confirmed as an efficacious approach to control P-glycoprotein function. The findings might render a basis for translational development of add-on approaches to improve brain penetration and efficacy of drugs.

The occurrence and localization of interictal and ictal EEG findings differs vastly for lesions in different brain regions. These findings should be used to carefully weigh the results from EEG studies particularly in patients with extratemporal epilepsies considered for epilepsy surgery.

improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.