Thinking Wetly: Causeways and Communities in East Anglian Hagiography

Water defined the landscapes of medieval East Anglia. Hitherto scholarly attention has focussed on the physical geography of the region, with landscape archaeology and excavations revealing sites of international importance and speaking to the potency and ubiquity of water as a ritual element. Surprisingly, however, very little attention has been paid to the symbolic importance of water in medieval East Anglian literature, and this article addresses this scholarly lacuna. Water features prominently in the literature from the region, particularly in the lives and legends of the numerous saints venerated at its many cult centres. This article begins by outlining some of the key ways in which water signifies in these contexts, before discussing a case study from the Liber Eliensis which, at first reading, seems to confound the received notion of water’s symbolic resonances but which, on closer consideration, reveals an additional, previously unidentified aspect of this most fluid of metaphors

Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy

In a systematic review of antiepileptic drugs, Philippe Ryvlin and colleagues find that children with drug-resistant partial epilepsy enrolled in trials seem to have a greater response to placebo than adults enrolled in such trials

Clinical Risk Factors Associated with Anti-Epileptic Drug Responsiveness in Canine Epilepsy

The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs’ owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy

Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry—A Study in Rats Subjected to Status Epilepticus by Kainate

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood–brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood–brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level

(R)-[11C]Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus

<p>Abstract</p> <p>Background</p> <p>Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.</p> <p>Methods</p> <p><it>(R)</it>-[¹¹C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on <it>(R)</it>-[¹¹C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. <it>(R)</it>-[¹¹C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).</p> <p>Results</p> <p>All data analysis approaches indicated only modest differences in brain distribution of <it>(R)</it>-[¹¹C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.</p> <p>Conclusions</p> <p>P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.</p