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After six sets of European Parliament elections, do voters primarily use these elections to punish their national governments or to express their views on European issues? We answer this question by looking at all European elections (1979–2004) in all 25 EU states. We find that almost 40% of the volatility in party vote-shares in European elections compared to national elections is explained by the transfer of votes from large and governing parties to small and opposition parties. Nevertheless, anti-EU parties and green parties on average do better in European elections than in national elections. But these “European effects” are minor, and the position a party takes on Europe is largely irrelevant to its performance. Hence, despite the growing powers of the European Parliament, neither positions on matters regarding European integration, nor on matters regarding “normal” left-right policy, have much of an effect on electoral outcomes.

Voting is a habit. People learn the habit of voting, or not, based on experience in their first few elections. Elections that do not stimulate high turnout among young adults leave a 'footprint' of low turnout in the age structure of the electorate as many individuals who were new at those elections fail to vote at subsequent elections. Elections that stimulate high turnout leave a high turnout footprint. So a country's turnout history provides a baseline for current turnout that is largely set, except for young adults. This baseline shifts as older generations leave the electorate and as changes in political and institutional circumstances affect the turnout of new generations. Among the changes that have affected turnout in recent years, the lowering of the voting age in most established democracies has been particularly important in creating a low turnout footprint that has grown with each election.

The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process—since it can recover structurally. Rather, the intestinal mucosa manifests a vast hypertrophic response resulting in the formation of large plateaus formed from partially reduced villi and their amalgamation with the now increased height and width of the inter‐villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat‐topped villi which continues to encourage both the continued use of irrelevant “atrophy” terminologies and a marked failure to perceive what random sections through mosaic plateaus actually look like. While reviewing the extensive 40+ year literature on mucosal analysis, we extracted data on intraepithelial lymphocytes (IEL) counts from 607 biopsies, and applied receiver‐operating characteristic (ROC)‐curve analysis. From that perspective, it appears that counting IEL/100 enterocyte nuclei in routine haematoxylin and eosin (H&E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut‐off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC‐curve analysis also revealed the somewhat lesser accuracies of either CD3+ or γδ+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten‐induced mucosal pathologies and how they could be optimally interpreted, as well as in promoting the ideal manner for physicians and pathologists to interact in interpreting intestinal mucosae submitted for analysis. Future trends should incorporate 3‐D printing and computerised modelling in order to exemplify the subtle micro‐anatomical features associated with the crypt‐villus interzone. The latter needs precise delineation with use of mRNA in‐section assays for brush border enzymes such as alkaline phosphate and esterase. Other additional approaches are needed to facilitate recognition and interpretation of the features of this important inter‐zone, such as wells, basins and hypertrophic alterations in the size of inter‐villous ridges. The 3‐D computerised models could considerably expand our understandings of the microvasculature and its changes—in relation both to crypt hypertrophy, in addition to the partial attrition and subsequent regrowth of villi from the inter‐villous ridges during the flattening and recovery processes, respectively.

The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analog of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN/GPi DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR<0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS. ► First report to set up a fMRI group analysis method for pigs ► STN vs EN/GPi stimulation show common sensorimotor network activation. ► PCA data also show that each target activates a distinctive neural network. ► Swine model may be a useful platform for global neuromodulatory DBS studies.

[...]gluten-sensitivity' arises by virtue of that primary, universally-agreed interaction: that is its definition, its antithesis being 'tolerized' (non-gluten-sensitised) through suppressive intestinal immune process. [...]we move conceptually into different territory regarding relationships between clinically based and pathologically based definitions.

Deep brain stimulation (DBS), a surgical technique to treat certain neurologic and psychiatric conditions, relies on pre-determined stimulation parameters in an open-loop configuration. The major advancement in DBS devices is a closed-loop system that uses neurophysiologic feedback to dynamically adjust stimulation frequency and amplitude. Stimulation-driven neurochemical release can be measured by fast-scan cyclic voltammetry (FSCV), but existing FSCV electrodes rely on carbon fiber, which degrades quickly during use and is therefore unsuitable for chronic neurochemical recording. To address this issue, we developed durable, synthetic boron-doped diamond-based electrodes capable of measuring neurochemical release in humans. Compared to carbon fiber electrodes, they were more than two orders-of-magnitude more physically-robust and demonstrated longevity in vitro without deterioration. Applied for the first time in humans, diamond electrode recordings from thalamic targets in patients (n = 4) undergoing DBS for tremor produced signals consistent with adenosine release at a sensitivity comparable to carbon fiber electrodes. (Clinical trials # NCT01705301).

Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

ObjectivesCounting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.DesignThe study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.ResultsThe mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.ConclusionOur ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.