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Abnormal alpha‐synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK‐565 probe was characterized by means of recombinant fibrils and brains from 10‐ to 11‐month‐old M83 mice. Concurrent wide‐field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x‐ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK‐565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post‐mortem brain slices from patients with PD and M83 mice. Administration of THK‐565 in M83 mice showed higher cerebral retention at 20 and 40 min post‐intravenous injection by wide‐field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK‐565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo. [ABSTRACT FROM AUTHOR]

In this article, we discuss Greek and Roman conceptions of liberty. The supposedly 'neo-Roman' view of liberty as non-domination is really derived from negative Greek models, we argue, while Roman authors devised an alternative understanding of liberty that rested on the equality of legal rights. In this 'paleo-Roman' model, as long as the law was the same for all, you were free; whether or not you participated in making the law was not a constitutive feature of liberty. In essence, this Roman theory was a theory of freedom as the rule of law and the guarantee of equal rights, especially due process rights. For this Roman concept of 'legal liberty,' as we call it, political participation was neither necessary nor sufficient. Theorized by Cicero and historicized by Livy, the Roman understanding of freedom flourished in early-modern times, proving important to paradigmatic republican authors such as Machiavelli and Rousseau as well as to Hobbes, whose work we discuss as a helpful point of comparison. [ABSTRACT FROM AUTHOR]

A feasible, inexpensive, rapid, and easy-to-use method to measure vestibular vertical movement perception is needed to assess the sacculus-mediated low-frequency otolith function of dizzy patients. To evaluate the feasibility of reaction time assessment in response to vertical motion induced by an elevator in healthy young individuals. We recorded linear acceleration/deceleration reaction times (LA-RT/LD-RT) of 20 healthy (13 female) subjects (mean age: 22 years ± 1 SD) as a measure of vertical vestibular motion perception. LA-RT/LD-RT were defined as the time elapsed from the start of elevator acceleration or deceleration to the time at which subjects in a sitting position indicated perceiving a change in velocity by pushing a button with their thumb. The light reaction time was measured as a reference. All 20 subjects tolerated the assessment with repeated elevator rides and reported no adverse events. Over all experiments, one upward and four downward rides had to be excluded for technical reasons (2.5%). The fraction of premature button presses varied among the four conditions, possibly related to elevator vibration (upward rides: LA-RT-up 66%, LD-RT-up 0%; downward rides: LA-RT-down 12%, LD-RT-down 4%). Thus LD-RT-up yielded the most robust results. The reaction time to earth-vertical deceleration elicited by an elevator provides a consistent indicator of linear vestibular motion perception in healthy humans. The testing procedure is inexpensive and easy to use. Deceleration on upward rides yielded the most robust measurements. [ABSTRACT FROM AUTHOR]

Having long been considered the mainstay in eosinophilic esophagitis (EoE) diagnosis and pathogenesis, the role of eosinophils has been questioned and might be less important than previously thought. It is well known now that EoE is a Th2-mediated disease with many more disease features than eosinophilic infiltration. With more knowledge on EoE, less pronounced phenotypes or nuances of the disease have become apparent. In fact, EoE might be only the tip of the iceberg (and the most extreme phenotype) with several variant forms, at least three, lying on a disease spectrum. Although a common (food induced) pathogenesis has yet to be confirmed, gastroenterologists and allergologists should be aware of these new phenomena in order to further characterize these patients. In the following review, we discuss the pathogenesis of EoE, particularly those mechanisms beyond eosinophilic infiltration of the esophageal mucosa, non-eosinophilic inflammatory cell populations, the new disease entity EoE-like disease, variant forms of EoE, and the recently coined term mast cell esophagitis. [ABSTRACT FROM AUTHOR]

While patients with infectious origin tended to show complete clinical remission after adequate therapy, patients with neoplastic aetiology did not recover [[12]]. Neither the cerebral or spinal MRI, nor the CSF results indicated Multiple Sclerosis (MS) specific findings CSF findings. The prevalence among patients with Multiple Sclerosis (MS) has been estimated between 17 and 41% [[6]]. In addition, the patient suffered from a COVID-19 infection 2 months before onset of ocular symptoms (at time of incubation, the patient had her first COVID-vaccination with Spikevax© (Moderna) administered) and an adequately substituted hypothyroidism. [Extracted from the article]

Objective: Physicians are increasingly confronted with patients presenting with symptoms of esophageal dysfunction resembling eosinophilic esophagitis (EoE), but absence of significant esophageal eosinophilia. The purpose of this study was to characterize and classify this group of EoE variants. Design: Patients from six EoE‐centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm2 (<15/hpf) in esophageal biopsies and absence of gastro‐esophageal reflux disease (GERD) were included. Clinical, endoscopic, (immuno)‐histological, and molecular features were determined and compared with EoE, GERD, and healthy controls. Results: We included 69 patients with EoE variants. Endoscopic abnormalities were found in 53.6%. We identified three histological subtypes: EoE‐like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non‐specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed—in contrast to EoE—no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE‐typical Th2‐response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, we found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE‐like (characterized by eotaxin‐3 expression), non‐specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression). Conclusion: All EoE variants are clinically and histologically active conditions despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype. [ABSTRACT FROM AUTHOR]

A brain stem/cerebellar neural integrator enables stable eccentric gaze. Cerebellar loss-of-function can cause an inability to maintain gaze eccentrically (gaze-evoked nystagmus). Moreover, after returning gaze to straight ahead, the eyes may drift toward the prior eye position (rebound nystagmus). Typically, gaze-evoked nystagmus decays during continuously held eccentric gaze. We hypothesized this adaptive behavior to be prerequisite for rebound nystagmus and thus predicted a correlation between the velocity decay of gaze-evoked nystagmus and the initial velocity of rebound nystagmus. Using video-oculography, eye position was measured in 11 patients with cerebellar degeneration at nine horizontal gaze angles (15° nasal to 25° temporal) before (baseline), during, and after attempted eccentric gaze at ± 30° for 20 s. We determined the decrease of slow-phase velocity at eccentric gaze and the slow-phase velocity of the subsequent rebound nystagmus relative to the baseline. During sustained eccentric gaze, eye drift velocity of gaze-evoked nystagmus decreased by 2.40 ± 1.47°/s. Thereafter, a uniform change of initial eye drift velocity relative to the baseline (2.40 ± 1.35°/s) occurred at all gaze eccentricities. The velocity decrease during eccentric gaze and the subsequent uniform change of eye drift were highly correlated (R2 = 0.80, p < 0.001, slope = 1.09). Rebound nystagmus can be explained as gaze-evoked nystagmus relative to a set point (position with least eye drift) away from straight-ahead eye position. To improve detection at the bedside, we suggest testing rebound nystagmus not at straight-ahead eye position but at an eccentric position opposite of prior eccentric gaze (e.g., 10°), ideally using quantitative video-oculography to facilitate diagnosis of cerebellar loss-of-function. [ABSTRACT FROM AUTHOR]

Why did the French government delay its endorsement of the Hoover Moratorium in the summer of 1931? Key policymakers were fully aware that their stance would exacerbate the German financial crisis, which ultimately dragged the European economy into the abyss. Most historical accounts identify the plan for an Austro-German customs union, which became known publicly in March 1931, as a major cause for the French 'non'. We suggest a different chronology by showing that the French government was reluctant to help Germany as early as the fall of 1930 when, in the wake of the Nazi victory in the Reichstag elections, a currency crisis threatened to ruin the German monetary and financial system and bring down the government. We also argue that the reason for this French reluctance to extend financial help to Germany was the traumatic experience resulting from the evacuation of the Rhineland in June 1930. This chauvinistic outburst in Germany not only frightened the French public, but also made it clear to French politicians how the lack of military cooperation with the Anglo-Saxon powers had made France highly vulnerable on its Eastern front. After June 1930 a financial bargain with Germany became unrealistic, due to domestic opposition. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions EsoCap is a thin mucoadhesive film designed to target the oesophageal mucosa. The device loaded with mometasone furoate (ESO‐101) is under investigation for the treatment of eosinophilic oesophagitis (EoE).To evaluate the efficacy, safety and tolerability of ESO‐101 in patients with active EoE.We conducted a randomised, placebo‐controlled, phase 2, proof‐of‐concept trial at 14 European sites in adults with EoE. Participants received placebo, uncoated EsoCap (n = 15), or EsoCap loaded with 800 μg of mometasone furoate (n = 28) once daily during 28 days. The primary outcome was the absolute change in the peak eosinophil count; secondary outcomes were histologic, clinical and endoscopic measures.Treatment with ESO‐101 resulted in reduction (mean ± SD) of 49.1 ± 88.4 eosinophils/high‐power field from baseline, compared with 6.6 ± 65.1 with placebo (p = 0.03). With ESO‐101, 48% and 44% of patients achieved < 15 and < 6 eosinophils/high‐power field, respectively; these were 0% with placebo. EoE Endoscopic Reference Score reduced significantly in patients treated with ESO‐101. In contrast, dysphagia and odynophagia severity decreased similarly in both groups. There were no serious treatment‐emergent adverse events. Mean serum cortisol did not change significantly throughout the trial. Notably, no oropharyngeal or oesophageal candidiasis was documented. The device was well tolerated.ESO‐101 was superior to placebo in reducing oesophageal eosinophilia. The device was safe and well tolerated in adults with EoE, supporting the continued development of ESO‐101 for the treatment of EoE (Trials.gov No.: NCT04849390; Eu‐CT No.: 2020–000082‐16). [ABSTRACT FROM AUTHOR]

The article focuses on crucial implication of this conception of the rule of law and doctrine of legal sources. It mentions original account of the source of natural law, which entailed an original account of its obligatory nature and when it comes to the epistemology of natural law. It also mentions adduce human sociability to solve the problem of how large and stable societies are possible and natural rights appeal to prudential reasons.

Despite dramatic advances in our understanding of the pathogenesis and course of disease in the relatively short timeframe since the discovery and first description of eosinophilic esophagitis (EoE) less than three decades ago, many open questions remain to be elucidated. For instance, we will need to better characterize atypical clinical presentations of EoE and other forms of esophageal inflammatory conditions with often similar clinical presentations, nut fulfilling current diagnostic criteria for EoE and to determine their significance and interrelationship with genuine EoE. In addition, the interrelationship of EoE with other immune-mediated diseases remains to be clarified. Hopefully, a closer look at the role of environmental factors and their interaction with genetic susceptibility often in context of atopic predisposition may enable identifying the candidate substances/agents/allergens and potentially earlier (childhood) events to trigger the condition. It appears plausible to assume that in the end—comparable to current concepts in other immune-mediated chronic diseases, such as for instance inflammatory bowel disease or asthma bronchiale—we will not be rewarded with the identification of a "one-and-only" underlying pathogenetic trigger factor, with causal responsibility for the disease in each and every EoE patient. Rather, the relative contribution and importance of intrinsic susceptibility, i.e., patient-driven factors (genetics, aberrant immune response) and external trigger factors, such as food (or aero-) allergens as well as early childhood events (e.g., infection and exposure to antibiotics and other drugs) may substantially differ among given individuals with EoE. Accordingly, selection and treatment duration of medical therapy, success rates and extent of required restriction in dietary treatment, and the need for mechanical treatment to address strictures and stenosis require an individualized approach, tailored to each patient. With the advances of emerging treatment options, the importance of such an individualized and patient-centered assessment will increase even further. [ABSTRACT FROM AUTHOR]

Lysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated. [ABSTRACT FROM AUTHOR]

Downbeat nystagmus (DBN) observed in head-hanging positions, may be of central or peripheral origin. Central DBN in head-hanging positions is mostly due to a disorder of the vestibulo-cerebellum, whereas peripheral DBN is usually attributed to canalolithiasis of an anterior semicircular canal. Here, we describe an atypical case of a patient who, after head trauma, experienced severe and stereotypic vertigo attacks after being placed in various head-hanging positions. Vertigo lasted 10–15 s and was always associated with a robust DBN. The provocation of transient vertigo and DBN, which both showed no decrease upon repetition of maneuvers, depended on the yaw orientation relative to the trunk and the angle of backward pitch. On a motorized, multi-axis turntable, we identified the two-dimensional Helmholtz coordinates of head positions at which vertigo and DBN occurred (y-axis: horizontal, space-fixed; z-axis: vertical, and head-fixed; x-axis: torsional, head-fixed, and unchanged). This two-dimensional area of DBN-associated head positions did not change when whole-body rotations took different paths (e.g., by forwarding pitch) or were executed with different velocities. Moreover, the intensity of DBN was also independent of whole-body rotation paths and velocities. So far, therapeutic approaches with repeated liberation maneuvers and cranial vibrations were not successful. We speculate that vertigo and DBN in this patient are due to macular damage, possibly an unstable otolithic membrane that, in specific orientations relative to gravity, slips into a position causing paroxysmal stimulation or inhibition of macular hair cells. [ABSTRACT FROM AUTHOR]

Zebrafish is an established animal model for the reproduction and study of neurobiological pathogenesis of human neurological conditions. The 'startle reflex' in zebrafish larvae is an evolutionarily preserved defence response, manifesting as a quick body-bend in reaction to sudden sensory stimuli. Changes in startle reflex habituation characterise several neuropsychiatric disorders and hence represent an informative index of neurophysiological health. This study aimed at establishing a simple and reliable experimental protocol for the quantification of startle reflex response and habituation. The fish were stimulated with 20 repeated pulses of specific vibratory frequency, acoustic intensity/power, light-intensity and interstimulus-interval, in three separate studies. The cumulative distance travelled, namely the sum of the distance travelled (mm) during all 20 stimuli, was computed as a group-level description for all the experimental conditions in each study. Additionally, by the use of bootstrapping, the data was fitted to a model of habituation with a first-order exponential representing the decay of locomotor distance travelled over repeated stimulation. Our results suggest that startle habituation is a stereotypic first-order process with a decay constant ranging from 1 to 2 stimuli. Habituation memory lasts no more than 5 min, as manifested by the locomotor activity recovering to baseline levels. We further observed significant effects of vibratory frequency, acoustic intensity/power and interstimulus-interval on the amplitude, offset, decay constant and cumulative distance travelled. Instead, the intensity of the flashed light did not contribute to significant behavioural variations. The findings provide novel insights as to the influence of different stimuli parameters on the startle reflex habituation and constitute a helpful reference framework for further investigation. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, defined I clinically i by the presence of symptoms of esophageal dysfunction and I histologically i by an eosinophil predominant infiltration in the esophageal mucosa.[1] Due to its chronicity, EoE requires both short-term and long-term treatments.[2] Therapeutic goals are (a) to control clinical activity (resolution of symptoms); and (b) to control biological activity to avoid stricture formation and bolus impaction, a potentially life-threatening event. Treatment of EoE consists of the 3 D's: Drugs, Diet, and Dilation.[2] Dilation should be seen as an add-on treatment since it does not affect underlying inflammation (Figure). Most importantly, any therapy should be maintained as cessation of treatment results in an EoE relapse within only few months.[11] If histological response is not achieved, we recommend switching from PPI ("PPI non-response") or elimination diet to STC. [Extracted from the article]

Herein, we describe a series of patients with biopsy-proven eosinophilic esophagitis who identify characteristic symptoms of FIRE following a specific food ingestion. However, the strong association with atopy, the rapid onset of symptoms, and symptoms distinct from dysphagia suggest a local possibly immunologic factor causing an immediate esophageal mucosal response. Recently, a phenomenon with a different symptom referred to as FIRE (food-induced immediate response in the esophagus) has been described in adults with EoE.2 Patients with eosinophilic esophagitis describe these esophageal symptoms as clearly distinct from dysphagia. [Extracted from the article]

Martti Koskenniemi is correct to view Hugo Grotius as a thinker committed to the rule of law. But there is a crucial difference between Grotius' and Koskenniemi's respective concepts of the rule of law. Grotius' concept of the rule of law is normative and requires a moral cognitivist outlook. Koskenniemi, on the other hand, holds a sociological concept of the rule of law. Koskenniemi is correct that, for the rule of law to find its 'normative voice', Grotius may well be of help. For this normative voice to make itself heard, however, it will have to rise above the sceptical reduction of the rule of law to normatively inert sociological facts. [ABSTRACT FROM AUTHOR]

• Cervical and ocular vestibular evoked myogenic potentials (cVEMPs, oVEMPs) in almost all cases of vestibular involvement can help both in diagnosis and in prognosis. • More research is needed to understand the applications of both c- and oVEMPs, especially the latter. • A significant percentage of published data have neglected one or more vital VEMP parameters. Cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs respectively) are now used by an increasing number of laboratories to evaluate otolith inner ear function and their pathways through the central nervous system. However, the literature is incomplete or unclear as to what information both c- and oVEMPs can add beyond what a good clinical examination can provide, and what other paramedical tests can provide also, and the present review aims to clarify what is known so far. The following review will describe what is known with regards to both c- and oVEMPs and their use. MEDLINE (accessed by PubMed, years 1994–2018) was searched with the following string: ("vestibular evoked myogenic potentials" [all fields]). Only articles published in English were evaluated. Both c- and oVEMPs are useful not only for confirming the presence of superior semicircular canal dehiscence (SSCD), but also for confirming the presence of acoustic neuromas when MRI is not available, bilateral vestibulopathies, inferior vestibular neuritis and vestibular dysfunction in inherited neuropathies. Further work is required, especially with respect to oVEMPs. The usefulness of both c- and oVEMPs goes beyond the confirmation of SSCDs, and is useful in many clinical cases. [ABSTRACT FROM AUTHOR]

The use of standard HVac disconnectors for bus-transfer switching in future HVdc gas-insulated switchgear (GIS) has been demonstrated successfully in past research through simulation and testing. Prolonged arcing times through reignitions caused by high frequency harmonics as well as the proposed extension of GIS disconnector switching cases, however, create an HVdc-specific demand for more advanced disconnector concepts capable of withstanding higher switching stresses and increased recovery voltages. A spring-loaded disconnector designed for use in HVac mixed technology switchgear was found to shorten the time to first current zero through an accelerated increase of the arcing voltage compared to standard disconnectors. Despite its increased switching performance, the reignition characteristics of this fast-acting disconnector were found to largely follow the previously established extinction criterion, which enables further simulation of similar technologies for HVdc applications. To additionally combat the issue of contamination of HVdc GIS by electrode erosion products, a prototype disconnector was improved using permanent magnets to evoke arc rotation. Erosion tests in air have shown an effective reduction of electrode erosion for long arcing times at currents typical for disconnector switching, whereas bus-transfer tests revealed promising enhancements of the reignition behavior. [ABSTRACT FROM AUTHOR]

When gas insulated switchgear (GIS) is operated at temperatures below the condensation temperature of the SF 6 used as the insulating medium, liquid droplets or puddles can form and influence the electric field distribution. For the surface conditions and electric field strengths and distributions relevant for GIS, the instability of liquid droplets represents the worst case. Finite element method calculations were carried out to model the interaction between the electric field and unstable liquid droplets, both for water (in air) and liquid SF 6. The model accurately reproduced experimental data available for water in the literature. The model was then used to assess how critical the presence of liquid SF6 droplets is for the dielectric performance of GIS. It was found that SF 6 droplets are much less critical than small (0.5 mm) metallic particles, the presence of which is assumed and taken into account in the design of GIS. Water droplets, on the other hand, can lead to high field enhancement and a corresponding reduction in the breakdown electric field strength. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) refers to a relatively new chronic inflammatory disease of the esophagus, which according to the current understanding underlies an immune-mediated pathogenesis driven by exposure to allergens. While several open questions remain regarding ethiopathogenesis as well as treatment options and their positioning, one thing has increasingly been recognized. The disease is on the rise and will increasingly be of importance in everyday's clinical practice, not only in expert physicians but also gastroenterologists with a broad clinical spectrum, allergologists and even general practitioners. The aim of this review is to provide a current overview on EoE treatment, including the rationale and endpoints of treatment in EoE, medical treatment options — providing the standard of current care, second-line options and outlook to emerging therapies — as well as dietary elimination approaches. [ABSTRACT FROM AUTHOR]

A common European Community driving licence was established in 1980. However, there are major differences among the countries as regards medical conditions that legally affect driving ability. This article discusses various assessment guidelines for dizzy patients. These range from a total absence of specified binding requirements in Finland or regulations open to clinical interpretation in Switzerland, to inappropriately strict regulations in Germany. We focus on requirements for patients with vestibular disorders in Germany which have been in force since 2014. These guidelines stipulate that for group 1 driving licence (private cars < 3.5 t, motorbikes): (1) patients with Menière’s disease (attacks without prodromes) must have had no attacks for 2 years before it is possible to drive again. (2) Patients with vestibular migraine without prodromes must not have had any attacks for 3 years. For a group 1 and group 2 driving licence (“professional driver”): (3) patients with bilateral vestibulopathy as a rule are considered to have a driving disability. Similarly, strict restrictions have been formulated for ocular motor disorders such as downbeat and upbeat nystagmus and for patients with functional (psychosomatic) forms of dizziness such as phobic postural vertigo. The authors represent a working group of the European Dizzynet focusing on the topic “fitness to drive with vertigo and balance disorders”. They agree that European guidelines must be revised and harmonized, for some are too strict and the required dizziness-free intervals are too long; others must be revised, for they are too lax. A common European standard is needed. [ABSTRACT FROM AUTHOR]

Background: In Norway, each municipality is responsible for providing first line emergency healthcare, and it is mandatory to have a primary care physician/general practitioner on call continuously. This mandate ensures that a physician can assist patients and ambulance personnel at the site of severe injuries or illnesses. The compulsory presence of the general practitioner at the scene could affect different parts of patient treatment, and it might save resources by obviating resources from secondary healthcare, like pre-hospital anaesthesiologists and other specialized resources. This systematic review aimed to examine how survival, time spent at the scene, the choice of transport destination, assessment of urgency, the number of admissions, and the number of cancellations of specialized pre-hospital resources were affected by the presence of a general practitioner at the scene of a suspected severe injury.Methods: We searched for published and planned systematic reviews and primary studies in the Cochrane Library, Medline, Embase, OpenGrey, GreyLit and trial registries. The search was completed in December 2017. Two individuals independently screened the references and assessed the eligibility of all potentially relevant studies.Results: The search for systematic reviews and primary studies identified 5981 articles. However, no studies met the pre-defined inclusion criteria.Conclusion: No studies met our inclusion criteria; consequently, it remains uncertain how the presence of a general practitioner at the injury scene might affect the selected outcomes. [ABSTRACT FROM AUTHOR]

The author discusses research published within the issue which investigated the effectiveness of dupilumab in treating eosinophilic esophagitis in adult and adolescent patients. Topics explored include the increasing prevalence of eosinophilic esophagitis in Western countries, the dupilumab and placebo dosage administered to patients in the study, and the concerns raised about the efficacy of the medication compared to swallowed topical glucocorticoids.

In order to accurately predict the performance of disconnectors conducting bus-transfer switching in gas insulated substations, the influencing factors of the switching process itself as well as the reignition characteristics need to be analyzed. For this, an LC-oscillating ac current source in combination with a nonstandardized full bus-transfer loop was built. Based on experiment data from a total of 347 reignitions and 570 extinctions, the reignition characteristic of the disconnector at current zero was investigated. Thereby, the derivation of a reignition criterion depending exclusively on the prediction of the instantaneous recovery voltage and the prospective arc voltage was possible. Using this criterion, time-dependent simulations of the bus-transfer process can be made to predict the performance of disconnectors for a wide variety of scenarios such as worst case bus-transfer current for varying circuit parameters and ratings. This minimizes the need for extensive testing during substation planning or disconnector development. [ABSTRACT FROM PUBLISHER]

Contemporary studies speculated that cerebellar network responsible for motion perception projects to the cerebral cortex via vestibulo-thalamus. Here, we sought for the physiological properties of vestibulo-thalamic pathway responsible for the motion perception. Healthy subjects and the patient with focal vestibulo-thalamic lacunar stroke spun a hand-held rheostat to approximate the value of perceived angular velocity during whole-body passive earth-vertical axis rotations in yaw plane. Vestibulo-ocular reflex was simultaneously measured with high-resolution search coils (paradigm 1). In primates, the vestibulo-thalamic projections remain medial and then dorsomedial to the subthalamus. Therefore, the paradigm 2 assessed the effects of high-frequency subthalamic nucleus electrical stimulation through the medial and caudal deep brain stimulation electrode in five subjects with Parkinson's disease. Paradigm 1 discovered directional mismatch of perceived rotation in a patient with vestibulo-thalamic lacune. There was no such mismatch in vestibulo-ocular reflex. Healthy subjects did not have such directional discrepancy of perceived motion. The results confirmed that perceived angular motion is relayed through the thalamus. Stimulation through medial and caudal-most electrode of subthalamic deep brain stimulator in paradigm 2 resulted in perception of rotational motion in the horizontal semicircular canal plane. One patient perceived riding a swing, a complex motion, possibly the combination of vertical canal and otolith-derived signals representing pitch and fore-aft motion, respectively. The results examined physiological properties of the vestibulo-thalamic pathway that passes in proximity to the subthalamic nucleus conducting pure semicircular canal signals and convergent signals from the semicircular canals and the otoliths. [ABSTRACT FROM AUTHOR]

In this Reply, I argue that pace Knud Haakonssen it is dubious that Adam Smith managed to 'blow up' Hugo Grotius's universalist system of natural jurisprudence. Rather, Smith emerges as a closet rationalist who put forward crypto-normative universalist claims himself and found that he could not in the end improve upon Grotius's system. Grotius was not seen by Smith as a 'casuist' tout court. I try to give an explanation for the tensions introduced into Smith's work by his incorporation of key aspects of Grotius's theory of justice. Furthermore, I try to clarify in what regard Grotius should be seen as a novel and original thinker. Lastly, I argue in favor of according ideas and arguments their own weight, against a facile contextualism that is always in danger of falling prey to the genealogical fallacy. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a rapidly emerging, chronic inflammatory, genetically impacted disease of the esophagus, defined clinically by symptoms of esophageal dysfunction and, pathologically, by an eosinophil-predominant tissue infiltration. However, in four EoE families, we have identified patients presenting with EoE-typical and corticosteroid-responsive symptoms, but without tissue eosinophilia. The aim of this study was to clinically and immunologically characterize these patients with EoE-like disease. Methods Five patients suffering from an EoE-like disease were evaluated with endoscopic, histologic, functional, and quantitative immunohistological examinations, and mRNA expression determination. Results The frequency of first-generation offspring of patients affected by EoE or EoE-like disease was 40%. Immunofluorescence analysis confirmed an almost complete absence of eosinophils in the esophageal tissues of patients with EoE-like disease, but revealed a considerable T-cell infiltration, comparable to EoE. In contrast to EoE, eotaxin-3 mRNA and protein were markedly reduced in EoE-like disease ( P < 0.05). The mRNA expression levels of three selected EoE genes ( eotaxin-3, MUC4, and CDH26) allowed to discriminate between EoE-like disease, EoE, and normal epithelium. Conclusions Patients suffering from 'EoE without eosinophilia' do not fulfill formally the diagnostic criteria for EoE. However, their clinical manifestation, immunohistology, and gene expression pattern, plus the fact that they bequeath EoE to their offspring, suggest a uniform underlying pathogenesis. Conventional EoE, with its prominent eosinophilia, therefore appears to be only one phenotype of a broader 'inflammatory dysphagia syndrome' spectrum. In this light, the role of the eosinophils, the definition of EoE, and its diagnostic criteria must likely be reconsidered. [ABSTRACT FROM AUTHOR]

There are now more than 3 billion Internet users on our planet. The connections afforded to all of those people, in theory, allow for an unprecedented amount of communication and public participation. The goal of this article is to examine how those potentials match up to actual patterns of participation. By focusing on Wikipedia, the world's largest and most used repository of user-generated content, we are able to gain important insights into the geographies of voice and participation. This article shows that the relative democratization of the Internet has not brought about a concurrent democratization of voice and participation. Despite the fact that it is widely used around the world, Wikipedia is characterized by highly uneven geographies of participation. The goal of highlighting these inequalities is not to suggest that they are insurmountable. Our regression analysis shows that the availability of broadband is a clear factor in the propensity of people to participate on Wikipedia. The relationship is not a linear one, though. As a country approaches levels of connectivity above about 450,000 broadband Internet connections, the ability of broadband access to positively affect participation keeps increasing. Complicating this issue is the fact that participation from the world's economic peripheries tends to focus on editing about the world's cores rather than their own local regions. These results ultimately point to an informational magnetism that is cast by the world's economic cores, virtuous and vicious cycles that make it difficult to reconfigure networks and hierarchies of knowledge production. [ABSTRACT FROM PUBLISHER]

Background Long-lasting food impactions requiring endoscopic bolus removal occur frequently in patients with eosinophilic esophagitis ( Eo E) and harbor a risk for severe esophageal injuries. We evaluated whether treatment with swallowed topical corticosteroids is able to reduce the risk of occurrence of this complication. Methods We analyzed data from the Swiss Eo E Cohort Study. Patients with yearly clinic visits, during which standardized assessment of symptoms, endoscopic, histologic, and laboratory findings was carried out, were included. Results A total of 206 patients (157 males) were analyzed. The median follow-up time was 5 years with a total of 703 visits (mean 3.41 visits/patient). During the follow-up period, 33 patients (16 % of the cohort) experienced 42 impactions requiring endoscopic bolus removal. We evaluated the following factors regarding the outcome 'bolus impaction' by univariate logistic regression modeling: swallowed topical corticosteroid therapy ( OR 0.503, 95%- CI 0.255-0.993, P = 0.048), presence of EoE symptoms ( OR 1.150, 95%- CI 0.4668-2.835, P = 0.761), esophageal stricture ( OR 2.832, 95%- CI 1.508-5.321, P = 0.001), peak eosinophil count >10 eosinophils/ HPF ( OR 0.724, 95%- CI 0.324-1.621, P = 0.433), blood eosinophilia ( OR 1.532, 95%- CI 0.569-4.118, P = 0.398), and esophageal dilation ( OR 1.852, 95%- CI 1.034-3.755, P = 0.017). In the multivariate model, the following factors were significantly associated with bolus impaction: swallowed topical corticosteroid therapy ( OR 0.411, 95%- CI 0.203-0.835, P = 0.014) and esophageal stricture ( OR 2.666, 95%- CI 1.259-5.645, P = 0.01). Increasing frequency of use of swallowed topical steroids was associated with a lower risk for bolus impactions. Conclusions Treatment of Eo E with swallowed topical corticosteroids significantly reduces the risk for long-lasting bolus impactions. [ABSTRACT FROM AUTHOR]

A concussion is a rare but potentially serious injury of football players. Thus, an immediate and valid diagnosis, estimate of severity and therapeutic management is required. To summarise the published information on management of concussion with respect to a safe return to play (RTP), a literature search was conducted. Current guidelines on concussion in sports and significant studies on concussion in football were analysed. After concussion, management and RTP decision should remain in the area of clinical judgement on an individualised basis according to the current international guidelines. If a concussion is suspected, the player should not be allowed to RTP the same day. The RTP programme should follow a gradual step-wise procedure. A concussed player should not RTP unless he/she is asymptomatic and the neurological and neuropsychological examinations are normal. Untimely RTP bears an increased risk of sustaining another more severe brain injury and repetitive brain injury of long-term sequelae. In football, the management of concussion should primarily follow the recommendations proposed by the Concussion in Sports Group. Information and education of players and their medical and coaching team help to protect the players’ health. Future studies on concussion should include validated and detailed information on RTP protocols. [ABSTRACT FROM AUTHOR]

The identification of a distinct syndrome, designated eosinophilic oesophagitis (EoE), with its own clinical and histopathological characteristics, was first described in the early 1990s. Meanwhile intense research has uncovered many molecular, immunological and clinical aspects of this chronic-inflammatory disorder. This article focuses exclusively on basic and clinical insights of EoE gathered during the last few years. Regarding aetiopathogenesis it has become clear that EoE is a food-triggered disease with milk and wheat as the dominant culprit food categories. However, it is still debated whether a disturbed mucosal integrity allowing allergens to cross the mucosal barrier, or changes in wheat and milk manufacturing might induce these inflammatory responses. Furthermore, basic science and clinical studies have accordingly confirmed that a chronic eosinophilic inflammation leads to a remodelling of the oesophagus with micro- and macro-morphological alterations, ending in a strictured oesophagus with impaired function. Fortunately, long-term therapeutic trials, using either topical corticosteroids or dietary allergen avoidance, have demonstrated that this sequela can be prevented or even reversed. This finding is of clinical relevance as it supports the initiation of a consistent anti-inflammatory therapy. Nevertheless, EoE is still an enigmatic disease and the long list of unanswered questions will certainly stimulate further research. [ABSTRACT FROM AUTHOR]

This review summarizes the most relevant articles from the field of neuro-ophthalmology published in the Journal of Neurology from January 2012 to July 2013. With the advent of video-oculography, several articles describe new applications for eye movement recordings as a diagnostic tool for a wide range of disorders. In myasthenia gravis, anti-Kv1.4 and anti-Lrp4 have been characterized as promising novel autoantibodies for the diagnosis of hitherto 'seronegative' myasthenia gravis. Several articles address new diagnostic and therapeutic approaches to neuromyelitis optica, which further sharpen its profile as a distinct entity. Additionally, 4-aminopyridine has become a standard therapeutic for patients with cerebellar downbeat nystagmus. Finally, revised diagnostic criteria have been proposed for chronic relapsing inflammatory optic neuropathy based on a careful literature review over the last decade. [ABSTRACT FROM AUTHOR]

We present a study that explores methodological steps towards (re)constructing collective narratives from the photo-taking behaviour of two groups (foreign tourists and inhabitants of Switzerland) by analysing spatial and temporal patterns in user-contributed, georeferenced photographs of Zurich, Switzerland. We reason that the photographers typically capture a scene or a moment because they want to remember or share it, thus these scenes or moments are meaningful to them. Various scholars suggest that the human experience (i.e. this meaningfulness) is what separates a place from the mathematical descriptions of space. While this notion is well known in larger geographic literature, it is under-explored in cartographic research. We respond to this research gap and reconstruct static and dynamic patterns of photo-taking and -sharing behaviour to assist in capturing the implicit meaning in the studied locations. These locations may be meaningful to only a certain group of people in certain moments; therefore, studying group differences in spatial and temporal photo-taking patterns will help building a collective and comparative story about the studied place. In our study, we focus on experiences of foreign versus domestic visitors, and in the process, we examine the potential (and feasibility) of georeferenced photographs for extracting such collective narratives using qualitative and quantitative visual analytical methods. [ABSTRACT FROM AUTHOR]

Stationary DC electric fields are determined by the resistivity distribution of the insulation materials. In the presence of interfaces between different insulation materials, charge accumulation at these boundary layers may have a significant influence on the electric field distribution and with it on the breakdown strength of the arrangement. In many previous works, surface charging of model spacers was investigated. However, the ion flow problem to properly account for the electric conduction in the gas has not yet been solved. The role of different ion sources and the behavior of the resulting ion currents in the gas phase on the charge accumulation process have to be investigated in more detail. In this paper, the transient charge accumulation process on a PTFE spacer surface with a focus on charges originating from the gas phase is investigated experimentally and by simulations. These charges are produced by natural radiation. The transition of the ohmic conduction regime in the gas to a saturated ion current with increasing voltage is analyzed. Furthermore, the importance of additional charge sources like partial discharges and field emission from the electrodes is highlighted. The experimental results indicate that additional charges are generated already at voltage levels significantly below the measured PD inception voltage. These charges originate from micro discharges on the electrodes and have to be taken into account when designing HVDC GIS applications. [ABSTRACT FROM AUTHOR]

Since symptoms and inflammatory activity are only modestly correlated [[4]], diagnosis and disease monitoring require a careful history and an upper endoscopy with structured tissue sampling and subsequent pathological examination of the specimens [[3]]. Eosinophilic esophagitis (EoE) is a hidden disease: Firstly, its concealed localization deep within the chest cavity confounds access; secondly, solid food dysphagia, the leading symptom of EoE, is often masked by adapted eating habits such as food modification and avoiding strategies, and finally, EoE is a chronic inflammatory disease with only minimal systemic manifestations. [Extracted from the article]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is often associated with atopic airway and skin diseases. More than 80% of Eo E patients are sensitized to aero- and/or food allergens. Immunoglobulin ( Ig) E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. Aim The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult Eo E patients. Methods Ig E in sera of 35 patients with active Eo E were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. Results Ig E sensitization to Candida albicans was found in 43% of Eo E patients. More than 80% of Eo E patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific Ig E to cross-reactive allergens. Among the latter, profilins were identified as most frequent Ig E cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult Eo E patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related ( PR) 10 and lipid transfer proteins ( LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. Conclusion Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult Eo E patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of Eo E. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells ( CRTH2) is a prostaglandin D2 ( PGD2) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory Eo E. Methods In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active Eo E, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 ( n = 14) or placebo ( n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. Results After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 ( P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. Conclusions An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated. [ABSTRACT FROM AUTHOR]

Large-scale integration of new renewables requires substantial increases of transmission capacity on existing transmission corridors. To limit land use, overhead transmission lines have been widely built as multicircuit lines. On these, changing one ac circuit to dc to increase transmission capacity leads to lines with hybrid ac/dc towers. Since practically no operational experience with such hybrid lines exists to date, questions such as superimposed ac and dc fields intensified by corona-generated space charges arise. In this paper, a method to simulate these ion-flow fields using the discontinuous Galerkin method is for the first time applied to hybrid towers. Ways to considerably reduce the computational effort of the problem are discussed. The results indicate that hybrid lines are feasible in reference to space-charge-related problems. Shielding the ground is possible at the expense of increased coupling between the ac and dc circuits. [ABSTRACT FROM AUTHOR]

Herein, we summarize articles in the field of neuro-otology published in the Journal of Neurology over the last year. Topics included acute and chronic vertigo as well as auditory and ocular motor disorders. Characteristic lesion locations in Pusher syndrome are reported and the usefulness of bedside ocular motor tests in vertebrobasilar stroke is revisited. Probing the vestibular system and its value in predicting the outcome in vegetative state is discussed. Several articles address new diagnostic and therapeutic approaches in different disorders associated with chronic vestibular, auditory or gait deficits. In a series of case reports, we focus on different eye movement disorders in the vertical plane, which are often difficult to assess. [ABSTRACT FROM AUTHOR]

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil-predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis ( Eo E) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that Eo E represents a T-helper ( Th)2-type inflammatory disease. Remodeling of the esophagus is a hallmark of Eo E, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single-nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the Eo E population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, Eo E seems to be primarily a food antigen-driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for Eo E include the 3 Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric Eo E are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between Eo E in adults and children. [ABSTRACT FROM AUTHOR]

Existing methods for land surface form characterisation often focus on relatively simple landform element classifications and do not evaluate results with large scale participant experiments. This piece of research takes a semantics-grounded approach to characterising the landform valley. Based on definitions three algorithms to characterise valleys in a fuzzy way are introduced. Comparison of the results to assessments regarding the degree of being in a valley gained from over 800 participants in a questionnaire survey yields significant amounts of explained variance (R2 = 0.35-0.37). Furthermore, accounting for very ambiguously perceived stimuli showing vast low places leads to markedly improved regressions (R2 = 0.45-0.49), weighting of the data with a measure of uncertainty in judgment even more so (R2 = 0.50-0.55). [ABSTRACT FROM AUTHOR]

At the same time as the modern idea of the state was taking shape, Hugo Grotius (1583-1645), Thomas Hobbes (1588-1679) and Samuel Pufendorf (1632-94) formulated three distinctive foundational approaches to international order and law beyond the state. They differed in their views of obligation in the state of nature (where ex hypothesi there was no state), in the extent to which they regarded these sovereign states as analogous to individuals in the state of nature, and in the effects they attributed to commerce as a driver of sociability and of norm-structured interactions not dependent on an overarching state. Each built on shared Roman and sixteenth-century foundations (section I). Section II argues: 1) that Grotius's natural law was not simply an anti-skeptical construction based on self-preservation (pace Richard Tuck), but continued a Roman legal tradition; 2) that Hobbes's account of natural law beyond the state was essentially prudential, not moral (pace Noel Malcolm); and 3) that commerce as a driver of social and moral order (Istvan Hont's interpretation of Pufendorf and Adam Smith) had a substantial and under-appreciated impact on international legal order. Each contributed to the thought of later writers (section III) such as Emer de Vattel (1714-67), David Hume (1711-76), and Adam Smith (1723-90), and eventually to the empirical legal methodologies of Jeremy Bentham (1748-1832) and Georg Friedrich von Martens (1756-1821). [ABSTRACT FROM AUTHOR]

The vestibular organs in the base of the skull provide important information about head orientation and motion in space. Previous studies have suggested that both angular velocity information from the semicircular canals and information about head orientation and translation from the otolith organs are centrally processed in an internal model of head motion, using the principles of optimal estimation. This concept has been successfully applied to model behavioral responses to classical vestibular motion paradigms. This study measured the dynamic of the vestibuloocular reflex during postrotatory tilt, tilt during the optokinetic afternystagmus, and off-vertical axis rotation. The influence of otolith signal on the VOR was systematically varied by using a series of tilt angles. We found that the time constants of responses varied almost identically as a function of gravity in these paradigms. We show that Bayesian modeling could predict the experimental results in an accurate and consistent manner. In contrast to other approaches, the Bayesian model also provides a plausible explanation of why these vestibulooculo motor responses occur as a consequence of an internal process of optimal motion estimation. [ABSTRACT FROM AUTHOR]