Anfallssemiologie und Anfallstestung in der EEG-Monitoring-Einheit

Zusammenfassung Die genaue Beobachtung und Testung der unterschiedlichen Symptome epileptischer Anfälle trägt entscheidend zur Identifikation der symptomatogenen Zone bei. Diese Informationen sind insbesondere für die prächirurgische Epilepsiediagnostik relevant. Um Anfallssymptome möglichst detailliert zu erfassen, ist eine Testung während der Anfallsaufzeichnung in der EEG-Monitoring-Einheit erforderlich. Eine adäquate Anfallstestung setzt wiederum die Kenntnis der neurobiologischen Grundlagen der unterschiedlichen Anfallssymptome voraus. Der vorliegende Artikel soll eine Übersicht über typische Anfallssemiologien, die Entstehung ihrer Symptome und ihre Testung geben und als Leitfaden insbesondere für Mitarbeiter dienen, die neu in einer EEG-Monitoring-Einheit eingearbeitet werden

Probing the relevance of the hippocampus for conflict-induced memory improvement

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction

Efficacy, Retention, and Tolerability of Brivaracetam in Patients With Epileptic Encephalopathies: A Multicenter Cohort Study From Germany

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Bioluminescence resonance energy transfer (BRET) for the study of mineralocorticoid receptor dimerization

Das Mineralokortikoid Aldosteron ist ein wichtiger Regulator der Salz- und Wasserhomöostase und damit auch des Blutdrucks. Seine physiologische Wirkung entfaltet es über den Mineralokortikoidrezeptor (MR), indem es zu einer Homodimerisierung bzw. Heterodimerisierung mit dem Glukokortikoidrezeptor führt. Zudem sind die pathophysiologischen Wirkungen des Aldosterons beispielsweise auf das Herz-Kreislauf-System in den Focus gerückt, welche zumindest teilweise auch vom MR abhängig sind. Zur weiteren Charakterisierung dieser Signalwege sollen Interaktionen des MR mit möglichen Zielproteinen untersucht werden. Biolumineszenz Resonanz Energietransfer (BRET) ist eine Methode zur Untersuchung von Proteininteraktionen. Um ein BRET-System für den MR zu erstellen, wurde der MR an eine Renilla Luciferase (Rluc) einerseits und das enhanced yellow fluorescent protein (EYFP) andererseits gekoppelt. Beide Fusionsproteine wurden auf ihre Funktionalität und Interaktion hin überprüft. Befinden sich die Fusionsproteine in räumlicher Nähe, regt das von der Luciferase emittierte Licht das fluoreszierende Protein an. Das aus Fluoreszenz und Lumineszenz berechnete BRET-Signal steigt und weist damit auf eine Proteininteraktion hin. Ansätze ohne fluoreszierenden Akzeptor korrigieren unspezifische Signaländerungen. Wir untersuchten den Effekt von Aldosteron und dem Aldosteronantagonisten Spironolacton sowie von Geldanamycin, das eine Dissoziation des MR von den Hitzeschockproteinen im Zytoplasma bewirkt. Aldosteron führte zu einer Steigerung des BRET-Signals, was die bereits bekannte Interaktion der Fusionsrezeptoren auch im BRET-System bestätigt. Geldanamycin bewirkte ebenfalls eine Signalsteigerung. Die gleichzeitige Gabe der beiden Substanzen sowie die Gabe von Spironolacton bewirkte keine Veränderung des BRET-Signals. Als Negativkontrolle verwendeten wir ein System mit an EYFP gekoppeltem MR und ungekoppelter Luciferase, also ohne Interaktionspartner für den EYFP-MR. Keine der oben genannten Substanzen führte hier zu einer Änderung des BRET-Signals. Das BRET-System kann damit die Grundlage für die Untersuchung der Interaktionen des MR mit weiteren Zielproteinen darstellen.The mineralocorticoid aldosterone plays an important role in salt and water homeostasis and blood pressure regulation. Physiologically, its homodimers or heterodimers with the glucocorticoid receptor act via the mineralocorticoid receptor (MR). Recently, the pathophysiological actions of aldosterone, e.g. on the cardiovascular system, have gained attention. These actions are at least in part dependent on the mineralocorticoid receptor. To characterize their signalling pathways, the interactions between the MR and possible target proteins are to be examined. Protein-protein interactions can be observed using bioluminescence resonance energy transfer (BRET). To establish a BRET assay for the MR, the receptor was genetically linked to a Renilla luciferase (Rluc) as one interaction partner and to an enhanced yellow fluorescent protein (EYFP) as a second one. Both fusion proteins were tested for their functionality and interaction. The two fusion proteins being at a close distance, the luciferase emission will excite the fluorescent protein. This results in an increase in BRET signal, thus indicating a protein-protein interaction. Samples without a fluorescent acceptor correct for non-specific signal alterations. We examined the effect of aldosterone, the antagonist spironolactone and of geldanamycine, which induces a dissociation of the MR and its heat shock proteins. Aldosterone induced an increase in BRET signal, thereby confirming the known interaction of the two fusion proteins in our BRET assay. Geldanamycine also caused an increase in BRET signal. Spironolactone as well as the simultaneous administration of aldosterone and geldanamycine did not provoke a change in BRET signal. As a negative control, we used samples containing an EYFP-MR fusion protein and an un-linked luciferase, i.e. samples lacking an interacting partner to the EYFP-MR. None of the above named substances resulted in a change in BRET signal. Thus, our BRET assay can be used to further study MR protein interactions

Anfallssemiologie und Anfallstestung in der EEG-Monitoring-Einheit

<jats:title>Zusammenfassung</jats:title><jats:p>Die genaue Beobachtung und Testung der unterschiedlichen Symptome epileptischer Anfälle trägt entscheidend zur Identifikation der symptomatogenen Zone bei. Diese Informationen sind insbesondere für die prächirurgische Epilepsiediagnostik relevant. Um Anfallssymptome möglichst detailliert zu erfassen, ist eine Testung während der Anfallsaufzeichnung in der EEG-Monitoring-Einheit erforderlich. Eine adäquate Anfallstestung setzt wiederum die Kenntnis der neurobiologischen Grundlagen der unterschiedlichen Anfallssymptome voraus. Der vorliegende Artikel soll eine Übersicht über typische Anfallssemiologien, die Entstehung ihrer Symptome und ihre Testung geben und als Leitfaden insbesondere für Mitarbeiter dienen, die neu in einer EEG-Monitoring-Einheit eingearbeitet werden.</jats:p&gt

Nuclear Shuttling Precedes Dimerization in Mineralocorticoid Receptor Signaling

SummaryThe mineralocorticoid receptor (MR), a member of the steroid receptor superfamily, regulates water-electrolyte balance and mediates pathophysiological effects in the renocardiovascular system. Previously, it was assumed that after binding aldosterone, the MR dissociates from HSP90, forms homodimers, and then translocates into the nucleus where it acts as a transcription factor (Guiochon-Mantel et al., 1989; Robertson et al., 1993; Savory et al., 2001). We found that, during aldosterone-induced nuclear translocation, MR is bound to HSP90 both in the cytosol and the nucleus. Homodimerization measured by eBRET and FRET takes place when the MR is already predominantly nuclear. In vitro binding of MR to DNA was independent of ligand but could be partially inhibited by geldanamycin. Overall, here we provide insights into classical MR signaling necessary for elucidating the mechanisms of pathophysiological MR effects and MR specificity