Progressive Splenomegalie und Makrozytose bei KCa3.1-defizienten Mäusen: Die physiologische Bedeutung des Gardos-Kanals im Erythrozyten

Der Gardos-Kanal (KCa3.1) vermittelt den Ca2+-abhängigen Ausstrom von K+ und Cl- (den Gardos-Effekt) im Erythrozyten. Hierdurch kommt es zu einer Hyperpolarisation der Zellmembran und einem osmotisch bedingten Schrumpfen der Zelle. Diesem Ca2+-aktivierten K+-Kanal wird daher eine entscheidende Rolle für die physiologische Volumenregulation in zirkulierenden Erythrozyten, sowie auch für Krankheiten mit einer pathologischen Volumenregulation zugeschrieben. Insbesondere in der Pathogenese der Sichelzellanämie nimmt der Gardos-Kanal eine zentrale Stellung ein, wodurch diesem Kanal ein besonderes Interesse zuteil wird. Hochpotente, selektive Gardos-Kanal-Inhibitoren, wie beispielsweise Senicapoc, werden aktuell in der Therapie der Sichelzellanämie evaluiert. Während die pathophysiologische Bedeutsamkeit des Gardos-Kanals in der Sichelzellanämie und anderen Erkrankungen intensiv untersucht wurde, ist die tatsächliche funktionelle Relevanz von KCa3.1 sowohl für die physiologische Volumenregulation als auch für die Mechanismen der Eryptose (in Anlehnung an die Apoptose kernhaltiger Zellen) unklar. Auch wurden die Folgen einer genetischen Störung der Expression bis dato nicht detailliert untersucht. Die vorliegende Studie erlaubt die Einordung der physiologischen Rolle. Bei einer Störung der genetischen Expression von KCa3.1 in Mäusen entwickeln diese Tiere eine progressive, moderate Splenomegalie und eine milde Makrozytose. Die Erythrozyten dieser Knock-out Mäuse weisen eine erhöhte Fragilität bei hypoosmotischem Stress im Sinne einer gestörten Volumenregulation und eine verminderte Deformierbarkeit bei der Filtration durch kleine Poren auf. Diese funktionellen Defekte führen zu einer erhöhten Sequestration in der Milz, begleitet von einer erhöhten Eisenablagerung, die hierauf mit einer Arbeitshypertrophie in Form einer stetig zunehmenden Splenomegalie reagiert. Weiterhin konnte mit dieser Studie gezeigt werden, dass der Gardos-Kanal eine zentrale Stellung in der physiologischen Volumenregulation im Erythrozyten einnimmt, die bei einem Ausfall nicht durch andere Systeme kompensiert werden kann. Anders als von anderen Autoren postuliert, konnte keine maßgebliche Rolle von KCa3.1 für die Eryptose nachgewiesen werden. Dabei stellt die vorliegende Studie die erste in vivo Studie zu diesem Themenkomplex dar

Fermi-surface collapse and dynamical scaling near a quantum critical point

Quantum criticality arises when a macroscopic phase of matter undergoes a continuous transformation at zero temperature. While the collective fluctuations at quantum-critical points are being increasingly recognized as playing an important role in a wide range of quantum materials, the nature of the underlying quantum-critical excitations remains poorly understood. Here we report in-depth measurements of the Hall effect in the heavy-fermion metal YbRh2Si2, a prototypical system for quantum criticality. We isolate a rapid crossover of the isothermal Hall coefficient clearly connected to the quantum-critical point from a smooth background contribution; the latter exists away from the quantum-critical point and is detectable through our studies only over a wide range of magnetic field. Importantly, the width of the critical crossover is proportional to temperature, which violates the predictions of conventional theory and is instead consistent with an energy over temperature, E/T, scaling of the quantum-critical single-electron fluctuation spectrum. Our results provide evidence that the quantum-dynamical scaling and a critical Kondo breakdown simultaneously operate in the same material. Correspondingly, we infer that macroscopic scale-invariant fluctuations emerge from the microscopic many-body excitations associated with a collapsing Fermi-surface. This insight is expected to be relevant to the unconventional finite-temperature behavior in a broad range of strongly correlated quantum systems.Comment: 5 pages, plus supporting materia

Predicția efectului stimulării cerebrale profunde asupra înghețării mersului la pacienții cu boala Parkinson

Department of Neurology no. 1, Nicolae Testemitanu SUMPhBackground. The response of freezing of gait (FOG) to deep brain stimulation of the subthalamic nucleus (STN-DBS) is controversial and depends on many poorly controlled factors. Objective of the study. A clinical predictor for the individual patient is needed to counsel the patient regarding this symptom. Material and Methods. A cohort of 124 patients undergoing STN-DBS was evaluated based on the video-documented Levodopa test at baseline in the OFF- and ON-drug condition and postoperatively in the best condition (ON-drug/ON-stim) and the worst condition (OFF-drug/ON-stim). We compared the freezing item of the Unified Parkinson's disease rating scale (#14), the UPDRS III total score, and FOG Severity Index. Results. We found ‘FOG during the turning task’ to be the best predictor with an ROC-value of 0.857 compared to 0.603 for the UPDRS Item 14 and 0.583 for the total UPDRS III. An improvement of 1 or 2 grades of the turning item during the preoperative levodopa test predicts an improvement during the worst condition postoperatively of 1 grade or more with an 80% probability. Conclusion. This FOG prediction test is simple and clinically useful. The test needs to be studied in a prospective study.Introducere. Răspunsul fenomenului de înghețare al mersului la stimularea cerebrală profundă al nucleului subtalamic (STN-DBS) este controversat și depinde de mulți factori slab controlați. Scopul lucrării. Este necesar un predictor clinic pentru fiecare pacient pentru a-l sfătui cu privire la acest simptom. Material și Metode. Un eșantion de 124 de pacienți supuși STN-DBS au fost evaluați în baza testului levodopa documentat video la baseline în starea OFF și ON medicație și postoperator în condițiile ON-med/ON-stim și OFF-med/ ON-stim. În ceea ce privește valoarea predictivă, am comparat itemul de înghețare a mersului al scalei de evaluare a bolii Parkinson unificate (UPDRS #14), scorul motor UPDRS. Rezultate. Am constatat, că evaluarea înghețării mersului la întoarcerea la 1800 în timpul mersului este cel mai eficient predictor cu o valoare ROC de 0,857, comparativ cu 0,603 pentru itemul 14 al UPDRS și 0,583 pentru scorul UPDRS III. O îmbunătățire cu 1 sau 2 grade a scorului de întoarcere în timpul testului preoperator de levodopa prezice o îmbunătățire în cea mai proastă stare postoperatorie de 1 grad sau mai mult cu o probabilitate de 80%. Concluzii. Acest test de predicție este simplu și util din punct de vedere clinic și necesită a fi studiat într-un studiu prospectiv

Mapping of subthalamic nucleus using microelectrode recordings during deep brain stimulation

Alongside stereotactic magnetic resonance imaging, microelectrode recording (MER) is frequently used during the deep brain stimulation (DBS) surgery for optimal target localization. The aim of this study is to optimize subthalamic nucleus (STN) mapping using MER analytical patterns. 16 patients underwent bilateral STN-DBS. MER was performed simultaneously for 5 microelectrodes in a setting of Ben's-gun pattern in awake patients. Using spikes and background activity several different parameters and their spectral estimates in various frequency bands including low frequency (2-7 Hz), Alpha (8-12 Hz), Beta (sub-divided as Low_Beta (13-20 Hz) and High_Beta (21-30 Hz)) and Gamma (31 to 49 Hz) were computed. The optimal STN lead placement with the most optimal clinical effect/ side-effect ratio accorded to the maximum spike rate in 85% of the implantation. Mean amplitude of background activity in the low beta frequency range was corresponding to right depth in 85% and right location in 94% of the implantation respectively. MER can be used for STN mapping and intraoperative decisions for the implantation of DBS electrode leads with a high accuracy. Spiking and background activity in the beta range are the most promising independent parameters for the delimitation of the proper anatomical site

Riscurile și beneficiile înregistrării cu microelectrod în chirurgia bolii Parkinson

Background. Microelectrode recording is believed to improve the outcome by enhancing the precision of electrodes used in deep brain stimulation in patients with Parkinson’s Disease. There is a trend that higher number of penetrations correlate with high rate of hemorrhagic complications. Objective of the study. Determine the clinical outcome of patients stimulated decentrally compared to those placed centrally. Additionally, to assess whether a higher number of penetrations correlate with higher rates of intracranial bleeding. Material and Methods. This monocentric study included 556 patients with bilateral STN-DBS and relies on a large prospectively established database. Data were available from 400 patients. The outcome parameter was the stimulation-induced improvement of the UPDRS for PD. We compared patients with both electrodes centrally to that bi-decentrally. Also, we determined the rate of surgical complications. Results. A decentral tract was chosen in 41% of the electrodes based on clinical grounds (central, n = 471 electrodes; decentral, n = 329). Motor symptom improvement was not different between patients with electrodes implanted bilaterally in the central (44.39% ± 22.71) or decentral (43,22% ± 17) trajectory bilaterally (p = 0.5571). Similar results were obtained for the hemibody score and subscores for akinesia, tremor, rigidity, postural instability and gait disorder. The overall bleeding rate was 2,78% and not depending on the number of penetrations. Conclusion. Outcomes between the groups with central or decentral electrode trajectories did not differ and, therefore, the use of mMER is likely to improve outcome quality. Comparison with other cohorts does not disclose a higher rate of bleeding complications in this cohort with mMER. Introducere. În chirurgia bolii Parkinson, înregistrarea cu microelectrod se utilizează pentru determinarea punctului optim pentru stimulare cerebrală profundă. Se consideră că numărul crescut de penetrații corelează cu rata mai mare a complicațiilor hemoragice postoperatorii. Scopul lucrării. De a determina efectul clinic al pacienților stimulați cu electrozi bicentral versus cei implantați decentral bilateral. De asemenea, de a evalua dacă numărul mai mare de penetrații corelează cu rata mai mare a sângerării intracraniene. Material și Metode. Acest studiu monocentric a inclus 556 de pacienți cu boala Parkinson, stimulați bilateral, bază pe o bază de date prospectivă. Datele complete au fost găsite la 400 de pacienți. Parametrul pentru comparație a fost scala UPDRS pentru BP. Studiul nostru a comparat pacienții cu ambii electrozi implantați bilateral central și decentral. De asemenea, s-a studiat rata sângerării postoperatorii. Rezultate. Traiectorie decentrală s-a ales în 41% din electrozi pe baza la rezultatul clinic (central - 471 electrozi, decentral - 329). Ameliorarea simptomelor motorii nu diferă între grupurile de pacienți cu electrozi implantați bilateral central (44.39% ± 22.71) sau decentral (43, 22% ± 17), p = 0.56. Aceleași rezultate s-au obținut pentru scorul hemibody și subscoruri ca: akinezia, tremorul, rigiditatea, tulburările de statică și mers. Incidența hemoragiei a fost de 2.78% și nu corelează cu numărul de penetrații cu microelectroade. Concluzii. Rezultatul clinic al pacienților cu ambii electrozi bilateral central și decentral nu diferă. Astfel, utilizarea MER poate ameliora rezultatul final. Totodată, incidența complicațiilor postoperatorii hemoragice în studiul nostru nu este mai mare decât în alte studii

Moderate Frequency Resistance and Balance Training Do Not Improve Freezing of Gait in Parkinson's Disease: A Pilot Study

Background and Aim: Individuals with Parkinson's disease (PD) and Freezing of Gait (FOG) have impaired postural control, which relate to the severity of FOG. The aim of this study was to analyze whether a moderate frequency resistance (RT) and balance training (BT), respectively, are effective to diminish FOG.Methods: This post-hoc sub-analysis of a randomized controlled training intervention study of PD patients with and without FOG reports about results from FOG patients. Twelve FOG patients performed RT and 8 BT (training 2x/week, 7 weeks). Testing was performed prior and post intervention. FOG was assessed with the FOG Questionnaire (FOGQ) and with the FOG score of a FOG provoking walking course. Balance performance was evaluated with the Fullerton Advanced Balance (FAB) scale. Tests were conducted by raters blinded to group allocation and assessment time point (only FOG score and FAB scale).Results: For the FOGQ and FOG score, no significant differences were found within and between the two training groups (p > 0.05) and effect sizes for the improvements were small (r < 0.1). Groups did not significantly improve in the FAB scale. FOG score changes and FAB scale changes within the RT group showed a trend toward significant negative correlation (Rho = −0.553, p = 0.098).Conclusions: Moderate frequency RT and BT was not effective in reducing FOG in this pilot study. The trend toward negative correlation between changes in FOG score and FAB scale suggests an interaction between balance (improvement) and FOG (improvement). Future studies should include larger samples and high frequency interventions to investigate the role of training balance performance to reduce the severity of FOG

The role of microelectrode recording during Deep Brain Stimulation of Subthalamic Nucleus in patients with Parkinson’s disease

Background: Deep brain stimulation of the subthalamic nucleus improves symptoms of Parkinson’s disease. However, the clinical outcome depends on the accurate location of the final electrode. Multiple microelectrode recording is believed to improve the precision, although it prolongs the duration of surgery. We hypothesize that patients implanted in the central trajectory have the same outcome as patients implanted decentrally. Material and methods: This study was carried out in UKSH Kiel and included 556 patients treated from 1999 until 2018 with bilateral STN-DBS (safety population). Pre- and postoperative efficacy data were available from 400 patients. The outcome parameter was the stimulation-induced improvement of the UPDRS for PD. We compared patients with both electrodes centrally to that bi-decentrally. The rate of surgical complications was determined with postoperative imaging. Results: A decentral tract was chosen in 41% of the electrodes (central, n = 471 electrodes; decentral, n = 329). Motor improvement was not different between patients with electrodes implanted bicentral (44.39% ± 22.71) or decentral (43.22% ± 17) trajectory bilaterally (p = 0.5571). Similar results were obtained for the hemi body score and subscores for akinesia, tremor, rigidity, postural instability and gait disorder. The overall bleeding rate was 2.78% and not dependent on the number of penetrations. Conclusions: Outcomes between the groups did not differ and, therefore, the use of mMER is likely to improve the outcome. Comparison with other cohorts does not disclose a higher rate of bleeding complications in this cohort with mMER

Hall effect measurements on YbRh2Si2 and relatives in the light of electronic structure calculations

We report experimental and theoretical investigations of the Hall effect in YbRh2Si2 and its reference compounds LuRh2Si2 and YbIr2Si2. Based on band-structure calculations we identify two bands dominating the Hall coefficient in all these compounds. For the case of LuRh2Si2 - the non-magnetic reference compound of YbRh2Si2 - the temperature dependence of the Hall coefficient is described quantitatively to arise from two hole-like bands. For YbIr2Si2 and YbRh2Si2, renormalized band calculations yield two bands of opposite character. In YbRh2Si2 these two bands almost compensate each other. We present strong indications that the sample dependences of the low-temperature Hall coefficient observed for YbRh2Si2 arise from slight variations of the relative scattering rates of the two bands. Minute changes of the composition appear to be the origin.Comment: 12 pages, 8 figure