Der Einfluss von Vitamin D auf das angeborene Immunsystem

Das angeborene Immunsystem dient der schnellen und wirksamen Abwehr von Pathogenen. Eine fein abgestimmte Regulation seiner Funktion ist entscheidend für die Integrität des Organismus. Verschiedene endogene Faktoren (z. B. Hormone oder Zytokine) sowie exogene Faktoren (z. B. Zigarettenrauch oder Umweltpathogene) können das komplexe Gleichgewicht beeinflussen. Zu den klassischen Funktionen von Vitamin D gehört die Regulierung des Kalzium- und Phosphatmetabolismus. Erst in den letzten Jahren wurde die Bedeutung von Vitamin D für die Physiologie des angeborenen und adaptiven Immunsystems erkannt. Die genauen molekularen Abläufe, über die Vitamin D seine Wirkung als Immunmodulator entfaltet, sind bisher nur teilweise verstanden. Ziel dieser Arbeit war die Charakterisierung des Einflusses von Vitamin D auf verschiedene Funktionen des angeborenen Immunsystems nach Kontakt mit bakteriellen Pathogenen. In einem weiteren Schritt sollten die Auswirkungen von Zigarettenrauch auf die beobachteten Vitamin-D-Effekte analysiert werden. Humane Makrophagen und neutrophile Granulozyten wurden mit Vitamin D in verschiedenen Konzentrationen sowie mit unterschiedlichen Toll-like-Rezeptor-Liganden inkubiert. Untersucht wurde die Expression des einzigen bisher bekannten humanen Cathelizidins hCAP-18/LL-37, die Ausschüttung proinflammatorischer Zytokine und die bakterielle Eliminationsrate unter Verwendung von quantitativer real time-PCR (qRT-PCR), Western-Blot, ELISA und eines bakteriellen Eliminationsassays. Weiter wurden häufig verwendete Modellsysteme, wie die Zelllinien MonoMac 6 und U937 sowie murine Makrophagen, unter den für primäre humane Zellen verwendeten Konditionen stimuliert und die erhobenen Befunde verglichen. Um eine mögliche Interaktion zwischen Zigarettenrauch und Vitamin D zu untersuchen, wurden primäre humane Makrophagen mit beiden Substanzen inkubiert und die Expression von hCAP-18/LL-37 Zytokinen analysiert . Die Ergebnisse der vorliegenden Arbeit belegen eine antimikrobielle und antiinflammatorische Wirkung von Vitamin D auf humane Makrophagen und neutrophile Granulozyten. In humanen Makrophagen und neutrophilen Granulozyten kommt es zu einer gesteigerten Synthese von LL-37, während die Ausschüttung der proinflammatorischen Zytokine TNF- und IL-1 vermindert ist. Diese Effekte gehen Zusammenfassung II mit einer Verbesserung der Eliminationsrate von lebenden Bakterien einher. Signifikante Effekte lassen sich dabei für Konzentrationen detektieren, die über den aktuellen Empfehlungen des Institute of Medicine für eine ausreichende Vitamin-D-Versorgung liegen. Bei der Analyse der Modellsysteme zeigte sich, dass Vitamin D die Synthese des murinen LL-37-Homologs mouse cathelicidin related antimicrobial peptide (mCRAMP) nicht verändert. In den untersuchten humanen Zelllinien kam es nach Vitamin D Gabe zu einer gesteigerten LL-37-Expression, jedoch blieb die Zytokinantwort unbeeinflusst. Zigarettenrauch interferierte mit der Funktion von Vitamin D als Immunmodulator, indem er die Vitamin-D-vermittelte antimikrobielle Wirkung hemmte. Ein Einfluss auf die antiinflammatorischen Effekte ließ sich nicht nachweisen. Die Ergebnisse dieser Arbeit unterstreichen die Bedeutung von Vitamin D für die Physiologie des Immunsystems. Seine Wirkung auf die Synthese endogener Antibiotika und die Entzündungsreaktion bieten interessante Ansatzpunkte für die Entwicklung neuer Therapiestrategien. Die Erhebungen der Dosis-Wirkungs-Beziehung in Zusammenschau mit aktuellen epidemiologischen Daten sowie die Interaktion zwischen Zigarettenrauch und Vitamin D könnten eine wichtige Rolle für die präventive Gesundheitsmassnahmen spielen

Changes in Stroke Rehabilitation during the Sars-Cov-2 Shutdown in Switzerland

INTRODUCTION: Many stroke survivors require continuous outpatient rehabilitation therapy to maintain or improve their neurological functioning, independ-ence, and quality of life. In Switzerland and many other countries, the shutdown to contain SARS-CoV-2 infections led to mobility restrictions and a decrease in therapy delivery. This study investigated the impact of the COVID-19 shutdown on stroke survivors' access to therapy, physical activity, functioning and mood. METHODS: A prospective observational cohort study in stroke subjects. At 4 time-points (before, during, after the shutdown, and at 3-month follow-up), the amount of therapy, physical activities, motor func-tion, anxiety, and depression were assessed. RESULTS: Thirty-six community-dwelling stroke subjects (median 70 years of age, 10 months post--stroke) were enrolled. Therapy reductions related to the shutdown were reported in 72% of subjects. This decrease was associated with significantly extended sedentary time and minimal deterioration in physical activity during the shutdown. Both parameters improved between reopening and 3-month follow-up. Depressive symptoms increased slightly during the observation period. Patients more frequently report-ed on self-directed training during shutdown. CONCLUSION: The COVID-19 shutdown had measurable immediate, but no persistent, effects on post--stroke outcomes, except for depression. Importantly, a 2-month reduction in therapy may trigger improvements when therapy is fully re-initiated thereafter

No evidence for motor-recovery-related cortical connectivity changes after stroke using resting-state fMRI

It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state (rs) functional MRI (fMRI). Here, we report a longitudinal data set collected from 19 patients with subcortical stroke and 11 controls. Patients were imaged up to five times over 1 year. We found no evidence, using rs-fMRI, for longitudinal poststroke cortical connectivity changes despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here, we argue instead that they are consistent with other emerging reasons to challenge the idea of motor-recovery-related cortical reorganization poststroke when conceived of as changes in connectivity between cortical areas. NEW & NOTEWORTHY We investigated longitudinal changes in functional connectivity after stroke. Despite substantial motor recovery, we found no differences in functional connectivity patterns between patients and controls, nor any changes over time. Assuming that rs-fMRI is an adequate method to capture connectivity changes between cortical regions after brain injury, these results provide reason to doubt that changes in cortico-cortical connectivity are the relevant mechanism for promoting motor recovery

Evidence for a subcortical origin of mirror movements after stroke: A longitudinal study

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system

Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation

© 2019 American Neurological Association Objective: Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients’ premovement IHI for one year following stroke. Methods: We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants. Results: We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation. Interpretation: These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502–513

Comparing a Novel Neuroanimation Experience to Conventional Therapy for High-Dose Intensive Upper-Limb Training in Subacute Stroke: The SMARTS2 Randomized Trial

BACKGROUND Evidence from animal studies suggests that greater reductions in poststroke motor impairment can be attained with significantly higher doses and intensities of therapy focused on movement quality. These studies also indicate a dose-timing interaction, with more pronounced effects if high-intensity therapy is delivered in the acute/subacute, rather than chronic, poststroke period. OBJECTIVE To compare 2 approaches of delivering high-intensity, high-dose upper-limb therapy in patients with subacute stroke: a novel exploratory neuroanimation therapy (NAT) and modified conventional occupational therapy (COT). METHODS A total of 24 patients were randomized to NAT or COT and underwent 30 sessions of 60 minutes time-on-task in addition to standard care. The primary outcome was the Fugl-Meyer Upper Extremity motor score (FM-UE). Secondary outcomes included Action Research Arm Test (ARAT), grip strength, Stroke Impact Scale hand domain, and upper-limb kinematics. Outcomes were assessed at baseline, and days 3, 90, and 180 posttraining. Both groups were compared to a matched historical cohort (HC), which received only 30 minutes of upper-limb therapy per day. RESULTS There were no significant between-group differences in FM-UE change or any of the secondary outcomes at any timepoint. Both high-dose groups showed greater recovery on the ARAT (7.3 ± 2.9 points; P = .011) but not the FM-UE (1.4 ± 2.6 points; P = .564) when compared with the HC. CONCLUSIONS Neuroanimation may offer a new, enjoyable, efficient, and scalable way to deliver high-dose and intensive upper-limb therapy