Rückenmarksstimulation (SCS) bei chronischen neuropathischen Schmerzen: Vergleich von BurstDR™- und Hochfrequenzstimulation (HF10™)

Hintergrund: BurstDR™ und HF10™ als neue Stimulationsformen der SCS-Therapie zeichnen sich im Vergleich zur konventionellen tonischen Stimulation durch effektivere Schmerzlinderung, Wirksamkeit bei schwierigen Patientengruppen (Nonresponder u. a.) und verminderte Parästhesien aus. Außerdem könnten sie sich durch Modulation des für affektiv-kognitive Aspekte zuständigen medialen Schmerzwegs auf diese positiv auswirken. Ziel der Studie war die vergleichende Betrachtung der Wirkung von BurstDR™ und HF10™ mit Fokus auf die affektiv-kognitive Schmerzverarbeitung. Die Untersuchung weiterer Schmerzaspekte und Zusammenhänge soll die klinische Situation möglichst umfassend abbilden. Methoden: 41 von 70 chronischen Schmerzpatienten, die am Universitätsklinikum Tübingen zwischen 2014 und 2016 einen BurstDR™- oder HF10™-Generator implantiert bekommen hatten, nahmen an der Studie teil. Anamnestische Daten, Schmerzstärke (NRS), Schmerzakzeptanz (CPAQ), Schmerzkatastrophisieren (PCS), Schmerzaufmerksamkeit (PVAQ), erlebte Behinderung im Alltag (PDI) und depressive Symptome (BDI-II) wurden mittels Fragebögen für den aktuellen Zeitpunkt T1 und retrospektiv für den Zeitpunkt T0 (Interpretation durch Recall Bias limitiert) vor Therapie erhoben. Ergebnisse: BurstDR™ bewirkte eine signifikante Verbesserung der untersuchten Schmerzaspekte. Für HF10™ zeigten sich positive Tendenzen (eingeschränkt aussagekräftig aufgrund kleiner Fallzahl). Im Verlauf der Studie erwies es sich als sinnvoll, die Untersuchung der BurstDR™-Gruppe in BurstDR™, BurstDR™/Tonisch und Tonisch zu differenzieren. Die Burst/Tonisch-Gruppe zeigte eine homogen positive Entwicklung. Zwischen den erfragten Schmerzaspekten bestanden in der untersuchten Patientengruppe mit wenigen Ausnahmen deutlich positive Korrelationen. Schlussfolgerung: Die positive Wirkung von BurstDR™ auf die affektiv-kognitiven Schmerzaspekte (Schmerzakzeptanz, Schmerzkatastrophisieren und Schmerzaufmerksamkeit) konnte bestätigt werden und könnte mit einer Modulation des medialen Schmerzweges zusammenhängen, für HF10™ waren hierzu keine abschließenden Aussagen möglich. Der Wechsel zwischen BurstDR™ und Tonisch könnte eine vielversprechende Ergänzung sein im Sinne einer effektiven Therapieoption. Die Wirksamkeit von BurstDR™ sowie die positiven Effekte des BurstDR™/Tonisch-Wechsels konnten gezeigt werden und sind vielversprechende Entwicklungen auf dem Weg zu einer individualisierten SCS der Zukunft

A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects

Biomaterials developed to treat bone defects have classically focused on bone healing via direct, intramembranous ossification. In contrast, most bones in our body develop from a cartilage template via a second pathway called endochondral ossification. The unsolved clinical challenge to regenerate large bone defects has brought endochondral ossification into discussion as an alternative approach for bone healing. However, a biomaterial strategy for the regeneration of large bone defects via endochondral ossification is missing. Here we report on a biomaterial with a channel-like pore architecture to control cell recruitment and tissue patterning in the early phase of healing. In consequence of extracellular matrix alignment, CD146+ progenitor cell accumulation and restrained vascularization, a highly organized endochondral ossification process is induced in rats. Our findings demonstrate that a pure biomaterial approach has the potential to recapitulate a developmental bone growth process for bone healing. This might motivate future strategies for biomaterial-based tissue regeneration

Identität und Akkulturation bei Migranten unterschiedlicher Herkunftskulturen

Im vorliegenden Forschungsprojekt wurden MigrantInnen und bereits eingebürgerte Personen über einen längeren Zeitraum hinweg (zunächst ca. ein Jahr) untersucht. Der Bericht stellt erste Ergebnisse einer Befragung aus dem Jahr 2007 nicht eingebürgerter MigrantInnen deutschlandweit dar, wobei ausführlich gezeigt wird, inwieweit individuelle Dispositionen, Auswanderungsgründe, spezifische Akkulturationsorientierungen, der Grad der soziokulturellen Anpassung, Einbürgerungsmotive und der soziodemografische Hintergrund mit der Integration der Befragten einhergehen. Die im Rahmen der Untersuchung eingesetzten Skalen wurden anhand einer Pilotstudie (N=48) und einer Stichprobe eingebürgerter MigrantInnen (N=272) validiert, deren Kennwerte im Forschungsbericht Nr.1 zum Projekt "Identität und Akkulturation von Migranten" (Maehler et al., 2008) dargestellt sind. Es werden zunächst der Untersuchungsverlauf skizziert und die Stichprobe beschrieben. Danach folgt die Darstellung der Kennwerte für die einzelnen Variablen und die dazugehörigen Items der gemessenen Konstrukte. Es werden ferner die Zusammenhänge zwischen den gemessenen Konstrukten analysiert und weiterführende Analysen mit ausgewählten Variablen vorgestellt. Abschließend erfolgt eine Zusammenfassung und Diskussion der bisherigen Ergebnisse. (ICI2

Arm swing responsiveness to dopaminergic medication in Parkinson’s disease depends on task complexity

The evidence of the responsiveness of dopaminergic medication on gait in patients with Parkinson’s disease is contradicting. This could be due to differences in complexity of the context gait was in performed. This study analysed the effect of dopaminergic medication on arm swing, an important movement during walking, in different contexts. Forty-five patients with Parkinson’s disease were measured when walking at preferred speed, fast speed, and dual-tasking conditions in both OFF and ON medication states. At preferred, and even more at fast speed, arm swing improved with medication. However, during dual-tasking, there were only small or even negative effects of medication on arm swing. Assuming that dual-task walking most closely reflects real-life situations, the results suggest that the effect of dopaminergic medication on mobility-relevant movements, such as arm swing, might be small in everyday conditions. This should motivate further studies to look at medication effects on mobility in Parkinson’s disease, as it could have highly relevant implications for Parkinson’s disease treatment and counselling

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome

Background: Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. Methods: In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. Results: We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. Conclusion: The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology

ATM induces MacroD2 nuclear export upon DNA damage

ADP-ribosylation is a dynamic post-translation modification that regulates the early phase of various DNA repair pathways by recruiting repair factors to chromatin. ADP-ribosylation levels are defined by the activities of specific transferases and hydrolases. However, except for the transferase PARP1/ARDT1 little is known about regulation of these enzymes. We found that MacroD2, a mono-ADP-ribosylhydrolase, is exported from the nucleus upon DNA damage, and that this nuclear export is induced by ATM activity. We show that the export is dependent on the phosphorylation of two SQ/TQ motifs, suggesting a novel direct interaction between ATM and ADP-ribosylation. Lastly, we show that MacroD2 nuclear export temporally restricts its recruitment to DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at the site of DNA damage. Together, our results identify a novel feedback regulation between two crucial DNA damage-induced signaling pathways: ADP-ribosylation and ATM activation

Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish–Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1–3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum–maximum)]: mMP 0.10 (< 0.01–5.53 μg/L), mEP 0.95 (0.07–41.4 μg/L), mBP 9.6 (0.6–10,900 μg/L), mBzP 1.2 (0.2–26 μg/L), mEHP 11 (1.5–1,410 μg/L), miNP 95 (27–469 μg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001–0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21–0.323, p = 0.002–0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = −0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome

BackgroundImmune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro.MethodsIn our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters.ResultsWe observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort.ConclusionThe cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology