Methylierungsanalyse des AQP5-Promotors bei Septikern und Kontrollpatienten in Abhängigkeit vom AQP5 A (-1364) C Promotorpolymorphismus

Der oben genannte SNP ist eine Genvariante des AQP5. Bis dato ist unklar, welcher Mechanismus dem Überlebensvorteil von C-Allelträgern zugrunde liegt sowie warum der SNP einen hohen Einfluss auf die AQP5-Expression hat. Potentielle Ursachen für den Einfluss des AQP5 A (-1364) C Promotorpolymorphismus auf die AQP5-Expression könnte eine an bestimmten Positionen Genotyp- abhängige differenzielle Methylierung des AQP5- Promotors sowie eine an bestimmten Positionen durch Sepsis induzierte Methylierung sein. Die Position -937 könnte eine mögliche Schlüsselrolle in der Pathogenese der Sepsis spielen, da in diesem Bereich Transkriptionsfaktoren binden, welche für die Inflammation und die AQP5-Expression essentiell sind. Zudem scheint sie einen möglichen Prädiktor für das Outcome bei septischen Patienten darzustellen

DNA methylation of a NF-κ\kappaB binding site in the aquaporin 5 promoter impacts on mortality in sepsis

Altered aquaporin 5 ($\it AQP5$) expression in immune cells impacts on key mechanisms of inflammation and is associated with sepsis survival. Since epigenetic regulation via DNA methylation might contribute to a differential $\it AQP5$ expression in sepsis, we tested the hypotheses that DNA methylation of the $\it AQP5$ promotor (1) influences $\it AQP5$ expression, (2) is associated with the 30-day survival of septic patients, and (3) alters the nuclear transcription factor NF-$\kappa$B binding. $\it AQP5$ mRNA expression was quantified by real-time PCR in whole blood samples of 135 septic patients. $\textit {In silico}$ computer analysis of the $\it AQP5$ promoter (nt-567 to nt-975) revealed seven putative inflammatory transcription factor binding sites and methylation of these sites was analyzed. Electrophoretic mobility shift assays were performed to assess the binding of nuclear NF-$\kappa$B to the $\it AQP5$ promoter region nt-937. After adjustment for multiple testing, a greater methylation rate was found at cytosine site nt-937 in the $\it AQP5$ promoter linked to NF-$\kappa$B binding in non-survivors compared to survivors (p = 0.002, p$_{adj}$ = 0.014). This was associated with greater $\it AQP5$ mRNA expression in non-survivors (p = 0.037). Greater ($\geq$16%) promoter methylation at nt-937 was also associated with an independently increased risk of death within 30 days (HR: 3.31; 95% CI: 1.54–6.23; p = 0.002). We detected a functionally important $\it AQP5$ promoter cytosine site (nt-937) linked to the binding of the inflammatorily acting nuclear transcription factor NF-$\kappa$B, with increased methylation in sepsis non-survivors. Thus, nt-937 $\it AQP5$ promoter methylation, presumably related to NF-$\kappa$B binding, is prognostically relevant in sepsis and demonstrates that epigenetic changes impact on sepsis outcome

Mechanical thrombectomy for acute ischemic stroke in COVID-19 patients: multicenter experience in 111 cases

Background Data on the frequency and outcome of mechanical thrombectomy (MT) for large vessel occlusion (LVO) in patients with COVID-19 is limited. Addressing this subject, we report our multicenter experience. Methods A retrospective cohort study was performed of consecutive acute stroke patients with COVID-19 infection treated with MT at 26 tertiary care centers between January 2020 and November 2021. Baseline demographics, angiographic outcome and clinical outcome evaluated by the modified Rankin Scale (mRS) at discharge and 90 days were noted. Results We identified 111 out of 11 365 (1%) patients with acute or subsided COVID-19 infection who underwent MT due to LVO. Cardioembolic events were the most common etiology for LVO (38.7%). Median baseline National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score were 16 (IQR 11.5-20) and 9 (IQR 7-10), respectively. Successful reperfusion (mTICI >= 2b) was achieved in 97/111 (87.4%) patients and 46/111 (41.4%) patients were reperfused completely. The procedure-related complication rate was 12.6% (14/111). Functional independence was achieved in 20/108 (18.5%) patients at discharge and 14/66 (21.2%) at 90 days follow-up. The in-hospital mortality rate was 30.6% (33/108). In the subgroup analysis, patients with severe acute COVID-19 infection requiring intubation had a mortality rate twice as high as patients with mild or moderate acute COVID-19 infection. Acute respiratory failure requiring ventilation and time interval from symptom onset to groin puncture were independent predictors for an unfavorable outcome in a logistic regression analysis. Conclusion Our study showed a poor clinical outcome and high mortality, especially in patients with severe acute COVID-19 infection undergoing MT due to LVO

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

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