Polychlorinated Biphenyls Disrupt Blood–Brain Barrier Integrity and Promote Brain Metastasis Formation

Bac k g r o u n d: Polychlorinated biphenyls (PCBs) comprise a ubiquitous class of toxic substances associated with carcinogenic and tumor-promoting effects as well as neurotoxic properties in the brain. However, the effects of PCBs on the development of tumor metastases are not fully understood. Objective: We evaluated the hypothesis that exposure to individual PCB congeners can facilitate the development of brain metastases in immunocompetent mice via the disruption of the integrity of the blood–brain barrier (BBB). Met h o d s: C57/Bl6 mice were exposed to individual PCBs by oral gavage, and 48 hr later they were injected with luciferase-labeled K1735 M2 melanoma cells into the internal carotid artery. The development of metastatic nodules was monitored by bioluminescent imaging. In addition, we evaluated the functional permeability of the BBB by measuring permeability of sodium fluorescein across the brain microvessels. Expression and colocalization of tight junction (TJ) proteins were studied by Western blotting and immunofluorescence microscopy. Res u l t s: Oral administration of coplanar PCB126, mono-ortho-substituted PCB118, and noncoplanar PCB153 (each at 150 µmol/kg body weight) differentially altered expression of the TJ proteins claudin-5, occludin, and zonula occludens-1 in brain capillaries. These alterations wer

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

Objective: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients. Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS. Gov identifier: NCT03759639

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Feilke revisited : 60 Stellenbesuche

Weitere Hrsg.: Thorsten Pohl, Sara Rezat, Torsten Steinhoff, Martin SteinseiferAnlässlich des 60. Geburtstags des Linguisten und Sprachdidaktikers Helmuth Feilke wurden Wegbegleiterinnen und Wegbegleiter gebeten, einzelne Stellen in seinen wissenschaftlichen Schriften erneut zu besuchen. Entstanden sind pointierte Kommentare, kurze wissenschaftliche Abhandlungen und Analysen, Varianten auch des kritischen und kontroversen Nach- und Weiterdenkens und Ansätze zur Neu- oder Re-Kontextualisierung. Je nach wissenschaftlicher Vita der Autorinnen und Autoren kann es sich um Stellen handeln, deren Rezeption zeitlich weit zurückliegt, oder um Passagen, die ganz aktuelle Fragen der eigenen Forschungsarbeit tangieren. Abgesehen davon, dass ein kurzes Format für die Beiträge gewählt und die Autorinnen und Autoren gebeten wurden, die ausgewählte Stelle knapp zu verorten und zu erläutern, war die Bearbeitungsform gänzlich freigestellt. So sind Texte in einer Bandbreite von pointierten Kommentaren, kurzen wissenschaftlichen Abhandlungen und Analysen, Varianten des Nach- und Weiterdenkens, Ansätze zur Neu- oder Re-Kontextualisierung bis hin zu Formen des kritischen Hinterfragens und der kontroversen Auseinandersetzung entstanden

BPPV: Comparison of the SémontPLUS With the Sémont Maneuver: A Prospective Randomized Trial

Objective: To compare the efficacy of the Sémont maneuver (SM) with the new "SémontPLUS maneuver" (SM+) in patients with posterior canal BPPV canalolithiasis (pcBPPVcan). Methods and Patients: In a prospective trinational (Germany, Italy, and Belgium) randomized trial, patients with pcBPPVcan were randomly assigned to SM or SM+; SM+ means overextension of the head by 60+° below earth horizontal line during the movement of the patient toward the affected side. The first maneuver was done by the physician, and the subsequent maneuvers by the patients 9 times/day on their own. Each morning the patient documented whether vertigo could be induced. The primary endpoints were: "How long (in days) does it take until no attacks can be induced?" and "What is the efficacy of a single SM/SM+?" Results: In the 194 patients analyzed (96 SM, 98 SM+), it took 2 days (median, range 1-21 days, mean 3.6 days) for recovery with SM and 1 day (median, range 1-8 days, mean 1.8 days) with SM+ (p = 0.001, Mann-Whitney U-test). There was no difference in the second primary endpoint (chi2-test, p = 0.39). Interpretation: This prospective trial shows that SM+ is more effective than SM when repeated therapeutic maneuvers are performed but not when a single maneuver is performed. It also supports the hypothesis of the biophysical model: overextension of the head during step 2 brings the clot of otoconia beyond the vertex of the canal, which increases the effectivity. Classification of Evidence: This study provides Class I evidence that SM+ is superior to SM for multiple treatment maneuvers of pcBPPVcan

Criss-cross gait: a clue to glucose transporter type 1 deficiency syndrome

[no abstract available

Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors

Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR-218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance