Seizures after Ischemic Stroke: A Matched Multicenter Study

Accidente cerebrovascular isquémico; Tratamiento de reperfusión; Factores de riesgoIschemic Stroke; Reperfusion treatment; Risk factorsAccident cerebrovascular isquèmic; Tractament de reperfusió; Factor de riscObjective The purpose of this study was to identify risk factors for acute symptomatic seizures and post-stroke epilepsy after acute ischemic stroke and evaluate the effects of reperfusion treatment. Methods We assessed the risk factors for post-stroke seizures using logistic or Cox regression in a multicenter study, including adults from 8 European referral centers with neuroimaging-confirmed ischemic stroke. We compared the risk of post-stroke seizures between participants with or without reperfusion treatment following propensity score matching to reduce confounding due to treatment selection. Results In the overall cohort of 4,229 participants (mean age 71 years, 57% men), a higher risk of acute symptomatic seizures was observed in those with more severe strokes, infarcts located in the posterior cerebral artery territory, and strokes caused by large-artery atherosclerosis. Strokes caused by small-vessel occlusion carried a small risk of acute symptomatic seizures. 6% developed post-stroke epilepsy. Risk factors for post-stroke epilepsy were acute symptomatic seizures, more severe strokes, infarcts involving the cerebral cortex, and strokes caused by large-artery atherosclerosis. Electroencephalography findings within 7 days of stroke onset were not independently associated with the risk of post-stroke epilepsy. There was no association between reperfusion treatments in general or only intravenous thrombolysis or mechanical thrombectomy with the time to post-stroke epilepsy or the risk of acute symptomatic seizures. Interpretation Post-stroke seizures are related to stroke severity, etiology, and location, whereas an early electroencephalogram was not predictive of epilepsy. We did not find an association of reperfusion treatment with risks of acute symptomatic seizures or post-stroke epilepsy

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model

IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up

Die Wirkung von selektiven Östrogenrezeptor [alpha] und [beta]-Agonisten auf Ovar und Uterus am Nagetier

Novel isotype selective estrogen receptor (ER) agonists, the selective ERAlphaagonist 16Alpha-LE2 and the selective ERBeta agonist 8Beta-VE2, were used in hypophysectomized rats or GnRH antagonist treated immature mice as well as in ovariectomized mature rats to elucidate the effect of subtype selective estrogens on the physiology of ovarian folliculogenesis, uterine proliferation and gene regulation, respectively. In immature hypophysectomized animals, the ERBeta agonist and the reference compound 17Beta-estradiol caused stimulation of early folliculogenesis, a decrease in follicular atresia and induction of ovarian gene expression. The ERBeta agonist exhibited the same efficiency and a similar high potency as 17Beta-estradiol in the respective studies. In contrast, the ERAlphaagonist had little or no effect on these parameters implying that direct estrogen effects on ovarian follicular development and gene regulation are mediated by ERBeta. In ovariectomized mature rats the ERAlpha agonist and the reference compound 17Beta-estradiol caused stimulation of uterine weight, cell proliferation and cell-compartment dependant gene regulation. The ERAlpha agonist exhibited the same efficiency and a similar high potency as 17Beta-estradiol in the respective studies. On the other hand, the ERBeta agonist did not stimulate uterine weight and cell proliferation in intact female rats and had no effect on gene regulation, showing that estrogen receptor Alpha is the dominant receptor in the uterus and responsible for mediating direct estrogen effects. This is in line with the assumption that stimulation of uterine growth and other known estrogen effects are mediated by ERAlpha but not by ERBeta and that ovarian ERBeta dominance is responsible for increased stimulation of folliculogenesis. This unique endocrine profile of selective estrogen receptor agonists provides new options for targeted pharmacotherapeutical indications as for example tailoring classical ovarian stimulation protocols by the use of ERBeta agonists or inventing new contraceptive agents by inhibition via an action on the hypothalamic-pituitary-ovarian axis by the use of ERAlpha agonists

Determination of Concentration-Dependent Diffusion Coefficients in Polymer–Solvent Systems: Analysis of Concentration Profiles Measured by Raman Spectroscopy during Single Drying Experiments Excluding Boundary Conditions and Phase Equilibrium

Diffusion coefficients in polymer solutions are strongly dependent on composition and temperature. In many cases sufficient data are not available due to time-consuming measurements and a high number of material systems of interest. In this work a new method is proposed that allows determination of concentration-dependent diffusion coefficients directly from spectroscopic data of single film drying experiments. The quantitative data of concentration profiles in the sample are used to calculate diffusion coefficients by Fick’s law. The results are independent of boundary conditions in the gas phase. Two polymer solutions of poly­(vinyl acetate) (PVAc) and the solvents methanol and toluene are investigated. The results are compared to diffusion data from the literature. Experimental proof of the independence from boundary conditions is provided. Diffusion coefficients down to values of approximately 10^–14 m² s^–1 are accessible. The diffusion data are in good agreement with literature data and suitable for modeling purposes

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

Prediction and inline compensation of springback in roll forming of high and ultra-high strength steels

With the rising interest in lightweight construction, the usage of high and ultra-high strength steels has increased remarkably during the last years. Unfortunately, these steel grades show more springback than mild steels do, which leads in consequence to lower dimensional accuracy. To improve the bended part’s geometry considerable trial-and-error work is necessary since the influence of different bending-parameters (e.g. the bending radius, sheet thickness, yield strength, Young’s modulus, the material’s strain hardening coefficient, …) on the amount of springback is still unknown. The aim of the paper at hand is therefore the investigation of springback for different parameter combinations. Furthermore, an online calibration system for occurring springback during roll forming is presented to compensate springback independent of material or process parameters