Characterization of microglia in the rat subventricular zone after neonatal hypoxia-ischemia

Background Recent findings indicate a regulatory role of microglia on neurogenesis in the subventricular zone (SVZ). SVZ microglia in the adult rat are sought to adopt a supportive phenotype after ischemic stroke. Early postnatal microglia are endogenously activated and may therefore express an increased sensitivity to neonatal hypoxia-ischemia (HI). Therefore, we sought to investigate the impact of HI on the microglial phenotype in the early postnatal SVZ. Methods Postnatal-day (P)7 rats underwent sham or right-hemispheric HI surgery. Microglia in the SVZ, the adjacent cortex and the corpus callosum were immunohistochemically analyzed at P10, P20 and P40. Further, the transcriptome of SVZ microglia isolated at P10 and P20 was analyzed. Lastly, the effect of P10 microglia on in vitro neurosphere generation was investigated. Results The SVZ microglial response upon HI, characterized by cellular accumulation, prolonged activation and phagocytosis, is SVZ-specific and does not occur in adjacent brain regions. At the transcriptomic level, SVZ microglia adopt a complex phenotype, that resembles neither the M1 or M2 polarization state, but instead shares commonly expressed genes with microglia in neurodegenerative diseases. Finally, SVZ microglia appear to show trophic support for neurosphere generation in vitro in a concentration dependent manner. Conclusions Microglia are an inherent cellular component of the early postnatal SVZ and undergo specific developmental changes that are disrupted by neonatal HI injury. The SVZ microglial response to HI is complex and beyond a simplified pro- or anti-inflammatory phenotype. Our findings represent a solid basis for future research on SVZ microglia

Micro-X-ray diffraction and chemical mapping of aged interfaces between cement pastes and Opalinus Clay

The safety of a geological repository designed for deep storage of nuclear waste rests on the long-lived isolation properties of the geological environment and the engineered barrier system. To study the chemical and physical behaviour of cementitious/clayey interfaces, such interfaces have been collected during repeat sampling campaigns of the CI Experiment (Cement-Clay Interaction Experiment) at the Mont Terri rock laboratory (St. Ursanne, Switzerland, www.mont-terri.ch) over the last decade. This study focuses on the advanced analysis by µ-XRD mapping to locate and identify the mineral phases on each side of the interface. The hydrates as portlandite, ettringite and C-S-H present in the Portland cement (PC) were dissolved in contact with the Opalinus Clay (OPA) up to different depths (~0.2 mm for portlandite; ~1 mm for ettringite; completely depleted for C-S-H up to 0.1 mm and less visible on a 1-mm-depth) while the ettringite from ESDRED (a low-pH cement type) seems to be destabilized to a larger depth ( ≥ 3 mm ). In contrast to former studies, calcite could not be clearly observed at the interface PC - OPA but was well developed at the interface ESDRED - OPA. The extent of reaction after 10 years is very small in both cases, and dissolution of clay minerals remains below detection. The identification of mineral phases involved in reactions facilitates the understanding of the processes, thus, will help to improve the reactive transport models used to simulate the evolution over long times

PSYCHIATRY

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Biotechnology in Lausanne: The Rh D Project

Hemolytic disease of the newborn is an often fatal condition of some newborn babies due to the immunogenicity of their Rh D positive erythrocytes in the Rh D negative mother. This condition can be prevented by injecting anti-Rh D antibodies. The current source of these antibodies is blood from immunized human donors. In order to avoid problems with limited supply and donor safety, the Rh D project was set up to develop recombinant monoclonal anti-Rh D antibodies as a possible replacement. In a multidisciplinary collaboration between the Zentrallaboratorium Blutspendedienst (ZlB) of the Swiss Red Cross, the Center of Biotechnology of the University and the EPFL (CBUE), and the Institute of Chemical and Biochemical Engineering (EPFl), co-funded by the Swiss National Science Foundation and ZLB, a candidate monoclonal anti-Rh D antibody has been selected, expressed in CHO cells, and a manufacturing process for large-scale production has been developed

Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury

Background: Neurofilament light chain (NfL) is a highly promising biomarker of neuroaxonal injury that has mainly been studied in adult neurodegenerative disease. Its involvement in neonatal disease remains largely unknown. Our aim was to establish NfL plasma concentrations in preterm and term infants in the first week of life.Methods: Plasma NfL was measured by single molecule array immunoassay in two neonatal cohorts: cohort 1 contained 203 term and preterm infants, median gestational age (GA) 37.9 weeks (interquartile range [IQR] 31.9–39.4), in whom venous and arterial umbilical cord blood was sampled at birth and venous blood at day of life (DOL) 3; cohort 2 contained 98 preterm infants, median GA 29.3 weeks (IQR 26.9–30.6), in whom venous blood was sampled at DOL 7.Results: Median NfL concentrations in venous blood increased significantly from birth (18.2 pg/mL [IQR 12.8–30.8, cohort 1]) to DOL 3 (50.9 pg/mL [41.3–100, cohort 1]) and DOL 7 (126 pg/mL [78.8–225, cohort 2]) (p < 0.001). In both cohorts NfL correlated inversely with birth weight (BW, Spearman's rho −0.403, p < 0.001, cohort 1; R −0.525, p < 0.001, cohort 2) and GA (R −0.271, p < 0.001, cohort 1; R −0.487, p < 0.001, cohort 2). Additional significant correlations were found for maternal age at delivery, preeclampsia, delivery mode, 5-min Apgar, duration of oxygen supplementation, sepsis, and brain damage (intraventricular hemorrhage or periventricular leukomalacia). Multivariable logistic regression analysis identified the independent predictors of NfL in cohort 1 as BW (beta = −0.297, p = 0.003), delivery mode (beta = 0.237, p = 0.001) and preeclampsia (beta = 0.183, p = 0.022) and in cohort 2 as BW (beta = −0.385, p = 0.001) and brain damage (beta = 0.222, p = 0.015).Conclusion: Neonatal NfL levels correlate inversely with maturity and BW, increase during the first days of life, and relate to brain injury factors such as intraventricular hemorrhage and periventricular leukomalacia, and also to vaginal delivery

The impact of competing stroke etiologies in patients with atrial fibrillation.

BACKGROUND Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce. METHODS We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed. RESULTS Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause. CONCLUSION In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients. CLINICAL TRIAL REGISTRATION NCT03826927

Global Cortical Atrophy Is Associated with an Unfavorable Outcome in Stroke Patients on Oral Anticoagulation.

INTRODUCTION Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA). METHODS Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death. RESULTS In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34-11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23-12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17-14.84, p = 0.028). CONCLUSION GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation

Impact of type of oral anticoagulants in patients with cerebral microbleeds after atrial fibrillation-related ischemic stroke or TIA: Results of the NOACISP-LONGTERM registry.

Background Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC). Methods Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists [VKAs] vs. direct oral anticoagulants [DOACs]) with clinical outcome. Results Of 310 AF-stroke patients treated with OAC [DOACs: n = 234 (75%); VKAs: n = 76 (25%)], CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 [1.614; 8.277]; p = 0.002; DOACs: HR 2.230 [1.233; 4.034]; p = 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups [VKAs 13/20(65%) vs. DOACs 19/66(29%); p < 0.01]. The VKA-group had a 2-fold higher IS [VKAs:4 (20%) vs. DOACs:6 (9%); p = 0.35] and a 10-fold higher ICH rate [VKAs: 3 (15%) vs. DOACs: 1 (1.5%); p = 0.038]. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 [0.17; 0.94]; p = 0.04). Conclusions In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs. Clinical trial registration http://www.clinicaltrials.gov, Unique identifier: NCT03826927

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. METHODS We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). RESULTS We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). CONCLUSIONS Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage