Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier

BACKGROUND: Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aβ) from brain are thought to contribute to Alzheimer\u27s disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood-brain barrier. METHODS: CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aβ1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. RESULTS: We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells. CONCLUSIONS: These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aβ transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease

Quadruple coaxial catheter system on transvenous embolization for dural arteriovenous fistula

Background: Although transvenous embolization (TVE) is an effective method for treating dural arteriovenous fistula (AVF), directing the catheter to the lesion site is difficult.Objective: We report on the utility of a quadruple coaxial catheter system for TVE.Materials and methods: The quadruple catheter system comprised a 6 Fr guiding sheath, 6 Fr guiding catheter, 4 Fr intermediate catheter, and a regular microcatheter. The system was utilized in 27 consecutive dural AVF cases treated with TVE. In this study, we reviewed our experience with this system, including the theory, method of use, and complications.Results: Stenosis or obstruction of the vascular access was identified in 12 cases. The catheter could not reach to the lesion in three cases of cavernous sinus (7.4%); therefore, transarterial embolization was employed. Angiographic results revealed that the cases consist of total occlusion (n = 16, 59.5%), subtotal (n = 10, 37.0%), and partial occlusion (n = 1, 3.7%). Complete resolution or improvement of symptoms was observed in 23 patients (85.2%), no improvement of symptoms was observed in three patients (7.4%), and deterioration of symptoms was observed in one patient (3.7%). Venous perforation occurred in one patient without any neurological deficit. The catheter system provided access to the lesion and provided stability during the mechanically demanding process navigating the catheter and placing the coils.Conclusion: We determined that the quadruple coaxial system was safe and efficient for TVE for dural AVF

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood-brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases

Do neutrophil extracellular traps implicate in atheromatous plaques from carotid endarterectomy? Re-analyzes of cDNA microarray data by surgeons

BackgroundCarotid artery stenosis is the cause of 15% of strokes. Neutrophil extracellular traps (NETs) and peptidyl arginine deiminase 4 (PAD4) are believed to be involved in thrombosis. This pilot study described the differential expression profile of NETs between atheromatous plaques and surrounding tissues.MethodsMicroarray datasets of carotid plaques were obtained from Gene Expression Omnibus. The normalized data were processed into comma-separated value matrix files using spreadsheet software. Analyzes of microarray data were conducted using integrated differential expression and pathway analysis.ResultThe clustering results illustrated that the classifications of plaque and control had reasonable biological validity. Pathway analysis revealed the relevance of immune response, cell signaling, and other pathways. Differentially expressed genes were detected between carotid plaques and control specimens. However, enrichment analyzes did not reveal a difference in PAD4 expression between the groups and that NET implication was only found in one cDNA microarray dataset.DiscussionThis pilot study does not necessarily dismiss the possibility of a relationship between NETs and atherothrombotic stroke. Gene expression could differ between endothelial cells and atheromas, and further studies are needed

Efficacy of DynaCT digital angiography in the detection of the fistulous point of dural arteriovenous fistulas.

BACKGROUND AND PURPOSE: Identifying the precise hemodynamic features, including the fistulous point, is essential for treatments of dural arteriovenous fistulas (DAVFs). This study illustrates the efficacy of DynaCT digital angiograms obtained from a 3D C-arm CT to directly visualize the location of the fistulous points in DAVFs. MATERIALS AND METHODS: This retrospective study observed 14 consecutive patients with DAVFs, which included 7 cavernous sinuses, 4 transverse-sigmoid sinuses, 2 convexity-superior sagittal sinuses, and 1 tentorial sinus. In the assessment of the practical applicability for the diagnosis of DAVFs, images obtained from 2D digital subtraction angiography (DSA) and DynaCT were comparatively evaluated. RESULTS: In all patients, DynaCT digital angiography could clearly demonstrate the feeding arteries, the fistulous points, and the draining veins. Significant anatomic landmarks for the fistulous points with relationships to osseous structures were also provided. Compared with 2D DSA, DynaCT digital angiograms demonstrated 12 additional findings in 8 patients (57%), including the detection of the fistulous points (n = 7), the feeders (n = 1), the retrograde leptomeningeal drainage (n = 1), the draining veins (n = 1), and the venous anomaly (n = 2). CONCLUSIONS: In comparison with 2D DSA, DynaCT may provide more detailed information to evaluate DAVFs. DynaCT digital angiograms have a high contrast and isotropic spatial resolution, allowing a reliable visualization of small vessels and fine osseous structures. Such detailed information, especially for the location of the fistulous points, could be very useful for either the endovascular or the surgical treatments of DAVFs

A score using left ventricular diastolic dysfunction to predict 90-day mortality in acute ischemic stroke: The DONE score

Purpose: The aim of this study was to identify whether diastolic dysfunction predicts death at 90 days after acute ischemic stroke.Methods: We retrospectively analyzed patients with ischemic stroke. All patients underwent transthoracic echocardiography to evaluate systolic function and diastolic function by means of assessing ejection fraction and septal E/e’.We evaluated the initial National Institute of Health Stroke Scale (NIHSS) score,arterial occlusion, and laboratory data. We used multivariate regression models to identify independent predictors of 90-day mortality. Results: Among 1208 patients, the overall 90-day mortality rate was 8%. In multivariate logistic regression analysis, a higher initial NIHSS score,plasma D-dimer level and E/e’ and occlusion of internal carotid artery or basilar artery were independent predictors of 90-day mortality.The DONE score derived from these valuables showed good discrimination with area under the curve (AUC) value of 0.82 (95% confidence interval [CI],0.78?0.87) to predict 90-day mortality. The DONE score also predicted poor outcome (modified Rankin scale score, 4?6) at 90 days (AUC, 0.82;95% CI 0.80?0.85). Conclusions: Higher E/e’ indicating diastolic dysfunction,may be associated with 90-day mortality in patients with acute ischemic stroke. The DONE score could readily predict poor outcome after acute ischemic stroke

Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells

With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro

MAP Kinase Pathways in Brain Endothelial Cells and Crosstalk with Pericytes and Astrocytes Mediate Contrast-Induced Blood–Brain Barrier Disruption

Neurointervention with contrast media (CM) has rapidly increased, but the impact of CM extravasation and the related side effects remain controversial. This study investigated the effect of CM on blood–brain barrier (BBB) integrity. We established in vitro BBB models using primary cultures of rat BBB-related cells. To assess the effects of CM on BBB functions, we evaluated transendothelial electrical resistance, permeability, and tight junction (TJ) protein expression using immunohistochemistry (IHC) and Western blotting. To investigate the mechanism of iopamidol-induced barrier dysfunction, the role of mitogen-activated protein (MAP) kinases in brain endothelial cells was examined. We assessed the effect of conditioned medium derived from astrocytes and pericytes under iopamidol treatment. Short-term iopamidol exposure on the luminal side induced transient, while on the abluminal side caused persistent BBB dysfunction. IHC and immunoblotting revealed CM decreased the expression of TJ proteins. Iopamidol-induced barrier dysfunction was improved via the regulation of MAP kinase pathways. Conditioned medium from CM-exposed pericytes or astrocytes lacks the ability to enhance barrier function. CM may cause BBB dysfunction. MAP kinase pathways in brain endothelial cells and the interactions of astrocytes and pericytes mediate iopamidol-induced barrier dysfunction. CM extravasation may have negative effects on clinical outcomes in patients