Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway

The poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 has been reported to improve endothelial dysfunction in the peripheral system. We addressed the role of PJ34 on the vascular tone and vasoreactivity during development in the mouse brain. Blood flows were measured in the basilar trunk using ultrasonography. Cerebral vasoreactivity or vasodilation reserve was estimated as a percentage increase in mean blood flow velocities (mBFV) recorded under normoxia-hypercapnia in control and after PJ34 administration. Non-selective and selective eNOS and nNOS inhibitors were used to evaluate the role of NO-pathway into the hemodynamic effects of PJ34. PJ34 increased mBFVs from 15.8 ± 1.6 to 19.1 ± 1.9 cm/s (p = 0.0043) in neonatal, from 14.6 ± 1.4 to 16.1 ± 0.9 cm/s (p = 0.0049) in adult, and from 15.7 ± 1.7 to 17.5 ± 2.0 cm/s (p = 0.0024) in aged mice 48 h after administration. These PJ34 values were similar to those measured in age-matched control mice under normoxia-hypercapnia. This recruitment was mediated through the activation of constitutive NO synthases in both the neonatal (38.2 ± 6.7 nmol/min/mg protein) and adult (31.5 ± 4.4 nmol/min/mg protein) brain, as compared to age-matched control brain (6.9 ± 0.4 and 6.3 ± 0.7 nmol/min/mg protein), respectively. In addition, quite selective eNOS inhibitor was able to inhibit the recruitment. PJ34 by itself is able to increase cerebral blood flow through the NO-pathway activation at least over 48 h after a single administration

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain

The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular unit including the blood-brain barrier (BBB), microglia, and astrocytes. Nine-day-old mice were subjected to permanent MCA occlusion (pMCAo), and treated with either PBS or PJ34 (10 mg/kg). Mean blood-flow velocities (mBFV) were measured in both internal carotid arteries (ICA) and basilar trunk (BT) using Doppler-ultrasonography. BBB opening was assessed through somatostatin-receptor type-2 internalization and immunohistochemistry at 24 and 48 h. Lesion areas were measured 8 days after ischemia. In PBS-treated mice, pMCAo involved a drop in mBFV in the left ICA (p < 0.001 vs. basal), whereas mBFV remained stable in both right ICA and BT. PJ34 prevented this drop in the left ICA (NS vs. basal) and increased mBFV in the right ICA (p = 0.0038 vs. basal). No modification was observed in the BT. In contrast to PBS, BBB disruption extent and astrocyte demise were reduced in PJ34 mice only in the rostral brain at 48 h and 8 days post-pMCAo, respectively. Accordingly, 8 days after pMCAo, affected areas were reduced in the rostral brain (Bregma +0.86 and +0.14 mm), whereas total tissue loss was not reduced after PJ34 (4.0 ± 3.1%) vs. PBS (5.8 ± 3.4%). These results show that PJ34 reduced BBB permeability, astrocyte demise, and tissue loss (particularly in the rostral territories), suggesting that collateral supply mainly proceeds from the anterior ICA’s branches in the ischemic neonatal mouse brain

Imaging Cerebral Arteries Tortuosity and Velocities by Transcranial Doppler Ultrasound Is a Reliable Assessment of Brain Aneurysm in Mouse Models

Background During the past few decades, several pathophysiological processes contributing to intracranial aneurysm (IA) rupture have been identified, including irregular IA shape, altered hemodynamic stress within the IA, and vessel wall inflammation. The use of preclinical models of IA and imaging tools is paramount to better understand the underlying disease mechanisms. Methods We used 2 established mouse models of IA, and we analyzed the progression of the IA by magnetic resonance imaging, transcranial Doppler, and histology. Results In both models of IA, we observed, by transcranial Doppler, a significant decrease of the blood velocities and wall shear stress of the internal carotid arteries. We also observed the formation of tortuous arteries in both models that were correlated with the presence of an aneurysm as confirmed by magnetic resonance imaging and histology. A high grade of tortuosity is associated with a significant decrease of the mean blood flow velocities and a greater artery dilation. Conclusions Transcranial Doppler is a robust and convenient imaging method to evaluate the progression of IA. Detection of decreased blood flow velocities and increased tortuosity can be used as reliable indicators of IA

Platelet adhesion and secretion of the CXCL4 chemokine play a protective role during intracranial aneurysm

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Carte topographique de la Ville et des Faubourgs de Rouen, levée, dressée et. dessinée par Mrs J.G. Héliot et Hthe. Boutigny, Géomètres Architectes, sous la direction de Mr Lafosse, Architecte de la Ville. Dédiée à Monsieur le Maire de Rouen. 1 : 10 000 . Gravé par Blondeau, ...

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Blood Flow and Shear Stress Allow Monitoring of Progression and Prognosis of Tumor Diseases

International audienceIn the presence of tumor angiogenesis, blood flow must increase, leading to an elevation of blood flow velocities (BFVels) and wall shear stress (WSS) in upstream native arteries. An adaptive arterial remodeling is stimulated, whose purpose lies in the enlargement of the arterial inner diameter, aiming for normalization of BFVels and WSS. Remodeling engages delayed processes that are efficient only several weeks/months after initiation, independent from those governing expansion of the neovascular network. Therefore, during tumor expansion, there is a time interval during which elevation of BFVels and WSS could reflect disease progression. Conversely, during the period of stability, BFVels and WSS drop back to normal values due to the achievement of remodeling processes. Ovarian peritoneal carcinomatosis (OPC), pseudomyxoma peritonei (PMP), and superficial arteriovenous malformations (AVMs) are diseases characterized by the development of abnormal vascular networks developed on native ones. In OPC and PMP, preoperative blood flow in the superior mesenteric artery (SMA) correlated with the per-operative peritoneal carcinomatosis index (OPC: n = 21, R = 0.79, p < 0.0001, PMP: n = 66, R = 0.63, p < 0.0001). Moreover, 1 year after surgery, WSS in the SMA helped in distinguishing patients with PMP from those without disease progression [ROC-curve analysis, AUC = 0.978 (0.902–0.999), p < 0.0001, sensitivity: 100.0%, specificity: 93.5%, cutoff: 12.1 dynes/cm 2 ]. Similarly, WSS in the ipsilateral afferent arteries close to the lesion distinguished stable from progressive AVM [ROC-curve analysis, AUC: 0.988, (0.919–1.000), p < 0.0001, sensitivity: 93.5%, specificity: 95.7%; cutoff: 26.5 dynes/cm 2 ]. Blood flow volume is indicative of the tumor burden in OPC and PMP, and WSS represents an early sensitive and specific vascular marker of disease progression in PMP and AVM

OC 10.3 Platelets mediate intracranial aneurysm formation and rupture in mice

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Fink , a new generation of broker for the LSST community

accepted in MNRASInternational audienceFink is a broker designed to enable science with large time-domain alert streams such as the one from the upcoming Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST). It exhibits traditional astronomy broker features such as automatised ingestion, annotation, selection and redistribution of promising alerts for transient science. It is also designed to go beyond traditional broker features by providing real-time transient classification which is continuously improved by using state-of-the-art Deep Learning and Adaptive Learning techniques. These evolving added values will enable more accurate scientific output from LSST photometric data for diverse science cases while also leading to a higher incidence of new discoveries which shall accompany the evolution of the survey. In this paper we introduce Fink, its science motivation, architecture and current status including first science verification cases using the Zwicky Transient Facility alert stream