Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticlederived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxideeliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and antiinflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen−glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, antiinflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.

Echocardiographic evaluation of right ventricular (RV) function is a challenge due to the complex anatomy of the RV. Several transthoracic echocardiographic methods have been suggested for the quantification of RV function. However, many of the parameters are time consuming and need dedicated hardware and software. We suspected that the majority of the established markers are not used on a wide basis. In a multinational online survey, we evaluated the use of current clinical standards for the quantification of RV function in clinical practice. Through the network of an Ultrasound Online Teaching Platform, echocardiographers were invited to participate in an open online survey. The participants were asked about the parameters (eyeballing, TAPSE, S', fractional area change, RIMP, 3D-EF, dp/dt, longitudinal strain) they used in clinical practice. A total of 1150 participants from 109 countries completed the survey. Only eyeballing (72%), TAPSE (69%), and S' (31%) were commonly used in clinical routine. These methods were applied significantly less common in low-income economies when compared to high-income economies. Twenty-three percent of all participants stated to rely on eyeballing only, when evaluating RV function in clinical routine. New technologies, such as global longitudinal strain (3%) and 3D echocardiography (1%) were rarely applied independent of region and economic strength. Eyeballing and TAPSE are the most widely used methods in echocardiography for the assessment of RV function. Although advanced parameters such as longitudinal strain and 3D echocardiography were shown to be highly accurate, they are rarely used in clinical routine.

Recent studies suggested that reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase is of functional importance in modulating vascular tone, and we have previously detected excessive superoxide production in tail-suspended hindlimb unweighting (HU) rat cerebral and carotid arteries. HU rat was a widely used model to simulate physiological effects on the vasculature. The present study tended to investigate whether NAD(P)H oxidase inhibition with apocynin influences vasoconstriction, endothelium-dependent relaxation, and nitrite/nitrate (NOx) content in HU rat cerebral and carotid arteries. Vascular contractile and dilate responses were assessed in a myograph organ bath. NOx content in cerebral and carotid arteries was measured. We found enhanced maximal contractile response and impaired endothelium-dependent relaxation in HU rat basilar (P < 0.01) and common carotid artery (P < 0.05); however, chronic treatment of apocynin (50 mg/kg/day) partially reversed abnormal vascular response. Furthermore, 21-day HU increased arterial NOx content (P < 0.01) in cerebral and carotid arteries compared with control rats; however, apocynin treatment restored it toward near-normal values. These data demonstrated that NAD(P)H oxidase-derived oxidative stress mediated abnormal vasoreactivity though nitric oxide mechanism in the settings of simulated microgravity.

To investigate the relationship between left ventricular (LV) myocardial mechanics evaluated by three-dimensional speckle tracking echocardiography (3D-STE) and degree of coronary artery stenosis in patients with coronary artery disease (CAD). Ninety-seven suspected CAD patients without LV regional wall motion abnormality (RWMA) observed visually form traditional echocardiography were divided into four groups according to coronary artery angiography (CAG): 23 patients in slight stenosis group [stenosis rate (SR) ≤25%], 26 patients in mild stenosis group (25< SR ≤50%), 28 patients in moderate stenosis group (50< SR ≤75%), and 20 patients in severe stenosis group (SR >75%). Global longitudinal strain (GLS), circumferential strain (GCS), radial strain (GRS), area strain (AS) and three dimensional strain (3D-Strain) were obtained. The parameters from 3D-STE were compared between different groups and then the diagnostic value of global strains indicating different graded coronary artery stenosis was analyzed by the receiver operating characteristic curve. (1) There were significant difference in GLS, GCS, GRS, GAS and 3D-Strain between the severe stenosis group and any other group while all 3D-STE parameters except GCS in the moderate stenosis group were remarkably different from those respectively in mild group. (2) Receiver operator characteristic curve (ROC) analysis showed that the area under the curve of GLS, GRS, GCS, GAS, 3D-Strain were 0.899, 0.873, 0.723, 0.856 and 0.863 respectively for the identification of stenosis rate >50%, and 0.896, 0.866, 0.797, 0.909 and 0.899 respectively for the identification of severe stenosis. GAS less than -29.13% allowed a sensitivity of 95% and a specificity of 71.4%, while 3D strain less than 41.35% allowed a sensitivity of 90% and a specificity of 80.5% for evaluating serve coronary artery stenosis. The myocardial mechanics from 3D-STE in the CAD patients were characteristic. It could be expected to identify serve coronary stenosis with a good sensitivity and an acceptable specificity by using GAS or 3D-strain especially in the suspected CAD patients without RWMA on conventional echocardiography.

Exposure to microgravity results in cardiovascular deconditioning, and cerebrovascular oxidative stress injury has been suggested to occur. To elucidate the mechanism for this condition, we investigated whether simulated microgravity induces mitochondrial dysfunction in rat arteries. Four-week hindlimb unweighting (HU) was used to simulate microgravity in rats. Mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), mitochondrial permeability transition pore (mPTP) opening, mitochondrial respiratory control ratio (RCR), MnSOD/GPx activity and expression, and mitochondrial malondialdehyde (MDA) were examined in rat cerebral and mesenteric VSMCs. Compared with the control rats, mitochondrial ROS levels, mPTP opening, and MDA content increased significantly (P<0.001, P<0.01, and P<0.01, respectively), Δψm, RCR, MnSOD/GPx activity (P<0.001 for Δψm and RCR; P<0.05 for MnSOD; and P<0.001 for GPx activity) and protein abundance of mitochondrial MnSOD/GPx-1 decreased (P<0.001 for MnSOD and GPx-1) in HU rat cerebral but not mesenteric arteries. Chronic treatment with NADPH oxidase inhibitor apocynin and mitochondria-targeted antioxidant mitoTempol promoted recovery of mitochondrial function in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, simulated microgravity resulted in cerebrovascular mitochondrial dysfunction, and crosstalk between NADPH oxidase and mitochondria participated in the process.

The complex anatomy and physiology of the right ventricle (RV) is a major limitation of visual echocardiographic gradation of RV systolic function (RVF). The aim of this study was to compare visual assessment (“eyeballing”) of RVF with gold standard magnetic resonance imaging (MRI)-derived right ventricular ejection fraction (RVEF). Medical professionals from a range of clinical settings and with varying degrees of echocardiography experience were recruited via an online ultrasound teaching platform. In an anonymized web-based test, participants graded RVF in 10 patients with varying degrees of RVF via “eyeballing” of an RV-focused four-chamber view. Two skills were evaluated: (1) ability to differentiate between normal and reduced RVF; and (2) ability to determine the correct degree of RV systolic dysfunction. A total of 868 participants from 99 countries were included. For detection of reduced RVF (MRI-RVEF < 50%), sensitivity was 97.1%, 96,8%, 96.5%, and 95.8% and specificity was 55.7%, 52.8%, 54.6%, and 42.5% for the expert, advanced, intermediate, and beginner groups, respectively. For determination of the correct degree of RV dysfunction, even experienced examiners assigned a diagnosis that was discordant with MRI in > 40% of cases. In the present cohort, “eyeballing” was associated with excellent sensitivity but poor specificity in terms of differentiation between normal and abnormal RVF. Even among experts, classification of the degree of RV dysfunction was imprecise. In accordance with current guidelines, the present data suggest that “eyeballing” should be combined with evaluation of other echocardiographic parameters of RVF.

2D STI combined with adenosine stress echocardiography could provide a new and reliable method to identify myocardium viability.

Adenosine A2A receptors (A2ARs) in distinct cellular types may exert different and even opposite effects on many neurologic disorders; A2ARs in bone marrow-derived cells (BMDCs) have been shown to play important roles in various brain injuries. We previously showed that global A2AR inactivation aggravates chronic cerebral hypoperfusion-induced white matter lesions (WMLs); however, the specific cell populations responsible for A2AR-mediated signaling remain unknown. In the present study, we developed chimeric mice in which A2ARs were either selectively inactivated or reconstituted in BMDCs by transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Chimeric mice were subsequently subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis, and the effects of BMDC A2ARs on WMLs were evaluated. The selective inactivation of A2AR in BMDCs aggravated chronic cerebral hypoperfusion-induced WMLs, promoted microglial activation, and increased proinflammatory cytokine expression, whereas the selective reconstitution or activation of A2AR in BMDCs using the agonist CGS21680 produced the opposite effects. These results demonstrate that A2ARs in BMDCs are important modulators of WMLs induced by chronic cerebral hypoperfusion; this modulation might be associated with the regulation of inflammatory cytokine production.