Mid-cerebral Artery Research Articles

Stroke Alters the Function of Enteric Neurons to Impair Smooth Muscle Relaxation and Dysregulates Gut Transit.

Gut dysmotility is common after ischemic stroke, but the mechanism underlying this response is unknown. Under homeostasis, gut motility is regulated by the neurons of the enteric nervous system that control contractile/relaxation activity of muscle cells in the gut wall. More recently, studies of gut inflammation revealed interactions of macrophages with enteric neurons are also involved in modulating gut motility. However, whether poststroke gut dysmotility is mediated by direct signaling to the enteric nervous system or indirectly via inflammatory macrophages is unknown. We examined these hypotheses by using a clinically relevant permanent intraluminal midcerebral artery occlusion experimental model of stroke. At 24 hours after stroke, we performed invivo and exvivo gut motility assays, flow cytometry, immunofluorescence, and transcriptomic analysis. Stroke-induced gut dysmotility was associated with recruitment of muscularis macrophages into the gastrointestinal tract and redistribution of muscularis macrophages away from myenteric ganglia. The permanent intraluminal midcerebral artery occlusion model caused changes in gene expression in muscularis macrophages consistent with an altered phenotype. While the size of myenteric ganglia after stroke was not altered, myenteric neurons from post-permanent intraluminal midcerebral artery occlusion mice showed a reduction in neuronal nitric oxide synthase expression, and this response was associated with enhanced intestinal smooth muscle contraction exvivo. Finally, chemical sympathectomy with 6-hydroxydopamine prevented the loss of myenteric neuronal nitric oxide synthase expression and stroke-induced slowed gut transit. Our findings demonstrate that activation of the sympathetic nervous system after stroke is associated with reduced neuronal nitric oxide synthase expression in myenteric neurons, resulting in impaired smooth muscle relaxation and dysregulation of gut transit.

DYNAMIC CEREBRAL BLOOD FLOW CHANGES ASSOCIATED WITH OFF PUMP CORONARY ARTERY BYPASS GRAFTING (OPCAB) ASSESSED BY A NOVEL, ROBOTIC ASSISTED, AUTONOMOUS, CONTINUOUS AND BILATERAL TRANSCRANIAL DOPPLER (TCD)

<h3>Background and Objectives</h3> There is ongoing controversy regarding the clinical and physiological benefit of OPCAB. While we have reported reduced perioperative mortality, neurological outcomes have not improved. Thus, further insights are needed to fully delineate the impact of OPCAB on the cerebral circulation. Here we present a novel strategy for continuous monitoring of mid cerebral artery (MCA) blood flow using the NovaGuide Robotic TCD system (NovaSignal Corp., Los Angeles CA USA) (figure 1). We have also employed cerebral tissue oximetry (Foresight, Edwards Lifesciences) to evaluate overall tissue oxygenation. <h3>Methods</h3> 7 elective OPCAB patients with no evidence of significant carotid disease were enrolled as part of our initial service evaluation. After anaesthesia induction, the patient head was stabilised in a specific cradle and robotic TCD probes were placed onto the patient's temporal region. The NovaGuide autonomously identified a transtemporal window, located the MCA vessels bilaterally and optimised the TCD signal. Baseline mean MCA flow was established prior to surgical manipulations and subsequent signals were automatically acquired for the entire duration of surgery. Data are reported as SEM +/- STD and group comparison was performed by ANOVA or t tests, as appropriate. <h3>Results</h3> There were no adverse events related to head positioning or access to central lines or placement of transoesophageal echo probes and routine monitoring. The device did not interfere with surgical conduct. Mean MCA flows at baseline were 43 +/-12 and 42 +/-13 cm/s for left and right MCA respectively. Pre-grafting events such as skin incision, sternotomy, and pericardiotomy increased LMCA flow by 14 +/- 35 24 +/- 27 and 17 +/- 20% with similar changes in RMCA flows. Mild Trendelenburg position and graded increase in MAP as pre-optimisation measures increased cerebral blood flow. While lifting and positioning the heart for grafting and placing the Octopus stabiliser generally reduced TCD levels, they remained higher than preoperative values (14+/-20; 31 +/- 36 and 9+/- 9 % increase for LAD, OM and PDA grafts, respectively). No significant changes were observed by clamping or anastomosing or reperfusing the respective coronary arteries. There was a transient increase in TCD signals upon replacing the heart in the pericardium after completing the anastomoses (28+/-7; 20 +/- 26 and 22 +/-29 % increase for LAD, OM and PDA positions, respectively). There were minor changes upon conducting the aortic anastomoses, but rare singular embolic events were noted occasionally upon releasing the aortic side clamp. Baseline left and right cerebral StO2 was identical (67+/-4 and 67+/-2) and showed little variation throughout surgery (<5%). <h3>Conclusion</h3> Continuous monitoring of bilateral TCD using the robotic TCD system is feasible during OPCAB. There are characteristic changes in TCD values at various phases of the operation, but our current optimisation strategy appears to preserve cerebral blood flow. Future validation studies are required which should address clinical correlates in high-risk patients including those with cerebrovascular disease.

The role of β2 adrenergic receptor on infection development after ischaemic stroke

Mechanisms underlying post-stroke immune impairments and subsequent development of fatal lung infection have been suggested to involve multiple pathways, including hyperactivation of the sympathetic nervous system (SNS), which results in the excessive release of catecholamines and activation of β-adrenergic receptors (βARs). Indeed, previous reports from experimental studies demonstrated that post-stroke infection can be inhibited with treatment of β-blockers. However, the effectiveness of β-blockers in reducing post-stroke infection has yielded mixed results in retrospective clinical trials and its use remain controversial. In this study, we performed mid-cerebral artery occlusion in mice either genetically deficient in β2-adrenergic receptor (β2AR) or treated with non-selective and selective βAR antagonists to explore the contributions of the SNS in the development of post-stroke lung infection. Stroke induced a systemic activation of the SNS as indicated by elevated levels of plasma catecholamines and UCP-1 activity. However, β2AR deficient mice showed similar degrees of post-stroke immune impairment and infection rate compared to wildtype counterparts, potentially due to compensatory mechanisms common in transgenic animals. To overcome this, we treated post-stroke wildtype mice with pharmacological inhibitors of the βARs, including the non-selective antagonist propranolol (PPL) and selective β2AR antagonist ICI-118551. Both pharmacological strategies to block the action of SNS signalling were unable to reduce infection in mice that underwent ischaemic stroke. Overall, our data suggests that other mechanisms independent or in combination with β2AR activation contribute to the development of post-stroke infection.

Efficiency of Leg Exoskeleton Use in Rehabilitation of Cerebral Stroke Patients

Abstract The study aimed to evaluate the effectiveness of functional and motor activity restoration, including the walking function, in patients after an ischemic stroke using the ExoAtlet lower limb exoskeleton. Patients and methods. A clinical study was carried out on 42 patients who had undergone a cerebral infarction in the mid cerebral artery system with a post-stroke paresis of the leg, and who had undergone a rehabilitation course in a round-theclock hospital during the early recovery period. Patients were randomized into two equal groups comparable in terms of the stroke severity: the patients in group 1 were receiving a standard rehabilitation program (control group), the patients in group 2 were additionally receiving a course of gait rehabilitation using the ExoAtlet exoskeleton - 10 sessions, 5 sessions per week for 14 days. Results. The study demonstrated the effectiveness of the ExoAtlet exoskeleton used in the rehabilitation of stroke patients over the standard course of rehabilitation. The advantages include a decrease in the hemiparesis degree, an increase in the muscle strength of the paretic limb, an improvement in balance, an improvement and acceleration of the walking process. The obtained results of the instrumental study confirmed the benefits of physical training on the Exoskeleton, which was demonstrated through an increase in stability and balance, as well as through a decrease in the energy consumption index for maintaining the stable verticalization. Conclusion. The usage of the ExoAtlet exoskeleton increases the effectiveness of rehabilitation measures and improves motor and functional activities of patients who have suffered a cerebral stroke.

Parameteric estimation in doppler’s effect forecasts

In present study, we have attempted the Umbilical artery evaluation which will further help us to recognize the high risk IUGR cases by the AEDV or the REDV. Objective of this paper is to estimate the utility of the umbilical artery including mid cerebral artery (MCA) parameters in Doppler’s effect forecasts of perinatal negative effects in medically diagnosed IUGR pregnancies. PI of MCA was studied in all our 50 cases. It is found that PI of MCA had the sensitivity of 87.5% & the low specificity of 46% in forecasting negative perinatal outcomes. In this study it is observed that in contrast to 88% in UA-PI and 66% in MCA-PI, the diagnostic precision of the MCA / UATPI ratio (90 per cent) was higher when taken separately.

The ability of various cerebroplacental ratio thresholds to predict adverse neonatal outcomes in term fetuses exhibiting late-onset fetal growth restriction.

Our primary aim was to evaluate the ability of various cerebroplacental ratio (CPR) reference values suggested by the Fetal Medicine Foundation to predict adverse neonatal outcomes in term fetuses exhibiting late-onset fetal growth restriction (LOFGR). Our secondary aim was to evaluate the effectiveness of other obstetric Doppler parameters used to assess fetal well-being in terms of predicting adverse neonatal outcomes. This was a retrospective cohort study of 317 pregnant women diagnosed with LOFGR at 37-40weeks of gestation between January 1, 2016, and September 1, 2019. Receiver operating characteristic (ROC) curves were drawn to determine the predictive performance of CPR <1, CPR <5th or <10th percentile, and umbilical artery pulsatility (PI) >95th percentile in terms of predicting adverse neonatal outcomes. Pregnant women exhibiting LOFGR who gave birth in our clinic during the study period at a mean of 38 gestational weeks (minimum 37+0; maximum 40+6 weeks); the median CPR was 1.51 [interquartile range (IQR) 1.12-1.95] and median birthweight 2,350g (IQR 2,125-2,575g). The CPR <5th percentile best predicted adverse neonatal outcomes [area under the curve (AUC) 0.762, 95% confidence interval (CI) 0.672-0.853, p<0.0001] and CPR <1 was the worst predictor (AUC 0.630, 95% CI 0.515-0.745, p=0.021). Of other Doppler parameters, neither the umbilical artery systole/diastole ratio nor the mid-cerebral artery to peak systolic velocity ratio (MCA-PSV) predicted adverse neonatal outcomes (AUC 0.598, 95% CI 0.480-0.598, p=0.104; AUC 0.521, 95% CI 0.396-0.521, p=0.744 respectively). The CPR values below the 5th percentile better predicted adverse neonatal outcomes in pregnancies complicated by LOFGR than the UA PI and CPR <1 by using Fetal Medicine Foundation reference ranges.

Brain computed tomography angiography in postcardiac arrest patients and neurologic outcome.

ObjectiveThis study aimed to analyze intracranial vessels using brain computed tomography angiography (CTA) and scoring systems to diagnose brain death and predict poor neurologic outcomes of postcardiac arrest patients.MethodsInitial brain CTA images of postcardiac arrest patients were analyzed using scoring systems to determine a lack of opacification and diagnose brain death. The primary outcome was poor neurologic outcome, which was defined as cerebral performance category score 3 to 5. The frequency, sensitivity, specificity, positive predictive value, negative predictive value, and area under receiver operating characteristic curve for the lack of opacification of each vessel and for each scoring system used to predict poor neurologic outcomes were determined.ResultsPatients with poor neurologic outcomes lacked opacification of the intracranial vessels, most commonly in the vein of Galen, both internal cerebral veins, and the mid cerebral artery (M4). The 7-score results (P=0.04) and 10-score results were significantly different (P=0.04) between outcome groups, with an area under receiver operating characteristic of 0.61 (range, 0.48 to 0.72). The lack of opacification of each intracranial vessel and all scoring systems exhibited high specificity (100%) and positive predictive values (100%) for predicting poor neurologic outcomes.ConclusionLack of opacification of vessels on brain CTA exhibited high specificity for predicting poor neurologic outcomes of patients after cardiac arrest.

T53

The simultaneous occurrence of acute ST-segment elevation myocardial infarction and acute ischemic stroke is an uncommon and complex clinical presentation. Although the medical treatment of both diseases is similar, data regarding optimal reperfusion therapy are limited. Nevertheless, use of tissue plasminogen activator may be a reasonable strategy for treatment of both diseases. We present a rare case of coexisting thrombosis of the coronary artery and mid cerebral artery that was managed successfully with tissue plasminogen activator thrombolytic therapy.

The state of the fetus circulation in congenital malformations of the fetus with placental dysfunction

Introduction. Improvement of perinatal care in Ukraine has led to a decrease in early neonatal mortality, but a decrease in antenatal losses has not occurred. In the structure of antenatal fetal death (AFD), congenital malformations (CM) account for about one fifth of reproductive losses and their percentage increases annually. A frequent complication during pregnancy with CM is placental dysfunction (PD), which occurs according to different authors in 19-69%. Primary dysfunction of the placenta with CM has a progressive nature, the consequence of which is AFD in various periods of pregnancy.The aim of the study - to reduce the frequency of antenatal fetal death in women with CM based on the determination of Doppler blood flow indicators in the feto-placental complex (FPC) and their timely delivery. Materials and Methods. The state of the feto-placental complex was monitored in 100 pregnant women with CM of the fetus in the period of 37-40 weeks of pregnancy. Studies were conducted in the uterine arteries (UA), umbilical arteries (UA), mid-cerebral artery (MCA) and fetal aorta (FA) with the definition of indicators of resistance index (RI), systolic-diastolic ratio (SDR) and pulse index (PI) . The control group (CG) consisted of 25 pregnant women, who gave birth to healthy children. The results of the study and their discussion. Examination and dynamic observation of 100 pregnant women with CM of the fetus allowed us to diagnose PD in the overwhelming number of pregnant women (41 pregnant - 41%), who manifested manifestations of fetal distress at 8.0 ± 2.71%, FGR at 29.76 ± 4.46% and FGR in combination with shallow water 3.24 ± 0.91%. For the purpose of a detailed analysis of the possible mechanisms of antenatal tanathogenesis, the patients were divided into two groups - with impaired blood flow in the FPC (OG1 - 41 pregnant) and without them (OG2 - 59 pregnant). It was pregnant OG1 that had manifestations of PD (distress, FGR and combination of FGR with low water). This separation allowed us to see the following picture of blood flow disorders.Analysis of the Doppler indices in UA showed that there is an increase in SDR in both UA, while the RI did not have a significant difference compared with CG and pregnant MG2. However, the correlation analysis did not indicate the presence of a relationship between blood flow disorders in UA and antenatal fetal death, which does not allow considering blood flow disorders in UA as stage of antenatal tanathogenesis.In pregnant MG1, a significantly higher RI index was found in UA compared with CG and MG2. PI did not have a significant difference compared with CG and pregnant women withCDF without PD. An analysis of blood flow in the MCA revealed a significant decrease in PI in pregnant MG1. A significant decrease in peripheral resistance to blood flow in the MCA can be a compensatory response to the deterioration of the fetal-placental blood circulation and is considered as indirect sign of brain congestion (the phenomenon of centralized blood flow). Analysis of the Doppler parameters in the AP testified to an increase in RI compared with the CG. An increase in RI in the aorta of the fetus may indicate a strain on the fetal heart during PD and may be a marker of the formation of congenital cardiomegaly in them.Conclusions. With CM of the fetus in combination with PD, deeper disturbances are observed in the utero-placental and placental-fetal complexes. In-time diagnosis of impaired blood flow allows in-time delivery of women with CM and reducing the risk of AFD.

Relationship between aortic pulse wave velocity and mid cerebral artery pulsatility index in patients with chronic obstructive pulmonary disease; pilot data from the ARCADE Study

BackgroundChronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with increased cardiovascular risk. COPD patients have increased aortic stiffness and increased risk of stroke. In addition, increased mid cerebral artery pulsatility index (MCAPI) is associated with increased arterial stiffness and risk of stroke in patients with Diabetes. However, the mechanisms relating to the increased risk of stroke in COPD remain unclear. Therefore, this study aims to investigate the relationship between aortic pulse wave velocity (aPWV) and the MCAPI in COPD patients.MethodsThis Cross-sectional evaluation included 20 COPD patients (mean ±SD, age 69.0 ±6.3 years) from the ACRADE study. aPWV was measured using the SphygmoCor system and MCAPI using transcranial Doppler ultrasound. In addition, forced expiratory volume in the first second/ forced vital capacity (FEV1/FVC) was measured using spirometry and quality of life was assessed using the St George’s Respiratory Questionnaire (SGRQ). Measures of frailty were assessed using Time-Up-and-Go test (TUG) and the Comprehensive Geriatric Assessment (CGA).ResultsMCAPI was significantly associated with aPWV (r = 0.518, P = 0.033). aPWV was significantly associated with SGRQ disease impact (r = 0.604, P = 0.010) and also associated with TUG (r=0.561, P=0.019) and CGA (r = 0.639, P = 0.006).ConclusionsThese pilot data highlight the association between increased aortic stiffness and increased pulsatile flow velocity transmitted to the cerebral circulation of COPD patients. In addition, COPD symptoms, impact and frailty are both associated with increased aortic stiffness. However, more research is needed to investigate cause and effect between COPD symptoms, impact and its relationship between aPWV and cerebral flow pulsatility.

Effect of hydrogen on mitochondrial membrane potential during focal cerebral ischemia-reperfusion in rats

Objective To investigate the effect of hydrogen on mitochondrial membrane potential during focal cerebral ischemia-reperfusion (I/R) in rats. Methods Eighty-four healthy adult male SPF Sprague-Dawley rats, weighing 220-240 g, were divided into 3 groups (n=28 each) using a random number table: sham operation group (Sham group), I/R group and hydrogen group (H2 group). Focal cerebral I/R was produced by mid-cerebral artery occlusion in I/R and H2 groups.Hydrogen 10 ml/kg was intraperitoneally injected immediately after onset of reperfusion and at 12 h of reperfusion in group H2.Neurological deficit was scored at 24 h of reperfusion.The rats were then sacrificed and brain tissues in cortex were removed for microscopic examination of the pathological changes and for determination of cerebral infarct size (by TTC staining), nerve cell apoptosis (by TUNEL), mitochondrial membrane potential(by JC-1 staining) and expression of Bcl-2 and Bax (by Western blot). Apoptotic index (AI) was calculated. Results Compared with Sham group, the neurological deficit score, percentage of cerebral infarct size and AI were significantly increased, the mitochondrial membrane potential was decreased, Bax expression in brain tissues was up-regulated, and Bcl-2 expression in brain tissues was down-regulated in I/R and H2 groups (P<0.05). Compared with I/R group, the neurological deficit score, percentage of cerebral infarct size and AI were significantly decreased, the mitochondrial membrane potential was increased, Bax expression in brain tissues was down-regulated, and Bcl-2 expression in brain tissues was up-regulated (P<0.05), and the pathological changes of brain tissues were significantly attenuated in H2 group. Conclusion The mechanism by which hydrogen reduces focal cerebral I/R injury is related to decreasing dissipation of mitochondrial membrane potential and inhibiting nerve cell apoptosis in rats. Key words: Hydrogen; Reperfusion injury; Brain; Membrane potential, mitochondrial

Activation of Endothelial Nitric Oxide Production by the Sigma Receptor Agonist Afobazole

Afobazole is a sigma‐1 receptor agonist that has been shown to enhance survival in a rat mid‐cerebral artery occlusion stroke model. The mechanism has been previously attributed to an inhibition of ischemia‐induced calcium dysregulation that lowers glial cell loss and infarct volume. A recently published finding is that afobazole can stimulate nitric oxide (NO) production from lymphatic endothelial cells. In the current study, we investigated the ability of afobazole to relax arterioles from the brain and potential interactions between the sigma‐1 receptor and endothelial NO synthase (eNOS). Parenchymal arterioles were isolated from brains of Sprague‐Dawley rats and mounted onto glass micropipettes in a 37 °C bath containing albumin‐physiological salt solution. Afobazole was applied to the bath at concentrations of 50, 100, 150, 200, and 250 μM. The ability of afobazole to elicit NO production from cultured human brain microvascular endothelial cells (HBMEC) was assessed using 4‐Amino‐5‐Methylamino‐2′,7′‐Difluorofluorescein Diacetate (DAF‐FM) loading and fluorescence microscopy. Phosphorylation of eNOS on Ser‐1177 in the absence or presence of afobazole was evaluated by Western blotting. Lastly, intracellular localization of eNOS and the sigma‐1 receptor were evaluated by immunofluorescence and laser confocal microscopy. The results show that 200 and 250 μM afobazole elicited significant dilation of parenchymal arterioles. Afobazole also elicited elevated NO production from HBMEC in association with elevated phosphorylation of eNOS on Ser‐177. Lastly, eNOS and the sigma‐1 receptor were found partially colocalized in what appears to be the Golgi complex in confocal image stacks of HBMEC. This study shows for the first time a novel mechanism by which afobazole can relax brain arterioles via eNOS‐mediated NO production. This mechanism is likely associated with previously reported improvements of outcomes following stroke induced brain injury.Support or Funding InformationSupported by NIH grant R01GM120774.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The role of argon in stroke

Stroke, also known as “cerebrovascular accident”, is an acute cerebrovascular disease that is caused by a sudden rupture of blood vessels in the brain or obstruction of the blood supply by blockage of blood vessels, thus including hemorrhagic and ischemic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, and accounts for 80% of the total number of strokes. However, the mortality rate of hemorrhagic stroke is relatively high. Internal carotid artery and vertebral artery occlusion and stenosis can cause ischemic stroke, and especially males over 40 years of age are at a high risk of morbidity. According to the survey, stroke in urban and rural areas has become the first cause of death in China. It is also the leading cause of disability in Chinese adults. In a word, stroke is characterized by high morbidity, high mortality and high disability rates. Studies have shown that many noble gases have the neuroprotective effects. For example, xenon has been extensively studied in various animal models of neurological injury including stroke, hypoxic-ischemic encephalopathy. Compared to xenon, Argon, as a noble gas, is abundant, cheap and widely applicable, and has been also demonstrated to be neuroprotective in many research studies. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals. Argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. Therefore the neuroprotective effects of argon may be of possible clinical use for opening a potential therapeutic window in stroke. It is important to illuminate the mechanisms of argon in nerve function and to explore the best use of this gas in stroke treatment.

Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke

Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- primary murine neurons and glia were exposed to oxygen glucose deprivation (OGD) and cell viability was assessed. Transient cerebral ischemia/reperfusion injury was induced by mid-cerebral artery occlusion (MCAO) in wild-type and IFNAR1-/- and IFNAR2-/- mice in vivo, and infarct size, and molecular parameters measured. To block IFNAR1 signalling, wild-type mice were treated with a blocking monoclonal antibody directed to IFNAR1 (MAR-1) and MCAO was performed. Quantitative PCR confirmed MCAO in wild-type mice induced a robust type-I interferon gene regulatory signature. Primary cultured IFNAR1-deficient neurons were found to be protected from cell death when exposed to OGD in contrast to primary cultured IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 n = 8) compared to wild-type controls (65.1 ± 4.8 mm3 n = 8). Western blot and immunohistochemistry showed alterations in Akt and Stat-3 phosphorylation profiles in the IFNAR1-/- brain. MAR-1 injection into WT mice (i.v. 0.5 mg 60 min prior to MCAO) resulted in a 60% decrease in infarct size when compared to the IgG control. IFNAR2-/- mice failed to display the neuroprotective phenotype seen in IFNAR1-/- mice after MCAO. Our data proposes that central nervous system signalling through IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.

The Molecular Pathway of Argon-Mediated Neuroprotection.

The noble gas argon has attracted increasing attention in recent years, especially because of its neuroprotective properties. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals, argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. As an inert molecule, argon did not show signs of adverse effects in the in vitro and in vivo model used, while being comparably cheap and easy to apply. However, the molecular mechanism by which argon is able to exert its protective and beneficial characteristics remains unclear. Although there are many pieces missing to complete the signaling pathway throughout the cell, it is the aim of this review to summarize the known parts of the molecular pathways and to combine them to provide a clear insight into the cellular pathway, starting with the receptors that may be involved in mediating argons effects and ending with the translational response.

Smooth muscle-generated methylglyoxal impairs endothelial cell-mediated vasodilatation of cerebral microvessels in type 1 diabetic rats.

Endothelial cell-mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia-reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs). Endothelial cell-mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia-reperfusion injury were assessed in brains of male Sprague-Dawley rats with streptozotocin-induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal-degrading enzyme glyoxalase-I (Glo-I) in cSMCs. After 7-8weeks of T1D, endothelial cell-mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF-κB activity and TNF-α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid-cerebral artery exacerbated ischaemia-reperfusion injury. In cSMCs, Glo-I protein was decreased, and the methylglyoxal-synthesizing enzyme, vascular adhesion protein 1 (VAP-1) and methylglyoxal were increased. Restoring Glo-I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP-1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia-reperfusion injury and increased microvessel perfusion. Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia-reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D.

Abstract 19271: Lack of Sufficient Pulsatile Flow in the Microvasculature May Contribute to Increased Microvascular Complications in Patients Implanted With Continuous Flow Left Ventricular Assist Devices

Background: In patients on continuous flow left ventricular assist devices (CF-LVAD) support, low pulsatility has been implicated in the development of microvascular complications such as gastrointestinal bleeds and strokes. The aim of this study was to measure and compare the microvascular flow profiles of both CF-LVAD patients and age matched healthy controls. Methods: The cuff based Mobil-O-Graph system (IEM) was used to measure supine blood pressure (BP) in 6 patients implanted with a CF-LVAD. Using the captured brachial pressures and associated waveform, the inbuilt ARCSolver algorithm was used to calculate central systolic and diastolic pressures, augmentation index (AIx) and aortic pulse wave velocity (aPWV). Pulsatility index (PI) of the central retinal (CR) and mid cerebral artery (MCA) was measured using a 12MHz linear probe with vivid-Q ultrasound and 2MHz transcranial Doppler ultrasound, respectively. Similar measurements were recorded in 13 healthy, age, mean pressure and aPWV matched controls. Results: Brachial and central pulse pressures were both significantly lower in CF-LVAD patients compared to controls. In addition, PI was significantly lower in the CF-LVAD group compared to controls in the CR and MCA (Table). Conclusion: Our data provide the first evidence that pulsatile flow is significantly lower in the microcirculation of CF-LVAD patients compared to healthy controls. This lack of pulsatile flow to appropriately stimulate the endothelium and replicate normal healthy haemodynamics, may in part be responsible for the increased risk of microvascular complications in CF-LVAD patients. As this is a pilot study, more mechanistic studies assessing macro and microvascular flow haemodynamics in CF-LVAD patients are needed to understand these associations further. Table.

Cognitive tasks during walking affect cerebral blood flow signal features in middle cerebral arteries and their correlation to gait characteristics.

Gait is a complex process involving both cognitive and sensory ability and is strongly impacted by the environment. In this paper, we propose to study of the impact of a cognitive task during gait on the cerebral blood flow velocity, the blood flow signal features and the correlation of gait and blood flow features through a dual task methodology. Both cerebral blood flow velocity and gait characteristics of eleven participants with no history of brain or gait conditions were recorded using transcranial Doppler on mid-cerebral artery while on a treadmill. The cognitive task was induced by a backward counting starting from 10,000 with decrement of 7. Central blood flow velocity raw and envelope features were extracted in both time, frequency and time-scale domain; information-theoretic metrics were also extracted and statistical significances were inspected. A similar feature extraction was performed on the stride interval signal. Statistical differences between the cognitive and baseline trials, between the left and right mid-cerebral arteries signals and the impact of the antropometric variables where studied using linear mixed models. No statistical differences were found between the left and right mid-cerebral arteries flows or the baseline and cognitive state gait features, while statistical differences for specific features were measured between cognitive and baseline states. These statistical differences found between the baseline and cognitive states show that cognitive process has an impact on the cerebral activity during walking. The state was found to have an impact on the correlation between the gait and blood flow features.

Asymptomatic carotid artery stenosis--is screening useful?

Stenoses of the carotid artery are associated with an increased stroke risk. Duplex ultrasound is the method of choice for screening for carotid artery stenosis. Unselected screening for carotid stenosis in unselected persons is not efficient and cannot be recommended. Screening by vascular ultrasound, however, is indicated in patients with neurologic symptoms from cerebral territories supplied by the anterior or mid cerebral artery, and in asymptomatic patients with carotid bruits, atherosclerotic disease in other vascular territories, after contralateral carotid artery revascularization, and after radiation therapy of the neck.

RIG-I Signaling in the Innate Immune Response After Stroke (INM1P.445)

Abstract Stroke is associated with an inflammatory response that contributes to deleterious outcomes. However, the molecular basis in the regulation of inflammation remains poorly understood. Here, we examine the activation of retinoic acid inducible gene-like (RIG) receptors (RLRs) and the involvement of RLR signaling in the regulation of type I IFNs following mid-cerebral artery occlusion (MCAO). In this study we show that in the rat hippocampus RIG-I and IFN-α expression are increased after MCAO. Similarly, we show that in astrocytes in culture, oxygen glucose deprivation (OGD) resulted in increased RIG-I and IFN-α expression. These data are consistent with immunohistochemical analysis of hippocampal sections, indicating that in glial fibrillary acidic protein (GFAP) positive cells there was an increase in RIG-I immunoreactivity after MCAO. Moreover, n-propyl gallate (n-PG) can be used to inhibit RIG-I/IFN-α signaling in astrocytes. In conclusion, these data indicate that RIG-I is involved in the inflammatory response after stroke.