Endothelial Cx40 limits myocardial ischaemia/reperfusion injury in mice

Aims Gap junctions are indispensable for the function of heart and blood vessels by providing electrical coupling and direct cell-to-cell transfer of small signalling molecules. Gap junction channels between neighbouring cells are composed of 12 connexins (Cx). Changes in Cx43 expression, localization, and channel properties in cardiomyocytes contribute to infarction and reperfusion injury of the heart. It is increasingly recognized that deleterious consequences of ischaemia/reperfusion (IR) are modulated by the inflammatory response and endothelial function. The role of the endothelial connexins, i.e. Cx40 and Cx37, in cardiac IR injury is, however, not known. Methods and results Following 30 min ischaemia and 24 h reperfusion, we found a significant increase in myocardial infarct size in mice with endothelial-specific deletion of Cx40 (Cx40del), but not in Cx37-deficient mice. The cardioprotective effect of endothelial Cx40 was associated with a decrease in neutrophil infiltration. Moreover, beneficial effects of endothelial Cx40 were not observed in isolated Langendorff-perfused hearts, suggesting direct involvement of endothelial-leucocyte interactions in the cardiac injury. Single-dose administration of methotrexate, a CD73 activator, reduced infarct size and neutrophil infiltration into the infarcted myocardium in Cx40del but not in control mice. Similar to Cx40del mice, CD73-deficient mice showed increased sensitivity to cardiac IR injury, which could not be conversed by methotrexate. Conclusion Endothelial Cx40, but not Cx37, is implicated in resistance of the heart to IR injury by activation of the CD73 pathway. Thus, the Cx40-CD73 axis may represent an interesting target for controlling reperfusion damage associated with revascularization in coronary diseas

New vs. Given

This squib begins with an argument emphasizing that the grammar of English makes a distinction between constituents that are focused and those that are merely new, hence not given. If the distinction is made via features, we need two features: one indicating focus and one indicating either given or new information. Which one of the two? Semantically, the choice doesn’t matter: whatever information is given is not new and the other way round. For the phonology, there is a difference, however. If the prosody of all-new constituents is default prosody, but the prosody of given constituents is special, we would want to indicate givenness, rather than newness

Limb-shaking transient ischemic attacks: case report and review of literature

BACKGROUND: Limb shaking Transient Ischemic Attack is a rare manifestation of carotid-occlusive disease. The symptoms usually point towards a seizure like activity and misdiagnosed as focal seizures. On careful history the rhythmic seizure like activity reveals no Jacksonian march mainly precipitated by maneuvers which lead to carotid compression. We here present a case of an elderly gentleman who was initially worked up as suffering from epileptic discharge and then later on found to have carotid occlusion. CASE PRESENTATION: Elderly gentleman presented with symptoms of rhythmic jerky movements of the left arm and both the lower limbs. Clinical suspicion of focal epilepsy was made and EEG, MRI-Brain with MRA were done. EEG and MRI-Brain revealed normal findings but the MRA revealed complete occlusion of right internal carotid artery. On a follow-up visit jerky movements of the left arm were precipitated by hyperextension and a tremor of 3–4 Hz was revealed. Based on this the diagnosis of low flow TIA was made the patient was treated conservatively with adjustment of his anti-hypertensive and anti-platelet medications. CONCLUSION: Diagnosis of limb-shaking TIA is important and should be differentiated from other disorders presenting as tremors. Timely diagnosis is important as these patients are shown to benefit from reperfusion procedures either surgical or radiological reducing their risk of stroke

Phosphodiesterase-5 Inhibition Mimics Intermittent Reoxygenation and Improves Cardioprotection in the Hypoxic Myocardium

Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. Aim of the study: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O2) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. Conclusions: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms

Long-term prognosis of symptomatic isolated middle cerebral artery disease in Korean stroke patients

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate the long-term mortality and recurrence rate of stroke in first-time stroke patients with symptomatic isolated middle cerebral artery disease (MCAD) under medical management.</p> <p>Methods</p> <p>We identified 141 first ever stroke patients (mean age, 64.4 ± 12.5 years; 53% male) with symptomatic isolated MCAD. MCAD was defined as significant stenosis of more than 50% or occlusion of the MCA as revealed by MR angiography. The median follow-up was 27.7 months. We determined a cumulative rate of stroke recurrence and mortality by Kaplan-Meier survival analyses and sought predictors using the Cox proportional hazard model.</p> <p>Results</p> <p>The cumulative composite outcome rate (stroke recurrence or any-cause death) was 14%, 19%, 22%, and 28% at years 1, 2, 3, and 5, respectively. The annual recurrence rate of stroke was 4.1%. The presence of diabetes mellitus was the only significant independent predictor of stroke recurrence or any cause of death in multivariate analyses of Cox proportional hazard model adjusted for any plausible potential confounding factors.</p> <p>Conclusions</p> <p>We estimated the long-term prognosis of stroke patients with isolated symptomatic MCAD under current medical management in Korea. Diabetes mellitus was found to be a significant predictor for stroke recurrence and mortality.</p

Imaging features and safety and efficacy of endovascular stroke treatment: a meta-analysis of individual patient-level data

Background: Evidence regarding whether imaging can be used effectively to select patients for endovascular thrombectomy (EVT) is scarce. We aimed to investigate the association between baseline imaging features and safety and efficacy of EVT in acute ischaemic stroke caused by anterior large-vessel occlusion. Methods: In this meta-analysis of individual patient-level data, the HERMES collaboration identified in PubMed seven randomised trials in endovascular stroke that compared EVT with standard medical therapy, published between Jan 1, 2010, and Oct 31, 2017. Only trials that required vessel imaging to identify patients with proximal anterior circulation ischaemic stroke and that used predominantly stent retrievers or second-generation neurothrombectomy devices in the EVT group were included. Risk of bias was assessed with the Cochrane handbook methodology. Central investigators, masked to clinical information other than stroke side, categorised baseline imaging features of ischaemic change with the Alberta Stroke Program Early CT Score (ASPECTS) or according to involvement of more than 33% of middle cerebral artery territory, and by thrombus volume, hyperdensity, and collateral status. The primary endpoint was neurological functional disability scored on the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included symptomatic intracranial haemorrhage, parenchymal haematoma type 2 within 5 days of randomisation, and mortality within 90 days. For the primary analysis, we used mixed-methods ordinal logistic regression adjusted for age, sex, National Institutes of Health Stroke Scale score at admission, intravenous alteplase, and time from onset to randomisation, and we used interaction terms to test whether imaging categorisation at baseline modifies the association between treatment and outcome. This meta-analysis was prospectively designed by the HERMES executive committee but has not been registered. Findings: Among 1764 pooled patients, 871 were allocated to the EVT group and 893 to the control group. Risk of bias was low except in the THRACE study, which used unblinded assessment of outcomes 90 days after randomisation and MRI predominantly as the primary baseline imaging tool. The overall treatment effect favoured EVT (adjusted common odds ratio [cOR] for a shift towards better outcome on the mRS 2·00, 95% CI 1·69–2·38; p&lt;0·0001). EVT achieved better outcomes at 90 days than standard medical therapy alone across a broad range of baseline imaging categories. Mortality at 90 days (14·7% vs 17·3%, p=0·15), symptomatic intracranial haemorrhage (3·8% vs 3·5%, p=0·90), and parenchymal haematoma type 2 (5·6% vs 4·8%, p=0·52) did not differ between the EVT and control groups. No treatment effect modification by baseline imaging features was noted for mortality at 90 days and parenchymal haematoma type 2. Among patients with ASPECTS 0–4, symptomatic intracranial haemorrhage was seen in ten (19%) of 52 patients in the EVT group versus three (5%) of 66 patients in the control group (adjusted cOR 3·94, 95% CI 0·94–16·49; pinteraction=0·025), and among patients with more than 33% involvement of middle cerebral artery territory, symptomatic intracranial haemorrhage was observed in 15 (14%) of 108 patients in the EVT group versus four (4%) of 113 patients in the control group (4·17, 1·30–13·44, pinteraction=0·012). Interpretation: EVT achieves better outcomes at 90 days than standard medical therapy across a broad range of baseline imaging categories, including infarcts affecting more than 33% of middle cerebral artery territory or ASPECTS less than 6, although in these patients the risk of symptomatic intracranial haemorrhage was higher in the EVT group than the control group. This analysis provides preliminary evidence for potential use of EVT in patients with large infarcts at baseline. Funding: Medtronic

Glucose modifies the effect of endovascular thrombectomy in patients with acute stroke: a pooled-data meta-analysis

Background and Purpose: Hyperglycemia is a negative prognostic factor following acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy in patients with large vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of endovascular thrombectomy in acute stroke. Methods: Seven randomized trials compared endovascular thrombectomy with standard care between 2010 and 2017 (HERMES Collaboration). 1764 patients with large vessel stroke were allocated to endovascular thrombectomy (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome [modified Rankin Scale (mRS) range: 0-6; lower scores indicating less disability] at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results: Median (IQR) serum glucose on admission was 120 (104-140) mg/dl [6.6mmol/l (5.7-7.7) mmol/l]. Endovascular thrombectomy (EVT) was better than standard care in the overall pooled-data analysis [common odds ratio (acOR), 2.00 (95% CI 1.69–2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose &lt; or &gt; 90mg/dl (5.0mmol/l) [(p=0.019 for interaction, acOR 3.81 (95% CI 1.73–8.41) for patients &lt; 90 mg/dl vs 1.83 (95% CI 1.53–2.19) for patients &gt; 90 mg/dl], and glucose &lt; or &gt; 100mg/dl (5.5mmol/l) [(p=0.004 for interaction, acOR 3.17 (95% CI 2.04–4.93) vs acOR 1.72 (95% CI 1.42–2.08)], but not between subgroups above these levels of glucose. Conclusions: Endovascular thrombectomy improved stroke outcomes compared to standard treatment regardless of glucose levels but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100mg/dl (5.0-5.5mmol/l). Whether tight control of glucose improves the efficacy of endovascular thrombectomy following large vessel stroke warrants appropriate testing