Secondary Infarction Research Articles

Optic nerve sheath diameter and optic nerve sheath diameter/eyeball transverse diameter ratio in prediction of malignant progression in ischemic stroke.

BackgroundThe optic nerve sheath diameter (ONSD)/eyeball transverse diameter (ETD) ratio has been suggested in the evaluation of intracranial pressure (ICP). The aim of this study was to evaluate the predictive value of ONSD and ONSD/ETD in relation to risk for secondary malignant middle cerebral artery infarction (MMI).MethodsA total of 91 patients with MCA occlusion were included in this study. Data were divided into two groups based on development of MMI or not. ONSD and ETD were measured by unenhanced computed tomography (CT). The differences in ONSD and the ONSD/ETD ratios between the MMI and non-MMI groups were compared. Receiver operating characteristic curve analyses were used to test the diagnostic value of ONSD and ONSD/ETD independently, to predict MMI.ResultsThe ONSD in the MMI group and non-MMI group were 5.744 ± 0.140 mm and 5.443 ± 0.315 mm, respectively (P = 0.001). In addition, the ONSD/ETD ratios in the MMI group and non-MMI group were 0.258 ± 0.008 and 0.245 ± 0.006, respectively (P = 0.001). The receiver operating characteristic (ROC) curve demonstrated an area under the curve (AUC) for ONSD of 0.812 [95% confidence interval (CI): 0.718–0.906, P = 0.001], with a sensitivity of 97.4% and a specificity of 66.0% at the cut-off value of 5.520 mm. The AUC for ONSD/ETD ratio in predicting occurrence of MMI was 0.895 (95% CI: 0.823–0.968, P = 0.001), with a sensitivity of 84.2% and a specificity of 92.5% at a cut-off value of 0.250.ConclusionIn acute stroke patients with massive cerebral infarction, an increased ONSD or ONSD/ETD ratio increases the odds of malignant progression and may be used as an indicator for emergent therapeutic interventions. In addition, the ONSD/ETD ratio may be more valuable than ONSD in predicting the malignant progression of acute stroke patients.

Xanthogranuloma of the Sellar Region: A Comprehensive Review of Neuroimaging in a Rare Inflammatory Entity.

Xanthogranuloma of the sellar region is a rare chronic inflammatory lesion resulting from secondary hemorrhage, inflammation, infarction, and necrosis of an existing Rathke’s cleft cyst, craniopharyngioma, or pituitary adenoma. Sellar xanthogranulomas are challenging to differentiate from other cystic lesions preoperatively due to the lack of characteristic imaging features. We performed a literature overview of the clinical and paraclinical features, treatment options, and long-term outcomes of patients with sellar xanthogranuloma, focusing on the preoperative radiological diagnosis. The hyperintense signal in both T1- and T2-weighted sequences, cystic or partially cystic morphology, ovoid shape, sellar epicenter, intra- and suprasellar location, intratumoral calcifications, linear rim contrast enhancement, and the absence of cavernous sinus invasion suggest xanthogranuloma in the preoperative differential diagnosis. An endoscopic endonasal gross total resection without radiotherapy is the preferred first-line treatment. Given the low rate of recurrence rate and low chance of endocrinological recovery, a mass reduction with decompression of the optic apparatus may represent an appropriate surgical goal. Identifying the xanthogranulomas’ mutational profile could complement histopathological diagnosis and give insight into their histo-pathogenesis. A better preoperative neuroimagistic diagnosis of sellar xanthogranulomas and differentiation from lesions with a poorer prognosis, such as craniopharyngioma, would result in an optimal personalized surgical approach.

Purpura Fulminans Triggered by the Formation of Anti-Endothelial Autoantibodies in a Patient with Chronic Lymphocytic Leukemia

Purpura fulminans (PF), a life-threatening disorder characterized by cutaneous microvascular thrombosis with secondary hemorrhagic infarction, is a rare complication of sepsis and may also be caused by severe protein C or protein S deficiency. Here, we describe the case of a 58-year-old man who developed PF in close association with the onset of chronic lymphocytic leukemia (CLL). PF initially manifested with an ecchymosis of the right upper leg in the absence of sepsis or disseminated intravascular coagulation. PF was likely triggered by antiendothelial IgG autoantibodies functionally interfering with the anticoagulant protein C-protein S-thrombomodulin system on EA.hy926 endothelial cells in a modified thrombin generation assay. Although plasma exchange and immunosuppressive therapy with cyclophosphamide were temporarily effective, PF eventually progressed and the patient died from septic shock during treatment-associated neutropenia. In rare occasions, CLL may be associated with autoimmune-mediated PF requiring prompt diagnosis and aggressive multimodal therapy.

Loss of Kir6.1 facilitates peri-infarct depolarizations in focal cerebral ischemia

ABSTRACT Objective Peri-infarct depolarizations (PIDs) are spontaneous waves that propagate slowly across the penumbra region following stroke, contributing to secondary infarct growth and negatively affecting stroke outcomes. KATP channels are generally spread in the brain. Under conditions of ischemia and/or hypoxia, KATP channels play a cytoprotective role in neurons. However, it is still unknown whether KATP channels are involved in the initiation and propagation of PIDs. Methods The Kir6.1 knockout (Kir6.1−/−) mice, Kir6.2 knockout (Kir6.2−/−) mice, and wild-type C57Bl6 mice (n = 8) were used. The middle cerebral artery occlusion (MCAO) stroke model was made and PIDs were detected by an optical intrinsic signal (OIS) imaging system. Results Much more PIDs appeared in Kir6.1−/−mice than that in Kir6.2−/− and WT mice in both the first hour and 4 hours following MCAO (3.9 ± 0.7 vs. 1.5 ± 0.3, p < 0,05; 3.9 ± 0.7 vs. 1.9 ± 0.3, p < 0.05; 20.0 ± 2.5 vs. 10.4 ± 2.4, p < 0.05; 20.0 ± 2.5 vs. 11.3 ± 1.4, p < 0.05). Furthermore, the first PID occurred much earlier in Kir6.1−/− mice than that in Kir6.2−/− mice and WT mice (21.3 ± 2.1 min vs. 34.1 ± 4.8 min, p < 0.05; 21.3 ± 2.1 min vs. 38.8 ± 3.4 min, p < 0.01). No significant differences in other characteristics of PIDs including originating sites, duration time, propagation patterns, and velocity were detected. Additionally, the migration of originating sites was observed. Conclusion This study shows that loss of Kir6.1, not Kir6.2 facilitates the induction of PIDs in focal cerebral ischemia, indicating that Kir6.1-forming channels in the brain may provide protection against PIDs.

Hemodynamic response and clinical outcome following intravenous milrinone plus norepinephrine\u2013based hyperdynamic hypertensive therapy in patients suffering secondary cerebral ischemia after aneurysmal subarachnoid hemorrhage

PurposeIntravenous and intra-arterial milrinone as a rescue measure for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been adopted by several groups, but so far, evidence for the clinical benefit is unclear and effect on brain perfusion is unknown. The aim of the actual analysis was to define cerebral hemodynamic effects and outcome of intravenous milrinone plus norepinephrine supplemented by intra-arterial nimodipine as a rescue strategy for DCI following aneurysmal SAH.MethodsOf 176 patients with aneurysmal SAH treated at our neurosurgical department between April 2016 and March 2021, 98 suffered from DCI and were submitted to rescue therapy. For the current analysis, characteristics of these patients and clinical response to rescue therapy were correlated with hemodynamic parameters, as assessed by CT angiography (CTA) and perfusion CT. Time to peak (TTP) delay in the ischemic focus and the volume with a TTP delay of more than 4 s (T4 volume) were used as hemodynamic parameters.ResultsThe median delay to neurological deterioration following SAH was 5 days. Perfusion CT at that time showed median T4 volumes of 40 cc and mean focal TTP delays of 2.5 ± 2.1 s in these patients. Following rescue therapy, median T4 volume decreased to 10 cc and mean focal TTP delay to 1.7 ± 1.9 s. Seventeen patients (17% of patients with DCI) underwent additional intra-arterial spasmolysis using nimodipine. Visible resolution of macroscopic vasospasm on CTA was observed in 43% patients with DCI and verified vasospasm on CTA, including those managed with additional intra-arterial spasmolysis. Initial WFNS grade, occurrence of secondary infarction, ischemic volumes and TTP delays at the time of decline, the time to clinical decline, and the necessity for additional intra-arterial spasmolysis were identified as the most important features determining neurological outcome at 6 months.ConclusionThe current analysis shows that cerebral perfusion in the setting of secondary cerebral ischemia following SAH is measurably improved by milrinone and norepinephrine–based hyperdynamic therapy. A long-term clinical benefit by the addition of milrinone appears likely. Separation of the direct effect of milrinone from the effect of induced hypertension is not possible based on the present dataset.

Efficacy and safety of intraventricular polymyxin B plus continuous ventricular drainage for the treatment of intracranial infection caused by drug-resistant Acinetobacter baumannii.

The bacterial resistance rate has risen in recent years, and polymyxin B has been used more frequently to treat severe intracranial infection. This study aimed to investigate the clinical efficacy and safety profiles of intraventricular polymyxin B plus continuous ventricular drainage for the treatment of intracranial infection caused by drug-resistant Acinetobacter baumannii (DR-AB). A retrospective study was performed on 21 patients who had an intracranial infection caused by DR-AB after neurosurgery at our hospital from May 2017 to July 2020. These patients were treated by intraventricular polymyxin B plus continuous ventricular drainage. The clinical features, treatment, cerebrospinal fluid (CSF)-related indicators, outcomes, and prognosis of these patients were analyzed. The external drainage tubes inserted into the lateral ventricle were kept unobstructed in all 21 patients. These patients received intraventricular polymyxin B 5 mg/day plus intravenous antibiotics. The treatment with intraventricular polymyxin B lasted for 18.19±12.36 days. The time to positive CSF culture was 10.50±10.60 days. The bacterial clearance rate of CSF was 95.2% (20/21). The clinical cure rate was 81.0% (17/21), and the mortality rate was 19.0% (4/21). As for the causes of death, 1 case died from purulent CSF with cerebral abscess, which was considered to be caused by extensive brain parenchymal infection, 2 cases died from spontaneous intraventricular hemorrhage after returning negative for CSF cultures, and 1 case died from secondary massive cerebral infarction after returning negative for CSF cultures. There were no significant changes in the serum creatinine level before and after treatment. For intracranial infection caused by DR-AB, early intraventricular polymyxin B plus continuous ventricular drainage could effectively clear the drug-resistant bacteria from CSF, thereby improving efficacy and reducing mortality. Renal functions before and after treatment were not changed significantly, proving that this combined treatment was safe and effective.

Early-stage serum Stanniocalcin 1 as a predictor of outcome in patients with aneurysmal subarachnoid hemorrhage.

Stanniocalcin-1 (STC1) takes part in anti-inflammatory and anti-oxidative processes, thus demonstrating neuroprotective properties. Early brain injuries associated with initial subarachnoid hemorrhage typically led to secondary cerebral infarction and poor outcomes. This retrospective study aimed to clarify the clinical significance of serum STC1 level in patients with subarachnoid hemorrhage.We collected demographic information, comorbidities, neurological status in detail. All blood samples were collected on admission. Enzyme-linked immunosorbent assay kits were used to detect the serum level of STC1. Spearman analysis was used to explore the relationship between STC1 and clinical severity. Multivariate logistic regression was used to investigate the prognostic role of STC1 in patients with aneurysmal subarachnoid hemorrhage (aSAH). Receiver operating characteristic curve was performed to investigate the power of STC1 in predicting outcome in aSAH patients.Serum STC1 concentration was significantly higher in aSAH patients than in healthy individuals. Serum concentration of STC1 positively correlated with Hunt-Hess grade (r = 0.62, P < .01) and Fisher grade (r = 0.48, P < .01), and negatively correlated with Glasgow Coma Scale on admission (r = −0.45, P < .01). Patients with delayed cerebral ischemia (DCI) had higher level of serum STC1 than those without DCI (13.12 ± 1.44 vs 8.56 ± 0.31, P < .01). Moreover, patients with poor outcome had higher concentration of STC1 than patients with good outcome (11.82 ± 0.62 vs 8.21 ± 0.35,P < 0.01). Results of univariate and multivariate logistic analysis revealed that Hunt-hess III–IV, DCI, and high STC1 level were independent risk factors associated with poor outcome of patients with aSAH. Further analysis revealed that combination of STC1 with Hunt-hess grade was more superior to 2 indicators alone in predicting clinical outcome of aSAH patients.STC1 can be used as a novel biomarker in predicting outcome of patients with aSAH, especially when combined with Hunt-hess grade.

The Clinical Efficacy of Ginkgo biloba Leaf Preparation on Ischemic Stroke: A Systematic Review and Meta-Analysis.

Background Ginkgo biloba leaf preparations (GLPs) are widely used in ischemic stroke, and uncertainty remains regarding their clinical efficacy. To evaluate systematically the clinical efficacy and safety of GLPs in the treatment of ischemic stroke, we examine evidence from randomized controlled trials (RCTs). Methods We examine studies published prior to November 2021 that were found from searching the following sources: PubMed, China National Knowledge Infrastructure (CNKI), WANFANG DATA, Chongqing VIP (CQVIP) databases, and Chinese Biomedical Literature (CBM). We evaluated the quality of the included references according to the Cochrane Manual of Systematic Evaluation and Meta-analysis (MA) performed using RevMan 5.2 software. Results We included a total of 13 RCTs with clinical therapeutic effects, the National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), hemorheology index, and adverse reaction index as evaluation criteria. There were 631 cases in the observation group and 629 cases in the control group. MA results showed the following: NIHSS WMD = −3.89, 95% CI: [−4.22, −3.56], I2 = 19%, P < 0.00001. This index is often used with nerve injury and can also be used to judge the recovery of nerve function. A lower score means less nerve damage and a better chance of recovery. The BI results were WMD = 11.30, 95% CI: [9.83, 12.77], I2 = 7%, P < 0.00001. This index was used to assess patients' ability to take care of themselves, with a higher score indicating a stronger ability to live independently. Clinical effective rate results were WMD = 3.79, 95% CI: [2.49, 5.78], I2 = 0%, P < 0.00001, and this measure can be used to evaluate the effect of treatment clearly and objectively. Hemorheological index results show that plasma viscosity has WMD = −0.16, 95% CI: [−0.20, −0.12], I2 = 40%, P < 0.00001 and fibrinogen (FIB) has WMD = −1.13, 95% CI: [−1.23, −1.04], I2 = 0%, P < 0.00001. Plasma viscosity is mainly related to the amount of fibrinogen, and fibrinogen degradation is an important function of the fibrinolytic system. The imbalance of the fibrinolytic system plays an important role in the pathogenesis of cerebral infarction. Fibrinogen is a risk factor of ischemic cerebrovascular disease. Studies have shown that the infarct size of patients with secondary cerebral infarction after CEREBRAL infarction is correlated with their FIB level. In addition, FIB elevation is also one of the risk factors for early infarction after thrombolysis. Therefore, FIB can be used as a detection index for the prevention of cerebral infarction recurrence adverse reactions. Our MA results for FIB show WMD = 0.81, 95% CI: [0.38, 1.73], I2 = 0%, P = 0.58, and RR < 1. Conclusion The existing clinical evidence shows that GLP has a good therapeutic effect on patients with ischemic stroke and can improve their hemorheology indices. In addition, GLP is shown to be relatively safe.

Infarct growth precedes cerebral thrombosis following experimental stroke in mice

Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.

Het posterieur reversibel encefalopathiesyndroom

Posterior reversible encephalopathy syndrome Being confronted with postoperative complications can be challenging. When a patient shows signs of postoperative neurological deficit, a wide range of possible explanations has to be considered. In this specific case, the diagnosis of posterior reversible encephalopathy syndrome (PRES) was made. PRES is characterised by neurological symptoms (headache, confusion, visual changes, paresis and/or convulsions) and certain findings on cerebral imaging (vasogenic oedema, predominantly in the posterior areas of the brain). It is linked to hypertensive disorders, (pre-)eclampsia, certain auto-immune diseases, the use of immunosuppressive medication and kidney failure. Treatment of the hypertension is crucial, but antiseizure drugs and treatment of the underlying disease may also be necessary. Most patients have a complete recovery within 2 weeks. A small minority, however, experiences residual neurologic deficits resulting from secondary cerebral infarction or haemorrhage.

Abstract 12446: Lipocalin10 Deficiency Exacerbates Myocardial Ischemia/Reperfusion Injury via Impairing Macrophage Efferocytosis

Introduction: Efficient clearance of dead cells by macrophages (termed as efferocytosis) is critical for timely repairing the injured heart after ischemia/reperfusion (I/R), as defective removal of dying cells could cause secondary necrosis and infarct expansion. Recent studies have shown that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue from patients with heart failure. However, the role of Lcn10 is virtually unknown during cardiac I/R, and its function in macrophage efferocytosis has never been explored. Hypothesis: Our initial data showed that Lcn10 expression was upregulated in bone marrow-derived macrophages (BMDMs) during efferocytosis. Thus, we hypothesize that knockout (KO) of Lcn10 would diminish macrophage efferocytosis, leading to exacerbated cardiac I/R injury. Methods/Results: Since Lcn10 is a secreted protein, we generated a global Lcn10-KO mouse model. After co-culturing BMDMs with GFP-labeled dead myocytes for 2h, we observed a 25% reduction on efferocytosis by KO-BMDMs, compared to wild-type (WT) controls. Using Lcn10-KO mCherry mouse model (cardiac-specific overexpression of mCherry in Lcn10-KO mice), we detected that KO cardiac macrophages ingested fewer dead myocytes at 3 days post-I/R, compared to WT-mCherry controls. Accordingly, cardiac contractile function, measured by echocardiography at the same time, was significantly declined in KO-mice, together with increased accumulation of apoptotic cells and higher serum levels of troponin I, a marker of cardiac damage, compared with WTs (n=7-10, p &lt;0.05). In addition, pre-treatment of KO-BMDMs with recombinant Lcn10 protein could rescue the impaired efferocytosis. Mechanistically, RNA-seq analysis showed that many downregulated genes (i.e., ItgaV, Itga6, Cx3cr1, and Msr) in KO-macrophages are associated with efferocytosis. Interestingly, we identified that Lcn10 contains a potential phosphatidylserine (PS)-binding motif (RxKRK), located at a helix-turn-helix structure, which is the primary “find-me” signal for efferocytosis. Conclusions: Our data indicate that Lcn10 is pivotal for macrophage efferocytosis to remove cardiac dead cells during I/R. Thus, Lcn10 could be used as a new mediator for the treatment of cardiac I/R injury.

Intervention-specific association of weight variability with major adverse cardiovascular events in overweight or obese adults with type 2 diabetes mellitus

Abstract Background Weight variability is associated with cardiovascular outcomes in diabetic patients. However, the effect of higher weight variability caused by intensive lifestyle intervention (ILI) on cardiovascular outcomes in diabetic patients is not well established. We aimed to evaluate the intervention-specific association between weight variability with major adverse cardiovascular event (MACE) among overweight or obese adults with diabetes. Methods In 3,859 participants from the Action for Health in Diabetes (Look AHEAD) trial, multivariate-adjusted Cox regression models were used to evaluate the associations of weight variability measured by variability independent of the mean (VIM) with MACE and secondary outcomes in intensive lifestyle intervention (ILI) and diabetes support &amp; education (DSE) arm, respectively. Results During a median follow-up of 9.6 years, 255 (12.9%) participants in the ILI arm and 247 (13.2%) participants in the DSE arm developed MACE. Participants with the highest quartile of weight variability (VIM Q4) experienced a 2.23-fold higher risk of MACE compared with the lowest quartile (VIM Q1) in the DSE arm (hazard ratio [HR] 2.23; 95% CI 1.51–3.30), but not the ILI arm (HR 1.05; 95% CI 0.73–1.50). Moreover, compared with the lowest weight variability (VIM Q1), participants with the highest weight variability (VIM Q4) were not associated with all secondary outcomes in the ILI arm (all P&amp;gt;0.05) but were associated with the higher risks of secondary cardiovascular composite outcome (HR 1.88; 95% CI 1.20–2.95), all-cause mortality (HR 3.19; 95% CI 1.75–5.82), and myocardial infarction (HR 1.95; 95% CI 1.12–3.37) in the DSE arm. Conclusions Among the overweight or obese individuals with type 2 diabetes mellitus, rising weight variability was independently associated with increased MACE risks in the DSE arm but not the ILI arm. Therefore, a guideline-recommended ILI strategy for weight loss should be adopted to improve cardiovascular outcomes without considering the effect of high weight variability. Funding Acknowledgement Type of funding sources: None.

Pulmonary cavitation in patients with COVID-19

Pulmonary cavitation in patients with COVID-19

018 The Role of Inflammatory Markers in Sleep in Individuals Post-Myocardial Infarction

Abstract Introduction Despite positive secondary prevention strategies post myocardial infarction (MI), including statin use and lifestyle changes, 32% of the annual MIs are recurrent (MIR). As coronary heart disease is related to atherosclerosis, a chronic inflammatory process, and sleep is associated with cardiovascular disease and innate immunity, understanding the role of sleep and inflammation and MIR is important in developing interventions to improve sleep, reduce inflammation, and delay or prevent MIR. This study aimed to explore the role of sleep quality and inflammatory markers on MIRs. Methods We conducted a secondary analysis of cross-sectional data of individuals (N=156) having at least one or more MIs within the last 3 to 7 years. Using the hypothalamus-pituitary-adrenal axis model (Irwin, 2019), we tested sleep quality (Pittsburgh Sleep Quality Index [PSQI]) predicting MIR, using inflammatory markers (hs C-Reactor Protein [CRP], Interleukin-1ß [IL-1ß] and Tumor Necrosis Factor alpha [TNFα]) as the simultaneous indirect paths. Race, sex and body mass index (BMI) were also examined using moderated mediation. Results The sample ranged in age from 34 to 92 (M = 65.37, SD = 12.13), BMI averaged 31.11 (SD = 7.34), and was comprised of mostly male (57.1%) and White adults (67.9%). PSQI predicted only IL-1ß (ß= .02; p &amp;lt; .01). IL-1ß predicted MIR (ß = .80, p = .05). The direct effect of PSQI to MIR was not significant (p =.12), the indirect path via IL-1ß was. This relationship was not moderated by race, sex, nor BMI. Conclusion IL-1ß is an inflammatory marker elevated after acute MI which does not reflect our selected sample. Inflammation may be an important marker of risk for MIR in those with poor sleep quality. Future studies should examine other markers of inflammation and sleep in those with MIR. Support (if any):

Interleukin 6 and Aneurysmal Subarachnoid Hemorrhage. A Narrative Review.

Interleukin 6 (IL-6) is a prominent proinflammatory cytokine. Neuroinflammation in general, and IL-6 signaling in particular, appear to play a major role in the pathobiology and pathophysiology of aneurysm formation and aneurysmal subarachnoid hemorrhage (SAH). Most importantly, elevated IL-6 CSF (rather than serum) levels appear to correlate with delayed cerebral ischemia (DCI, “vasospasm”) and secondary (“vasospastic”) infarctions. IL-6 CSF levels may also reflect other forms of injury to the brain following SAH, i.e., early brain damage and septic complications of SAH and aneurysm treatment. This would explain why many researchers have found an association between IL-6 levels and patient outcomes. These findings clearly suggest CSF IL-6 as a candidate biomarker in SAH patients. However, at this point, discrepant findings in variable study settings, as well as timing and other issues, e.g., defining proper clinical endpoints (i.e., secondary clinical deterioration vs. angiographic vasospasm vs. secondary vasospastic infarct) do not allow for its routine use. It is also tempting to speculate about potential therapeutic measures targeting elevated IL-6 CSF levels and neuroinflammation in SAH patients. Corticosteroids and anti-platelet drugs are indeed used in many SAH cases (not necessarily with the intention to interfere with detrimental inflammatory signaling), however, no convincing benefit has been demonstrated yet. The lack of a robust clinical perspective against the background of a relatively large body of data linking IL-6 and neuroinflammation with the pathophysiology of SAH is somewhat disappointing. One underlying reason might be that most relevant studies only report correlative data. The specific molecular pathways behind elevated IL-6 levels in SAH patients and their various interactions still remain to be delineated. We are optimistic that future research in this field will result in a better understanding of the role of neuroinflammation in the pathophysiology of SAH, which in turn, will translate into the identification of suitable biomarkers and even potential therapeutic targets.

Patient pathways for cardiovascular diseases in Malaysia and the Philippines: a systematic review

Background: Cardiovascular diseases (CVDs) are the leading cause of premature mortality in the world and are a growing public health concern in low- and middle-income countries (LMICs), including those in South East Asia. Their management requires coordinated responses by a range of healthcare providers, which should preferably be based on knowledge of the national context. We systematically review evidence on the pathways followed by patients with CVD in Malaysia and the Philippines to understand patient journeys, along with the barriers at each stage. Methods: We searched seven bibliographic databases and grey literature sources to identify material focused on the pathways followed by patients with CVD in Malaysia and the Philippines, and performed a narrative synthesis. Results: The search yielded 25 articles, 3 focused on the Philippines and 22 on Malaysia. Most articles were quantitative analyses that focused on hypertensive patients. Three examined secondary prevention post myocardial infarction, and one each examined acute myocardial infarction, heart failure, and atrial fibrillation. Reported barriers reflected capability (knowledge of behaviours to achieve control or the capacity to conduct these behaviours), intention (attitudes or motivations toward the behaviours to achieve control), and aspects of the health care system (availability, accessibility, affordability and acceptability of services). Conclusions: There are large gaps in our understanding of patient pathways in Malaysia and the Philippines that limit the development of evidence-based strategies to effectively address the CVD burden in South East Asian countries and in LMICs more broadly. Addressing these evidence gaps will require longitudinal mixed-methods studies following patients from initial diagnosis to long-term management.

Immune Cell Infiltration into the Brain After Ischemic Stroke in Humans Compared to Mice and Rats: a Systematic Review and Meta-Analysis

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research.

Interleukin 6 in cerebrospinal fluid is a biomarker for delayed cerebral ischemia (DCI) related infarctions after aneurysmal subarachnoid hemorrhage

Interleukin 6 (IL-6) is a prominent proinflammatory cytokine and has been discussed as a potential biomarker for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage. In the present study we have analyzed the time course of serum and cerebrospinal fluid (CSF) IL-6 levels in 82 patients with severe aneurysmal subarachnoid hemorrhage (SAH) requiring external ventricular drains in correlation to angiographic vasospasm, delayed cerebral ischemia, secondary infarctions and other clinical parameters. We observed much higher daily mean IL-6 levels (but also large interindividual variations) in the CSF than the serum of the patients with a peak between days 4 and 14 including a maximum on day 5 after SAH. Individual CSF peak levels correlated significantly with DCI (mean day 4–14 peak, DCI: 26,291 ± 24,159 pg/ml vs. no DCI: 16,184 ± 13,163 pg/ml; P = 0.023). Importantly, CSF IL-6 levels differed significantly between cases with DCI and infarctions and patients with DCI and no infarction (mean day 4–14 peak, DCI with infarction: 37,209 ± 26,951 pg/ml vs. DCI, no infarction: 15,123 ± 11,239 pg/ml; P = 0.003), while findings in the latter patient group were similar to cases with no vasospasm (mean day 4–14 peak, DCI, no infarction: 15,123 ± 11,239 vs. no DCI: 15,840 ± 12,979; P = 0.873). Together, these data support a potential role for elevated CSF IL-6 levels as a biomarker for DCI with infarction rather than for DCI in general. This fits well with a growing body of evidence linking neuroinflammation to ischemia and infarction, but (together with the large interindividual variations observed) limits the diagnostic usefulness of CSF IL-6 levels in SAH patients.

Genome-Wide Screen and Validation of Microglia Pro-Inflammatory Mediators in Stroke.

Stroke activates microglia pro-inflammatory response that not only induces the early neuronal injuries but also causes the secondary brain infarction. Yet, the underlying mechanisms for how microglia become activated in stroke are still unknown. Here, using the next-generation of RNA sequencing we find a total of 778 genes increasingly expressed in brain of stroke mice. Of these, we identified Hmgb2 as a microglia pro-inflammatory mediator by promoting the transcription of Ctss. Inhibition of either Hmgb2 or Ctss blocks microglia pro-inflammatory response and protects against brain damages and improves the neurological functions of stroke mice. This study uncovers Hmgb2 and Ctss as the major microglia inflammatory response mediators in stroke and hence warrants the promising targets for stroke therapies.

Ischemia Modified Albumin and miR-126 Play Important Role in Diagnosis of Posterior Circulation Transient Ischemic Attack and Prediction of Secondary Cerebral Infarction

Transient ischemic attack (TIA) is a super warning for cerebral infarction stroke, thus probe of sensitive biomarker for TIA diagnosis and prognosis can contribute to make an optimal intervention plan. This study was conducted to explore the value of ischemic modified albumin (IMA) and microRNA-12miR-126 on the diagnosis of posterior circulation TIA and the prediction of secondary cerebral infarction. This study was conducted as a longitudinal prospective research. The levels of serum IMA and miR-126 at 3h, 6h and 12h after TIA onset were analyzed in 106 patients, then the predictive value of IMA and miR-126 for secondary cerebral infarction were tested. A significant increase of serum IMA and a decrease of miR-126 were observed after TIA onset (P = 0.000),simultaneously a significant negative correlation was found between serum IMA for 3 h and miR-126 for 12 hr=-0.401, P = 0.000. Both IMA and miR-126 were significant associated with the secondary cerebral infarction. Early detection of IMA and miR-126 is of great value in diagnosing posterior circulation TIA and predicting the secondary cerebral infarction.