Hyperacute Phase Research Articles

Stroke Care Services in Africa: A Systematic Review

Background: Stroke is the second leading cause of death and adult-onset disability globally. Although its incidence is reducing in developed countries, low- and middle-income countries, especially African countries, are witnessing an increase in cases of stroke, leading to high morbidity and mortality. Evidently, a new paradigm is needed on the continent to tackle this growing burden of stroke in its preventative and treatment aspects. Aims and Objectives: The aim of this study was to determine the scope of stroke care services, where they exist, and their relationship with currently existing health systems. Methods: A detailed literature search was undertaken referring to PubMed and Google Scholar for articles from January 1960 to March 2018, using a range of search terms. Of 93 publications, 45 papers were shortlisted, and 21 reviewed articles on existing stroke services were included. Results: The literature on models of stroke services in Africa is sparse. We identified focused systems of care delivery in the hyperacute, acute, and rehabilitative phases of stroke in a few African countries. There is a continent-wide paucity of data on the organization of prehospital stroke services. Only 3 African countries (South Africa, Egypt, and Morocco) reported experiences on thrombolysis. Also, the uptake of dedicated stroke units appears limited across the continent. Encouragingly, there are large-scale secondary prevention models on the continent, mostly within the context of experimental research projects, albeit with promising results. We found only 1 article on the interventional aspects of stroke care in our review, and this was a single-center report. Conclusions: The literature on the organization of stroke services is sparse in Africa. Dedicated action at policy, population, community, and hospital-based levels is urgently needed toward the organization of stroke services to tame the burgeoning burden of stroke on the African continent.

Characterization of the rat cerebrospinal fluid proteome following acute cerebral ischemia using an aptamer-based proteomic technology

The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke.

Protocol for a prospective collaborative systematic review and meta-analysis of individual patient data from randomized controlled trials of vasoactive drugs in acute stroke: The Blood pressure in Acute Stroke Collaboration, stage-3.

Rationale Despite several large clinical trials assessing blood pressure lowering in acute stroke, equipoise remains particularly for ischemic stroke. The "Blood pressure in Acute Stroke Collaboration" commenced in the mid-1990s focussing on systematic reviews and meta-analysis of blood pressure lowering in acute stroke. From the start, Blood pressure in Acute Stroke Collaboration planned to assess safety and efficacy of blood pressure lowering in acute stroke using individual patient data. Aims To determine the optimal management of blood pressure in patients with acute stroke, including both intracerebral hemorrhage and ischemic stroke. Secondary aims are to assess which clinical and therapeutic factors may alter the optimal management of high blood pressure in patients with acute stroke and to assess the effect of vasoactive treatments on hemodynamic variables. Methods and design Individual patient data from randomized controlled trials of blood pressure management in participants with ischemic stroke and/or intracerebral hemorrhage enrolled during the ultra-acute (pre-hospital), hyper-acute (<6 h), acute (<48 h), and sub-acute (<168 h) phases of stroke. Study outcomes The primary effect variable will be functional outcome defined by the ordinal distribution of the modified Rankin Scale; analyses will also be carried out in pre-specified subgroups to assess the modifying effects of stroke-related and pre-stroke patient characteristics. Key secondary variables will include clinical, hemodynamic and neuroradiological variables; safety variables will comprise death and serious adverse events. Discussion Study questions will be addressed in stages, according to the protocol, before integrating these into a final overreaching analysis. We invite eligible trials to join the collaboration.

Ischemic Volume and Neurological Deficit: Correlation of Computed Tomography Perfusion with the National Institutes of Health Stroke Scale Score in Acute Ischemic Stroke

The National Institutes of Health Stroke Scale (NIHSS) is the most adopted stroke patients' evaluation tool in emergency settings to assess the severity of stroke and to determine the patients' eligibility for specific treatments. Computed tomography perfusion (CTP) is crucial to identify salvageable tissue that can benefit from the reperfusion treatment. The aim of this study is to identify the relation between the NIHSS scores and the hypoperfused volumes evaluated by CTP in patients with hyperacute ischemic stroke. This retrospective study was conducted on 105 patients with ischemic stroke who underwent NIHSS assessment and CTP in the hyperacute phase. Hypoperfused volume was evaluated by CTP maps processed with semi-automatic algorithm. An analysis was conducted to determine the degree of correlation between the NIHSS scores and the ischemic lesion volumes and to investigate the relation between the anterior and the posterior circulation strokes, as well as between the right and the left hemispheric strokes. A significant correlation was found between ischemic volume and NIHSS score at baseline (r = .82; P < .0001) in the entire cohort. A high NIHSS-volume correlation was identified in the anterior circulation stroke (r = .76; P < .0001); whereas, it was nonsignificant in the posterior circulation stroke. NIHSS score and volume correlated for the left and the right hemispheric strokes (r = .83 and .81; P < .0001), showing a slightly higher slope in the left. This study showed a strong correlation between the baseline NIHSS score and the ischemic volume estimated by CTP. We confirmed that NIHSS is a reliable predictor of perfusion deficits in acute ischemic stroke. CTP allows fast imaging assessment in the hyperacute phase. The results highlight the importance of these diagnostic tools in the assessment of stroke severity and in acute decision-making.

Diagnosis of Hyperacute and Acute Ischaemic Stroke: The Potential Utility of Exosomal MicroRNA-21-5p and MicroRNA-30a-5p

Background: Early and accurate diagnosis of ischaemic stroke (IS) requires the use of an optimized biomarker. Exosomal microRNAs have the potential to serve as biomarkers owing to their stability and specificity. We investigated the expression levels of plasma-derived exosomal microRNA-21-5p and microRNA-30a-5p in the different phases of IS. Methods: One hundred forty-three patients with IS and 24 non-stroke controls were enrolled. The patients were divided into the following 5 groups: 1 group for the hyperacute phase IS (HIS, within 6 h); two for the acute phase IS (AIS, including days 1–3 and days 4–7); one for the subacute phase IS (SIS, days 8–14); and one for the recovery phase IS (RIS, days >14). Plasma exosomes were isolated using a QIAGEN exoRNeasy kit and examined by transmission electron ­microscopy, nanoparticle tracking, and flow cytometry. The expression levels of miRNA-21-5p and miRNA-30a-5p were detected by quantitative real-time polymerase chain reaction. Results: The plasma exosomal miR-21-5p levels in SIS and RIS were significantly higher than that in controls (p < 0.05 and p < 0.01 respectively). The levels of miR-30a-5p in HIS were significantly higher (p < 0.05) and in AIS (days 1–3) were lower than that in controls (p < 0.05). In AIS (days 1–3), both miRNAs were decreased compared with the HIS group (p = 0.053 and 0.001, respectively). The area under the curve (AUC) of the miR-21-5p was 0.714 for SIS (95% CI 0.570–0.859, p = 0.007), 0.734 for RIS (95% CI 0.596–0.871, p = 0.003); the AUC of the miR-30a-5p was 0.826 for HIS (95% CI 0.665–0.988, p = 0.001), 0.438 for AIS (days 1–3; 95% CI 0.240–0.635, p = 0.516). Conclusions: The plasma-derived exosomal miR-21-5p and miRNA-30a-5p in combination are promising biomarkers for diagnosing IS and distinguishing among HIS, SIS, and RIS, especially miRNA-30a-5p for the diagnosis of the HIS phase. Our results provide a new reference for clinicians to apply in early-stage diagnosis and identifies the possible value of biomarkers for IS thrombolysis therapy.

Progressive Assessment of Ischemic Injury to White Matter Using Diffusion Tensor Imaging: A Preliminary Study of a Macaque Model of Stroke.

Background:Previous Diffusion Tensor Imaging (DTI) studies have demonstrated the temporal evolution of stroke injury in grey matter and white matter can be characterized by DTI indices. However, it still remains not fully understood how the DTI indices of white matter are altered progressively during the hyperacute (first 6 hours) and acute stage of stroke (≤ 1 week). In the present study, DTI was employed to characterize the temporal evolution of infarction and white matter injury after stroke insult using a macaque model with permanent ischemic occlusion.Methods and materials:Permanent middle cerebral artery (MCA) occlusion was induced in rhesus monkeys (n=4, 10-21 years old). The brain lesion was examined longitudinally with DTI during the hyperacute phase (2-6 hours, n=4), 48 hours (n=4) and 96 hours (n=3) post-occlusion.Results:Cortical infarction was seen in all animals. The Mean Diffusivity (MD) in lesion regions decreased substantially at the first time point (2 hours post stroke) (35%, p <0.05, compared to the contralateral side) and became pseudo-normalized at 96 hours. In contrast, evident FA reduction was seen at 48 hours (39%, p <0.10) post-stroke. MD reduction in white matter bundles of the lesion area was much less than that in the grey matter during the hyper-acute phase but significant change was observed 4 hours (4.2%, p < 0.05) post stroke . Also, MD pseudonormalisation was seen at 96 hours post stroke. There was a significant correlation between the temporal changes of MD in white matter bundles and those in whole lesion areas during the entire study period. Meanwhile, no obvious fractional anisotropy (FA) changes were seen during the hyper-acute phase in either the entire infarct region or white matter bundles. Significant FA alteration was observed in entire lesion areas and injured white matter bundles 48 and 96 hours post stroke. The stroke lesion in grey matter and white matter was validated by pathological findings.Conclusion: The temporal evolution of ischemic injury to the grey matter and white matter from 2 to 96 hours after stroke onset was characterized using a macaque model and DTI. Progressive MD changes in white matter bundles are seen from hyperacute phase to acute phase after permanent MCA occlusion and temporally correlated with the MD changes in entire infarction regions. MD reduction in white matter bundles is mild in comparison with that in the grey matter but significant and progressive, indicating it may be useful to detect early white matter degeneration after stroke.

Prehospital Advanced Diagnostics and Treatment of Acute Stroke: Protocol for a Controlled Intervention Study

BackgroundAcute ischemic stroke (AIS) is a medical emergency. The outcome is closely linked to the time elapsing from symptom onset to treatment, and seemingly small delays can mean the difference between full recovery and physical and cognitive dysfunction. Recanalization to allow blood to reenter the affected area is most efficient immediately after symptoms occur, and intravenous thrombolysis must be initiated no later than 4.5 hours after the symptom onset. A liable diagnosis is mandatory to administer the appropriate treatment. Prehospital diagnosis and, in cases where contraindications are ruled out, prehospital initiation of intravenous thrombolysis have been shown to significantly decrease the time from alarm to the treatment.ObjectiveThe objective of this paper is to investigate the effectiveness of prehospital thrombolysis as measured by (1) time spent from symptom onset to treatment and (2) the number of patients treated within 4.5 hours. In addition, we want to conduct explorative studies. These will include (1) the use of biomarkers for diagnostic and prognostic use where we will collect blood samples from various time points, including the hyperacute phase and (2) the study of magnetic resonance imaging (MRI) images at day 1 to determine the infarct volume and if the time to thrombolysis has an influence on this.MethodsThis is a prospective controlled intervention study. The intervention will involve a computed tomography (CT) and thrombolysis in a physician-manned ambulance called a mobile stroke unit (MSU). The control will be the conventional pathway where the patient is transported to the hospital for CT, and thrombolysis as per current procedure.ResultsPatient inclusion has started and a total of 37 patients are enrolled (control and intervention combined). The estimated time to completed inclusion is 36 months, starting from May 2017. The results of this study will be analyzed and published at the end of the trial.ConclusionsThis trial aims to document the feasibility of saving time for all stroke patients by providing prehospital diagnostics and treatment, as well as transport to appropriate level of care, in a safe environment provided by anesthesiologists trained in prehospital critical care.Trial RegistrationClinicalTrials.gov NCT03158259; https://clinicaltrials.gov/show/NCT03158259 (Archived by WebCite at http://www.webcitation.org/6wxNEUMUD)

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood–brain barrier dysfunction

Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L-1 vs. 3.50 (0.23) U L-1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10-3 ) and poor outcome ((6.4 [3.9-7.0]) × 10-3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10-3 ) or better outcome ((4.0 [2.8-5.0]) × 10-3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10-3 vs. (3.7 [2.8-5.0]) × 10-3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke.

Abstract TP400: Acute Catecholamine Surge Reflects the Prognosis in Patients With Aneurysmal Subarachnoid Hemorrhage

Objective: We investigated that the characteristics of serum catecholamine concentration at the hyper-acute phase of aneurysmal subarachnoid hemorrhage (SAH) and its relationship between patient outcome and delayed vasospasm. Methods: Patients with aneurysmal SAH (n=170) were prospectively enrolled between 2008 and 2011. Baseline demographic data and physiological parameters, including plasma concentrations of adrenaline (AD), noradrenaline (NA) and dopamine (DP) were evaluated. Results: On admission, plasma AD, NA and DP levels were significantly higher in patients with a poor clinical grade on admission (Hunt and Kosnik: IV-V), compared to those with a good clinical grade on admission (Hunt and Kosnik: I-III). AD showed a significantly high concentration immediately after the onset of SAH and then rapidly decreased. The levels of NA peaked within 6 hours after onset, then significantly decreased. The time course of the elevation of DP showed a similar trend to that of NA. The each catecholamine levels significantly correlated with each other. Multivariate analyses demonstrated age, poor clinical grade, plasma AD and NA levels were predictors of poor patient outcome. Poor clinical grade, Fisher scale and plasma AD level were predictors of the development of delayed vasospasm. Conclusion: The present study suggests that sympathetic activation in patients in the acute phase of SAH reflects the severity of SAH, and is closely related to the development of delayed vasospasm, leading to the subsequent immune response and inflammatory reactions. Suppressing catecholamine surge in hyper-acute phase may contribute to prevention of vasospasm and improvement of patient outcome.

Blood Pressure Variability in Acute Ischemic Stroke: Influence of Infarct Location in the Insular Cortex

Background: The aim of this study was to elucidate the influence of insular infarction on blood pressure (BP) variability and outcomes according to the region of the insular cortex affected. Methods: A total of 90 patients diagnosed with acute unilateral ischemic stroke were registered. The BP variability was calculated over 24 h after admission (hyperacute) and for 2–3 days after admission (acute). Patients were classified into groups of right and left, and then right anterior, right posterior, left anterior, and left posterior insular infarction. Results: Patients with insular infarction showed a significantly larger infarct volume, higher modified Rankin scale scores, and lower SD and coefficient of variation (CV) of ­systolic BP in the hyperacute phase than shown by patients without insular infarction (p < 0.01, p < 0.01, p = 0.02, and p = 0.03, respectively). The SD and CV of systolic BP in the hyperacute phase showed significant differences among the 3 groups with right insular infarction, with left insular infarction, and without insular infarction (p < 0.05 and p < 0.05, respectively). There was a tendency for the systolic BP variability to be lower in patients with right anterior insular infarction than in patients with infarcts in other areas. Conclusion: The right insular cortex, especially the anterior part, might be a hub for autonomic nervous regulation.

Association Between Hyperacute Stage Blood Pressure Variability and Outcome in Patients With Spontaneous Intracerebral Hemorrhage.

Increased blood pressure (BP) variability, in addition to high BP, may contribute to adverse outcome in intracerebral hemorrhage. However, degree and association with outcome of BP variability (BPV) in the hyperacute period, 15 minutes to 5 hours after onset, have not been delineated. Among consecutive patients with intracerebral hemorrhage enrolled in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium), BPs were recorded by paramedics in the field and during the first 24 hours of hospital course. BP was analyzed in the hyperacute period, from 0 to 4-6 hours, and in the acute period, from 0 to 24-26 hours after onset. BPV was analyzed by SD, coefficient of variation, and successive variation. Among 386 patients with intracerebral hemorrhage, first systolic BP at median 23 minutes (interquartile range, 14-38.5) after onset was median 176 mm Hg, second systolic BP on emergency department arrival at 57 minutes (interquartile range, 45-75) after onset was 178 mm Hg, and systolic BP 24 hours after arrival was 138 mm Hg. Unfavorable outcome at 3 months (modified Rankin Scale, 3-6) occurred in 270 (69.9%). Neither mean nor maximum systolic BP was associated with outcome in multivariable analysis. However, all 3 parameters of BPV, in both the hyperacute and the acute stages, were associated with poor outcome. In the hyperacute phase, BPV was associated with poor outcome with adjusted odds ratios of 3.73 for the highest quintile of SD, 4.78 for the highest quintile of coefficient of variation, and 3.39 for the highest quintile of successive variation. BPV during the hyperacute first minutes and hours after onset in patients with intracerebral hemorrhage was independently associated with poor functional outcome. Stabilization of BPV during this vulnerable period, in the pre-hospital and early emergency department course, is a potential therapeutic target for future clinical trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Measures taken by public health centers in Kumamoto, Japan, during the hyperacute phase to subacute phase of the Kumamoto earthquake

Measures taken by public health centers in Kumamoto, Japan, during the hyperacute phase to subacute phase of the Kumamoto earthquake

Blood Pressure Management for Acute Ischemic and Hemorrhagic Stroke: The Evidence.

Hypertension is the most common modifiable risk factor for stroke (both ischemic and hemorrhagic types). In the hyperacute phase, a majority of patients shows an elevated blood pressure (BP) at the time of presentation because of sympathetic hyperactivity or a physiological response to tissue ischemia. Therefore, BP may decrease spontaneously in a few hours and may drop further when complete recanalization is achieved. In stroke guidelines, an elevated BP is usually left untreated up to a systolic BP (SBP) of 220 mm Hg and a diastolic BP of 120 mm Hg. This recommendation is based on the BP level that corresponds to the upper limit of the pressure autoregulation zone above which cerebral blood flow is directly dependent on BP. However, in patients in whom administration of recombinant tissue-type plasminogen activator is indicated, BP should be controlled to a level < 185/110 mm Hg before infusion and should be maintained at levels < 180/105 mm Hg to limit the risk of intracerebral hemorrhage (ICH). In cases where endovascular thrombectomy is considered, the optimal intra- and postprocedural BP target have not yet been clearly identified. Expert opinion recommends that intraprocedural BP reduction could be associated with a risk of poor outcomes, and therefore, SBP may be reduced only to 120 to 140 mm Hg after successful reperfusion therapy. However, this recommendation is primarily based on observational studies and requires validation in prospective trials. It has been observed that in patients presenting with an ICH, there is no perihematomal penumbra noted and rapid BP reduction is generally well tolerated without a risk of neurological worsening. Multiple trials describing acute reduction of BP recommend SBP reduction only to 140 mm Hg because while there is no benefit of better functional outcomes below that level, there exists a definite risk of increased renal complications.

Endovascular management of extracranial occlusions at the hyperacute phase of stroke with tandem occlusions

Background and purposeThe management of cervical artery occlusions in hyperacute stroke with tandem cervical/intracranial occlusions has not yet become standardized, especially when the circle of Willis is effective. MethodsWe retrospectively analyzed the safety and accuracy of current approaches to manage the cervical occlusion in consecutive patients with tandem occlusions addressed for intracranial mechanical thrombectomy (MT) in our department from January 2012 to May 2017. The different approaches that could be performed in a same patient during the same procedure or hospitalization were analyzed separately. ResultsWe reported 64 approaches to manage the cervical occlusion in 49 patients with tandem occlusion (14% of MT): medical treatment alone in 16/64 (25%), stenting/angioplasty in 16/64 (25%), occlusion with coils in 12/64 (19%), angioplasty alone in 9/64 (14%), stent-retriever in 8/64 (12%), and/or thromboaspiration in 3/64 (5%). Early ipsilateral embolic recurrence occurred after 9/64 (14%) of them. It was strongly associated with the presence of a cervical intraluminal thrombus (P=0.001) and was then lower after occlusion with coils and stent-retriever compared to medical treatment alone and thromboaspiration (P=0.002). Occlusion with coils had a lower rate of radiological intracranial hemorrhage at 48-hour compared to other approaches (P=0.009). The 3-month rates of favorable outcome (P=0.806) and mortality (P=0.878) were similar. One delayed stroke was imputable to an occlusion with coils, for a median (Q1–Q3) follow-up of 10 (3–20) months. ConclusionsCervical occlusion with coils and thrombectomy with stent-retrievers may be relevant to prevent early embolic recurrence in cervical occlusions with intraluminal thrombus. Stent-retrievers should be further assessed as a first-line approach, since delayed stroke may occur following occlusion with coils. Medical treatment alone may be sufficient when no cervical intraluminal thrombus is present, the Willis polygon is effective, and the cervical occlusion can be crossed easily to perform the intracranial thrombectomy.

Integrated treatment modality of cathodal-transcranial direct current stimulation with peripheral sensory stimulation affords neuroprotection in a rat stroke model.

Cathodal-transcranial direct current stimulation induces therapeutic effects in animal ischemia models by preventing the expansion of ischemic injury during the hyperacute phase of ischemia. However, its efficacy is limited by an accompanying decrease in cerebral blood flow. On the other hand, peripheral sensory stimulation can increase blood flow to specific brain areas resulting in rescue of neurovascular functions from ischemic damage. Therefore, the two modalities appear to complement each other to form an integrated treatment modality. Our results showed that hemodynamics was improved in a photothrombotic ischemia model, as cerebral blood volume and hemoglobin oxygen saturation ([Formula: see text]) recovered to 71% and 76% of the baseline values, respectively. Furthermore, neural activities, including somatosensory-evoked potentials (110% increase), the alpha-to-delta ratio (27% increase), and the [Formula: see text] ratio (27% decrease), were also restored. Infarct volume was reduced by 50% with a 2-fold preservation in the number of neurons and a 6-fold reduction in the number of active microglia in the infarct region compared with the untreated group. Grip strength was also better preserved (28% higher) compared with the untreated group. Overall, this nonpharmacological, nonintrusive approach could be prospectively developed into a clinical treatment modality.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies.

Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I–V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies.

Diverse Functions and Mechanisms of Pericytes in Ischemic Stroke

Background: Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke.Methods: Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided.Results: During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery.Conclusion: This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets.

Neuroprotective Effects of Trigeminal Nerve Stimulation in Severe Traumatic Brain Injury

Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as ‘secondary injury’. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO2), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.