Case Report: Microchip Implantation Within the Cervical Spine, a Neurologic Evaluation, and Surgical Correction.

A 5 mo old male Japanese chin was examined 1 mo following the sudden onset of pelvic limb weakness and ataxia immediately after microchip placement. Neurological examination revealed an ambulatory paraparesis, which was worse on the right side, with additional weakness noted in the right thoracic limb. Lesion localization was C6-T2 spinal cord segments, worse on the right. Radiographic imaging of the cervical spine revealed a microchip at the location of the C7-T1 intervertebral space. Computed tomography revealed a microchip within the spinal canal causing spinal cord compression at the level of the C7-T1 intervertebral disc space. Surgical removal of the microchip was performed, and the patient recovered well. A 6 wk follow-up neurologic examination showed persistent mild ataxia in the pelvic limbs. This case supports previously reported cases of permanent spinal cord damage caused by microchip placement. Surgical removal of the microchip resulted in the improvement of neurologic signs. Although extraction of the microchip did not resolve all neurologic deficits, surgery prevented further migration and possible damage to the spinal cord.

Blood Pressure Trajectory Groups and Outcome After Endovascular Thrombectomy: A Multicenter Study.

BACKGROUND: Elevated blood pressure after endovascular thrombectomy (EVT) has been associated with an increased risk of hemorrhagic transformation and poor functional outcomes. However, the optimal hemodynamic management after EVT remains unknown, and the blood pressure course in the acute phase of ischemic stroke has not been well characterized. This study aimed to identify patient subgroups with distinct blood pressure trajectories after EVT and study their association with radiographic and functional outcomes. METHODS: This multicenter retrospective cohort study included consecutive patients with anterior circulation large-vessel occlusion ischemic stroke who underwent EVT. Repeated time-stamped blood pressure data were recorded for the first 72 hours after thrombectomy. Latent variable mixture modeling was used to separate subjects into five groups with distinct postprocedural systolic blood pressure (SBP) trajectories. The primary outcome was functional status, measured on the modified Rankin Scale 90 days after stroke. Secondary outcomes included hemorrhagic transformation, symptomatic intracranial hemorrhage, and death. RESULTS: Two thousand two hundred sixty-eight patients (mean age [±SD] 69±15, mean National Institutes of Health Stroke Scale 15±7) were included in the analysis. Five distinct SBP trajectories were observed: low (18%), moderate (37%), moderate-to-high (20%), high-to-moderate (18%), and high (6%). SBP trajectory group was independently associated with functional outcome at 90 days (P<0.0001) after adjusting for potential confounders. Patients with high and high-to-moderate SBP trajectories had significantly greater odds of an unfavorable outcome (adjusted odds ratio, 3.5 [95% CI, 1.8-6.7], P=0.0003 and adjusted odds ratio, 2.2 [95% CI, 1.5-3.2], P<0.0001, respectively). Subjects in the high-to-moderate group had an increased risk of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.82 [95% CI, 1-3.2]; P=0.04). No significant association was found between trajectory group and hemorrhagic transformation. CONCLUSIONS: Patients with acute ischemic stroke demonstrate distinct SBP trajectories during the first 72 hours after EVT that have differing associations with functional outcome. These findings may help identify potential candidates for future blood pressure modulation trials.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study.

BACKGROUND: A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort. METHODS: This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups. RESULTS: Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P=0.02). CONCLUSIONS: In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Endovascular Treatment of Acute Stroke.

PURPOSE OF REVIEW: In the USA, around 30% of 795,000 strokes per year are due to proximal large-vessel occlusion, and these are a major cause of death and disability. We review the most recent advances regarding treatment of ischemic stroke amenable to mechanical thrombectomy. RECENT FINDINGS: In the last four years, clinical trial evidence has expanded the time window for successful endovascular treatment to 24 h. Current research is aimed at expanding patient selection to mild strokes, large ischemic cores and occlusions of smaller, more distal blood vessels. Further, we have developed understanding of how to manage blood pressure after thrombectomy and even had promising results for a neuroprotective agent in these patients. Thrombectomy has transformed the treatment of ischemic stroke due to large-vessel occlusion. Recent research has focused on expanding patient candidacy for endovascular treatment and improving medical management to support better neurologic outcomes.

Central Triage of Acute Stroke Patients Across a Distributive Stroke Network Is Safe and Reduces Transfer Denials.

Background and Purpose: Mechanical thrombectomy has dramatically increased patient volumes transferred to comprehensive stroke centers (CSCs), resulting in transfer denials for patients who need higher level of care only available at a CSC. We hypothesized that a distributive stroke network (DSN), triaging low severity acute stroke patients to a primary stroke center (PSC) upon initial telestroke consultation, would safely reduce transfer denials, thereby providing additional volume to treat severe strokes at a CSC. Methods: In 2017, a DSN was implemented, in which mild stroke patients were centrally triaged, via telestroke consultation, to a PSC based upon a simple clinical severity algorithm, while higher acuity/severity strokes were triaged to the CSC. In an observational cohort study, data on acute ischemic stroke patients presenting to regional community hospitals were collected pre- versus post-DSN implementation. Safety outcomes and rate of CSC transfer denials were compared pre-DSN versus post-DSN. Results: The pre-DSN cohort (n=150), triaged to the CSC, had a similar rate of symptomatic intracerebral hemorrhage and discharge location compared with the post-DSN cohort (n=150), triaged to the PSC. Time to stroke unit admission was faster post-DSN (2 hours 40 minutes) versus pre-DSN (3 hours 29 minutes; P<0.001). Transfer denials were reduced post-DSN (3.8%) versus pre-DSN (1.8%; P=0.02), despite an increase in telestroke consultation volume over the same period (median, 3 calls per day pre-DSN versus 5 calls per day post-DSN; P=0.001). No patients who were triaged to the PSC required subsequent transfer to the CSC. Conclusions: A DSN, triaging mild ischemic stroke patients from community hospitals to a PSC, safely reduced transfer denials to the CSC, allowing greater capacity at the CSC to treat higher acuity stroke patients.

Anticoagulation Timing in Cardioembolic Stroke and Recurrent Event Risk.

OBJECTIVE: Guidelines recommend initiating anticoagulation within 4 to 14 days after cardioembolic stroke. Data supporting this did not account for key factors potentially affecting the decision to initiate anticoagulation, such as infarct size, hemorrhagic transformation, or high-risk features on echocardiography. METHODS: We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with ischemic stroke and atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0-3 days, 4-14 days, or >14 days), and outcomes were recurrent stroke/transient ischemic attack/systemic embolism, symptomatic intracerebral hemorrhage (sICH), and major extracranial hemorrhage (ECH) within 90 days. RESULTS: Among 2,084 patients, 1,289 met the inclusion criteria. The combined endpoint occurred in 10.1% (n = 130) subjects (87 ischemic events, 20 sICH, and 29 ECH). Overall, there was no significant difference in the composite endpoint between the 3 groups (0-3 days: 10.3%, 64/617; 4-14 days: 9.7%, 52/535; >14 days: 10.2%, 14/137; p = 0.933). In adjusted models, patients started on anticoagulation between 4 and 14 days did not have a lower rate of sICH (vs 0-3 days; odds ratio [OR] = 1.49, 95% confidence interval [CI] = 0.50-4.43), nor did they have a lower rate of recurrent ischemic events (vs >14 days; OR = 0.76, 95% CI = 0.36-1.62, p = 0.482). INTERPRETATION: In this multicenter real-world cohort, the recommended (4-14 days) time frame to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required to determine the optimal timing of anticoagulation initiation. ANN NEUROL 2020;88:807-816.

Blood Pressure Goals and Clinical Outcomes after Successful Endovascular Therapy: A Multicenter Study.

OBJECTIVE: Elevated systolic blood pressure (SBP) after successful revascularization (SR) via endovascular therapy (EVT) is a known predictor of poor outcome. However, the optimal SBP goal following EVT is still unknown. Our objective was to compare functional and safety outcomes between different SBP goals after EVT with SR. METHODS: This international multicenter study included 8 comprehensive stroke centers and patients with anterior circulation large vessel occlusion who were treated with EVT and achieved SR. SR was defined as modified thrombolysis in cerebral ischemia 2b to 3. Patients were divided into 3 groups based on SBP goal in the first 24 hours after EVT. Inverse probability of treatment weighting (IPTW) propensity analysis was used to assess the effect of different SBP goals on clinical outcomes. RESULTS: A total of 1,019 patients were included. On IPTW analysis, the SBP goal of <140mmHg was associated with a higher likelihood of good functional outcome and lower odds of hemicraniectomy compared to SBP goal of <180mmHg. Similarly, SBP goal of <160mmHg was associated with lower odds of mortality compared to SBP goal of <180mmHg. In subgroup analysis including only patients with pre-EVT SBP of ≥140mmHg, an SBP of <140mmHg was associated with a higher likelihood of good functional outcome, lower odds of symptomatic intracranial hemorrhage, and lower odds of requirement for hemicraniectomy compared to SBP goal of <180mmHg. INTERPRETATION: SBP goals of <140 and < 160mmHg following SR with EVT appear to be associated with better clinical outcomes than SBP of <180mmHg. ANN NEUROL 2020;87:830-839.

Ischaemic stroke on anticoagulation therapy and early recurrence in acute cardioembolic stroke: the IAC study.

BACKGROUND AND PURPOSE: A subset of ischaemic stroke patients with atrial fibrillation (AF) have ischaemic stroke despite anticoagulation. We sought to determine the association between prestroke anticoagulant therapy and recurrent ischaemic events and symptomatic intracranial haemorrhage (sICH). METHODS: We included consecutive patients with acute ischaemic stroke and AF from the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study from eight comprehensive stroke centres in the USA. We compared recurrent ischaemic events and delayed sICH risk using adjusted Cox regression analyses between patients who were prescribed anticoagulation (ACp) versus patients who were naïve to anticoagulation therapy prior to the ischaemic stroke (anticoagulation naïve). RESULTS: Among 2084 patients in IAC, 1518 had prior anticoagulation status recorded and were followed for 90 days. In adjusted Cox hazard models, ACp was associated with some evidence of a higher risk higher risk of 90-day recurrent ischaemic events only in the fully adjusted model (adjusted HR 1.50, 95% CI 0.99 to 2.28, p=0.058) but not increased risk of 90-day sICH (adjusted HR 1.08, 95% CI 0.46 to 2.51, p=0.862). In addition, switching anticoagulation class was not associated with reduced risk of recurrent ischaemic events (adjusted HR 0.41, 95% CI 0.12 to 1.33, p=0.136) nor sICH (adjusted HR 1.47, 95% CI 0.29 to 7.50, p=0.641). CONCLUSION: AF patients with ischaemic stroke despite anticoagulation may have higher recurrent ischaemic event risk compared with anticoagulation-naïve patients. This suggests differing underlying pathomechanisms requiring different stroke prevention measures and identifying these mechanisms may improve secondary prevention strategies.

Non-Vitamin K Antagonist Oral Anticoagulants for the Treatment of Cerebral Venous Sinus Thrombosis: a Retrospective, Matched Cohort Analysis.

BACKGROUND: The management of cerebral venous sinus thrombosis (CVT) is a common problem facing vascular neurologists. American Heart Association/American Stroke Association guidelines suggest the use of heparin followed by vitamin K antagonists (VKAs) for anticoagulation in CVT. In recent years, the evidence base has solidified for the use of non-vitamin K antagonist oral anticoagulants (NOACs) in lower extremity deep vein thrombosis. Because data supporting their use in CVT are limited, with the strongest evidence comprising one randomized controlled trial of dabigatran, we sought to review our experience with NOACs in the treatment of CVT at a tertiary care center to address efficacy and safety. METHODS: We retrospectively reviewed charts of all patients with CVT treated with an NOAC at our tertiary care facility in the years 2011-2019. We collected data on demographics, risk factors for CVT, clinical features at presentation, imaging results, anticoagulation regimen, bleeding complications, and disability at follow-up. We compared disability at follow-up and major hemorrhagic events with age-matched and sex-matched controls treated with VKAs over the same time period and with historical controls. RESULTS: We identified 29 patients with CVT treated with an NOAC, 27 of whom had follow-up within our system. NOACs that were used for treatment included apixaban (20 patients), rivaroxaban (6 patients) and dabigatran (1 patient). NOAC use was associated with stabilization of a clot or partial recanalization in 55.6% of patients and complete recanalization in 14.8% at a median follow-up time of 6 months. The median modified Rankin Score (mRS) at follow-up was 0, with one death. Three patients (11.1%) had major bleeding complications, including two with symptomatic worsening of intracranial hemorrhage. Comparisons of 27 age-matched and sex-matched controls treated with VKAs showed no significant differences in terms of partial recanalization (55.6% vs. 63.0%, p = 0.29), complete recanalization (14.8% vs. 25.9%, p = 0.73), mRS at follow-up (median 0 vs. 0, p = 0.23), or major bleeding (11.1% vs. 11.1%, p > 0.99). Comparisons with the historical International Study on Cerebral Vein and Dural Sinus Thrombosis cohort showed similar functional outcomes: 92.6% of patients treated with NOACs and 88.9% of patients treated with VKAs at the Washington University School of Medicine in St. Louis, as well as 86.2% of patients treated with VKAs in the historical study cohort, had mRS of 0-2 at follow-up (p = 0.60). Rates of major bleeding compared with this cohort were also similar (11.1% vs. 11.1% vs. 14.5%, p = 0.80). CONCLUSIONS: The safety and efficacy results of NOAC use for CVT were similar to those for age-matched and sex-matched controls treated with VKAs, as well as historical published controls. Assessment of NOAC efficacy and safety in CVT in multicenter cohort studies and randomized controlled trials is warranted.

Anticoagulation Type and Early Recurrence in Cardioembolic Stroke: The IAC Study.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke and atrial fibrillation, treatment with low molecular weight heparin increases early hemorrhagic risk without reducing early recurrence, and there is limited data comparing warfarin to direct oral anticoagulant (DOAC) therapy. We aim to compare the effects of the treatments above on the risk of 90-day recurrent ischemic events and delayed symptomatic intracranial hemorrhage. METHODS: We included consecutive patients with acute ischemic stroke and atrial fibrillation from the IAC (Initiation of Anticoagulation after Cardioembolic) stroke study pooling data from stroke registries of 8 comprehensive stroke centers across the United States. We compared recurrent ischemic events and delayed symptomatic intracranial hemorrhage between each of the following groups in separate Cox-regression analyses: (1) DOAC versus warfarin and (2) bridging with heparin/low molecular weight heparin versus no bridging, adjusting for pertinent confounders to test these associations. RESULTS: We identified 1289 patients who met the bridging versus no bridging analysis inclusion criteria and 1251 patients who met the DOAC versus warfarin analysis inclusion criteria. In adjusted Cox-regression models, bridging (versus no bridging) treatment was associated with a high risk of delayed symptomatic intracranial hemorrhage (hazard ratio, 2.74 [95% CI, 1.01-7.42]) but a similar rate of recurrent ischemic events (hazard ratio, 1.23 [95% CI, 0.63-2.40]). Furthermore, DOAC (versus warfarin) treatment was associated with a lower risk of recurrent ischemic events (hazard ratio, 0.51 [95% CI, 0.29-0.87]) but not delayed symptomatic intracranial hemorrhage (hazard ratio, 0.57 [95% CI, 0.22-1.48]). CONCLUSIONS: Our study suggests that patients with ischemic stroke and atrial fibrillation would benefit from the initiation of a DOAC without bridging therapy. Due to our study limitations, these findings should be interpreted with caution pending confirmation from large prospective studies.

Early ischaemic and haemorrhagic complications after atrial fibrillation-related ischaemic stroke: analysis of the IAC study.

INTRODUCTION: Predictors of long-term ischaemic and haemorrhagic complications in atrial fibrillation (AF) have been studied, but there are limited data on predictors of early ischaemic and haemorrhagic complications after AF-associated ischaemic stroke. We sought to determine these predictors. METHODS: The Initiation of Anticoagulation after Cardioembolic stroke study is a multicentre retrospective study across that pooled data from consecutive patients with ischaemic stroke in the setting of AF from stroke registries across eight comprehensive stroke centres in the USA. The coprimary outcomes were recurrent ischaemic event (stroke/TIA/systemic arterial embolism) and delayed symptomatic intracranial haemorrhage (d-sICH) within 90 days. We performed univariate analyses and Cox regression analyses including important predictors on univariate analyses to determine independent predictors of early ischaemic events (stroke/TIA/systemic embolism) and d-sICH. RESULTS: Out of 2084 patients, 1520 patients qualified; 104 patients (6.8%) had recurrent ischaemic events and 23 patients (1.5%) had d-sICH within 90 days from the index event. In Cox regression models, factors associated with a trend for recurrent ischaemic events were prior stroke or transient ischemic attack (TIA) (HR 1.42, 95% CI 0.96 to 2.10) and ipsilateral arterial stenosis with 50%-99% narrowing (HR 1.54, 95% CI 0.98 to 2.43). Those associated with sICH were male sex (HR 2.68, 95% CI 1.06 to 6.83), history of hyperlipidaemia (HR 2.91, 95% CI 1.08 to 7.84) and early haemorrhagic transformation (HR 5.35, 95% CI 2.22 to 12.92). CONCLUSION: In patients with ischaemic stroke and AF, predictors of d-sICH are different than those of recurrent ischaemic events; therefore, recognising these predictors may help inform early stroke versus d-sICH prevention strategies.

Factors associated with therapeutic anticoagulation status in patients with ischemic stroke and atrial fibrillation.

BACKGROUND AND PURPOSE: Understanding factors associated with ischemic stroke despite therapeutic anticoagulation is an important goal to improve stroke prevention strategies in patients with atrial fibrillation (AF). We aim to determine factors associated with therapeutic or supratherapeutic anticoagulation status at the time of ischemic stroke in patients with AF. METHODS: The Initiation of Anticoagulation after Cardioembolic stroke (IAC) study is a multicenter study pooling data from stroke registries of eight comprehensive stroke centers across the United States. Consecutive patients hospitalized with acute ischemic stroke in the setting of AF were included in the IAC cohort. For this study, we only included patients who reported taking warfarin at the time of the ischemic stroke. Patients not on anticoagulation and patients who reported use of a direct oral anticoagulant were excluded. Analyses were stratified based on therapeutic (INR ≥2) versus subtherapeutic (INR <2) anticoagulation status. We used binary logistic regression models to determine factors independently associated with anticoagulation status after adjustment for pertinent confounders. In particular, we sought to determine whether atherosclerosis with 50% or more luminal narrowing in an artery supplying the infarct (a marker for a competing atherosclerotic mechanism) and small stroke size (≤ 10 mL; implying a competing small vessel disease mechanism) related to anticoagulant status. RESULTS: Of the 2084 patients enrolled in the IAC study, 382 patients met the inclusion criteria. The mean age was 77.4 ± 10.9 years and 52.4% (200/382) were women. A total of 222 (58.1%) subjects presented with subtherapeutic INR. In adjusted models, small stroke size (OR 1.74 95% CI 1.10-2.76, p = 0.019) and atherosclerosis with 50% or more narrowing in an artery supplying the infarct (OR 1.96 95% CI 1.06-3.63, p = 0.031) were independently associated with INR ≥2 at the time of their index stroke. CONCLUSION: Small stroke size (≤ 10 ml) and ipsilateral atherosclerosis with 50% or more narrowing may indicate a competing stroke mechanism. There may be important opportunities to improve stroke prevention strategies for patients with AF by targeting additional ischemic stroke mechanisms to improve patient outcomes.

Blood Pressure and Outcome After Mechanical Thrombectomy With Successful Revascularization.

Background and Purpose- Successful reperfusion can be achieved in more than two-thirds of patients treated with mechanical thrombectomy. Therefore, it is important to understand the effect of blood pressure (BP) on clinical outcomes after successful reperfusion. In this study, we investigated the relationship between BP on admission and during the first 24 hours after successful reperfusion with clinical outcomes. Methods- This was a multicenter study from 10 comprehensive stroke centers. To ensure homogeneity of the studied cohort, we included only patients with anterior circulation who achieved successful recanalization at the end of procedure. Clinical outcomes included 90-day modified Rankin Scale, symptomatic intracerebral hemorrhage (sICH), mortality, and hemicraniectomy. Results- A total of 1245 patients were included in the study. Mean age was 69±14 years, and 51% of patients were female. Forty-nine percent of patients had good functional outcome at 90-days, and 4.7% suffered sICH. Admission systolic BP (SBP), mean SBP, maximum SBP, SBP SD, and SBP range were associated with higher risk of sICH. In addition, patients in the higher mean SBP groups had higher rates of sICH. Similar results were found for hemicraniectomy. With respect to functional outcome, mean SBP, maximum SBP, and SBP range were inversely associated with the good outcome (modified Rankin Scale score, 0-2). However, the difference in SBP parameters between the poor and good outcome groups was modest. Conclusions- Higher BP within the first 24 hours after successful mechanical thrombectomy was associated with a higher likelihood of sICH, mortality, and requiring hemicraniectomy.

Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbα.

Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non-microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue-specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up-regulation of CXCL-1 (2·4-fold) and CCL5 (1·4-fold) acting as a compensatory mechanism in platelet-reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet-mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.

"You understand that whole big situation they're in": interpretative phenomenological analysis of peer-assisted learning.

BACKGROUND: Peer-assisted learning (PAL) increasingly features within medical school curricula. While there is evidence of its effectiveness, less is known about how it promotes learning. Cognitive and social congruence between peer-tutor and student have been described as important concepts underpinning teaching and learning in PAL. We employed interpretative phenomenological analysis for an in-depth exploration of how medical students experience PAL sessions. METHODS: We conducted the study at The University of Manchester within a near-peer scheme aimed at developing clinical skills within clinical clerkship students. We conducted individual interviews with three peer tutors and five students. We undertook interpretive phenomenological analysis of interview transcripts. We subsequently synthesised an account of the study participants' lived experiences of PAL sessions from individual personal accounts to explore how medical students experience peer-assisted learning. This analysis was then used to complement and critique a priori educational theory regarding the mechanisms underlying PAL. RESULTS: Students experienced PAL sessions as a safe and egalitarian environment, which shaped the type and style of learning that took place. This was facilitated by close relationships with peer-tutors, with whom they shared a strong sense of camaraderie and shared purpose. Peer-tutors felt able to understand their students' wider sociocultural context, which was the most important factor underpinning both the PAL environment and tutor-student relationship. Participants contrasted this relative safety, camaraderie and shared purpose of PAL with teaching led by more senior tutors in clinical settings. CONCLUSIONS: This study provides a rich description of the important factors that characterise medical students' experiences of PAL sessions. Participants felt a strong sense of support in PAL sessions that took into account their wider sociocultural context. Multiple factors interplayed to create a learning environment and tutor-student relationship that existed in contrast to teaching led by more senior, clinical tutors. The insight generated via IPA complemented existing theory and raised new lines of enquiry to better understand how the peer relationship fosters learning in PAL at medical school. We make recommendations to use insights from PAL for faculty and curriculum development.

Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity.

The immune system is implicated in a wide range of disorders affecting the brain and is, therefore, an attractive target for therapy. Interleukin-1 (IL-1) is a potent regulator of the innate immune system important for host defense but is also associated with injury and disease in the brain. Here, we show that IL-1 is a key mediator driving an innate immune response to inflammatory challenge in the mouse brain but is dispensable in extracerebral tissues including the lung and peritoneum. We also demonstrate that IL-1α is an important ligand contributing to the CNS dependence on IL-1 and that IL-1 derived from the CNS compartment (most likely microglia) is the major source driving this effect. These data reveal previously unknown tissue-specific requirements for IL-1 in driving innate immunity and suggest that IL-1-mediated inflammation in the brain could be selectively targeted without compromising systemic innate immune responses that are important for resistance to infection. This property could be exploited to mitigate injury- and disease-associated inflammation in the brain without increasing susceptibility to systemic infection, an important complication in several neurological disorders.

Expression of adiponectin and its receptors is altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines.

OBJECTIVES: Recent evidence suggests that higher body mass index is associated with a modest increase in ovarian cancer risk. Reduced serum levels of adiponectin are correlated with obesity and increased cancer risk. The objectives of the present study are to determine if expressions of adiponectin and its receptors, AdipoR1 and AdipoR2, are altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines and to determine if plasma adiponectin levels are altered in the chicken model of ovarian cancer. METHODS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations in ovaries and chicken ovarian cancer (COVCAR) cell lines were determined by quantitative real-time polymerase chain reaction analysis. Existence of adiponectin isoforms in the ovaries and COVCAR cells was identified by nondenaturing gel electrophoresis. Adiponectin, AdipoR1, and AdipoR2 protein amounts were determined by Western blot analysis. Plasma total adiponectin levels were determined by an enzyme immunoassay. RESULTS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations were significantly lower in cancerous ovaries and COVCAR cell lines compared with normal ovaries and normal ovarian surface epithelial (NOSE) cells, respectively. Adiponectin in ovary and COVCAR cell lines appeared as a heavy-molecular-weight isoform that is greater than 720-kd mass. In addition, a lower-molecular-weight adiponectin isoform was found in COVCAR cells but not in NOSE cells. Adiponectin and AdipoR1 protein concentrations were not different in COVCAR cell lines compared with NOSE cells. However, AdipoR2 protein concentrations were significantly higher in cancerous ovaries but lower in COVCAR cell lines compared with normal ovaries and NOSE cells, respectively. Plasma adiponectin concentrations were not different in chickens that had ovarian carcinoma compared with control animals. CONCLUSIONS: Expression of adiponectin in ovarian tumors and in metastatic ovarian tumor cells is likely to affect cellular metabolism and proliferation through activating AdipoR1 and/or AdipoR2. Plasma adiponectin levels may not be predictive of advanced stages of ovarian tumor in the chicken model.

The use of a kaolin-based hemostatic dressing to attenuate bleeding in dogs: A series of 4 cases.

OBJECTIVE: To describe the use of a synthetic hemostatic dressing, QuikClot Combat Gauze (QCG), in dogs with bleeding wounds. CASE SERIES SUMMARY: Two dogs presented with bleeding traumatic wounds, and QCG was used to achieve hemostasis during stabilization of these dogs. In the other 2 dogs, QCG was used to help attenuate bleeding associated with a surgical procedure. NEW OR UNIQUE INFORMATION PROVIDED: While hemostatic dressings have been widely studied and used in human medicine, there is minimal information on the use and efficacy of these hemostatic dressings in veterinary medicine. This case series describes the use of QCG in dogs with hemorrhaging wounds. QCG could be a valuable resource in veterinary emergency and critical care settings.

Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices.

Macrophage can adopt several phenotypes, process call polarization, which is crucial for shaping inflammatory responses to injury. It is not known if microglia, a resident brain macrophage population, polarizes in a similar way, and whether specific microglial phenotypes modulate cell death in response to brain injury. In this study, we show that both BV2-microglia and mouse bone marrow derived macrophages (BMDMs) were able to adopt different phenotypes after LPS (M1) or IL-4 (M2) treatment in vitro, but regulated cell death differently when added to mouse organotypic hippocampal brain slices. BMDMs induced cell death when added to control slices and exacerbated damage when combined with oxygen-glucose deprivation (OGD), independently of their phenotype. In contrast, vehicle- and M2-BV2-microglia were protective against OGD-induced death. Direct treatment of brain slices with IL-4 (without cell addition) was protective against OGD and induced an M2 phenotype in the slice. In vivo, intracerebral injection of LPS or IL-4 in mice induced microglial phenotypes similar to the phenotypes observed in brain slices and in cultured cells. After injury induced by middle cerebral artery occlusion, microglial cells did not adopt classical M1/M2 phenotypes, suggesting that another subtype of regulatory phenotype was induced. This study highlights functional differences between macrophages and microglia, in response to brain injury with fundamentally different outcomes, even if both populations were able to adopt M1 or M2 phenotypes. These data suggest that macrophages infiltrating the brain from the periphery after an injury may be cytotoxic, independently of their phenotype, while microglia may be protective.

Sphingosine regulates the NLRP3-inflammasome and IL-1ß release from macrophages.

Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1ß secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1ß from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1ß release. IL-1ß release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation.