bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3
Authors: Nishikawa Hirofumi , Liu Lei , Nakano Fumi , Kawakita Fumihiro , Kanamaru Hideki , Nakatsuka Yoshinari , Okada Takeshi , Suzuki Hidenori 
Published: October 2018

Background and Purpose—
Plasma levels of galectin-3—a matricellular protein—are increased after aneurysmal subarachnoid hemorrhage (SAH), but the functional significance remains undetermined. This study was conducted to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier disruption.

Methods—
C57BL/6 male adult mice (n=251) underwent sham or filament perforation SAH modeling, followed by a random intracerebroventricular injection of vehicle or drug at 30 minutes post-modeling. First, vehicle-treated and 0.8, 4, 16, or 32 µg MCP-treated mice were assessed by neuroscore and brain water content at 24 and 48 hours post-modeling. Second, Evans blue extravasation, Western blotting, coimmunoprecipitation and immunostaining were performed in vehicle-treated or 4 µg MCP-treated mice at 24 hours post-modeling. Third, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore and Evans blue extravasation were evaluated at 24 hours post-modeling. Fourth, vehicle or R-galectin-3 was administered to MCP-treated SAH mice at 24 hours, and neuroscore and IgG immunostaining were evaluated at 48 hours post-SAH.

Results—
Among tested dosages, 4 µg MCP showed the best neuroprotective effects as to preventing neurological impairments and brain edema at 24 to 48 hours post-SAH. Four micrograms MCP attenuated post-SAH blood-brain barrier disruption and galectin-3 upregulation in brain capillary endothelial cells, associated with inactivation of ERK (extracellular signal-related kinase) 1/2, STAT (signal transducer and activator of transcription)-3, and MMP (matrix metalloproteinase)-9, and the consequent preservation of a tight junction protein ZO-1 (zonula occludens-1). Coimmunoprecipitation assay demonstrated physical interactions between galectin-3 and TLR (Toll-like receptor) 4. R-galectin-3 blocked the neuroprotective effects of MCP.

Conclusions—
MCP prevents post-SAH blood-brain barrier disruption possibly by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. This study suggests galectin-3 to be a novel therapeutic target against post-SAH early brain injury.
Is Functional Outcome Different in Posterior and Anterior Circulation Stroke?
Authors: Sommer Peter , Posekany Alexandra , Serles Wolfgang , Marko Martha , Scharer Sebastian , Fertl Elisabeth , Ferrari Julia , Lang Wilfried , Vosko Milan , Szabo Simon , Kiechl Stefan , Knoflach Michael , Greisenegger Stefan ,   on behalf of the Austrian Stroke Unit Registry Collaborators
Published: October 2018

Background and Purpose—
Posterior circulation stroke (PCS) account for 20% of all ischemic strokes. There is limited evidence whether functional outcome of PCS is comparable to that of anterior circulation stroke (ACS). We aimed to analyze whether 3-month functional outcome is different in PCS and ACS.

Methods—
Patients with acute ischemic stroke prospectively enrolled within the Austrian Stroke Unit Registry were stratified by infarct localization according to the Oxfordshire Community Stroke Project Classification. Propensity score matching was used to control for covariate imbalances and to match patients with PCS and ACS. Patients were matched for stroke severity, recombinant tissue-type plasminogen activator treatment, and demographic and vascular risk factors. Main outcomes were the distribution of modified Rankin Scale after 3 months and multiple proportional odds models to estimate the influence of the infarct localization on the functional outcome.

Results—

From a total of 90 484 patients enrolled within the Austrian Stroke Unit Registry, 9208 (4604 PCS/4604 ACS) were matched, of those 954 (477 in each group) were treated with recombinant tissue-type plasminogen activator. We detected a significant shift towards better 3-month functional outcome in patients with ACS compared with PCS (odds ratio [OR], 1.19; 95% CI, 1.1–1.28;
P
<0.0001). In particular, functional outcome was worse in PCS with onset-to-door-time >270 minutes (OR, 1.34; 95% CI, 1.17–1.54;
P
<0.0001) and in PCS with unknown onset-to-door-time (OR, 1.26; 95% CI, 1.13–1.42;
P
<0.0001); however, we did not detect any difference in functional outcome between ACS and PCS in patients with an onset-to-door-time ≤270 minutes (1–180 minutes: OR, 0.92, 95% CI, 0.78–1.09,
P
=0.3554; 181–270 minutes: OR, 1.04, 95% CI, 0.79–1.37,
P
=0.7689). In patients treated with recombinant tissue-type plasminogen activator, functional outcome was not significantly different between PCS and ACS.

Conclusions—
PCS was associated with worse outcome compared with ACS in patients arriving later than 4.5 hours at hospital or in those with unknown onset of symptoms. Our results urge for implementation of symptoms found in the posterior circulation into preclinical patient-triage tools.
Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage
Authors: Murphy Meredith P. , Kuramatsu Joji B. , Leasure Audrey , Falcone Guido J. , Kamel Hooman , Sansing Lauren H. , Kourkoulis Christina , Schwab Kristin , Elm Jordan J. , Gurol M. Edip , Tran Huy , Greenberg Steven M. , Viswanathan Anand , Anderson Christopher D. , Schwab Stefan , Rosand Jonathan , Shi Fu-Dong , Kittner Steven J. , Testai Fernando D. , Woo Daniel , Langefeld Carl D. , James Michael L. , Koch Sebastian , Huttner Hagen B. , Biffi Alessandro , Sheth Kevin N. 
Published: October 2018

Background and Purpose—
Whether to resume oral anticoagulation treatment after intracerebral hemorrhage (ICH) remains an unresolved question. Previous studies focused primarily on recurrent stroke after ICH. We sought to investigate the association between cardioembolic stroke risk, oral anticoagulation therapy resumption, and functional recovery among ICH survivors in the absence of recurrent stroke.

Methods—

We conducted a joint analysis of 3 observational studies: (1) the multicenter RETRACE study (German-Wide Multicenter Analysis of Oral Anticoagulation Associated Intracerebral Hemorrhage); (2) the Massachusetts General Hospital ICH study (n=166); and (3) the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage; n=131). We included 941 survivors of ICH in the setting of active oral anticoagulation therapy for prevention of cardioembolic stroke because of nonvalvular atrial fibrillation and without evidence of ischemic stroke and recurrent ICH at 1 year from the index event. We created univariable and multivariable models to explore associations between cardioembolic stroke risk (based on CHA
2
DS
2
-VASc scores) and functional recovery after ICH, defined as achieving modified Rankin Scale score of ≤3 at 1 year for participants with modified Rankin Scale score of >3 at discharge.

Results—

In multivariable analyses, the CHA
2
DS
2
-VASc score was associated with a decreased likelihood of functional recovery (odds ratio, 0.83 per 1 point increase; 95% CI, 0.79–0.86) at 1 year. Anticoagulation resumption was independently associated with a higher likelihood of recovery, regardless of CHA
2
DS
2
-VASc score (odds ratio, 1.89; 95% CI, 1.32–2.70). We found an interaction between CHA
2
DS
2
-VASc score and anticoagulation resumption in terms of association with increased likelihood of functional recovery (interaction
P
=0.011).

Conclusions—
Increasing cardioembolic stroke risk is associated with a decreased likelihood of functional recovery at 1 year after ICH, but this association was weaker among participants resuming oral anticoagulation therapy. These findings support, including recovery metrics, in future studies of anticoagulation resumption after ICH.
Thrombus Permeability in Admission Computed Tomographic Imaging Indicates Stroke Pathogenesis Based on Thrombus Histology
Authors: Berndt Maria , Friedrich Benjamin , Maegerlein Christian , Moench Sebastian , Hedderich Dennis , Lehm Manuel , Zimmer Claus , Straeter Alexandra , Poppert Holger , Wunderlich Silke , Schirmer Lucas , Oberdieck Paul , Kaesmacher Johannes , Boeckh-Behrens Tobias 
Published: October 2018

Background and Purpose—
Intracranial thrombi can be characterized according to their permeability as measured by contrast agent penetration. Thrombus composition and its associated pathogenesis are important factors affecting treatment and secondary prevention. We aimed to explore the histopathologic factors explaining the heterogeneity of thrombus permeability measures and evaluated potential correlations with stroke pathogenesis.

Methods—

Thrombus densities were measured in thin-slice noncontrast computed tomography and automatically aligned computed tomographic angiography images of 133 patients with large-vessel occlusions of the middle cerebral artery. Change in thrombus attenuation (Δ
t
) and corrected void fraction (ε; attenuation increase corrected for contralateral artery densities) were calculated. First, these thrombus perviousness measures were correlated with histological thrombus components (especially fractions of fibrin-platelet accumulation and red blood cells) and stroke pathogenesis (n=32). For validation, an association between perviousness and pathogenesis was assessed in a second, independent cohort (n=101).

Results—

Thrombus perviousness estimates were correlated with both fibrin/platelets fractions (Δ
t
: r=0.43,
P
=0.016/ε: r=0.45,
P
=0.01) and inversely with red blood cells counts (Δ
t
: r=−0.46,
P
=0.01/ε: r=−0.49,
P
=0.006). In the first cohort, Δ
t
was substantially higher in samples from patients with cardioembolic stroke pathogenesis as compared with noncardioembolic-derived thrombi (
P
=0.026). In the validation cohort, thrombus perviousness measures differed significantly between cardioembolic (Δ
t
: median [ interquartile range]=12.53 [8.70–17.90]; ε: median [interquartile range]=0.054 [0.036–0.082]) and noncardioembolic thrombi (Δ
t
: median [interquartile range]=3.2 [2.17–6.44],
P
<0.001; ε: median [interquartile range]=0.020 [0.011–0.027],
P
<0.001) and were associated with pathogenesis (Δ
t
: β=0.45,
P
=0.016/ε: β=83.6,
P
=0.013) in a binary logistic regression model.

Conclusions—
Permeable thrombi showed a strong correlation with lower fractions of red blood cells counts and more fibrin/platelets conglomerations, concurrent with an association with cardioembolic origin. This novel information about thrombus perviousness may be valuable as a new and simple to acquire imaging marker for identifying stroke pathogenesis using early and readily available imaging.
Risk of Nursing Home Admission in Cerebral Small Vessel Disease
Authors: Bergkamp Mayra I. , Wissink Joost G.J. , van Leijsen Esther M.C. , Ghafoorian Mohsen , Norris David G. , van Dijk Ewoud J. , Platel Bram , Tuladhar Anil M. , de Leeuw Frank-Erik 
Published: October 2018

Background and Purpose—
Since cerebral small vessel disease (SVD) is associated with cognitive and motor impairment and both might ultimately lead to nursing home admission, our objective was to investigate the association of SVD markers with nursing home admission.

Methods—
The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort of 503 independent living individuals with SVD. Date of nursing home admission was retrieved from the Dutch municipal personal records database. Risk of nursing home admission was calculated using a competing risk analysis, with mortality as a competing risk.

Results—

During follow-up (median 8.7 years, interquartile range 8.5–8.9), 31 participants moved to a nursing home. Before nursing home admission, 19 participants were diagnosed with dementia, 6 with parkinsonism, and 10 with stroke. Participants with the lowest white matter volume had an 8-year risk of nursing home admission of 13.3% (95% CI, 8.6–18.9), which was significantly different from participants with middle or highest white matter volume (respectively, 4.8% [95% CI, 2.3–8.8] and 0%;
P
<0.001). After adjusting for baseline age and living condition, the association of white matter volume and total brain volume with nursing home admission was significant, with, respectively, hazard ratios of 0.88 [95% CI, 0.84–0.95] (
P
value 0.025) and 0.92 [95% CI, 0.85–0.98] (
P
<0.001) per 10 mL. The association of white matter hyperintensities and lacunes with nursing home admission was not significant.

Conclusions—
This study demonstrates that in SVD patients, independent from age and living condition, a lower white matter volume and a lower total brain volume is associated with an increased risk of nursing home admission. Nursing home admission is a relevant outcome in SVD research since it might be able to combine both cognitive and functional consequences of SVD in 1 outcome.
TLR7 (Toll-Like Receptor 7) Facilitates Heme Scavenging Through the BTK (Bruton Tyrosine Kinase)–CRT (Calreticulin)–LRP1 (Low-Density Lipoprotein Receptor–Related Protein-1)–Hx (Hemopexin) Pathway in Murine Intracerebral Hemorrhage
Authors: Wang Gaiqing , Guo Zhenni , Tong Lusha , Xue Fang , Krafft Paul R. , Budbazar Enkhjargal , Zhang John H. , Tang Jiping 
Published: October 2018

Background and Purpose—
Heme and iron are considered to be key factors responsible for secondary insults after intracerebral hemorrhage (ICH). Our previous study showed that LRP1 (low-density lipoprotein receptor–related protein-1)–Hx (hemopexin) facilitates removal of heme. The TLR7 (Toll-like receptor 7)–BTK (Bruton tyrosine kinase)–CRT (calreticulin) pathway regulates the expression of LRP1-Hx. This study is designed to clarify whether TLR7 activation facilitates heme scavenging and to establish the potential role of the BTK-CRT-LRP1-Hx signaling pathway in the pathophysiology of ICH.

Methods—
ICH was induced by stereotactic, intrastriatal injection of type VII collagenase. Mice received TLR7 agonist (imiquimod) via intraperitoneal injection after ICH induction. TLR7 inhibitor (ODN2088), BTK inhibitor (LFM-A13), and CRT agonist (thapsigargin) were given in different groups to further evaluate the underlying pathway. Mice were randomly divided into sham, ICH+vehicle (normal saline), ICH+Imiquimod (2.5, 5, and 10 μg/g), ICH+ODN2088, ICH+LFM-A13, ICH+thapsigargin, and ICH+ODN2088+thapsigargin. Imiquimod was administered twice daily starting at 6 hours after ICH; ODN2088 was administered by intracerebroventricular injection at 30 minutes, and LFM-A13 or thapsigargin was administered by intraperitoneal injection at 3 hours after ICH induction. Neurological scores, cognitive abilities, as well as brain edema, blood-brain barrier permeability, hemoglobin level, brain expression of TLR7/BTK/CRT/LRP1/Hx were analyzed.

Results—
Low dosage imiquimod significantly attenuated hematoma volume, brain edema, BBB permeability, and neurological deficits after ICH. Imiquimod also increased protein expressions of TLR7, BTK, CRT, LRP1, and Hx; ODN2088 reduced TLR7, BTK, CRT, LRP1, and Hx expressions.

Conclusions—
TLR7 plays an important role in heme scavenging after ICH by modulating the BTK-CRT-LRP1-Hx pathway. TLR7 may offer protective effects by promoting heme resolution and reduction of brain edema after ICH.
Impact of Hyperglycemia According to the Collateral Status on Outcomes in Mechanical Thrombectomy
Authors: Kim Joon-Tae , Liebeskind David S. , Jahan Reza , Menon Bijoy K. , Goyal Mayank , Nogueira Raul G. , Pereira Vitor M. , Gralla Jan , Saver Jeffrey L. 
Published: October 2018

Background and Purpose—
Understanding the influence of hyperglycemia on outcomes in terms of the pretreatment collateral status might contribute to the achievement of case-specific glucose management in acute ischemic stroke. We sought to investigate whether the glucose level can influence the pretreatment collateral status and functional outcomes of endovascular thrombectomy in acute ischemic stroke and whether the impact of hyperglycemia on outcomes can be modified by the pretreatment collateral status.

Methods—
We analyzed the Triple-S database, which includes individual patient data pooled from 3 prospective Solitaire stent retriever studies (SWIFT [Solitaire With the Intention for Thrombectomy], SWIFT PRIME [SWIFT as Primary Endovascular Treatment], and STAR [Solitaire Flow Restoration Thrombectomy for Acute Revascularization]). Patients were eligible if they had acute ischemic stroke with moderate to severe neurological deficits, harbored angiographically confirmed large vessel occlusion, and were treatable by endovascular thrombectomy within 8 hours of onset. Pretreatment catheter angiograms were scored for collateral grades by a core imaging laboratory. The main outcome was 3-month good outcome (modified Rankin Scale score of 0–2).

Results—

Angiographic data on collaterals were available in 309 patients (age, 67±12 years; glucose, 131±55 mg/dL). Overall, the glucose level at presentation was not associated with pretreatment collateral status but was significantly lower in patients with a good outcome at 90 days (124 versus 140 mg/dL). Collateral grades modified the effect of glucose on good outcomes at 90 days (
P
int
=0.03). Among patients with poor collaterals (collateral grades, 0–2), higher glucose levels did not alter the outcome, whereas among patients with good collaterals (3–4), higher glucose levels reduced the likelihood of a good outcome at 90 days (per 10 mg/dL increase: odds ratio, 0.81; 95% CI, 0.69–0.95).

Conclusions—
Our study revealed that higher glucose levels reduce the likelihood of a good outcome among patients with good collaterals, but their effects on the outcome are less significant for patients with poor collaterals. The results suggest that good collaterals at presentation may be targets for more intensive glucose control and future studies relating to glucose management.
Ischemic Stroke Increases Heart Vulnerability to Ischemia-Reperfusion and Alters Myocardial Cardioprotective Pathways
Authors: Meloux Alexandre , Rigal Eve , Rochette Luc , Cottin Yves , Bejot Yannick , Vergely Catherine 
Published: October 2018

Background and Purpose—
For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo and how they influence cardiac vulnerability to ischemia-reperfusion injury.

Methods—
Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue staining, and assessment of neurological deficit 2 hours, 24 hours, and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to ischemia-reperfusion injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LVs) were analyzed with Western blotting and quantitatve real-time polymerase chain reaction.

Results—
Our stroke model produced large cerebral infarcts with severe neurological deficit. Cardiac contractile dysfunction was observed with an early but persistent reduction of LV fractional shortening in vivo and of LV developed pressure ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LV developed pressure and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 (growth differentiation factor 15) increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 (adrenoceptor β1) and cardioprotective Survivor Activating Factor Enhancement signaling pathways.

Conclusions—
Our findings indicate that stroke not only impairs cardiac contractility but also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms of stroke-induced myocardial alterations after cerebral embolization remain to be established, insofar as they may involve the sympathetic nervous system and nitro-oxidative stress.
Outcomes of Endovascular Treatment for Acute Intracranial Atherosclerosis–Related Large Vessel Occlusion
Authors: Baek Jang-Hyun , Kim Byung Moon , Heo Ji Hoe , Kim Dong Joon , Nam Hyo Suk , Kim Young Dae 
Published: October 2018

Background and Purpose—
Endovascular treatment for acute intracranial atherosclerosis–related large vessel occlusion (ICAS [+]-LVO) is one of the challenging issues in modern mechanical thrombectomy era. We evaluated procedural and clinical outcomes of endovascular treatment for the ICAS (+)-LVO. We also compared their outcomes with those of large vessel occlusion not associated with intracranial atherosclerosis (ICAS [−]-LVO).

Methods—
We retrospectively reviewed consecutive patients with acute stroke who underwent endovascular treatment for LVO. Patients were assigned to the ICAS (+)-LVO group or the ICAS (−)-LVO group primarily based on catheter angiogram. Procedural and clinical outcomes were compared between the ICAS (+)-LVO and ICAS (−)-LVO groups.

Results—

The present study included 318 patients. Fifty-six patients (17.6%) had an ICAS (+)-LVO. Recanalization was achieved in 45 patients in the ICAS (+)-LVO group (80.4%), which was comparable with the ICAS (−)-LVO group (88.5%;
P
=0.097). However, recanalization using a stent retriever was less successful in the ICAS (+)-LVO (28.9%) than the ICAS (−)-LVO group (93.5%). Of the remaining patients in the ICAS (+)-LVO group, 84.3% of patients required specific rescue treatments appropriate for ICAS, including balloon angioplasty, stenting, and intra-arterial glycoprotein IIb/IIIa inhibitor infusion. The rates of favorable outcomes (46.4% versus 46.9%), death, and symptomatic intracranial hemorrhage were not significantly different between the 2 groups. Glycoprotein IIb/IIIa inhibitor use was not significantly associated with symptomatic intracranial hemorrhage.

Conclusions—
ICAS (+)-LVO was often refractory to mechanical thrombectomy. With specific rescue treatments appropriate for ICAS, patients in the ICAS (+)-LVO group had a recanalization rate comparable with patients in the ICAS (−)-LVO. With comparable recanalization rate, the clinical outcomes did not differ between patients with ICAS (+)-LVO and ICAS (−)-LVO.