The Benefit of Thrombectomy in Patients With Low ASPECTS Is a Matter of Shades of Gray—What Current Trials May Have Missed

Randomized trials supporting the benefit of endovascular treatment in acute ischemic stroke patients with a large early infarction are not yet available. Few retrospective studies exist that suggest a potential positive treatment effect on functional outcome, as well as procedural safety. However, potential benefit or harm of MT in patients with low initial ASPECTS is still a subject of current debate, and in particular, how to select these patients for treatment. The purpose of this pilot study was to evaluate how early tissue water uptake in acute ischemic brain might determine lesion fate and functional outcome in low ASPECTS patients undergoing MT. We observed that the degree of early water uptake measured by quantitative NWU was significantly associated with functional outcome in low ASPECTS patients, yielding a higher diagnostic power compared to other parameters such as ASPECTS, age, or NIHSS. No conclusive evidence of a beneficial effect of successful reperfusion was observed in patients with low ASPECTS and high NWU, which highlights the potential of NWU as a tool to specify patient selection.

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Abstract W MP38: Apolipoprotein A-I (ApoA-I) Mimetic Peptide, D-4F, Regulates miRNA Expression and Improves Functional Outcome after Stroke in Diabetic Rats

Stroke ◽

10.1161/str.45.suppl_1.wmp38 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Ruizhuo Ning ◽

Michael Chopp ◽

Alex Zacharek ◽

Tao Yan ◽

Cynthia Roberts ◽

...

Keyword(s):

Functional Outcome ◽

Mirna Expression ◽

Target Gene ◽

M2 Macrophage ◽

Lesion Volume ◽

Ischemic Brain ◽

Mimetic Peptide ◽

Hdl Function ◽

Functional Benefit ◽

Gene And Protein Expression

Introduction: Diabetes mellitus (DM) in patients is associated with low high-density lipoprotein cholesterol (HDL-C) and impairment of the anti-oxidative capacity of HDL-C. Several miRNAs have been identified as having a physiological role in tissues in which diabetes complications occur. D-4F is an economical ApoA-I mimetic peptide which increases HDL function. We therefore investigated the therapeutic effect and underlying mechanisms of D-4F treatment of stroke induced functional benefit effects in type one DM (T1DM) rats. Methods: T1DM was induced in Wistar rats by streptozotocin (60mg/kg, ip) .Subsequently they were subjected to embolic middle cerebral artery occlusion. D-4F (10 mg/kg i.p.) was administered at 2h, 24h and 48h after stroke. Functional outcomes, brain blood barrier (BBB) leakage and lesion volume were evaluated. Results: D-4F treatment of stroke in T1DM rats significantly decreased Evans Blue dye leakage (15.85±1.52 ng/mg vs contro: 30.57± 5.88 ng/mg) and significantly improved functional outcome compared to non-treatment T1DM-control. D-4F treatment significantly increased miR-124a and miR-181c, but decreased miR-200b expression in the ischemic brain. Using laser capture, D-4F also significantly increased ischemic brain endothelial cell miR-126 expression compared to non-treatment control. In addition, D-4F treatment significantly decreased miR-181c target gene tumor necrosis factor-a (TNF-a), and miR-124a target gene monocyte chemoattractant protein-1 (MCP1) expression. D-4F also decreased proinflammatory nuclear NFkB (26.07±3.17 vs 37.43±3.47), Toll-like receptor 4 (TLR4, 7.26±0.69 vs 10.5±1.2), matrix metalloproteinase 9 (MMP9, 0.16±0.04 vs 0.48±0.09) expression, and increased CD163 (M2 macrophage marker, 120.98±8.13 vs 85.02± 9.47) number compared to T1DM-MCAo control rats. Conclusion: D-4F treatment of stroke in T1DM rats regulates miRNA expression and their target gene and protein expression and induces anti-inflammatory effects and promotes M2 macrophage polarization which may contribute to D-4F decreased BBB leakage and induced functional benefit effects after stroke in T1DM rats.

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Brain-derived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome

Experimental Biology and Medicine ◽

10.1177/1535370218815612 ◽

2018 ◽

Vol 243 (15-16) ◽

pp. 1207-1211 ◽

Cited By ~ 1

Author(s):

Martin Pedard ◽

Céline Brenière ◽

Nicolas Pernet ◽

Catherine Vergely ◽

Yannick Béjot ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Outcome ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Stroke Outcome ◽

Stroke Patients ◽

Peripheral Blood Mononuclear ◽

Ischemic Brain ◽

Blood Mononuclear Cells

Stroke outcome is dependent on brain-derived neurotrophic factor (BDNF)-dependent neuroplasticity. As peripheral blood mononuclear cells (PBMC) contain BDNF, diapedesis of these cells might be followed by BDNF delivery to the ischemic brain. To test this hypothesis, we investigated the association between BDNF levels in PBMC and functional outcome in patients with ischemic stroke. BDNF was measured in PBMC that were isolated from ischemic stroke patients ( n = 40) just before (day 0) and after (days 1 and 3) fibrinolysis. Three months after stroke, patients were stratified using the modified Rankin Scale (mRS) according to the unfavorable (mRS scores 3–6) and favorable (mRS scores 0–2) functional outcome. We used univariate and multivariate logistic regressions to assess the relationship between BDNF levels in PBMC and functional outcome. BDNF levels in PBMC decreased from day 0 to day 3 in patients with unfavorable outcome, while they remained stable in patients with favorable outcome. Patients with favorable outcome exhibited at day 3 higher PBMC-BDNF levels than patients with unfavorable outcome and the levels were associated with good outcome (odd ratio: 12.0; 95% confidence interval, 1.4–106.2, P = 0.023). PBMC-BDNF levels remained a predictor of stroke outcome after adjusting from cardiovascular risk, interval between admission and fibrinolysis, stroke severity from hospital admission to discharge, lymphocytes count, neutrophils/lymphocytes ratio at admission. Favorable functional outcome in ischemic stroke patients that benefited from fibrinolysis was predicted by a high BDNF level in PBMC, suggesting that PBMC might serve as a cellular vector to deliver BDNF to the ischemic brain. Impact statement There are a great number of arguments suggesting that BDNF could be involved in stroke recovery dependent of neuroplasticity. Methods that can enhance BDNF levels in the ischemic brain could therefore have great clinical value. Peripheral blood mononuclear cells (PBMC) that contain BDNF and infiltrate early and sustainably the ischemic brain might be used as a cellular vector to deliver BDNF to the ischemic brain and consequently promote recovery. This work is important in this field to show if this BDNF derived from BDNF could exert a positive action on stroke recovery. Our main results showed that a high BDNF level at day 3 after hospital admission was associated with a 12.4 fold increase in favorable outcome after adjusting for still recognized prognostic markers. The new information in this field is this finding identifies PBMC as an attractive cellular vector to deliver BDNF to the ischemic brain.

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Efficacy of Zoledronic Acid in Patients with Systemic Osteoporosis and Problem of «Non Respondents» to the Treatment

N.N. Priorov Journal of Traumatology and Orthopedics ◽

10.17816/vto201522439-43 ◽

2015 ◽

Vol 22 (4) ◽

pp. 39-43

Author(s):

S. S Rodionova ◽

Yu. V Buklemishev

Keyword(s):

Bone Formation ◽

Treatment Effect ◽

Biochemical Tests ◽

Zolendronic Acid ◽

Bone Formation Markers ◽

Study Results ◽

Positive Treatment Effect ◽

Positive Treatment ◽

The Relationship ◽

Mineral Bone Density

Prospective study of zolendronic acid efficacy was performed in 112 patients with systemic osteoporosis. Study results confirmed the presence of patients who did not response to the treatment: in 15.7 % of observations reduction of mineral bone density (BMD) continued to progress. No significant differences in initial deviations of resorption and bone formation markers, peculiarities of calcium homeostasis were detected in “non respondents”. At the same time by the 12th month after treatment initiation the relationship between BMD increase with preservation of marked decrease of resorption marker (deoxypyridinoline) and bone formation marker (osteocalcin) was noted, that pointed out the expediency of prognostic model creation. Evaluation of the influence of certain risk factors (age, results of blood and urine biochemical tests, data of densitometry including the results of femoral neck BMD in some patients) using discriminant analysis showed that 81.5% of patients were correctly referred to the groups of patients who responded and not responded to treatment. Out of all initially studied parameters the most significant were 7 that in 78.6% of cases (method sensitivity) enabled to identify the patients with negative treatment effect and in 82.1% of cases (method specificity) - with positive treatment effect.

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Appetite-Suppressing and Satiety-Increasing Bioactive Phytochemicals: A Systematic Review

Nutrients ◽

10.3390/nu11092238 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2238 ◽

Cited By ~ 1

Author(s):

Johann Stuby ◽

Isaac Gravestock ◽

Evelyn Wolfram ◽

Giuseppe Pichierri ◽

Johann Steurer ◽

...

Keyword(s):

Systematic Review ◽

Plant Extracts ◽

Caloric Intake ◽

Efficacy And Safety ◽

Inclusion Criteria ◽

Positive Treatment Effect ◽

Positive Treatment ◽

Prevalence Of Obesity ◽

Bioactive Phytochemicals ◽

Overweight Or Obesity

The prevalence of obesity is increasing worldwide. Bioactive phytochemicals in food supplements are a trending approach to facilitate dieting and to improve patients’ adherence to reducing food and caloric intake. The aim of this systematic review was to assess efficacy and safety of the most commonly used bioactive phytochemicals with appetite/hunger-suppressing and/or satiety/fullness-increasing properties. To be eligible, studies needed to have included at least 10 patients per group aged 18 years or older with no serious health problems except for overweight or obesity. Of those studies, 32 met the inclusion criteria, in which 27 different plants were tested alone or as a combination, regarding their efficacy in suppressing appetite/hunger and/or increasing satiety/fullness. The plant extracts most tested were derived from Camellia sinensis (green tea), Capsicum annuum, and Coffea species. None of the plant extracts tested in several trials showed a consistent positive treatment effect. Furthermore, only a few adverse events were reported, but none serious. The findings revealed mostly inconclusive evidence that the tested bioactive phytochemicals are effective in suppressing appetite/hunger and/or increasing satiety/fullness. More systematic and high quality clinical studies are necessary to determine the benefits and safety of phytochemical complementary remedies for dampening the feeling of hunger during dieting.

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Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion

Acta Endocrinologica ◽

10.1530/eje-10-1078 ◽

2011 ◽

Vol 164 (5) ◽

pp. 725-732 ◽

Cited By ~ 112

Author(s):

Joseph G Verbalis ◽

Suzanne Adler ◽

Robert W Schrier ◽

Tomas Berl ◽

Qiong Zhao ◽

...

Keyword(s):

Antidiuretic Hormone ◽

Health Survey ◽

Hormone Secretion ◽

Fluid Restriction ◽

Efficacy And Safety ◽

Inappropriate Antidiuretic Hormone Secretion ◽

Antidiuretic Hormone Secretion ◽

Days Of Therapy ◽

Positive Treatment Effect ◽

Positive Treatment

ObjectiveTolvaptan, an oral antagonist of the vasopressin V2 receptor, has been found to improve hyponatremia in patients with mixed etiologies. This study analyzed a subgroup of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) to evaluate the efficacy and safety of tolvaptan in this group.Design and patientsHyponatremic patients in the SALT-1 and SALT-2 studies with a diagnosis of SIADH were identified based on clinical diagnosis by individual study investigators. Subjects were randomized to receive oral placebo (n=52) or tolvaptan 15 mg daily, with further titration to 30 and 60 mg daily, if necessary, based on the response of serum [Na+] (n=58).ResultsIn patients with SIADH, improvement in serum [Na+] was significantly greater (P<0.0001) with tolvaptan than placebo over the first 4 days of therapy as well as the entire 30-day study, with minimal side effects of increased thirst, dry mouth, and urination. Only 5.9% of tolvaptan-treated patients had overly rapid correction of hyponatremia as defined by current guidelines. After discontinuation of tolvaptan, serum [Na+] declined to values similar to placebo. A significant positive treatment effect favoring tolvaptan on the physical component, and a near-significant trend on the mental component, was found using the SF-12 Health Survey. Tolvaptan was associated with a significantly reduced incidence of fluid restriction.ConclusionsResults for the SIADH subgroup were analogous to those of the combined SALT population regarding efficacy and safety but demonstrated a greater improvement in the physical component of the SF-12 Health Survey than in the full mixed etiology SALT patient group.

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Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome

Stroke ◽

10.1161/strokeaha.120.033547 ◽

2021 ◽

Author(s):

Suresh L. Mehta ◽

Anil K. Chokkalla ◽

TaeHee Kim ◽

Saivenkateshkomal Bathula ◽

Bharath Chelluboina ◽

...

Keyword(s):

Functional Outcome ◽

Rna Sequencing ◽

Brain Damage ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Focal Ischemia ◽

Developmental Expression ◽

Lesion Volume ◽

Sequencing Analysis ◽

Ischemic Brain

Background and Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia. Using FosDT knockout rats, we presently evaluated the role of FosDT in poststroke brain damage. Methods: FosDT knockout rats were generated using CRISPR-Cas9 genome editing on a Sprague-Dawley background. Male and female FosDT −/− and FosDT +/+ cohorts were subjected to transient middle cerebral artery occlusion. Postischemic sensorimotor deficits were evaluated between days 1 and 7 and lesion volume on day 7 of reperfusion. The developmental expression profile of FosDT was determined with real-time polymerase chain reaction and mechanistic implications of FosDT in the ischemic brain were conducted with RNA-sequencing analysis and immunostaining of pathological markers. Results: FosDT expression is developmentally regulated, with the adult cerebral cortex showing significantly higher FosDT expression than neonates. FosDT −/− rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture, and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT −/− rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. RNA-sequencing analysis showed that improved poststroke functional outcome in FosDT −/− rats is partially associated with curtailed induction of inflammatory genes, reduced apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusions: Our study shows that FosDT is developmentally dispensable, mechanistically important, and a functionally promising target to reduce ischemic brain damage and facilitate neurological recovery.

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Relationships Between Brain and Body Temperature, Clinical and Imaging Outcomes after Ischemic Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.52 ◽

2013 ◽

Vol 33 (7) ◽

pp. 1083-1089 ◽

Cited By ~ 28

Author(s):

Bartosz Karaszewski ◽

Trevor K Carpenter ◽

Ralph GR Thomas ◽

Paul A Armitage ◽

Georgina Katherine S Lymer ◽

...

Keyword(s):

Body Temperature ◽

Functional Outcome ◽

Brain Temperature ◽

Tissue Response ◽

Tympanic Temperature ◽

Resonance Spectroscopy ◽

Stroke Severity ◽

Poor Functional Outcome ◽

Ischemic Lesion ◽

Ischemic Brain

Pyrexia soon after stroke is associated with severe stroke and poor functional outcome. Few studies have assessed brain temperature after stroke in patients, so little is known of its associations with body temperature, stroke severity, or outcome. We measured temperatures in ischemic and normal-appearing brain using 1 H-magnetic resonance spectroscopy and its correlations with body (tympanic) temperature measured four-hourly, infarct growth by 5 days, early neurologic (National Institute of Health Stroke Scale, NIHSS) and late functional outcome (death or dependency). Among 40 patients (mean age 73 years, median NIHSS 7, imaged at median 17 hours), temperature in ischemic brain was higher than in normal-appearing brain on admission (38.6°C-core, 37.9°C-contralateral hemisphere, P = 0.03) but both were equally elevated by 5 days;both were higher than tympanic temperature. Ischemic lesion temperature was not associated with NIHSS or 3-month functional outcome;in contrast, higher contralateral normal-appearing brain temperature was associated with worse NIHSS, infarct expansion and poor functional outcome, similar to associations for tympanic temperature. We conclude that brain temperature is higher than body temperature;that elevated temperature in ischemic brain reflects a local tissue response to ischemia, whereas pyrexia reflects the systemic response to stroke, occurs later, and is associated with adverse outcomes.

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Abstract WMP38: ABCA1/HDL Pathway Mediates GW3965 Induced Neurorestoration and White Matter Remodeling After Stroke

Stroke ◽

10.1161/str.47.suppl_1.wmp38 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Xu Cui ◽

Jieli Chen ◽

Alex Zacharek ◽

Yisheng Cui ◽

Cynthia Roberts ◽

...

Keyword(s):

White Matter ◽

Functional Outcome ◽

Cortical Neurons ◽

Growth Factor Receptor ◽

Hdl Cholesterol ◽

Blood Levels ◽

Oligodendrocyte Progenitor Cells ◽

Lesion Volume ◽

Ischemic Brain ◽

B Mice

ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter in the central nervous system, plays an important role in the formation of brain HDL-cholesterol. ABCA1 is up-regulated by the transcription factors, liver X receptors (LXRs). Our previous study using brain-specific ABCA1 deficient (floxed, nestin-Cre positive, ABCA1-B/-B) and ABCA1 floxed-control (ABCA1fl/fl) mice showed that ABCA1 has anti-inflammatory effects and reduces white matter (WM) damage in ischemic stroke models. Here, we further test whether GW3965, a synthetic LXR agonist treatment of stroke increases ABCA1 and HDL, and thereby improves WM-remodeling and functional outcome. Adult male ABCA1fl/fl and ABCA1-B/-B mice were subjected to permanent extraluminal distal middle cerebral artery occlusion (dMCAo) by transcranial ligation method. Animals were gavaged with saline or GW3965 (10 mg/kg) starting 24h after dMCAo and daily till sacrificed 14 days after dMCAo. There were no differences in the lesion volume and blood levels of total cholesterol and triglyceride before and after dMCAo between ABCA1-B/-B and ABCA1fl/fl mice. However, GW3965 treatment significantly increased blood HDL levels in ABCA1fl/fl mice, but not in ABCA1-B/-B mice 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl stroke mice, but not in ABCA1-B/-B stroke mice, also increased: 1) WM-density identified by Luxol Fast Blue (myelin marker), Bielshowsky silver (axon marker), and SMI31 (phosphorylated neurofilament marker) staining; 2) the number of platelet-derived growth factor receptor alpha positive oligodendrocyte progenitor cells; 3) ABCA1, synaptophysin and myelin basic protein expression in the ischemic brain; 4) functional outcome 7 and 14 days after dMCAo, compared with non-treatment ABCA1fl/fl stroke mice (p<0.05, n=9/group). GW3965 and HDL treatment significantly increase axonal/neurite outgrowth in cultured primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. Treatment of stroke with GW3965 significantly increased blood level of HDL, increased ABCA1 expression and WM-remodeling in the ischemic brain. Increasing ABCA1 may contribute to GW3965 induced neurorestoration and WM remodeling after stroke.

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Effect of IV alteplase on the ischemic brain lesion at 24–48 hours after ischemic stroke

Neurology ◽

10.1212/wnl.0000000000006575 ◽

2018 ◽

Vol 91 (22) ◽

pp. e2067-e2077 ◽

Cited By ~ 2

Author(s):

Grant Mair ◽

Rüdiger von Kummer ◽

Zoe Morris ◽

Anders von Heijne ◽

Nick Bradey ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Outcome ◽

Brain Imaging ◽

Controlled Trial ◽

Meta Analysis ◽

Brain Mri ◽

Brain Lesion ◽

Ischemic Lesion ◽

Ischemic Brain

ObjectiveTo determine whether alteplase alters the development of ischemic lesions on brain imaging after stroke.MethodsThe Third International Stroke Trial (IST-3) was a randomized controlled trial of IV alteplase for ischemic stroke. We assessed CT or brain MRI at baseline (pretreatment) and 24 to 48 hours posttreatment for acute lesion visibility, extent, and swelling, masked to all other data. We analyzed associations between treatment allocation, change in brain tissue appearances between baseline and follow-up imaging, and 6-month functional outcome in IST-3. We performed a meta-analysis of randomized trials of alteplase vs control with pre- and postrandomization imaging.ResultsOf 3,035 patients recruited in IST-3, 2,916 had baseline and follow-up brain imaging. Progression in either lesion extent or swelling independently predicted poorer 6-month outcome (adjusted odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.88–0.96, p < 0.001; OR = 0.73, 95% CI 0.66–0.79, p < 0.001, respectively). Patients allocated alteplase were less likely than controls to develop increased lesion visibility at follow-up (OR = 0.77, 95% CI 0.67–0.89, p < 0.001), but there was no evidence that alteplase reduced progression of lesion extent or swelling. In meta-analysis of 6 trials including IST-3 (n = 4,757), allocation to alteplase was associated with a reduction in ischemic lesion extent on follow-up imaging (OR = 0.85, 95% CI 0.76–0.95, p = 0.004).ConclusionAlteplase was associated with reduced short-term progression in lesion visibility. In meta-analysis, alteplase reduced lesion extent. These findings may indicate that alteplase improves functional outcome by reducing tissue damage.Classification of evidenceThis study provides Class II evidence that IV alteplase impedes the progression of ischemic brain lesions on imaging after stroke.

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