- Iron nanoparticle contrast enhanced microwave imaging for emergent stroke: A pilot study. [Journal Article]
- JCJ Clin Neurosci 2018 Oct 31
- Emergent stroke is mostly evaluated using hospital based imaging. Quick imaging allows for rapid administration of IV thrombolysis and outcome improvement. Microwave imaging (MI) is an emerging porta...
Emergent stroke is mostly evaluated using hospital based imaging. Quick imaging allows for rapid administration of IV thrombolysis and outcome improvement. Microwave imaging (MI) is an emerging portable imaging modality. Iron oxide nanoparticles are known to interact with microwave frequency electromagnetic radiation. In this manuscript, we provide proof of concept for a novel iron oxide nanoparticle enhanced microwave imaging device for differentiating emergent ischemic stroke from hemorrhagic stroke. A MI device was constructed. Attenuation of the microwave signal transmitted with or without iron oxide nanoparticles was measured over a 1-2 GHz frequency range in a silicone brain phantom, in New Zealand white rabbits, and in a human. Observed differences in signal attenuation were used to reconstruct an image following induction of a left sided anterior circulation stroke in a New Zealand white rabbit. An increase in microwave signal attenuation exists across a frequency range of 1.3-2 GHz when iron oxide nanoparticles are introduced into a silicone phantom model, in New Zealand white rabbits, and in a human volunteer. Using this increase in signal attenuation following nanoparticle administration, we localize induced ischemia in a New Zealand white rabbit. To the best of out knowledge, we provide the first evidence that superparamagnetic Iron oxide nanoparticles may be used as contrast in the setting of MI. Our data suggest infusion of intravenous iron oxide nanoparticles with follow on microwave imaging may ultimately allow for more timely administration of thrombolytic mediation in the setting of acute ischemic stroke.
- Quality of Care and Outcomes for Patients With Stroke in the United States Admitted During the International Stroke Conference. [Journal Article]
- JAJ Am Heart Assoc 2018 Nov 06; 7(21):e009842
- Background Patients presenting to hospitals during non-weekday hours experience worse outcomes, often attributed to reduced staffing. The American Heart Association International Stroke Conference ( ...
Background Patients presenting to hospitals during non-weekday hours experience worse outcomes, often attributed to reduced staffing. The American Heart Association International Stroke Conference ( ISC ) is well attended by stroke clinicians. We sought to determine whether patients with acute ischemic stroke ( AIS ) admitted during the ISC receive less guideline-adherent care and experience worse outcomes. Methods and Results We performed a retrospective cohort study of US hospitals participating in Get With The Guidelines-Stroke and assessed use of intravenous tissue plasminogen activator, other quality measures, and outcomes for patients with AIS admitted during the ISC compared with those admitted the weeks before and after the conference. A total of 69 738 patients with AIS were included: mean age, 72 years; 52% women; 29% nonwhite. There was no difference between the average weekly number of AIS cases admitted during ISC weeks versus non- ISC weeks (1984 versus 1997; P=0.95). Patient and hospital characteristics were similar between ISC and non- ISC time periods. There were no significant differences in 14 quality metrics and 5 clinical outcomes between patients with AIS treated during the ISC versus non- ISC weeks. Patients with AIS who presented within 2 hours of onset had no difference in the likelihood of receiving intravenous tissue plasminogen activator within 3 hours (adjusted odds ratio, 0.89; 95% confidence interval, 0.77-1.03; P=0.13) or the likelihood of receiving intravenous tissue plasminogen activator within 60 minutes of arrival (adjusted odds ratio, 0.92; 95% confidence interval, 0.83-1.02; P=0.13). Conclusions Patients with acute stroke admitted to Get With The Guidelines-Stroke hospitals during ISC received the same quality care and had similar outcomes as patients admitted at other times.
- Handling of Missing Outcome Data in Acute Stroke Trials: Advantages of Multiple Imputation Using Baseline and Postbaseline Variables. [Journal Article]
- JSJ Stroke Cerebrovasc Dis 2018 Oct 06
- CONCLUSIONS: For acute stroke trials, multiple imputation using baseline and postbaseline observations is an advantageous approach to missing outcome data-handling, yielding high accuracy, reduced directional bias, and greater preservation of study power.
- Acute Blood Pressure Management in Acute Ischemic Stroke and Spontaneous Cerebral Hemorrhage. [Review]
- CTCurr Treat Options Neurol 2018 Aug 18; 20(9):39
- We discuss the evidence and guidelines for acute blood pressure (BP) management for patients presenting with acute ischemic stroke or spontaneous cerebral hemorrhage.
We discuss the evidence and guidelines for acute blood pressure (BP) management for patients presenting with acute ischemic stroke or spontaneous cerebral hemorrhage.
- Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. [Journal Article]
- JTJ Thromb Thrombolysis 2018; 46(4):440-450
- Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence,...
Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence, we conducted a study to evaluate the efficacy and safety of tenecteplase compared with alteplase in acute ischemic stroke. Electronic databases were searched for randomized clinical trials (RCTs) comparing tenecteplase with alteplase in acute ischemic stroke patients eligible for thrombolysis. We evaluated various efficacy and safety outcomes using random-effects models for both pairwise and Bayesian network meta-analyses along with meta-regression analyses. We included 5 RCTs with a total of 1585 patients. Compared with alteplase, tenecteplase treatment was associated with significantly greater complete recanalization (odd ratio [OR] 2.01; 95% confidence interval [CI] 1.04-3.87; p = 0.04) and early neurological improvement (OR 1.43; 95% CI 1.01-2.03; p = 0.05). There were no differences between the two thrombolytics in terms of excellent recovery (modified Rankin Scale [mRS] 0-1; OR 1.17; 95% CI 0.95-1.44; p = 0.13), functional independence (mRS 0-2; OR 1.24; 95% CI 0.78-1.98), poor recovery (mRS 4-6; OR 0.78; 95% CI 0.49-1.25; p = 0.31), complete/partial recanalization (OR 1.51; 95% CI 0.70-3.26; p = 0.30), any intracerebral hemorrhage (OR 0.81; 95% CI 0.56-1.17; p = 0.26), symptomatic intracerebral hemorrhage (OR 0.98; 95% CI 0.52-1.83; p = 0.94), or mortality (OR 0.83; 95% CI 0.54-1.26; p = 0.38). In network meta-analysis, there were better efficacy and imaging-based outcomes with tenecteplase 0.25 mg/kg without increased risk of safety outcomes. Our results demonstrate that in acute ischemic stroke, thrombolysis with tenecteplase is at least as effective and safe as alteplase.
- Using the behavioral flexibility operant task to detect long-term deficits in rats following middle cerebral artery occlusion. [Journal Article]
- BBBehav Brain Res 2019 Jan 01; 356:1-7
- Stroke is a leading cause of death and disability and currently only has one FDA approved pharmacological treatment (tissue plasminogen activator), which is only administered to a fraction of stroke ...
Stroke is a leading cause of death and disability and currently only has one FDA approved pharmacological treatment (tissue plasminogen activator), which is only administered to a fraction of stroke patients due to contraindications. New treatments are desperately needed but most treatments fail in clinical trials, even after showing benefit in animal models of stroke. To increase the translatability of animal stroke research to humans, sensitive functional measures for both the acute and chronic stages in animal models of stroke are needed. The objective of this study was to determine the sensitivity of certain behavioral tasks, up to seven weeks following occlusion of the middle cerebral artery (MCAo) in rats. A battery of behavioral tasks, including rotorod, cylinder, and limb-placement, was conducted weekly for seven weeks. Also, a behavioral flexibility operant task was introduced at the end of the study to measure cognitive deficits. All functional outcome measures showed significant differences between stroke and control groups, indicating that these tasks are sensitive enough to detect deficits in a long-term MCAo study in rats. This provides useful information for those trying to increase translatability in their own stroke research by providing long-term sensitive testing paradigms in a relevant stroke model.
- Update on the electrolytic IVC model for pre-clinical studies of venous thrombosis. [Journal Article]
- RPRes Pract Thromb Haemost 2018; 2(2):266-273
- CONCLUSIONS: The EIM is a valuable model of VT that can now be performed at low cost and may be beneficial in investigations of the fibrinolytic system.
- Circadian rhythms may not influence the outcomes of thrombolysis in patients with ischemic stroke: A study from China. [Journal Article]
- CIChronobiol Int 2018 Jul 11; :1-10
- Circadian rhythms can affect physical or mental activities as well as the time of stroke onset. The impact of circadian rhythms on acute ischemic stroke (AIS) patients treated by recombinant alteplas...
Circadian rhythms can affect physical or mental activities as well as the time of stroke onset. The impact of circadian rhythms on acute ischemic stroke (AIS) patients treated by recombinant alteplase (rt-PA) is still incongruent. This study aims to consider whether the outcomes of thrombolysis differ depending on stroke onset time and rt-PA infusion time in patients with AIS. A total of 447 AIS patients, who underwent rt-PA intravenous infusion within 4.5 hours after stroke onset, were enrolled in this study consecutively from June 2010 through December 2016. All of the patients were grouped based on the stroke onset time and rt-PA infusion time into two exact 12-hour intervals as daytime (06:01-18:00) and nighttime (18:01-06:00) and further divided into four subgroups at 6-hour time intervals (00:01-06:00, 06:01-12:00, 12:01-18:00 and 18:01-24:00). Major neurological improvement at 1 hour, 24 hours and 7 days, 7-day mortality rate and 24-hour hemorrhage transformation was recorded. The results showed that a total of 295 patients (66.4%) appeared with AIS and 252 (56.4%) were treated during daytime. Higher NIHSS at admission was observed when stroke occurred in nighttime, especially during 00:01-06:00. Patients with stroke onset in nighttime especially during 18:01-24:00 had a significant shorter onset-door time and onset-needle time. No differences of the major neurological improvement at 1 hour, 24 hours and 7 days, 24-hour hemorrhagic transformation and 7-day fatality rate were found among either 12-hour time frames or 6-hour time frames according to the time of stroke onset or rt-PA infusion. In conclusion, there was no evidence to predict that circadian rhythms could influence the outcomes of AIS patients treated with rt-PA in China, although stroke onset during nighttime might aggravate neurological impairment before treatment. Further, multicenter and prospective clinical trials with larger number of subjects are still needed to draw more reliable conclusions.
- Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection. [Journal Article]
- JNJ Neurosci 2018 Jul 18; 38(29):6527-6545
- Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in t...
Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.
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- Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence. [Review]
- ADAging Dis 2018; 9(3):507-522
- Ischemic stroke is a major cause of death and disability globally, and its incidence is increasing. The only treatment approved by the US Food and Drug Administration for acute ischemic stroke is thr...
Ischemic stroke is a major cause of death and disability globally, and its incidence is increasing. The only treatment approved by the US Food and Drug Administration for acute ischemic stroke is thrombolytic treatment with recombinant tissue plasminogen activator. As an alternative, therapeutic hypothermia has shown excellent potential in preclinical and small clinical studies, but it has largely failed in large clinical studies. This has led clinicians to explore the combination of therapeutic hypothermia with other neuroprotective strategies. This review examines preclinical and clinical progress towards developing highly effective combination therapy involving hypothermia for stroke patients.