Contrast-enhanced sonothrombolysis in acute ischemic stroke patients without intracranial large-vessel occlusion.

BACKGROUND: Contrast-enhanced sonothrombolysis (CEST) leads to a more rapid recanalization in acute ischemic stroke caused by intracranial large-vessel occlusion (LVO). Animal studies have shown that CEST also may be safe and efficient in treating the ischemic microcirculation in the absence of LVO. The exact mechanism behind this treatment effect is not known. We aimed to assess safety and efficacy of CEST in acute ischemic stroke patients included in the Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS) without LVO on admission CT angiography (CTA). METHODS: NOR-SASS was a randomized controlled trial of CEST in ischemic stroke patients treated with intravenous thrombolysis within 4.5 hours after stroke onset. Patients were randomized to either CEST or sham CEST. In this study, patients were excluded if they had partial or total occlusion on admission CTA, ultrasound-resistant bone window, had received CEST with incorrect insonation as compared to stroke location on Magnetic resonance imaging (MRI), or were stroke mimics. RESULTS: Of the 183 patients included in NOR-SASS, a total of 83 (45.4%) patients matched the inclusion criteria, of which 40 received CEST and 43 sham CEST. There were no patients with symptomatic intracranial hemorrhage (sICH) in the CEST group. Rates of asymptomatic ICH, microbleeds, and mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days were similar in both groups. CONCLUSION: CEST is safe in ischemic stroke patients without intracranial LVO. There were no differences in clinical outcomes between the treatment groups.

Visual field defect after ischemic stroke-impact on mortality.

OBJECTIVES: We aimed to investigate the impact of visual field defects (VFD) on mortality in ischemic stroke patients. MATERIALS AND METHODS: All patients with acute infarction and a clinically detected VFD from February 2006 to December 2013 in the NORSTROKE Registry (n = 506) were included and compared with ischemic stroke patients with normal visual fields (n = 2041). A record of patients who had died per ultimo April 2015 was obtained from the central registry at Haukeland University Hospital. RESULTS: Patients with VFD were significantly older (75.0 vs 69.8, P < .001) than patients with normal visual fields. The majority of patients with VFD was male, had higher cardiovascular morbidity prestroke, and were more likely to have shorter median time from symptom onset to admission (1.7 hours vs 2.7 hours, P < .001). Baseline National Institute of Health Stroke Scale (NIHSS) score was higher (12.7 vs 3.5, P < .001) as was modified Rankin Scale (mRS) score (3.5 vs 1.9, P < .001) and Barthel Index was lower (51.9 vs 84.8, P < .001) day 7. VFD was associated with increased mortality on Kaplan-Meier plots. Hazard ratio was significantly higher for patients with VFD after adjusting for age, sex, employment prior to infarction, married prior to infarction, institutionalization prior to infarction, prior myocardial infarction, atrial fibrillation, smoking, Barthel Index score and i.v. thrombolysis with Cox regression (hazard ratios [HR] 1.30, CI 1.07-1.56, P = .007). CONCLUSIONS: Having a visual field defect after ischemic stroke is independently associated with increased mortality. This should be addressed when selecting candidates for thrombolysis and in the rehabilitation process.

Elevated body temperature in ischemic stroke associated with neurological improvement.

OBJECTIVES: Some studies suggest that high body temperature within the first few hours of ischemic stroke onset is associated with improved outcome. We hypothesized an association between high body temperature on admission and detectable improvement within 6-9 hours of stroke onset. MATERIALS AND METHODS: Consecutive ischemic stroke patients with NIHSS scores obtained within 3 hours and in the interval 6-9 hours after stroke onset were included. Body temperature was measured on admission. RESULTS: A total of 315 patients with ischemic stroke were included. Median NIHSS score on admission was 6. Linear regression showed that NIHSS score 6-9 hours after stroke onset was inversely associated with body temperature on admission after adjusting for confounders including NIHSS score <3 hours after stroke onset (P<.001). The same result was found in patients with proximal middle cerebral occlusion on admission. CONCLUSIONS: We found an inverse association between admission body temperature and neurological improvement within few hours after admission. This finding may be limited to patients with documented proximal middle cerebral artery occlusion on admission and suggests a beneficial effect of higher body temperature on clot lysis within the first three hours.

Less thrombolysis in posterior circulation infarction-a necessary evil?

OBJECTIVES: Patients with posterior circulation infarction (PCI) have more subtle symptoms than anterior circulation infarction (ACI) and could come too late for acute intervention. This study aimed to describe the clinical presentation, management, and outcome of PCI in the NORSTROKE registry. METHODS: All patients with PCI admitted to the Department of Neurology at Haukeland University Hospital and registered in the NORSTROKE database 2006-2013 were included (n=686). Patients with ACI (n=1758) were used for comparison. RESULTS: Patients with PCI were younger (68.2 vs 71.8, P<.001), had longer median time from symptom onset to admission (3.8 hours vs 2.2 hours, P<.001), and were less likely to arrive at hospital within 4.5 hours from symptom onset (56.2% vs 72.5%, P<.001, ictus known). Patients with PCI scored lower on baseline National Institute of Health Stroke Scale (NIHSS) total score (3.2 vs 6.3, P<.001), and lower or equally on all items of NIHSS, except for ataxia in two limbs. Patients with PCI were less likely to receive i.v. thrombolytic treatment (9.9% vs 21.5%, OR 0.66, CI 0.47-0.94). On day 7, patients with PCI scored lower on NIHSS (2.8 vs 4.9, P<.001), modified Rankin Scale (2.0 vs 2.3, P<.001), and higher on Barthel Index (84.5 vs 76.0, P<.001). CONCLUSIONS: Our study is, to our knowledge, the largest series reporting comprehensively on PCI verified by diffusion-weighted imaging. PCI patients are younger than ACI and have better outcome. PCI and ACI are equally investigated in the acute setting, but thrombolysis rates remain 50% lower in PCI.

Acute cerebral infarcts in multiple arterial territories associated with cardioembolism.

OBJECTIVES: It is generally believed that cardioembolism is the main cause of multiple acute cerebral infarcts (MACI). However, there are surprisingly few DWI studies and results are conflicting. Based on a large prospective study we hypothesized that MACI are associated with cardioembolism. MATERIALS AND METHODS: We studied 2697 patients with acute cerebral infarcts between February 2006 and October 2013 who were prospectively registered in The Bergen NORSTROKE Registry. Among them, 2220 (82.3%) patients underwent magnetic resonance imaging (MRI) and 2125 (96%) of these 2220 patients had DWI lesions. Only patients with DWI lesions were included. MACI were defined as at least two DWI lesions in at least two different arterial territories. RESULTS: MACI were detected in 187/2125 (8.8%) patients with DWI lesions. MACI patients were older and more often females. MACI were associated with cardioembolism (P = 0.042), especially atrial fibrillation (P = 0.002). Other associations were symptomatic internal carotid artery (ICA) stenosis (P = 0.014), asymptomatic ICA stenosis (P = 0.036), and higher NIHSS score on admission (P < 0.001). Among patients with no cardioembolism, 34 (35%) with MACI had symptomatic ICA stenosis versus 268 (25.0%) with non-MACI (P = 0.037); 20 (20%) with MACI had asymptomatic ICA stenosis versus 134 (13%) with non-MACI (P = 0.031). In the logistic regression analysis, cardiac embolism and symptomatic ICA stenosis were independently associated with MACI. CONCLUSIONS: Acute cerebral infarcts in more than one arterial territory occur among almost 10% of the patients and are associated with cardioembolism.

Serial NIHSS scores in patients with acute cerebral infarction.

AIM: To study time course of neurological deficits in patients with acute cerebral infarction admitted shortly after stroke onset. METHODS: Serial NIHSS scores were obtained whenever feasible in patients admitted because of cerebral infarction within 3 h of symptom onset. Patients receiving and not receiving thrombolysis were compared. Short-term outcome was defined as NIHSS score and modified Rankin score 7 days after stroke onset. The hyperacute phase was defined as the time between stroke onset and the 6- to 9-h interval after stroke onset, acute phase as the time between the 6- to 9-h interval and the 21 to 27-h interval, and the subacute phase as the time between the 21- to 27-h interval and 7 days after stroke onset. RESULTS: Serial NIHSS scores were obtained in 552 patients within three hours of stroke onset. There was a significant improvement (P < 0.001) comprising 62% of the total improvement in the hyperacute phase. There was no significant improvement in the acute phase and a small significant improvement in the subacute phase (P < 0.01). CONCLUSION: Our study demonstrates a hyperacute phase with rapid improvement probably due to early recanalization, an acute phase with no significant improvement and slow improvement in the subacute phase. Different pathophysiological mechanisms are likely involved in the different phases.

Influence of dissolved gases on sonochemistry and sonoluminescence in a flow reactor.

In the present work, the influence of gas addition is investigated on both sonoluminescence (SL) and radical formation at 47 and 248 kHz. The frequencies chosen in this study generate two distinct bubble types, allowing to generalize the conclusions for other ultrasonic reactors. In this case, 47 kHz provides transient bubbles, while stable ones dominate at 248 kHz. For both bubble types, the hydroxyl radical and SL yield under gas addition followed the sequence: Ar>Air>N2>>CO2. A comprehensive interpretation is given for these results, based on a combination of thermal gas properties, chemical reactions occurring within the cavitation bubble, and the amount of bubbles. Furthermore, in the cases where argon, air and nitrogen were bubbled, a reasonable correlation existed between the OH-radical yield and the SL signal, being most pronounced under stable cavitation at 248 kHz. Presuming that SL and OH originate from different bubble populations, the results indicate that both populations respond similarly to a change in acoustic power and dissolved gas. Consequently, in the presence of non-volatile pollutants that do not quench SL, sonoluminescence can be used as an online tool to qualitatively monitor radical formation.

Vision problems in ischaemic stroke patients: effects on life quality and disability.

BACKGROUND AND PURPOSE: Vision problems after cerebral infarction are an increasingly acknowledged problem. Our aim was to investigate the effect on quality of life and post-stroke disability. METHODS: Patients admitted to the Stroke Unit, Department of Neurology, Haukeland University Hospital, between February 2006 and July 2008 with acute cerebral infarction were prospectively registered in the NORSTROKE Registry. Patients received a postal questionnaire at least 6 months after stroke. The questionnaire included 15D©, EuroQol 5D (EQ-5D(™) ), the Hospital Anxiety and Depression Scale (HADS), the Fatigue Severity Scale (FSS) and the Barthel Index (BI). RESULTS: Of 328 responders, 83 (25.4%) reported a vision problem. Vision problems were associated with older age (71.8 years vs. 66.5 years, P = 0.001), higher National Institutes of Health Stroke Scale score on admission (5.9 vs. 3.8, P < 0.001), higher modified Rankin Scale day 7 (2.0 vs. 1.4, P < 0.001) and lower BI day 7 (85.7 vs. 93.9, P = 0.002). Patients with vision problems had lower median EQ-5D utility score (0.62 vs. 0.80, P < 0.001), lower median 15D utility score (0.73 vs. 0.89, P < 0.001), higher median HADS score (12 vs. 5, P < 0.001), higher median FSS score (5.6 vs. 4.3, P < 0.001) and lower median BI (95 vs. 100, P < 0.001) on long-term follow-up. Patients with self-reported vision problems scored lower on all sub-scores of BI on follow-up (all P < 0.001). CONCLUSION: One in four patients reported a vision problem on follow-up after cerebral infarction. Vision problems after cerebral infarction reduce quality of life and are associated with increased disability. Thorough diagnostic evaluation and targeted rehabilitation is important.

Can the cardiovascular family history reported by our patients be trusted? The Norwegian Stroke in the Young Study.

BACKGROUND AND PURPOSE: Family history (FH) is used as a marker for inherited risk. Using FH for this purpose requires the FH to reflect true disease in the family. The aim was to analyse the concordance between young and middle-aged ischaemic stroke patients' reported FH of cardiovascular disease (CVD) with their parents' own reports. METHODS: Ischaemic stroke patients aged 15-60 years and their eligible parents were interviewed using a standardized questionnaire. Information of own CVD and FH of CVD was registered. Concordance between patients and parents was tested by kappa statistics, sensitivity, specificity, predictive values and likelihood ratios. Regression analyses were performed to identify patient characteristics associated with non-concordance of replies. RESULTS: There was no difference in response rate between fathers and mothers (P = 0.355). Both parents responded in 57 cases. Concordance between patient and parent reports was good, with kappa values ranging from 0.57 to 0.7. The patient-reported FH yielded positive predictive values of 75% or above and negative predictive values of 90% or higher. The positive likelihood ratios (LR+) were 10 or higher and negative likelihood ratios (LR-) were generally 0.5 or lower. Interpretation regarding peripheral arterial disease was limited due to low parental prevalence. Higher age was associated with impaired concordance between patient and parent reports (odds ratio 1.05; 95% confidence interval 1.01-1.09; P = 0.020). CONCLUSIONS: The FH provided by young and middle-aged stroke patients is in good concordance with parental reports. FH is an adequate proxy to assess inherited risk of CVD in young stroke patients.

Recurrent ischemic stroke is associated with the burden of risk factors.

AIM: To determine the characteristics of acute ischemic stroke patients admitted to hospital with history of prior ischemic stroke(s). We hypothesized that there is an association between the number of risk factors and prior ischemic stroke irrespective of age. METHODS: All patients with acute ischemic stroke admitted to Haukeland University Hospital between 2006 and 2013 were registered in the NORSTROKE database. Variables included prior ischemic stroke(s) (based on self-report and patient records), risk factors, TOAST classification, and CT and MRI findings. Comparison was made between patients with prior ischemic stroke and first-ever ischemic stroke. Multivariate analyses were performed. RESULTS: In total, 2697 patients were included and 461 (17.1%) had a history of prior ischemic stroke(s). Logistic regression analyses showed that prior ischemic stroke was associated with the number of risk factors, leukoaraiosis, hypertension, atrial fibrillation, and atherosclerosis. CONCLUSION: History of prior ischemic stroke in patients with acute ischemic stroke was associated with the burden of risk factors, atherosclerosis, and atrial fibrillation compared to first-ever ischemic stroke. This has important implications for secondary preventive treatment.

Early neurological worsening in acute ischaemic stroke patients.

OBJECTIVES: Neurological worsening in acute ischaemic stroke patients is common with significant morbidity and mortality. AIMS: To determine the factors associated with early neurological worsening within the first 9 h after onset of acute ischaemic stroke. MATERIALS & METHODS: The National Institute of Health Stroke Scale (NIHSS) was used to assess stroke severity. Early neurological worsening was defined as NIHSS score increase ≥4 NIHSS points within 9 h of symptom onset compared to NIHSS score within 3 h of symptom onset. Patients with early neurological worsening were compared to patients with unchanged or improved NIHSS scores. RESULTS: Of the 2484 patients admitted with ischaemic stroke, 552 patients had NIHSS score within 3 h of symptom onset, and 44 (8.0%) experienced early neurological worsening. The median NIHSS on admission was 8.4 in both groups. Early neurological worsening was associated with low body temperature on admission (P = 0.01), proximal compared to distal MCA occlusion (P = 0.007) and with ipsilateral internal carotid artery stenosis >50% or occlusion (P = 0.04). Early neurological worsening was associated with higher NIHSS day 7 (P < 0.001) and higher mortality within 7 days of stroke onset (P = 0.005). CONCLUSIONS: Early neurological worsening has serious consequences for the short-term outcome for patients with acute ischaemic stroke and is associated with low body temperature on admission, and with extracranially and intracranially large-vessel stenosis or occlusion.

Age dependency of ischaemic stroke subtypes and vascular risk factors in western Norway: the Bergen Norwegian Stroke Cooperation Study.

OBJECTIVES: Age dependency of acute ischaemic stroke aetiology and vascular risk factors have not been adequately evaluated in stroke patients in Norway. Aims of this study were to evaluate how stroke subtypes and vascular risk factors vary with age in a western Norway stroke population. MATERIALS AND METHODS: Patients aged 15-100 years consecutively admitted to our neurovascular centre with acute ischaemic stroke between 2006 and 2012 were included. The study population was categorized as young (15-49 years), middle-aged (50-74 years) or elderly (≥ 75 years). Stroke aetiology was defined by TOAST criteria. Risk factors and history of cardiovascular disease were recorded. RESULTS: In total, 2484 patients with acute cerebral infarction were included: 1418 were males (57.3%). Mean age was 70.8 years (SD ± 14.9), 228 patients were young, 1126 middle-aged, and 1130 were elderly. The proportion of large-artery atherosclerosis and of small-vessel occlusion was highest among middle-aged patients. The proportion of cardioembolism was high at all ages, especially among the elderly. The proportion of stroke of other determined cause was highest among young patients. Some risk factors (diabetes mellitus, active smoking, angina pectoris, prior stroke and peripheral artery disease) decreased among the elderly. The proportions of several potential causes increased with age. CONCLUSION: The proportion of stroke subtypes and vascular risk factors are age dependent. Age 50-74 years constitutes the period in life where cardiovascular risk factors become manifest and stroke subtypes change.

III-V-on-silicon anti-colliding pulse-type mode-locked laser.

An anti-colliding pulse-type III-V-on-silicon passively mode-locked laser is presented for the first time based on a III-V-on-silicon distributed Bragg reflector as outcoupling mirror implemented partially underneath the III-V saturable absorber. Passive mode-locking at 4.83 GHz repetition rate generating 3 ps pulses is demonstrated. The generated fundamental RF tone shows a 1.7 kHz 3 dB linewidth. Over 9 mW waveguide coupled output power is demonstrated.

Narrow-linewidth short-pulse III-V-on-silicon mode-locked lasers based on a linear and ring cavity geometry.

Picosecond-pulse III-V-on-silicon mode-locked lasers based on linear and ring extended cavity geometries are presented. In passive mode-locked operation a 12 kHz -3dB linewidth of the fundamental RF tone at 4.7 GHz is obtained for the linear cavity geometry and 16 kHz for the ring cavity geometry. Stabilization of the repetition rate of these devices using hybrid mode-locking is also demonstrated.

Characterization of stable and transient cavitation bubbles in a milliflow reactor using a multibubble sonoluminescence quenching technique.

The bubble type, generated by an ultrasonic field, was studied in a batch and flow reactor using a multibubble sonoluminescence (MBSL) quenching technique with propanol and acetone. The influence of frequency and transducer configuration was evaluated using the same piezoelectric element in both setups. Results show that the bubble type not only depends on the frequency, but also on the input power or transducer configuration. Additionally, the effect of flow on sonoluminescence yield and bubble type was studied in the continuous setup at various frequencies. As the flow becomes turbulent, the sonoluminescence signal reaches a plateau for three out of four frequencies, and a transition from transient to stable cavitation occurs for frequencies below 200 kHz.

Mild stroke: safety and outcome in patients receiving thrombolysis.

OBJECTIVES: The aim of this study was to compare the short-term clinical outcome of patients with acute cerebral ischemia and mild symptoms receiving rt-PA with that of patients with acute cerebral ischemia and mild symptoms not treated with rt-PA, and to investigate the frequency of symptomatic intracranial hemorrhage (sICH) in these patients. MATERIALS AND METHODS: All patients with confirmed ischemic stroke/TIA and mild symptoms were included. Mild symptoms were defined as NIHSS score≤5 on admission. Functional outcome was assessed with modified Rankin Scale (mRS) at day 7 or at earlier discharge. Excellent outcome was defined as mRS=0. sICH was defined according to both NINDS and ECASS III criteria. RESULTS: Of 2753 patients with confirmed ischemic stroke/TIA admitted between February 2006 and February 2013, 966 (35.3%) were excluded because of having admission NIHSS>5. A total of 1791 patients presented with mild symptoms on admission (NIHSS≤5), of which 158 (8.8%) patients received rt-PA. Treatment with rt-PA and early admission were independently associated with excellent outcome. Higher NIHSS score on admission and prior ischemic stroke were independently associated with poor outcome. Three (1.9%) sICH were diagnosed in rt-PA-treated patients and one (0.1%) in patients not receiving rt-PA. CONCLUSIONS: This study highlights the efficacy of rt-PA in patients with acute cerebral ischemia presenting with mild symptoms and confirms the low-risk profile of this treatment.

Diffusion-weighted lesions in acute ischaemic stroke patients with migraine.

OBJECTIVES: There is increasing knowledge about an association between migraine and ischaemic stroke. Cortical spreading depression (CSD) is the probable biological substrate of migrainous aura. To investigate the influence of CSD on the apparent stroke - migraine association, we hypothesized that magnetic resonance (MR) diffusion weighted images of acute ischaemic stroke patients would reveal an association between small cortical infarctions and migraine. METHODS: We included all patients admitted to the Bergen stroke unit between 2006 and 2012 with verified acute ischaemic stroke by MR imaging. Patients were grouped in a migraine and a no-migraine group. Baseline data and clinical characteristics were analysed between the groups. Imaging data were analysed with respect to infarct location and size. Multivariate analyses were performed to adjust for confounders and provide risk estimates for observed associations. RESULTS: A total of 1703 subjects were enrolled, 787 subjects were excluded due to uncertain or unobtainable migraine diagnosis, leaving 196 and 720 subjects in the migraine and no-migraine group, respectively. The migraine group was younger and included a higher proportion of females. There were more infarctions due to cardio-embolism (P=0.015) and fewer due to small vessel disease (P=0.018) in the migraine group. A higher rate of patients in the migraine group presented symptoms from the posterior circulation (P=0.008). Migraine was associated with cortical infarctions (OR 1.8 CI: 1.3-2.5, P=0.001). Migraine was also associated with small infarctions (OR 1.9 CI: 1.04-3.5, P=0.038). CONCLUSIONS: Migraine was associated with small cortical infarctions. This association may be due to cortical spreading depression.

Is smoking associated with favourable outcome in tPA-treated stroke patients?

BACKGROUND: Smoking has been associated with improved outcome in thrombolysed patients with myocardial infarction and higher recanalization rates in stroke patients treated with tissue plasminogen activator (tPA). We hypothesized a positive association between smoking and favourable outcome in stroke patients treated with tPA and no such association in acute stroke patients not treated with tPA, suggesting a beneficial effect of smoking on thrombolysis with tPA. METHODS: Stroke patients treated with tPA and stroke patients not treated with tPA, but presenting within 6 h after stroke onset, were included in two separate groups. Three groups were defined according to smoking habits: current smoking, previous smoking and no smoking. Functional outcome by modified Rankin Scale (mRS) was assessed after 1 week or at discharge, if discharged earlier. Favourable outcome was defined as mRS 0 or 1. RESULTS: A total of 399 patients were treated with tPA (94 current smokers, 148 previous smokers and 157 non-smokers), whereas 424 patients were not treated with tPA (90 current smokers, 164 previous smokers and 170 non-smokers). Current smoking was independently associated with favourable outcome in patients treated with tPA when adjusted for confounders (OR 2.08, 95% CI 1.09-3.95, P = 0.025). There was no such association in acute stroke patients not treated with tPA (OR 1.26, 95% CI 0.67-2.36, P = 0.472). CONCLUSION: Our study showed an association between current smoking and favourable short-term outcome in stroke patients treated with tPA, but not in acute stroke patients not treated with tPA. This may indicate a more effective thrombolysis with tPA in smokers.

Body temperature and major neurological improvement in tPA-treated stroke patients.

BACKGROUND: Major neurological improvement (MNI) at 24 hours represents a marker of early recanalization in ischaemic stroke. Although low body temperature is considered neuroprotective in cerebral ischaemia, some studies have suggested that higher body temperature may promote clot lysis in the acute phase of ischaemic stroke. We hypothesized that higher body temperature was associated with MNI in severe stroke patients treated with tPA, suggesting a beneficial effect of higher body temperature on clot lysis and recanalization. METHODS: Patients with ischaemic stroke or transient ischaemic attack (TIA) treated with tPA between February 2006 and August 2012 were prospectively included and retrospectively analysed. Body temperature was measured upon admission. MNI was defined by a ≥8 point improvement in NIHSS score at 24 hours as compared to NIHSS score on admission. No significant improvement (no-MNI) was defined by either an increase in NIHSS score or a decrease of ≤2 points at 24 hours in patients with an admission NIHSS score of ≥8. RESULTS: Of the 2351 patients admitted with ischaemic stroke or TIA, 347 patients (14.8%) were treated with tPA. A total of 32 patients (9.2%) had MNI and 56 patients (16.1%) had no-MNI. Patients with MNI had higher body temperatures compared with patients with no-MNI (36.7°C vs 36.3°C, P = 0.004). Higher body temperature was independently associated with MNI when adjusted for confounders (OR 5.16, P = 0.003). CONCLUSION: Higher body temperature was independently associated with MNI in severe ischaemic stroke patients treated with tPA. This may suggest a beneficial effect of higher body temperature on clot lysis and recanalization.