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1.  Evolution of intracerebral hemorrhage after intravenous tPA: reversal of harmful effects with mast cell stabilization 
Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean±s.d. 83.5±14.3 versus 66.7±14.7 μL; P=0.256) or hemispheric expansion (14.5±5.0 versus 11.5±5.0% P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4±1.7 versus 14.5±5.0% P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings.
PMCID: PMC3887361  PMID: 24169849
collagenase injection; ICH; mast cells; rat; thrombolysis; tPA
2.  Incidence of Stroke According to Presence of Diabetic Nephropathy and Severe Diabetic Retinopathy in Patients With Type 1 Diabetes 
Diabetes Care  2013;36(12):4140-4146.
Type 1 diabetes is associated with a markedly increased risk of stroke, but only a few studies on the incidence of stroke in type 1 diabetes exist. Therefore, we assessed the incidence of stroke in patients with type 1 diabetes and studied the impact of diabetic nephropathy (DN) and severe diabetic retinopathy (SDR) on this risk.
We studied 4,083 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. Mean age was 37.4 ± 11.8 years, duration of diabetes was 21.6 ± 12.1 years, and 52% were men. Strokes were identified from medical records, death certificates, and the National Hospital Discharge Register and classified based on medical files and brain images.
During 36,680 person-years of follow-up, 149 (4%) patients suffered an incident stroke (105 infarctions and 44 hemorrhages). Of the infarctions, 58 (55%) were lacunar. The incidence of stroke, cerebral infarction, and cerebral hemorrhage was 406 (95% CI 344–477), 286 (234–347), and 120 (87–161) per 100,000 person-years, respectively. In an adjusted analysis, microalbuminuria increased the risk of stroke with a hazard ratio (HR) of 3.2 (1.9–5.6), macroalbuminuria 4.9 (2.9–8.2), and end-stage renal disease 7.5 (4.2–13.3), and SDR increased the risk with an HR of 3.0 (1.9–4.5). The risk of cerebral infarction, cerebral hemorrhage, and lacunar infarction increased in a similar manner. The proportion of lacunar versus nonlacunar infarction did not change across DN groups.
The presence of SDR and DN, independently, increases the risk of stroke, cerebral infarction, and cerebral hemorrhage in patients with type 1 diabetes.
PMCID: PMC3836162  PMID: 24101700
3.  Clinical signs in young patients with stroke related to FAST: results of the sifap1 study 
BMJ Open  2014;4(11):e005276.
The present study aimed to evaluate the frequency of warning signs in younger patients with stroke with a special regard to the ‘FAST’ scheme, a public stroke recognition instrument (face, arm, speech, timely).
Primary stroke care in participating centres of a multinational European prospective cross-sectional study (Stroke in Young Fabry Patients; sifap1). Forty-seven centres from 15 European countries participate in sifap1.
5023 acute patients with stroke (aged 18–55 years) patients (96.5% Caucasians) were enrolled in the study between April 2007 and January 2010.
Primary and secondary outcome measures
sifap1 was originally designed to investigate the relation of juvenile stroke and Fabry disease. A secondary aim of sifap1 was to investigate stroke patterns in this specific group of patients. The present investigation is a secondary analysis addressing stroke presenting symptoms with a special regard to signs included in the FAST scheme.
4535 patients with transient ischaemic attack (TIA; n=1071), ischaemic stroke (n=3396) or other (n=68) were considered in the presented analysis. FAST symptoms could be traced in 76.5% of all cases. 35% of those with at least one FAST symptom had all three symptoms. At least one FAST symptom could be recognised in 69.1% of 18–24 years-old patients, in 74% of those aged 25–34 years, in 75.4% of those aged 35–44 years, and 77.8% in 45–55 years-old patients. With increasing stroke severity signs included in the FAST scheme were more prevalent (National Institute of Health Stroke Scale, NIHSS<5: 69%, NIHSS 6–15: 98.9%, NIHSS>15: 100%). Clustering clinical signs according to FAST lower percentages of strokes in the posterior circulation (65.2%) and in patients with TIA (62.3%) were identified.
FAST may be applied as a useful and rapid tool to identify stroke symptoms in young individuals aged 18–55 years. Especially in patients eligible for thrombolysis FAST might address the majority of individuals.
Study registration
The study was registered in (No. NCT00414583).
PMCID: PMC4225229  PMID: 25380809
4.  Subarachnoid Hemorrhage in Type 1 Diabetes 
Diabetes Care  2013;36(11):3754-3758.
To estimate for the first time the incidence of subarachnoid hemorrhage (SAH) in type 1 diabetes.
Using the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study cohort of 4,083 patients with type 1 diabetes (mean age of 37.4 ± 11.8 years at enrollment), we analyzed the incidence of first-ever SAH events.
During the follow-up time of 36,680 person-years (median 9.4 years), 15 patients with type 1 diabetes experienced an aneurysmal or nonaneurysmal SAH, and thus the crude incidence of SAH was 40.9 (95% CI 22.9–67.4) per 100,000 person-years. One patient had a verified aneurysmal SAH, and four patients died suddenly of an SAH, which was most likely caused by an aneurysm. SAHs in 10 out of 15 patients were classified as nonaneurysmal SAH, and thus the crude incidence of nonaneurysmal SAH was 27.3 (13.1–50.1) per 100,000 person-years. None of the nonaneurysmal SAHs were fatal. In univariate analysis, current smokers had a hazard ratio of 4.82 (95% CI 1.31–17.81) for nonaneurysmal SAH.
The incidence of nonaneurysmal SAH is high among patients with type 1 diabetes. Our findings suggest that nonaneurysmal SAH is a distinct new microvascular complication in type 1 diabetes.
PMCID: PMC3816906  PMID: 23877984
5.  Lessons from everyday stroke care for clinical research and vice versa: comparison of a comprehensive and a research population of young stroke patients 
BMC Neurology  2014;14:45.
Translating knowledge derived from medical research into the clinical setting is dependent on the representativeness of included patients. Therefore we compared baseline data of patients included in a recent large study addressing young stroke in comparison to a large representative stroke registry.
We analysed baseline data of 5023 patients (age 18-55 years) with an acute cerebrovascular event included in the sifap1 (Stroke in Young Fabry Patients) study. For comparison 17007 stroke patients (age 18-55 years) documented (2004-2010) in a statutory stroke registry of the Institute of Quality Assurance Hesse of the Federal State of Hesse (GQH), Germany.
Among 17007 juvenile (18-55 years) patients identified in the GQH registry 15997 had an ischaemic stroke or TIA (91%) or an intracranial haemorrhage (9%). In sifap1 5023 subjects were included. Sex distribution was comparable (men: 59% sifap1 versus 60.5% GQH) whereas age differed between the groups: median age was 46 years in sifap1 versus 49 years in GQH. Slightly higher percentages for diabetes mellitus and hypertension in the GQH registry were noted. There were no differences in stroke severity as assessed by NIHSS (median 3) and mRS (median 2). In patients with ischaemic stroke or TIA (n = 4467 sifap1; n = 14522 GQH) higher rates of strokes due to small artery occlusion and atherosclerosis occurred in older age groups; cardioembolism and strokes of other determined cause occurred more frequently in younger patients.
The comparison of baseline characteristics between the sifap1 study and the GQH registry revealed differences mainly determined by age.
PMCID: PMC3984721  PMID: 24607068
Ischemic stroke; Stroke in the young; Stroke severity; Stroke registry
6.  The Norwegian Stroke in the Young Study (NOR-SYS): Rationale and design 
BMC Neurology  2013;13:89.
Ischemic stroke in young adults is a major health problem being associated with a higher vascular morbidity and mortality compared to controls, and a stroke recurrence rate of 25% during the first decade. The assumed cause of infarction and the detected risk factors determine the early- and long-term treatment. However, for many patients the cause of stroke remains unknown. Risk factor profile and etiology differ in young and elderly ischemic stroke patients, and atherosclerosis is the determined underlying condition in 10 to 15%. However, subclinical atherosclerosis is probably more prevalent and may go unrecognized.
Ultrasound imaging is a sensitive method for the detection of arterial disease and for measurement of adipose tissue. The relationship between intima-media thickness (IMT), plaques, cardiovascular risk factors including visceral adipose tissue (VAT) and ischemic events has repeatedly been shown.
We have established The Norwegian Stroke in the Young Study (NOR-SYS) as a three-generation research program with the goal to increase our knowledge on heredity and the development of arterial disease and ischemic stroke. Extended standardized ultrasound examinations are done in order to find subclinical vessel disease for early and better prophylaxis.
NOR-SYS is a prospective long-term research program. Standardized methods are used for anamnestic, clinical, laboratory, imaging, and ultrasound data collection in ischemic stroke patients aged ≤60 years, their partners and joint adult offspring. The ultrasound protocol includes the assessment of intracranial, carotid and femoral arteries, abdominal aorta, and the estimation of VAT. To date, the study is a single centre study with approximately 400 patients, 250 partners and 350 adult offspring expected to be recruited at our site.
NOR-SYS aims to increase our knowledge about heredity and the development of arterial vascular disease in young patients with ischemic stroke and their families. Moreover, optimization of diagnostics, prophylaxis and early intervention are major targets with the intention to reduce stroke recurrence and other clinical arterial events, physical disability, cognitive impairment and death.
NOR-SYS is reviewed and approved by the Regional Committee for Medical and Health Research Ethics, Western-Norway (REK-Vest 2010/74), and registered in NCT01597453.
PMCID: PMC3721997  PMID: 23865483
Ischemic stroke; Stroke in the young; Atherosclerosis; Arterial disease; Ultrasound; Heredity; Vascular risk; Long-term outcome; Mortality
7.  Alterations in Spontaneous Brain Oscillations during Stroke Recovery 
PLoS ONE  2013;8(4):e61146.
Amplitude or frequency alterations of spontaneous brain oscillations may reveal pathological phenomena in the brain or predict recovery from brain lesions, but the temporal evolution and the functional significance of these changes is not well known. We performed follow-up recordings of spontaneous brain oscillations with whole-head MEG in 16 patients with first-ever stroke in the middle cerebral artery territory, affecting upper limb motor function, 1–7 days (T0), 1 month (T1), and 3 months (T2) after stroke, with concomitant clinical examination. Clinical test results improved significantly from T0 to T1 or T2. During recovery (at T1 and T2), the strength of temporo–parietal ∼10-Hz oscillations in the affected hemisphere (AH) was increased as compared with the unaffected hemisphere. Abnormal low-frequency magnetic activity (ALFMA) at ∼1 Hz in the AH was detected in the perilesional cortex in seven patients at T0. In four of these, ALFMA persisted at T2. In patients with ALFMA, the lesion size was significantly larger than in the rest of the patients, and worse clinical outcome was observed in patients with persisting ALFMA. Our results indicate that temporo–parietal ∼10-Hz oscillations are enhanced in the AH during recovery from stroke. Moreover, stroke causes ALFMA, which seems to persist in patients with worse clinical outcome.
PMCID: PMC3623808  PMID: 23593414
8.  European Research Priorities for Intracerebral Haemorrhage 
Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH.
PMCID: PMC3712813  PMID: 21986448
Intracerebral haemorrhage; Oedema; Stroke; Mortality; Disability; Outcome; Pathophysiology; Epidemiology; Imaging
9.  Stroke in the Young 2012 
Stroke Research and Treatment  2012;2012:656913.
PMCID: PMC3443592  PMID: 22991686
10.  Stroke in the Young 
Stroke Research and Treatment  2012;2011:271979.
PMCID: PMC3270574  PMID: 22315704
11.  Carotid Embolectomy and Endarterectomy for Symptomatic Complete Occlusion of the Carotid Artery as a Rescue Therapy in Acute Ischemic Stroke 
Case Reports in Neurology  2011;3(3):301-308.
Emergency endarterectomy of an occluded internal carotid artery (ICA) has not been investigated as an option of rescue therapy for severe acute ischemic stroke in the era of intravenous (IV) thrombolysis treatment neither as a primary treatment nor after failed IV thrombolysis. Data from the pre-IV thrombolysis era are conflicting and therefore emergency endarterectomy has not been recommended. The number of patients reaching the emergency room within the IV thrombolysis time window has vastly grown due to advanced acute stroke treatment protocols. The efficacy of mechanical thrombectomy as a primary or add-on to IV thrombolysis therapy option is being actively investigated. We herein report 2 cases of acute ischemic stroke with computerized tomography (CT) angiography-documented occlusion of an ICA that were treated with emergency carotid endarterectomy and embolectomy to restore cerebral blood flow. Both cases presented with severe stroke symptoms and signs not responding to IV thrombolysis and showed severe CT-perfusion deficits mainly representing ischemic penumbra. Blood flow was surgically restored after 5 h of symptom onset. Both patients achieved a favorable outcome. We conclude that timely surgical approach of acute ICA occlusion after failed thrombolysis as a rescue therapy may be a viable option in well-selected patients.
PMCID: PMC3250650  PMID: 22220158
Internal carotid artery; Carotid endarterectomy; Acute stroke treatment; Embolectomy
12.  Optimized Mouse Model for the Imaging of Tumor Metastasis upon Experimental Therapy 
PLoS ONE  2011;6(11):e26810.
Development of new cancer treatments focuses increasingly on the relation of cancer tissue with its microenvironment. A major obstacle for the development of new anti-cancer therapies has been the lack of relevant animal models that would reproduce all the events involved in disease progression from the early-stage primary tumor until the development of mature metastatic tissue. To this end, we have developed a readily imageable mouse model of colorectal cancer featuring highly reproducible formation of spontaneous liver metastases derived from intrasplenic primary tumors. We optimized several experimental variables, and found that the correct choice of cell line and the genetic background, as well as the age of the recipient mice, were critical for establishing a useful model system. Among a panel of colorectal cancer cell lines tested, the epithelial carcinoma HT29 line was found to be the most suitable in terms of producing homogeneous tumor growth and metastases. In our hands, SCID mice at the age of 125 days or older were the most suitable in supporting consistent HT29 tumor growth after splenic implantation followed by reproducible metastasis to the liver. A magnetic resonance imaging (MRI) protocol was optimized for use with this mouse model, and demonstrated to be a powerful method for analyzing the antitumor effects of an experimental therapy. Specifically, we used this system to with success to verify by MRI monitoring the efficacy of an intrasplenically administered oncolytic adenovirus therapy in reducing visceral tumor load and development of liver metastases. In summary, we have developed a highly optimized mouse model for liver metastasis of colorectal cancer, which allows detection of the tumor load at the whole body level and enables an accurate timing of therapeutic interventions to target different stages of cancer progression and metastatic development.
PMCID: PMC3207818  PMID: 22073198
13.  Adenoviruses with an αvβ integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases 
Colorectal cancer is often a deadly disease and cannot be cured at metastatic stage. Oncolytic adenoviruses have been considered as a new therapeutic option for treatment of refractory disseminated cancers, including colorectal cancer. The safety data has been excellent but tumor transduction and antitumor efficacy especially in systemic administration needs to be improved.
Here, the utility of αvβ integrin targeting moiety Arg-Gly-Asp (RGD) in the Lys-Lys-Thr-Lys (KKTK) domain of the fiber shaft or in the HI-loop of adenovirus serotype 5 for increased tumor targeting and antitumor efficacy was evaluated. To this end, novel spleen-to-liver metastatic colorectal cancer mouse model was used and the antitumor efficacy was evaluated with magnetic resonance imaging (MRI).
Both modifications (RGD in the HI-loop or in the fiber shaft) increased gene transfer efficacy in colorectal cancer cell lines and improved tumor-to-normal ratio in systemic administration of the vector.
Antitumor potency was not compromised with RGD modified viruses suggesting increased safety profile and tumor specificity.
PMCID: PMC2936307  PMID: 20727221
14.  Spinal Epidural Hematoma as a Complication of Intravenous Thrombolysis in an Acute Ischemic Stroke Patient 
Case Reports in Neurology  2010;2(1):32-36.
An 80-year-old white male suffered a stroke, fell to the floor, and suffered acute right hemiparesis and facial palsy. After an intravenous alteplase infusion 2.5 h later, the patient first complained of numbness in his right arm, then neck pain, followed by left leg numbness and slowly progressing paraparesis. MRI of the spine demonstrated an acute spinal dorsal epidural hematoma extending from the C6 to the T6 level; 12 h later, he underwent hematoma evacuation and laminectomy. Three months after surgery, the patient was paraplegic with moderate sensory loss below mamillary level. Acute ischemic stroke is often associated with a sudden fall, which, after thrombolysis, may result in unusual hemorrhagic complications.
PMCID: PMC2914369  PMID: 20689632
Cerebral infarction; Thrombolysis; Spinal epidural hematoma
15.  Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection 
Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells.
PMCID: PMC2830184  PMID: 20298534

Results 1-15 (15)