Beneficial effects of exercise, testosterone, vitamin D, calcium and protein in older men-A randomized clinical trial.

BACKGROUND: Due to increasing older populations worldwide, injuries, disabilities and deaths caused by falls among the elderly represent a growing human and societal problem. We aimed to improve health among men of at least 70 years of age with low-normal to low testosterone and mobility problems by using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium and protein. METHODS: This was a single-centre, randomized, placebo-controlled, double-blind trial with 148 older men with a median age of 77 (73-81) years, testosterone levels at median 8 (5-9) nmol/L (full range from 1.1 to 12.9 nmol/L) and mobility problems, recruited at University Hospital of Copenhagen, Herlev Hospital, Denmark. Participants were randomized into four arms for 20 weeks: (1) TU therapy (n = 37); (2) progressive resistance training with supplements of calcium, vitamin D and protein (n = 36); (3) both interventions combined (n = 36); or (4) no intervention (n = 39). The main outcome measure was the 30-s chair stand test, due to test performance correlating with the risk of serious fall injuries and lower extremity muscle strength. Outcome measurements were performed at baseline and after 20 weeks. RESULTS: After the intervention, the combination group receiving progressive resistance training, TU and supplements achieved a median score of 13 (11-15) compared to the control group at 10 (0-14) in the 30-s chair stand test (P = 0.003). This median improvement of 3.0 was clinically important. Compared to the control group, participants in the combination group also increased quality of life (P < 0.05) and reduced both tiredness (P < 0.05) and leg fat (P < 0.05) and had higher variability in the RR interval (P < 0.01). The group receiving TU reduced gynoid and leg fat compared to the control group (both P < 0.05). Blood tests improved for several variables, especially in the combination group. There was no statistically significant increase in adverse effects from either the supplements or training. CONCLUSIONS: In men ≥70 years old with low-normal to low testosterone and mobility problems, supplements of testosterone, calcium, vitamin D and protein combined with progressive resistance training improved 30-s chair stand test performance, muscle strength and quality of life. Both tiredness and leg fat were reduced, and RR interval variability was increased. Significant adverse effects were not observed.

Long-term immune cell profiling in stroke patients with or without infections.

PURPOSE: Infections are frequent complications in acute ischemic stroke and may be caused by an altered immune response influencing brain damage. We compared long-term immune responses in stroke patients with or without infections during the recovery period by performing a long-term profiling of clinically relevant inflammatory parameters from stroke onset until day 49. MATERIALS AND METHODS: Thirty-four stroke patients were retrospectively included and divided into two groups depending on infection status. Group 1 had no infections (N = 17) and group 2 had post-admission infection (N = 17). The patients were evaluated carefully for infections and evolution of the peripheral inflammatory response. Neutrophils, monocytes, lymphocytes, total leukocytes and C-reactive protein were evaluated in relation to the occurrence and development of infections. In both patient groups, an acute boost in neutrophils and monocytes were observed whereas the opposite was true for lymphocytes. RESULTS: In Group 1, neutrophils and monocytes approached normal levels after 20-30 days, but remained elevated in Group 2. We found an increase in neutrophils (p = 0.01) and leukocytes (p < 0.01) as well as C-reactive protein (p < 0.01) among infected patients. Lymphocytes remained depressed in Group 2, while Group 1 slowly approached baseline levels. In both groups, CRP levels initially increased with a slow return to baseline levels. From day 0 to 49 after stroke, uninfected patients generally experienced a decline in leukocytes, neutrophils and monocytes (all p < 0.05), while no similar changes happened among infected patients. CONCLUSIONS: Our study provides an overview of general immune cell kinetics after stroke related to infection status. Immune cell numbers were severely disturbed for weeks after the insult, independent of infection status, although infected patients achieved the highest cell counts of neutrophils, leukocytes and for C-reactive protein. The sustained depression of lymphocytes, especially and paradoxically among infected patients, warrants future studies into the mechanisms behind this, with potential for future therapies aimed at restoring normal immunity and thereby improving patient outcome.

Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign.

BACKGROUND AND PURPOSE: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88). CONCLUSIONS: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.

How to identify fatigue in stroke patients: an investigation of the post-stroke fatigue case definition validity.

BACKGROUND: Fatigue is a common and often debilitating stroke sequela, and it is important to accurately define and detect post-stroke fatigue. Often questionnaires are used but a case definition has been developed and proposed as a better tool. OBJECTIVES: The aim of the study was to determine validity and inter-rater agreement of the case definition of post-stroke fatigue, and to determine optimal cutoff scores for marked fatigue on the Multidimensional Fatigue Inventory-20 and the Fatigue Severity Scale-7 questionnaires. METHODS: Stroke patients were interviewed with the structured interview schedule for the case definition and asked to complete the two questionnaires. To examine the inter-rater agreement of the case definition a second interviewer did another interview blinded to the result of the first interview. RESULTS: Seventy patients were enrolled, 44% women. The median age was 74 years (interquartile range: 67-80) and the median time from stroke to interview was 8 days. The median Fatigue Severity Scale-7 score and the median Multidimensional Fatigue Inventory-20 (General Fatigue subscale) score were higher in the case definition positive than in the negative group (p < .001). The kappa value for the inter-rater agreement was 0.63. A cutoff score of 4.9 for the Fatigue Severity Scale-7 and a cutoff score of 12 on the Multidimensional Fatigue Inventory-20 were optimal to identify marked fatigue according to the case definition. CONCLUSIONS: The case definition was valid and had a substantial inter-rater agreement. A score ≥ 5 using the Fatigue Severity Scale-7 or a score ≥ 12 using the Multidimensional Fatigue Inventory-20 (General Fatigue subscale) may be used to detect potentially debilitating post-stroke fatigue in stroke survivors.

Therapist-Assisted Progressive Resistance Training, Protein Supplements, and Testosterone Injections in Frail Older Men with Testosterone Deficiency: Protocol for a Randomized Placebo-Controlled Trial.

BACKGROUND: Fall accidents are a major cause of mortality among the elderly and the leading cause of traumatic brain injury. After a fall, many elderly people never completely recover and need help in coping with everyday life. Due to the increasing older population in the world, injuries, disabilities, and deaths caused by falls are a growing worldwide problem. Muscle weakness leads to greatly increased risk of falling, decreased quality of life, and decline in functional capacity. Muscle mass and muscle power decrease about 40% from age 20 to 80 years, and the level of testosterone decreases with age and leads to impaired muscle mass. In addition, 20% of men older than 60 years-and 50% older than 80 years-have low levels of testosterone. Treatments after a fall are significant financial burdens on health and social care, and it is important to find treatments that can enhance function in the elderly people. OBJECTIVE: The purpose of this study is to investigate whether testosterone and progressive resistance training alone or combined can improve muscle strength and reduce the risk of falls in older men. Additionally, we will examine whether such treatments can improve quality of life, functional capacity, including sexual function, and counteract depression. METHODS: This is a randomized placebo-controlled, double-blind trial in which frail older men with testosterone deficiency are treated with testosterone supplemental therapy and therapist-assisted progressive resistance training for 20 weeks, with the possibility to continue treatment for 1 year. Four study arms of 48 participants each are provided based on factorial assignment to testosterone supplemental therapy and progressive resistance training. The 4 groups are as follows: controls given placebo injections without physical exercise for 20 weeks, testosterone-alone group given testosterone injections without physical exercise for 20 weeks, training-alone group given placebo injections for 20 weeks combined with 16 weeks of progressive strength training, and combination group given testosterone injections for 20 weeks combined with 16 weeks of progressive strength training. Performance in the 30-second chair stand test to measure improvement of general strength, balance, and power in lower extremities is the primary endpoint. Secondary endpoints comprising tests of cognition, muscle strength, and quality of life are applied before and after the training. RESULTS: Funding was provided in October 2016. Results are expected to be available in 2020. Sample size was calculated to 152 participants divided into 4 equal-sized groups. Due to age, difficulty in transport, and the time-consuming intervention, up to 25% dropouts are expected; thus, we aim to include at least 192 participants. CONCLUSIONS: This investigation will evaluate the efficacy of testosterone supplemental therapy alone or combined with progressive resistance training. Additionally, improvements in quality of life and cognition are explored. TRIAL REGISTRATION: Clinicaltrials.gov NCT02873559; https://clinicaltrials.gov/ct2/show/NCT02873559 (Archived by WebCite at http://www.webcitation.org/6x0BhU2p3).

Therapist-Assisted Rehabilitation of Visual Function and Hemianopia after Brain Injury: Intervention Study on the Effect of the Neuro Vision Technology Rehabilitation Program.

BACKGROUND: Serious and often lasting vision impairments affect 30% to 35% of people following stroke. Vision may be considered the most important sense in humans, and even smaller permanent injuries can drastically reduce quality of life. Restoration of visual field impairments occur only to a small extent during the first month after brain damage, and therefore the time window for spontaneous improvements is limited. One month after brain injury causing visual impairment, patients usually will experience chronically impaired vision and the need for compensatory vision rehabilitation is substantial. OBJECTIVE: The purpose of this study is to investigate whether rehabilitation with Neuro Vision Technology will result in a significant and lasting improvement in functional capacity in persons with chronic visual impairments after brain injury. Improving eyesight is expected to increase both physical and mental functioning, thus improving the quality of life. METHODS: This is a prospective open label trial in which participants with chronic visual field impairments are examined before and after the intervention. Participants typically suffer from stroke or traumatic brain injury and will be recruited from hospitals and The Institute for the Blind and Partially Sighted. Treatment is based on Neuro Vision Technology, which is a supervised training course, where participants are trained in compensatory techniques using specially designed equipment. Through the Neuro Vision Technology procedure, the vision problems of each individual are carefully investigated, and personal data is used to organize individual training sessions. Cognitive face-to-face assessments and self-assessed questionnaires about both life and vision quality are also applied before and after the training. RESULTS: Funding was provided in June 2017. Results are expected to be available in 2020. Sample size is calculated to 23 participants. Due to age, difficulty in transport, and the time-consuming intervention, up to 25% dropouts are expected; thus, we aim to include at least 29 participants. CONCLUSIONS: This investigation will evaluate the effects of Neuro Vision Technology therapy on compensatory vision rehabilitation. Additionally, quality of life and cognitive improvements associated to increased quality of life will be explored. TRIAL REGISTRATION: ClinicalTrials.gov NCT03160131; https://clinicaltrials.gov/ct2/show/NCT03160131 (Archived by WebCite at http://www.webcitation.org/6x3f5HnCv).

Performance of short ECG recordings twice daily to detect paroxysmal atrial fibrillation in stroke and transient ischemic attack patients.

Aims Prolonged cardiac monitoring after stroke is recommended though there is no consensus on optimal methods. Short-term ECG recordings with a "thumb-ECG" device have shown promising preliminary results regarding effectiveness and cost benefit. We aimed to examine the performance of thumb-ECG and five days' Holter monitoring in a prospective trial. A secondary endpoint was the inter-observer agreement of the thumb-ECG. Methods Patients older than 65 years with no history of atrial fibrillation who suffered an acute stroke or transient ischemic attack of unknown origin were prospectively included. Patients were monitored for atrial fibrillation with five days' Holter and concurrent 30 s thumb-ECG twice daily, the latter continuing for 30 days. Inter-observer agreement for the thumb-ECG was determined. Results One hundred patients were included and 95 patients were analyzed. Paroxysmal atrial fibrillation was diagnosed in 20 patients with the thumb-ECG recordings and 17 patients on the Holter monitoring. Only 10 were diagnosed with both methods. The difference between the detection rates of the two devices was not significant ( p = 0.63). The inter-observer agreement of the thumb-ECG had a kappa value of 0.65. Conclusion Thirty days' thumb-ECG recordings twice daily for 30 s detect a high proportion of paroxysmal atrial fibrillation in a stroke or transient ischemic attack cohort. The proportion was comparable to five days' Holter monitoring but the agreement between the two methods was poor and the trial was not powered to detect a minor difference between the devices. The inter-observer agreement for the thumb-ECG was substantial. www.clinicalTrials.gov UI: NCT02261766.

Stroke rehabilitation at home before and after discharge reduced disability and improved quality of life: a randomised controlled trial.

OBJECTIVE: To evaluate if home-based rehabilitation of inpatients improved outcome compared to standard care. DESIGN: Interventional, randomised, safety/efficacy open-label trial. SETTING: University hospital stroke unit in collaboration with three municipalities. SUBJECTS: Seventy-one eligible stroke patients (41 women) with focal neurological deficits hospitalised in a stroke unit for more than three days and in need of rehabilitation. INTERVENTIONS: Thirty-eight patients were randomised to home-based rehabilitation during hospitalization and for up to four weeks after discharge to replace part of usual treatment and rehabilitation services. Thirty-three control patients received treatment and rehabilitation following usual guidelines for the treatment of stroke patients. MAIN MEASURES: Ninety days post-stroke the modified Rankin Scale score was the primary endpoint. Other outcome measures were the modified Barthel-100 Index, Motor Assessment Scale, CT-50 Cognitive Test, EuroQol-5D, Body Mass Index and treatment-associated economy. RESULTS: Thirty-one intervention and 30 control patients completed the study. Patients in the intervention group achieved better modified Rankin Scale score (Intervention median = 2, IQR = 2-3; Control median = 3, IQR = 2-4; P=0.04). EuroQol-5D quality of life median scores were improved in intervention patients (Intervention median = 0.77, IQR = 0.66-0.79; Control median = 0.66, IQR = 0.56 - 0.72; P=0.03). The total amount of home-based training in minutes highly correlated with mRS, Barthel, Motor Assessment Scale and EuroQol-5D™ scores (P-values ranging from P<0.00001 to P=0.01). Economical estimations of intervention costs were lower than total costs of standard treatment. CONCLUSION: Early home-based rehabilitation reduced disability and increased quality of life. Compared to standard care, home-based stroke rehabilitation was more cost-effective.

Modafinil May Alleviate Poststroke Fatigue: A Randomized, Placebo-Controlled, Double-Blinded Trial.

BACKGROUND AND PURPOSE: Poststroke fatigue is common and reduces quality of life. Current evidence for intervention is limited, and this is the first placebo-controlled trial to investigate treatment of poststroke fatigue with the wakefulness promoting drug modafinil. METHODS: The trial was randomized, double-blinded, and placebo-controlled. Patients were treated with 400-mg modafinil or placebo for 90 days. Assessments were done at inclusion, 30, 90, and 180 days. The primary end point was fatigue at 90 days measured by the Multidimensional Fatigue Inventory-20 general fatigue domain. Secondary end points included the Fatigue Severity Scale, the Montreal Cognitive Assessment, the modified Rankin Scale and the Stroke-specific quality of Life questionnaire. Adult patients with a recent stroke achieving a score of ≥12 on the Multidimensional Fatigue Inventory-20 general fatigue domain were consecutively included. Exclusion criteria were severe cognitive disabilities and contraindications for modafinil treatment. RESULTS: One thousand one hundred twenty-one patients with stroke were screened and 41 patients included, 21 received modafinil. The primary end point, the Multidimensional Fatigue Inventory-20 general fatigue score, did not differ between groups. Patients in the modafinil group obtained better scores on the Fatigue Severity Scale (P=0.02) and in some subscales of the stroke-specific quality of life questionnaire (0.001

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. METHOD: A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9-12, and avoidance of corticosteroids. CONCLUSION: These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

The effects of citicoline on acute ischemic stroke: a review.

Early reopening of the occluded artery is, thus, important in ischemic stroke, and it has been calculated that 2 million neurons die every minute in an ischemic stroke if no effective therapy is given; therefore, "Time is Brain." In massive hemispheric infarction and edema, surgical decompression lowers the risk of death or severe disability defined as a modified Rankin Scale score greater than 4 in selected patients. The majority, around 80%-85% of all ischemic stroke victims, does not fulfill the criteria for revascularization therapy, and also for these patients, there is no effective acute therapy. Also there is no established effective acute treatment of spontaneous intracerebral bleeding. Therefore, an effective therapy applicable to all stroke victims is needed. The neuroprotective drug citicoline has been extensively studied in clinical trials with volunteers and more than 11,000 patients with various neurologic disorders, including acute ischemic stroke (AIS). The conclusion is that citicoline is safe to use and may have a beneficial effect in AIS patients and most beneficial in less severe stroke in older patients not treated with recombinant tissue plasminogen activator. No other neuroprotective agent had any beneficial effect in confirmative clinical trials or had any positive effect in the subgroup analysis. Citicoline is the only drug that in a number of different clinical stroke trials continuously had some neuroprotective benefit.

Comparison of quantitative estimation of intracerebral hemorrhage and infarct volumes after thromboembolism in an embolic stroke model.

BACKGROUND: Strokes have both ischemic and hemorrhagic components, but most studies of experimental stroke only address the ischemic component. This is likely because investigations of hemorrhagic transformation are hindered by the lack of methods based on unbiased principles for volume estimation. AIMS: We evaluated different methods for estimating the volume of infarcts, hemorrhages, after embolic middle cerebral artery occlusion with or without thrombolysis. METHODS: An experimental thromboembolytic rat model was used in this study. The rats underwent surgery and were placed in two groups. Group 1 was treated with saline, and group 2 was treated with 20 mg/kg recombinant tissue plasminogen activator to promote intracerebral hemorrhages. Stereology, semiautomated computer estimation, and manual erythrocyte counting were used to test the precision and efficiency of determining the size of the infarct and intracerebral hemorrhage. RESULTS: No differences were observed in the infarct volume or amount of bleeding when comparing the three methods of volume estimation. Although semiautomated computer estimation and manual erythrocyte counting provided similar results as the stereological measurements, the stereological method was the most efficient and advantageous. CONCLUSIONS: We found that stereology was the superior method for quantification of hemorrhagic volume, especially for rodent petechial bleeding, which is otherwise difficult to measure. Our results suggest the possibility of measuring both the ischemic and the hemorrhagic components of stroke, two parameters that may be differentially regulated when therapeutic regimens are tested.

Dysphagia screening and intensified oral hygiene reduce pneumonia after stroke.

OBJECTIVES: Dysphagia occurs in approximately 51%-78% of patients with acute stroke. The incidence of pneumonia caused by aspiration in dysphagic patients increases both mortality and the need for hospitalization. The aim of this study was to investigate whether the incidence of aspiration pneumonia could be reduced in such patients by an early screening for dysphagia and intensified oral hygiene. MATERIAL AND METHODS: In this controlled trial, 146 hospitalized acute stroke patients with moderate or severe dysphagia were included in three groups: an intervention group (n = 58), one internal control group (n = 58, retrospectively selected from same clinic), and one external control group (n = 30) from a comparable stroke unit in a neighboring hospital. The intervention consisted of early screening with a clinical method of dysphagia screening, the Gugging Swallowing Screen, and intensified oral hygiene. RESULTS: The incidence of x-ray verified pneumonia was 4 of 58 (7%) in the intervention group compared with 16 of 58 (28%) in the internal control group (p < .01) and with 8 of 30 (27%) in the external control group (p < .05). CONCLUSIONS: Early and systematic dysphagia screening by the Gugging Swallowing Screen method and intensified oral hygiene reduced the incidence of x-ray verified pneumonia.

Effects of computer-assisted oral anticoagulant therapy.

BACKGROUND: Computer-assistance and self-monitoring lower the cost and may improve the quality of anticoagulation therapy. The main purpose of this clinical investigation was to use computer-assisted oral anticoagulant therapy to improve the time to reach and the time spent within the therapeutic target range compared to traditional oral anticoagulant therapy by physicians. METHODS: 54 patients were randomized equally into 3 groups. Patients in two groups used CoaguChek® systems to measure international normalized ratio (INR) values and had dosages of anticoagulation treatment calculated in a computer system by an algorithm specific to each group. The third group received traditional anticoagulation treatment by physicians. The obtained INR values were compared regarding the time to reach, and the time spent within, the therapeutic target range, corresponding to INR values from 2 to 3. RESULTS: Patients randomized to computer-assisted anticoagulation and the CoaguChek® system reached the therapeutic target range after 8 days compared to 14 days by prescriptions from physicians (p = 0.04). Time spent in the therapeutic target range did not differ between groups. The median INR value measured throughout the study from all patients by CoaguChek® at 2.5 (2.42-2.62) was lower than measured by a hospital-based Clinical and Biochemical Laboratory at 2.6 (2.45-2.76), (p = 0.02). CONCLUSIONS: The therapeutic target range was reached faster by the use of computer-assisted anticoagulation treatment than prescribed by physicians, and the total time spent within the therapeutic target range was similar. Thus computer-assisted oral anticoagulant therapy may reduce the cost of anticoagulation therapy without lowering the quality. INR values measured by CoaguChek® were reliable compared to measurements by a clinical and biochemical laboratory.

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.

Acute but not delayed amphetamine treatment improves behavioral outcome in a rat embolic stroke model.

OBJECTIVES: The objective of this study was to examine the effects of d-amphetamine (amph) upon recovery after embolic stroke in rats. METHODS: Ninety-three rats were embolized in the right middle cerebral artery and assigned to: (1) controls; (2) combination (acute amph and later amph-facilitated retraining); (3) late amph (later amph-facilitated retraining alone); and (4) acute amph (acute amph alone). Animals in the combination and in the acute amph groups received a high dose of amph immediately after embolization, while later amph-facilitated retraining in the combination and late amph groups was done by administering a low dose of amph on post-stroke days 2, 5, 8, and 11 followed by retraining in Montoya's Staircase Test. RESULTS: Rats receiving acute amph immediately after embolization achieved an 11% increase in median blood pressure (P<0.05). An investigation of performances with the ipsilateral paws during days 14-21 showed that the acute amph group performed better than the control group (P<0.02). Infarct volumes were lower among animals in the acute amph group than in both the combination and the late amph groups (P<0.05), while the controls did not differ from any group. DISCUSSION: In conclusion, results showed that the acute amph group performed the best, while the late amph and the combination groups performed the worst. Amphetamine treatment in acute stroke may be warranted due to reduced detrimental effects of hypotension and improved brain plasticity.

The site of embolization related to infarct size, oedema and clinical outcome in a rat stroke model - further translational stroke research.

BACKGROUND AND PURPOSE: Reliable models are essential for translational stroke research to study the pathophysiology of ischaemic stroke in an effort to find therapies that may ultimately reduce oedema, infarction and mortality in the clinic. The purpose of this study was to investigate the relation between the site of arterial embolization and the subsequent oedema, infarction and clinical outcome in a rat embolic stroke model. METHODS: Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. The site of occlusion was demonstrated by arteriography. Following histological preparation and evaluation, the size of the hemispheres and the infarcts were measured by quantitative histology and planimetry. Another parallel stroke model study was subsequently examined to investigate if the conclusions from the first study could be applied to the second study. RESULTS: The median size of the infarct was 40% of the ipsilateral hemisphere in both the 19 animals with occlusion localised to the intracranial part of the internal carotid artery and in the 11 animals where the main trunk of the middle cerebral artery was occluded. In 5 animals, occlusion of the extracranial part of the internal carotid artery resulted in significantly smaller infarcts compared to other groups (p < 0.01). Another independent study re-confirmed these results. Furthermore, significant correlations (R > 0.76, p < 0.0001) were found between 1) cortical, subcortical, and total infarct volumes, 2) oedema in percent of the left hemisphere, 3) clinical score before termination and 4) postoperative weight loss. CONCLUSIONS: Distal occlusions of the intracranial part of the internal carotid or middle cerebral arteries resulted in comparable large sized infarctions and oedema. This indicates that investigators do not need a similar number of such occlusions in each experimental group. Contrary to observations in the clinic, distal internal carotid artery occlusions did not result in worse outcome than middle cerebral stem occlusions, but this finding may be explained by the controlled emboli size in this experimental stroke model.

Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset.

BACKGROUND AND PURPOSE: Antiplatelets (APs) may increase the risk of symptomatic intracerebral hemorrhage (ICH) following intravenous thrombolysis after ischemic stroke. METHODS: We assessed the safety of thrombolysis under APs in 11,865 patients compliant with the European license criteria and recorded between 2002 and 2007 in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register (SITS-ISTR). Outcome measures of univariable and multivariable analyses included symptomatic ICH (SICH) per SITS Monitoring Study (SITS-MOST [deterioration in National Institutes of Health Stroke Scale >or=4 plus ICH type 2 within 24 hours]), per European Cooperative Acute Stroke Study II (ECASS II [deterioration in National Institutes of Health Stroke Scale >or=4 plus any ICH]), functional outcome at 3 months and mortality. RESULTS: A total of 3782 (31.9%) patients had received 1 or 2 AP drugs at baseline: 3016 (25.4%) acetylsalicylic acid (ASA), 243 (2.0%) clopidogrel, 175 (1.5%) ASA and dipyridamole, 151 (1.3%) ASA and clopidogrel, and 197 (1.7%) others. Patients receiving APs were 5 years older and had more risk factors than AP naïve patients. Incidences of SICH per SITS-MOST (ECASS II respectively) were as follows: 1.1% (4.1%) AP naïve, 2.5% (6.2%) any AP, 2.5% (5.9%) ASA, 1.7% (4.2%) clopidogrel, 2.3% (5.9%) ASA and dipyridamole, and 4.1% (13.4%) ASA and clopidogrel. In multivariable analyses, the combination of ASA and clopidogrel was associated with increased risk for SICH per ECASS II (odds ratio, 2.11; 95% CI, 1.29 to 3.45; P=0.003). However, we found no significant increase in the risk for mortality or poor functional outcome, irrespective of the AP subgroup or SICH definition. CONCLUSIONS: The absolute excess of SICH of 1.4% (2.1%) in the pooled AP group is small compared with the benefit of thrombolysis seen in randomized trials. Although caution is warranted in patients receiving the combination of ASA and clopidogrel, AP treatment should not be considered a contraindication to thrombolysis.

Effects of microplasmin on recovery in a rat embolic stroke model.

OBJECTIVES: The purpose of the present study was to examine the effects of microplasmin on behavioral performance and infarct volume after middle cerebral artery occlusion (MCAO) in rats. Some experiments support that microplasmin may have neuroprotective and thrombolytic properties. METHODS: Eighty rats underwent surgery and were embolized in the right carotid territory with a fibrin-rich embolus and randomly assigned into three groups: 5 mg/kg microplasmin, 10 mg/kg microplasmin or saline (control). Groups treated with microplasmin received 50% bolus injection 10 minutes after embolization and 50% continuous infusion during the following hour. Animals from all groups were trained to obtain high baseline scores in Montoya's staircase test before embolization and were retested during 7-14 days after surgery. RESULTS: When pre-maturely dead animals were excluded, no differences were observed among groups regarding infarct volumes. Furthermore, mortality was significantly lower in Group 1 than in Group 2 (p<0.05) and when performances were evaluated 7-14 days after surgery, Group 1 was significantly better than Group 2 concerning fine motor performance (p<0.05) and also achieved more normal bodyweight (p<0.05). DISCUSSION: Among surviving animals, 5 mg/kg microplasmin treatment had no effect compared to saline-treated control animals; 5 mg/kg microplasmin reduced mortality and improved both behavioral rehabilitation and bodyweight compared to 10 mg/kg microplasmin treatment, while saline-treated animals did not differ from animals treated with 10 mg/kg microplasmin. Overall, these results indicate a potential beneficial effect of 5 mg/kg microplasmin treatment, while 10 mg/kg may worsen outcomes.