| 1. |
- Dahlqvist, Per, et al.
(författare)
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Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats
- 2003
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Ingår i: Neuroscience. - 1873-7544 .- 0306-4522. ; 119:3, s. 643-652
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Tidskriftsartikel (refereegranskat)abstract
- Housing rats in an enriched environment improves functional outcome after ischemic stroke, this may reflect neuronal plasticity in brain regions outside the lesion. Which components of the enriched environment that are of greatest importance for recovery after brain ischemia is uncertain. We have previously found that enriched environment and social interaction alone both improve functional recovery after focal cerebral ischemia, compared with isolated housing with voluntary wheel-running. In this study, the aim was to separate components of the enriched environment and investigate the effects on some potential mediators of improved functional recovery; such as the inducible transcription factors nerve growth factor-induced gene A (NGFI-A) and NGFI-B, and the glucocorticoid and serotonin systems. After permanent middle cerebral artery occlusion, rats were divided into four groups: individually housed with no equipment (deprived group), individually housed with free access to a running wheel (running group), housed together in a large cage with no equipment (social group) or in a large cage furnished with exchangeable bars, chains and other objects (enriched group). mRNA expression of inducible transcription factors, serotonin and glucocorticoid receptors was determined with in situ hybridisation 1 month after cerebral ischemia. Rats housed in enriched or social environments showed significantly higher mRNA expression of NGFI-A and NGFI-B in cortical regions outside the lesion and in the CA1 (cornu ammonis region of the hippocampus), compared with isolated rats with or without a running wheel. NGFI-A and NGFI-B mRNA expression in cortex and in CA1 was significantly correlated to functional outcome. 5-Hydroxytryptamine receptor 1A (5-HT1A) mRNA expression and binding, as well as 5-HT2A receptor mRNA expression were decreased in the hippocampus (CA4 region) of the running wheel rats. Mineralocorticoid receptor gene expression was increased in the dentate gyrus amongst wheel-running rats. No group differences were found in plasma corticosterone levels or mRNA levels of glucocorticoid receptor, corticotropin-releasing hormone, 5-HT2C or c-fos. In conclusion, we have found that social interaction is a major component of the enriched environment regarding the effects on NGFI-A and NGFI-B expression. These transcription factors may be important mediators of improved functional recovery after brain infarctions, induced by environmental enrichment. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.
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| 2. |
- Hellgren, Johan, et al.
(författare)
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Rituximab in multiple sclerosis at general hospital level
- 2020
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 141:6, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The use of rituximab (RTX) in multiple sclerosis (MS) is a rapidly increasing choice of disease-modifying therapy. Efficacy outside specialized university hospital-based care is not yet systematically investigated. Our aim was to evaluate off-label RTX treatment for MS at a general hospital in Sweden. Materials and Methods: Subjects with definite MS with at least one rituximab infusion were eligible for inclusion in this retrospective, observational study. Effect was evaluated by monitoring clinical disability, annual relapse rate, new lesions on MRI, and safety by the incidence and severity of adverse events. Results: Among the 83 included subjects, 15 had clinical worsening of disease during the median 23.5 (1-76) months of follow-up after RTX initiation: 7/66 with relapsing-remitting multiple sclerosis (RRMS) and 8/17 with progressive subtypes (PMS). Cumulative survival without worsening was 86% in RRMS and 30% in PMS. The annual relapse rate before RTX vs follow-up dropped from 0.38 to 0.05 (P < .00001). Subjects with new enhancing lesions on MRI during the first year before RTX initiation vs the year after dropped from 0.94 to 0.024 (P < .00001) and was only seen in RRMS (1.05-0.31, P = .00003). Adverse events were mainly mild. Thirty-six out of 53 non-infusion–related adverse events were infections, of which four were serious, including a case of pneumonia with concomitant late-onset neutropenia. Conclusions: Rituximab was as effective and safe when given at a general hospital outpatient clinic compared with results from previous university hospital-based studies. Vigilance is required concerning severe adverse events.
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| 3. |
- Perfilieva, Ekaterina, et al.
(författare)
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Gender and strain influence on neurogenesis in dentate gyrus of young rats
- 2001
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 21:3, s. 211-217
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether rat hippocampal neurogenesis varies with strain and gender, the authors examined proliferating progenitor cells and their progeny in young male and female Sprague-Dawley (SD) and spontaneously hypertensive rats (SHR) using the thymidine analog bromodeoxyuridine (BrdU) combined with immunohistochemistry for the neuronal marker Calbindin D28k and glial fibrillary acidic protein. Rats were given 7 consecutive daily BrdU injections and were killed 1 day or 4 weeks later to allow for discrimination between proliferation and cell survival. Stereologic analysis of the numbers of BrdU-immunoreactive cells in the dentate gyrus revealed both a strain difference with significantly higher cell proliferation and net neurogenesis in SHR than in SD and a gender difference with males from both strains producing significantly more cells than their female counterparts. Whereas the number of progenitors four weeks after BrdU injections was still significantly greater in male than in female SHRs, resulting in a greater net neurogenesis in the male, the number of BrdU-immunoreactive cells did not differ between male and female SD rats, suggesting a greater survival of newly generated cells in the dentate gyrus in female than in male SD rats. No sex or strain difference was observed in the relative ratio of neurogenesis and gliogenesis.
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| 4. |
- Risedal, Anette, et al.
(författare)
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Environmental influences on functional outcome after a cortical infarct in the rat.
- 2002
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Ingår i: Brain Research Bulletin. - 0361-9230 .- 1873-2747. ; 58:3, s. 315-321
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Tidskriftsartikel (refereegranskat)abstract
- The effect of postoperative housing conditions on functional outcome and brain-derived neurotrophic factor (BDNF) gene expression was evaluated 1 month after a distal ligation of the right middle cerebral artery (MCA) in spontaneously hypertensive rats. Two days postoperatively the rats were randomized into four groups; individually housed with no equipment (deprived group), individually housed with free access to a connected running wheel (running group), housed together in a large cage with no equipment (social group) or in the same size of cage furnished with bars, chains and various things to manipulate (enriched group). The enriched rats had significantly higher scores when crossing a rotating horizontal rod than deprived and running rats. The social group performed significantly better than the deprived group. The BDNF gene expression in the ipsi- and contralateral cortex, thalamus, hippocampus and cerebellum did not significantly differ between the groups. The weight of the adrenal glands was significantly increased in running rats suggesting that postischemic running may be stressful. We conclude that the beneficial effect of postischemic environmental enrichment is likely to be a combination of social and various physical activities, and that BDNF gene expression 1 month after a cortical infarct did not correlate with functional outcome.
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| 5. |
- Risedal, Anette, et al.
(författare)
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Infarct volume and functional outcome after pre- and postoperative administration of metyrapone, a steroid synthesis inhibitor, in focal brain ischemia in the rat
- 1999
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 6:4, s. 481-486
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Tidskriftsartikel (refereegranskat)abstract
- High blood levels of glucocorticoids are associated with increased mortality, confusion and poor functional outcome in stroke patients. It has been proposed that inhibition of glucocorticoids in acute stroke might be beneficial, but experimental data are conflicting and no long-term follow-up study has been reported. We have studied whether pre- or postoperative administration of metyrapone, a steroid synthesis inhibitor, can influence long-term outcome after ligation of the right middle cerebral artery (MCA) distal to the striatal branches in hypertensive rats. Metyrapone (200 mg/kg) was administered either 30 min before or 1, 12 and 24 h after MCA occlusion. Limb placements and ability to traverse a rotating pole were evaluated pre- and postoperatively. Infarct size, histology and GFAP immunoreactivity were evaluated on 5 microm coronal sections from brains perfused in situ 4 weeks after the ischemic event. Pretreatment did not influence outcome, whereas postoperative administration of metyrapone significantly increased infarct volume (P < 0.05). Post-treated rats performed significantly worse than vehicle-treated rats on the rotating pole 3 weeks after the operation (P < 0.05). Our results do not support the hypothesis that inhibition of glucocorticoid synthesis improves outcome after cerebral ischemia.
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| 6. |
- Risedal, Anette
(författare)
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Stroke and Functional Recovery - An experimental study on environmental influence and gene expression after cortical infarcts in the rat
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Stroke is the third leading cause of death in the western world, and the number one cause of disability. 85% of all strokes are ischemic. Most stroke survivors will experience recovery of function. The mechanisms behind this improvement are partly unknown, but may involve elements of both compensation and restoration. Exposure to an enriched environment (EE) that stimulates social interaction, expanded learning abilities and spontaneous physical activity which also consists elements of training, alters behaviour and brain morphology with an increase in dendritic branching and number of synapses in intact animals. Enriched housing after a cortical infarct improves functional outcome. This thesis is based on studies of cortical infarcts in rats and demonstrates that management and housing conditions after an experimental stroke significantly alters functional outcome. To examine the influence of different environmental conditions on functional recovery and potential mediators of brain plasticity, we compared rats housed in an enriched or social environment with rats housed in isolation with or without access to a running wheel. EE or social interaction resulted in significantly higher mRNA expression of NGFI-A and NGFI-B in regions outside the infarct and this was correlated to better outcome compared to running or isolated housing. The observed differences in functional recovery were not related to changes in gene expression of BDNF. Housing animals in an EE with the opportunity to engage in various activities without specific training significantly improves functional outcome and does not increase tissue loss. However additional training initiated 24 h after MCAo resulted in an increase in infarct volume without affecting functional outcome as early trained rats housed in EE improved more than standard rats in the behavioural tests used. Stroke induces a stress reaction with an increase in glucocorticoid (GC) levels, suggested to exaggerate neuronal damage and negatively affect outcome. We found that inhibition of GCs increases tissue loss, and failed to improve outcome, a result that partly might be due to dampening of the anti-inflammatory response provided by corticosterone. In conclusion the present thesis shows that postischemic EE can influence recovery and NGFI-A gene expression that may be related to better outcome. Enriched housing supporting voluntary activities improves outcome and does not increase tissue loss after a cortical infarct. However additional training initiated 24 h after MCA occlusion can increase infarct volume without negative effects on outcome. The stress response seen after stroke may have a beneficial effect as inhibition of GSs increases tissue loss and negatively affects outcome.
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| 7. |
- Svenningsson, Anders, et al.
(författare)
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Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial
- 2022
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:8, s. 693-703
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Tidskriftsartikel (refereegranskat)abstract
- Background B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. Methods RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. Findings Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0.19 (95% CI 0.06-0.62; p=0.0060). Infusion reactions (105 events [40.9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47.4 per 100 patient-years]) and flush (65 events [47.4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. Interpretation RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.
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| 8. |
- Zhao, Li Ru, et al.
(författare)
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Enriched environment influences brain-derived neurotrophic factor levels in rat forebrain after focal stroke
- 2001
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Ingår i: Neuroscience Letters. - 0304-3940. ; 305:3, s. 169-172
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Tidskriftsartikel (refereegranskat)abstract
- Tissue levels of brain-derived neurotrophic factor (BDNF) protein were studied using enzyme immunoassay in different forebrain regions in the ipsi- and contralateral hemispheres of rats housed under enriched or standard conditions after the middle cerebral artery ligation. BDNF levels in the ipsilateral to ligation side was significantly higher only in the frontal cortex of standard as compared to enriched rats. However, BDNF overall was more abundant in standard than in enriched group. In addition, BDNF levels detected in the hippocampus and frontal cortex on the ischemic side of standard rats was higher as compared to contralateral side. The present study shows that housing conditions after permanent middle cerebral artery ligation leads to differential regulation of BDNF protein levels in forebrain regions which might have important implication for post-ischemic recovery.
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