| 1. |
- Traylor, Matthew, et al.
(author)
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Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
- 2021
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In: The Lancet Neurology. - 1474-4422. ; 20:5, s. 351-361
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Journal article (peer-reviewed)abstract
- Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
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| 2. |
- Björkman, Jan-Arne, et al.
(author)
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Cardiac sympathetic nerve stimulation triggers coronary t-PA release.
- 2003
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In: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 23:6, s. 1091-7
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Journal article (peer-reviewed)abstract
- OBJECTIVE: This study was undertaken to determine whether stimulation of sympathetic cardiac nerves induces release of the thrombolytic enzyme tissue-type plasminogen activator (t-PA) in the coronary vascular bed. METHODS AND RESULTS: Anesthetized pigs were studied in an open chest model. Bilateral vagotomy was performed, and sympathetic cardiac nerves were activated by electrical stimulation (1 and 8 Hz). To evaluate possible mediating effects of increased heart rate and enhanced local blood flow, tachycardia was induced by pacing and hyperemia by local infusion of sodium nitroprusside and clevedipine. Furthermore, to study the effects of alpha- and beta-adrenergic receptor stimulation, phenylephrine and isoprenaline were infused locally. In response to low- and high-frequency sympathetic stimulation, mean coronary net release of total t-PA increased approximately 6- and 25-fold, respectively. Active t-PA showed a similar response pattern. Neither tachycardia nor coronary hyperemia stimulated t-PA release. In contrast, beta-adrenergic stimulation by isoprenaline induced an approximately 6-fold increase in coronary t-PA release, whereas no significant change in release rates occurred in response to alpha-adrenergic stimulation by phenylephrine. CONCLUSIONS: Stimulation of cardiac sympathetic nerves induces a marked coronary release of t-PA, and part of this response may be mediated through stimulation of beta-adrenergic receptors.
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| 3. |
- Giang, Kok Wai, 1984, et al.
(author)
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Long-term trends in the prevalence of patients hospitalized with ischemic stroke from 1995 to 2010 in Sweden
- 2017
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
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Journal article (peer-reviewed)abstract
- Objective The prevalence of stroke is expected to increase partly because of prolonged life expectancy in the general population. The objective of this study was to investigate trends in the prevalence of patients hospitalized with ischemic stroke (IS) in Sweden from 1995-2010. The Swedish inpatient and cause-specific death registries were used to estimate the absolute numbers and prevalence of patients who were hospitalized with and survived an IS from 1995-2010. The overall number of IS increased from 129,418 in 1995 to 148,778 in 2010. In 1995, the prevalence of IS was 189 patients per 10,000 population. An increase in overall prevalence was observed until 2000, and then it remained stable, followed by a decline with an annual percentage change of (APC)-0.8% (95% CI -1.0 to 0.6) and with a final prevalence of 199 patients per 10,000 population in 2010. The prevalence of IS in people aged <45 years increased from 6.4 in 1995 to 7.6 patients per 10,000 population in 2010, with an APC of 2.1% (95% CI 0.9 to 3.4) from 1995-1998 and 0.7% (95% CI 0.6-0.9) from 1998-2010. Among those aged 45-54 years, the prevalence rose through the mid to late 1990s, followed by a slight decrease (APC:-0.7%, 95% CI -1.1 to -0.4) until 2006 and then remained stable with a prevalence of 43.8 patients per 10,000 population in 2010. Among >= 85 years, there was a minor decrease (APC: -0.3%, 95% CI -0.5 to -0.1) in overall prevalence after 2002 from 1481 to 1453 patients per 10,000 population in 2010. The overall prevalence of IS increased until 2000, but then remained stable followed by a slight decline. However, the prevalence of IS in the young increased through the study period. The absolute number of IS survivors has markedly increased, mainly because of demographic changes.
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| 4. |
- Giang, Kok Wai, 1984, et al.
(author)
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Trends in risk of recurrence after the first ischemic stroke in adults younger than 55 years of age in Sweden
- 2016
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In: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:1, s. 52-61
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Journal article (peer-reviewed)abstract
- Background: Previous studies on stroke recurrence in younger adults often contain small sample size which makes it difficult to study trends in stroke recurrence over a long period of time. Aims: The aim of the present study was to investigate temporal trends in the risk of recurrence in younger patients with a first ischemic stroke. Methods: All men and women aged 18-54 years who had survived at least 28 days after a first ischemic stroke from 1987 to 2006 were identified in the Swedish Inpatient Register. The patients were stratified into four 5-year periods according to their admission period and were followed up for a total of four years after the index event with regard to recurrent ischemic stroke. A Cox regression model was used to analyze the risk of recurrent ischemic stroke. Results: Of the 17,149 ischemic stroke patients who were identified, 2432 (14.2%) had a recurrent ischemic stroke event within four years. From the first to the last periods (1987-1991 versus 2002-2006), the four-year risk of recurrent ischemic stroke decreased by 55% (hazard ratio 0.45, 95% confidence interval 0.39-0.53) in men and 59% (hazard ratio 0.41, 95% confidence interval, 0.33-0.50) in women. The cumulative four-year risk was 11.8% (95% CI 10.55-13.25) in men and 9.8% (95% CI 8.40-11.46) in women during the last five-year period (2002-2006). Conclusions: The risk of recurrence among younger ischemic stroke patients has decreased over the past 20 years. Despite these improvements, younger patients are still at a high risk for recurrent ischemic stroke.
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| 5. |
- Hrafnkelsdottir, Thordis, 1965, et al.
(author)
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Regulation of local availability of active tissue-type plasminogen activator in vivo in man
- 2004
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In: J Thromb Haemost. - 1538-7933. ; 2:11, s. 1960-8
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Journal article (peer-reviewed)abstract
- Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6- and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.
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| 6. |
- Hultman, Karin, 1980, et al.
(author)
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Expression of Plasminogen Activator Inhibitor-1 and Protease Nexin-1 in Human Astrocytes: Response to Injury-Related Factors.
- 2010
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In: Journal of Neuroscience Research. - 1097-4547. ; 88:11, s. 2441-2449
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Journal article (peer-reviewed)abstract
- Astrocytes play a diverse role in central nervous system (CNS) injury. Production of the serine protease inhibitors (serpins) plasminogen activator inhibitor-1 (PAI-1) and protease nexin-1 (PN-1) by astrocytes may counterbalance excessive serine protease activity associated with CNS pathologies such as ischemic stroke. Knowledge regarding the regulation of these genes in the brain is limited, so the objective of the present study was to characterize the effects of injury-related factors on serpin expression in human astrocytes. Native human astrocytes were exposed to hypoxia or cytokines, including interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-10, transforming growth factor-alpha (TGF-alpha), and TGF-beta for 0-20 hr. Serpin mRNA expression and protein secretion were determined by real-time RT-PCR and ELISA, respectively. Localization of PAI-1 and PN-1 in human brain tissue was examined by immunohistochemistry. Hypoxia and all assayed cytokines induced a significant increase in PAI-1 expression, whereas prolonged treatment with IL-1beta or TNF-alpha resulted in a significant down-regulation. The most pronounced induction of both PAI-1 and PN-1 was observed following early treatment with TGF-alpha. In contrast to PAI-1, the PN-1 gene did not respond to hypoxia. Positive immunoreactivity for PAI-1 in human brain tissue was demonstrated in reactive astrocytes within gliotic areas of temporal cortex. We show here that human astrocytes express PAI-1 and PN-1 and demonstrate that this astrocytic expression is regulated in a dynamic manner by injury-related factors.
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| 7. |
- Jern, Christina, 1962, et al.
(author)
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Changes of plasma coagulation and fibrinolysis in response to mental stress.
- 1989
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In: Thrombosis and haemostasis. - 0340-6245. ; 62:2, s. 767-71
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Journal article (peer-reviewed)abstract
- To study the effects of standardized mental stress (arithmetic and the Stroop color word test) on plasma coagulation and fibrinolysis, blood samples were obtained before, during, and after 20 minutes of mental stress from 10 healthy, non-smoking young males aged 22 to 30 years. Reactions were compared with those observed during physical exercise and infusion of adrenaline. Both von Willebrand factor antigen and factor VIII coagulant activity increased significantly in response to mental stress (95 +/- 28 vs 123 +/- 56%; p less than 0.05 and 125 +/- 54 vs 217 +/- 170%; p less than 0.05, respectively). There was also a significant increase of factor VII coagulant activity (86 +/- 31 vs 108 +/- 51%; p less than 0.05). Furthermore, mental stress caused an activation of the fibrinolytic system with an elevation of tissue plasminogen activator activity and tissue plasminogen activator antigen (0.80 +/- 0.48 vs 1.23 +/- 0.96 IU/ml; p = 0.076 and 4.38 +/- 1.87 vs 5.78 +/- 2.58 IU/ml; p less than 0.01). Fibrinogen concentration increased during stress (1.95 +/- 0.29 vs 2.11 +/- 0.27 g/l; p less than 0.05). Similar but more pronounced responses were observed during exercise and adrenaline infusion. Parallel to the increases in coagulation and fibrinolytic factors there were significant increases in heart rate, and systolic and diastolic blood pressure. It is concluded that mental stress has significant effects on plasma coagulation and fibrinolysis, and that it could thus affect important risk factors for cardiovascular disease.
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| 8. |
- Jern, Christina, 1962, et al.
(author)
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Haematological changes during acute mental stress.
- 1989
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In: British journal of haematology. - 0007-1048. ; 71:1, s. 153-6
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Journal article (peer-reviewed)abstract
- To study haematological effects of emotional stress, blood samples were obtained from 29 healthy, normotensive, non-smoking males aged 20-34 years before, during and after 10 min of mental arithmetic. There were significant increases in peripheral blood cell count, haemoglobin concentration, and haematocrit in response to mental stress. Parallel to these changes significant increases in heart rate, and systolic and diastolic blood pressure were observed. The relative increments of leucocyte (8%) and platelet (3.5%) count were significantly higher than the increase in haemoglobin concentration (2%). There was a significant positive correlation between the blood pressure increase and the mobilization of leucocytes, whereas the increase in erythrocyte count, haemoglobin concentration, and haematocrit showed significant positive correlations with heart rate reactivity. It is concluded that mental stress causes an increase in leucocyte and platelet count that could not solely be accounted for by the concurrent haemoconcentration.
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| 9. |
- Jern, Sverker, 1954, et al.
(author)
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'Polycythaemia of stress' in subjects with Type A and Type B behaviour patterns.
- 1991
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In: Journal of psychosomatic research. - 0022-3999. ; 35:1, s. 91-8
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Journal article (peer-reviewed)abstract
- To determine the importance of emotional stress for relative polycythaemia, we studied 11 subjects with the Type A and 11 subjects with the Type B behaviour patterns during short-term mental stress. All subjects were healthy, normotensive non-smoking young males aged 20-34 yr. without any medication. During rest there were no significant differences in heart rate, blood pressure, or plasma catecholamines between the two groups, but the A-group had significantly higher haemoglobin concentration (147 vs 140 g/l; p less than 0.005) and haematocrit (43.8 vs 42.1%: p = 0.05) than the B-group. In the whole group, there was a positive correlation between resting diastolic blood pressure and haemoglobin concentration (r = 0.53; p less than 0.05). In response to 10 min of mental arithmetic, haematocrit, haemoglobin and erythrocyte count rose approximately 2% (p less than 0.001 throughout). The stress-induced changes were not significantly different between the A- and B-groups. It is concluded that mild relative polycythaemia could be induced by acute emotional stress. In subjects with the Type A behaviour pattern a slight haemoconcentration is present already at rest, which further increases during stress.
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| 10. |
- Jern, Sverker, 1954, et al.
(author)
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Short-term reproducibility of a mental arithmetic stress test.
- 1991
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In: Clinical science (London, England : 1979). - 0143-5221. ; 81:5, s. 593-601
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Journal article (peer-reviewed)abstract
- 1. To evaluate the short-term reproducibility of heart rate, oscillometrically determined blood pressure, antecubital venous plasma catecholamine concentrations and subjective responses to strictly standardized mental arithmetic, we performed two identical tests 1 h apart in 14 young, healthy and normotensive male subjects (age 22-35 years). 2. Heart rate and blood pressure responses to the two stress tests were highly correlated, when expressed both as correlations between levels attained during stress (rs greater than 0.80 throughout) and as absolute reactivity measures (all rs greater than 0.75). Also, subjective stress responses were highly correlated, when considering both levels during stress and reactivity (r = 0.97 and r = 0.85, respectively). Stress levels of catecholamines were correlated, but the change scores (reactivity) were unrelated. 3. The measurement error SD for heart rate was 2.6 and 3.0 beats/min for reactivity and stress levels, respectively. The corresponding SD for blood pressure ranged between 2.7 and 4.4 mmHg. Subjective stress experience showed an SD of a similar magnitude. The responses of plasma catecholamine concentrations were subject to considerable variability. 4. It is concluded that haemodynamic and subjective stress responses and stress levels during the mental arithmetic stress test show acceptable reproducibility and high test-retest correlations. However, stress-induced changes in venous plasma catecholamine concentrations show low reproducibility.
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| 11. |
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| 12. |
- Ladenvall, Per, 1972, et al.
(author)
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Tissue-type plasminogen activator -7,351C/T enhancer polymorphism is associated with a first myocardial infarction.
- 2002
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In: Thrombosis and haemostasis. - 0340-6245. ; 87:1, s. 105-9
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Journal article (peer-reviewed)abstract
- We recently identified a polymorphic Sp1 binding site in an enhancer at the tissue-type plasminogen activator (tPA) locus (tPA -7,351C/T), which was associated with vascular tPA release. Subjects homozygous for the -7,351C allele had twice the tPA release rate compared to subjects carrying the -7,351T allele. In this study we tested the hypothesis that the tPA -7,351C/T polymorphism is associated with myocardial infarction (MI). In a population-based prospective nested case-control study within northern Sweden, genotypes were determined among 61 MI cases and 120 controls. In a multivariate model, the tPA -7,351C/T polymorphism (OR 2.68 for T allele carriers; 95% CI 1.31-5.50), tPA antigen (OR 1.16; 95% CI 1.07-1.25) and apo A-I (OR, 0.997; 95% CI 0.995-0.999) were independently associated with a first MI. These findings suggest that genetic markers of local tPA release and circulating steady-state tPA levels carry independent prognostic information.
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| 13. |
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| 14. |
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| 15. |
- Novak, Masuma, 1969, et al.
(author)
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Occupational status and incidences of ischemic and hemorrhagic stroke in Swedish men: a population-based 35-year prospective follow-up study
- 2013
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In: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 28:8, s. 697-704
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Journal article (peer-reviewed)abstract
- This study examined variations in stroke incidence across occupational classes over a 35-year follow-up period. We analyzed a random population-based sample of 6,994 men aged 47-56 years at baseline without prior history of stroke. Standardized incidence rates, subdistribution hazard ratios (SHRs) from competing risk regressions and cumulative incidence were calculated, after accounting for risk of death attributed to causes other than stroke. A total of 1,442 strokes were identified over the 35-year period with crude incidences of 5.50 (ischemic) and 1.16 (hemorrhagic) per 1,000 person-years. In the whole group, occupational class was not associated with either ischemic or hemorrhagic stroke. However, older men (>/=51 years at baseline) with unskilled manual occupations had a significantly lower risk of ischemic stroke than those with high officials (referent). No association between occupation and stroke of either type was detected for men younger than 51 years. There was an inverse and graded risk of death from causes other than stroke; men in high official positions had the lowest cumulative risk and unskilled manual workers had the highest risk (P < 0.0001). The association between occupation and ischemic stroke in older men persisted after accounting for competing risks of death (SHR 0.62; 95 % CI 0.46-0.84). In conclusion, low socioeconomic status was not associated with an increased risk of incident hemorrhagic or ischemic stroke. Older men with the lowest occupational status i.e. unskilled manual had a significantly lower risk of ischemic stroke, even after controlling for other risk factors and competing risks of death.
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| 16. |
- Olsson, Sandra, 1976, et al.
(author)
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Lack of association between genetic variations in the KALRN region and ischemic stroke
- 2011
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In: Clinical Biochemistry. - : Elsevier BV. - 1873-2933 .- 0009-9120. ; 44:12, s. 1018-1020
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Journal article (peer-reviewed)abstract
- Objectives: To investigate whether KALRN gene variation is associated with ischemic stroke (IS). Design and methods: Associations to overall IS and IS subtypes were investigated in SAHLSIS, which comprises 844 patients with IS and 668 controls. Results: Associations between KALRN SNPs and overall IS and cardioembolic stroke were detected. Associations for overall IS were investigated in two additional Swedish samples, but could not be replicated. Conclusion: KALRN gene variation is not associated with overall IS. (C) 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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| 17. |
- Redfors, Petra, et al.
(author)
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Living alone predicts mortality in patients with ischemic stroke before 70 years of age: a long-term prospective follow-up study
- 2016
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In: BMC neurology. - : Springer Science and Business Media LLC. - 1471-2377 .- 1471-2377. ; 16
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Living alone is associated with increased mortality after myocardial infarction but little data is available about whether this applies to prognosis after stroke. We aimed to examine the association between living situation and long-term mortality in patients with ischemic stroke and a control group, and to explore whether this association is modified by patient gender. METHODS: This is a prospective case-control study of 600 patients with ischemic stroke before 70 years of age and 600 age- and sex-matched controls who have been included in the Sahlgrenska Study on Ischemic Stroke. Mortality data were collected through national registers and medical records. We used Cox regression models for identifying predictors of mortality. RESULTS: In the entire sample, mean age was 57 years, proportion of males 64 %, proportion living alone 28 %, and median follow-up 8.6 years. Mortality rates were 36 % among patients living alone, 17 % among cohabitant patients, 15 % among controls living alone, and 9 % among cohabitant controls. Living alone was an independent predictor of all-cause mortality in cases after adjustment for stroke severity, stroke subtype, and vascular risk factors including physical activity, alcohol consumption, and socioeconomic status. A significant interaction was found between gender and living situation; the adjusted hazard ratio for mortality was 3.47 (95 % Confidence Interval 2.13-5.65) in male patients living alone, whereas no significant association was observed in women. Living alone was also a predictor of vascular mortality among cases and of all-cause mortality among controls. CONCLUSIONS: Living alone is associated with increased long-term mortality after ischemic stroke in men. Further prospective studies are needed to confirm the observed gender difference and to identify modifiable factors underlying this increased risk.
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| 18. |
- Rosengren, Annika, 1951, et al.
(author)
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Twenty-Four-Year Trends in the Incidence of Ischemic Stroke in Sweden From 1987 to 2010
- 2013
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In: Stroke. - 0039-2499. ; 44:9, s. 2388-93
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: The incidence of stroke in Sweden increased between 1989 and 2000 among people aged 65 years are lacking. METHODS: Through the Swedish Hospital Discharge and Cause of Death registries, we identified all cases of nonfatal and fatal ischemic stroke (IS) among people aged 18 to 84 years during 1987-2010 in Sweden. RESULTS: Of the 391 081 stroke cases identified, 1.6% were 18 to 44 years, 16.7% were 45 to 64 years, and 81.7% were 65 to 84 years. Among people aged 18 to 44 years, there was a continuous increase in the incidence of stroke of 1.3% (95% confidence interval, 0.8%-1.8%) per year for men and 1.6% (1.0%-2.3%) per year for women. Among men and women aged 45 to 64 years, slightly declining rates were observed from the late 1990s, with a mean annual decrease of 0.4% (0.1%-0.7%) among men and 0.6% (0.2%-1.0%) among women. Among men aged 65 to 84 years, a decrease of 3.7% in IS (3.4%-4.0%) per year was observed from the late 1990s. This was more marked in women, where an initial decrease of 2.5% (2.1%-2.9%) per year was followed by an accelerated decrease of 5.1% (4.4%-5.8%) after 2005. Mortality from IS decreased markedly in all age groups.Conclusions-The incidenceof IS in elderly people in Sweden is now decreasing, whereas the decline in IS incidence in the middle-aged people is much less steep. The increasing incidence of stroke in the young, particularly if carried forward to an older age, is concerning.
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| 19. |
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| 20. |
- Tjärnlund-Wolf, Anna, 1974, et al.
(author)
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Species-Specific Regulation of t-PA and PAI-1 Gene Expression in Human and Rat Astrocytes
- 2014
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In: Gene Regulation and Systems Biology. - 1177-6250. ; 8, s. 113-118
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Journal article (peer-reviewed)abstract
- In recent years, the role and physiological regulation of the serine protease tissue-type plasminogen activator (t-PA) and its inhibitors, including plasminogen activator inhibitor type-1 (PAI-1), in the brain have received much attention. However, as studies focusing these issues are difficult to perform in humans, a great majority of the studies conducted to date have utilized rodent in vivo and/or in vitro models. In view of the species-specific structural differences present in both the t-PA and the PAI-1 promoters, we have compared the response of these genes in astrocytes of rat and human origin. We reveal marked quantitative and qualitative species-specific differences in gene induction following treatment with various physiological and pathological stimuli. Thus, our findings are of importance for the interpretation of previous and future results related to t-PA and PAI-1 expression.
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| 21. |
- Åberg, Daniel, 1973, et al.
(author)
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Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke.
- 2011
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96:7
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Journal article (peer-reviewed)abstract
- GH has positive cognitive effects when given to GH-IGF-I-deficient patients. GH and IGF-I exert both neuroprotective and regenerative effects on experimental stroke. We investigated whether the endogenous serum IGF-I (s-IGF-I) levels correlated with recovery of functional independence in patients who had suffered an ischemic stroke.
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| 22. |
- Åberg, N David, 1970, et al.
(author)
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Altered levels of circulating insulin-like growth factor I (IGF-I) following ischemic stroke are associated with outcome - a prospective observational study
- 2018
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In: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: Insulin-like growth factor I (IGF-I) has neuroprotective effects in experimental ischemic stroke (IS). However, in patients who have suffered IS, various associations between the levels of serum IGF-I (s-IGF-I) and clinical outcome have been reported, probably reflecting differences in sampling time-points and follow-up periods. Since changes in the levels of post-stroke s-IGF-I have not been extensively explored, we investigated whether decreases in the levels of s-IGF-I between the acute time-point (median, 4 days) and 3 months (Delta IGF-I, further transformed into Delta IGF-I-quintiles, Delta IGF-I-q) are associated with IS severity and outcome. Methods: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) conducted in Gothenburg, Sweden, patients with IS who had s-IGF-I measurements available were included (N = 354; 65% males; mean age, 55 years). Baseline stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) and converted into NIHSS-quintiles (NIHSS-q). Outcomes were assessed using the modified Rankin Scale (mRS) at 3 months and 2 years. Results: In general, the levels of s-IGF-I decreased (positive Delta IGF-I), except for those patients with the most severe NIHSS-q. After correction for sex and age, the 3rd Delta IGF-I-q showed the strongest association to mRS 0-2 [Odds Ratio (OR) 5.11, 95% confidence interval (CI) 2.18-11.9], and after 2 years, the 5th Delta IGF-I-q (OR 3.63, 95% CI 1.40-9.38) showed the strongest association to mRS 0-2. The associations remained significant after multivariate correction for diabetes, smoking, hypertension, and hyperlipidemia after 3 months, but were not significant (p = 0.057) after 2 years. The 3-month associations withstood additional correction for baseline stroke severity (p = 0.035), whereas the 2-year associations were further attenuated (p = 031). Conclusions: Changes in the levels of s-IGF-I are associated primarily with temporally near 3-month outcomes, while associations with long-term 2-year outcomes are weakened and attenuated by other factors. The significance of the change in post-stroke s-IGF-I is compatible with a positive role for IGF-I in IS recovery. However, the exact mechanisms are unknown and probably reflects combinations of multiple peripheral and central actions.
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| 23. |
- Åberg, N David, 1970, et al.
(author)
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Association Between Levels of Serum Insulin-like Growth Factor I and Functional Recovery, Mortality, and Recurrent Stroke at a 7-year Follow-up.
- 2020
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In: Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. - : Georg Thieme Verlag KG. - 1439-3646. ; 128:5, s. 303-310
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Journal article (peer-reviewed)abstract
- The association of serum insulin-like growth factor I (s-IGF-I) with favorable outcome after ischemic stroke (IS) beyond 2 years is unknown. We investigated whether the levels of s-IGF-I 3 months post-stroke were associated with functional recovery up to 7 years after IS, considering also mortality and recurrent strokes.Patients (N=324; 65% males; mean age, 55 years) with s-IGF-I levels assessed 3 months after the index IS were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The modified Rankin Scale (mRS) was used to evaluate outcomes at 3 months, 2 and 7 years after IS, and recovery was defined as an improvement, no change, or deterioration in the shifts of mRS score. Baseline stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS).The mRS score distributions were better in the above-median s-IGF-I group (>146.7ng/ml). The s-IGF-I level was not associated with recurrent stroke (N=79) or death (N=44), although it correlated with recovery (r=0.12, P=0.035). In the regression analysis, s-IGF-I associated with recovery between 3 months and 7 years (but not between 2 and 7 years). The associations did not withstand adjustment for age and sex. For comparison, the corresponding associations between 3 months and 2 years withstood all adjustments.The association for s-IGF-I with long-term post-stroke recovery persists after 7 years, which is also reflected in the mRS score distributions at all time-points. The effects are however modest, and not driven by mortality or recurrent stroke.
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| 24. |
- Åberg, N David, 1970, et al.
(author)
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Genetic variation at the IGF1 locus shows association with post-stroke outcome and to circulating IGF1.
- 2013
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In: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X. ; 169:6, s. 759-65
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Journal article (peer-reviewed)abstract
- In humans, serum IGF1 (s-IGF1) is associated with outcome after ischemic stroke (IS). Therefore variation at the IGF1 locus could also associate with both IS and s-IGF1. We investigated whether genetic variation at the IGF1 locus is associated with i) s-IGF1, ii) IS occurrence, iii) IS severity, and iv) post-stroke outcome.
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| 25. |
- Österlund, Barbro, et al.
(author)
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Impaired myocardial t-PA release in patients with coronary artery disease
- 2008
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In: Acta Anaesthesiol Scand. - : Wiley. - 1399-6576. ; 52:10, s. 1375-84
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Journal article (peer-reviewed)abstract
- AIMS: Myocardial ischemia remains a significant perioperative complication in coronary artery disease (CAD) patients. We hypothesized that noxious stimuli during major surgery are associated with an acute release of tissue-type plasminogen activator (t-PA) into the coronary circulation, and that this response is reduced by CAD. METHODS AND RESULTS: Two patient groups, with (n=14) and without (n=8) CAD, were studied during the initial phase of heart surgery. After retrograde great cardiac vein catheterizations during closed-chest conditions, coronary arterial-venous concentration gradients of t-PA and plasminogen activator inhibitor type-1 (PAI-1) were measured together with coronary blood flow measurements, allowing derivation of coronary net release rates. Pre-surgery atrial pacing, performed to evaluate the influence of increases in heart rate (+ 40 beats/min) and coronary blood flow (+ 80 ml/min), did not significantly alter coronary net release of t-PA or PAI-1 in either patient group. Sternotomy induced a prominent increase in coronary net release of both total and active t-PA in the non-CAD group. This response was considerably reduced in the CAD group. CONCLUSIONS: This study provides the first analysis of coronary t-PA release during major surgery and demonstrates a deficient local endothelial t-PA release in patients with CAD. This suggests a reduced local fibrinolytic capacity in CAD patients, which may explain the increased risk for coronary thrombosis in this patient group.
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