| 1. |
- Darreh-Shori, Taher, et al.
(author)
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Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
- 2013
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:11, s. 2465-2481
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Journal article (peer-reviewed)abstract
- Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.
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| 2. |
- Lindblom, Rickard P F, et al.
(author)
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Even small aneurysms can bleed : a ruptured small idiopathic aneurysm of the internal thoracic artery
- 2013
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In: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9293 .- 1569-9285. ; 17:3, s. 583-585
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Journal article (peer-reviewed)abstract
- Internal thoracic artery (ITA) aneurysms are rare, but a rupture is potentially fatal. Most cases of ITA aneurysms are iatrogenic, caused by, for instance, previous sternotomy or pacemaker implantation. Other known aetiologies are vasculopathies, either of inflammatory origin or as part of connective tissue disorders like Marfan's syndrome, Ehler-Dahnlos syndrome or neurofibromatosis Type 1. Idiopathic ITA aneurysms are exceedingly scarce. The present case illustrates an unusual scenario, which posed diagnostic challenges, where spontaneous rupture of an idiopathic or possibly very late post-traumatic aneurysm of the left ITA led to a life-threatening bleeding, successfully treated by endovascular coiling with standby preparation for conversion to open surgery. This case demonstrates the importance of the careful interpretation of radiological findings and the significance of multidisciplinary collaboration between radiologist and clinician.
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| 3. |
- Aeinehband, Shahin, et al.
(author)
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Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Journal article (peer-reviewed)abstract
- Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.
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| 4. |
- Dominguez, Cecilia A, et al.
(author)
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Variability in C-type lectin receptors regulates neuropathic pain-like behavior after peripheral nerve injury
- 2014
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In: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 10
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Neuropathic pain is believed to be influenced in part by inflammatory processes. In this study we examined the effect of variability in the C-type lectin gene cluster (Aplec) on the development of neuropathic pain-like behavior after ligation of the L5 spinal nerve in the inbred DA and the congenic Aplec strains, which carries seven C-type lectin genes originating from the PVG strain.RESULTS: While both strains displayed neuropathic pain behavior early after injury, the Aplec strain remained sensitive throughout the whole study period. Analyses of several mRNA transcripts revealed that the expression of Interleukin-1β, Substance P and Cathepsin S were more up-regulated in the dorsal part of the spinal cord of Aplec rats compared to DA, indicating a stronger inflammatory response. This notion was supported by flow cytometric analysis revealing increased infiltration of activated macrophages into the spinal cord. In addition, macrophages from the Aplec strain stimulated in vitro displayed higher expression of inflammatory cytokines compared to DA cells. Finally, we bred a recombinant congenic strain (R11R6) comprising only four of the seven Aplec genes, which displayed similar clinical and immune phenotypes as the Aplec strain.CONCLUSION: We here for the first time demonstrate that C-type lectins, a family of innate immune receptors with largely unknown functions in the nervous system, are involved in regulation of inflammation and development of neuropathic pain behavior after nerve injury. Further experimental and clinical studies are needed to dissect the underlying mechanisms more in detail as well as any possible relevance for human conditions.
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| 5. |
- Janiec, Mikael, et al.
(author)
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Graft failure and recurrence of symptoms after coronary artery bypass grafting
- 2018
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In: Scandinavian Cardiovascular Journal. - : TAYLOR & FRANCIS LTD. - 1401-7431 .- 1651-2006. ; 52:3, s. 113-119
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Journal article (peer-reviewed)abstract
- Objectives: Saphenous vein grafts (SVGs) most often used in coronary artery bypass grafting (CABG) are subject to graft disease and have poor long-term patency, however the clinical implication of this is not completely known. We aim to assess the influence of graft failure on the postoperative recurrence of coronary artery disease (CAD) symptoms in relation to the contribution from progression of atherosclerosis in the native coronary vessels.Design: Within the SWEDEHEART registry we identified 46,663 CABG cases between 2001 and 2015 with patient age 40-80 years where single internal mammary artery (IMA) anastomosis (IMA), single IMA with one (1SVG) or multiple SVG anastomoses (2+ SVG) had been performed. Clinical characteristics as well as mortality and postoperative incidence of coronary angiography were recorded and multivariable adjusted hazard ratios were calculated. Indications for the angiographies and occurrence of graft failure were also registered.Results: The adjusted hazard ratio for death was similar for the three groups. The adjusted hazard ratio for being submitted to angiography as compared to 2+ SVG was (95% CI) 1.24 (1.06-1.46) for IMA and 1.21 (1.15-1.28) for 1SVG. Failed grafts were found at the first postoperative angiography with preceding CAD symptoms in 21.4% of patients in the IMA group, 41.6% in the 1SVG group and 61.1% in the 2+ SVG group.Conclusions: A substantial amount of angiographies occur in patients without any graft failure and a large part of postoperative recurrence of CAD symptoms and are likely attributed to IMA failure or progression of atherosclerosis in the native coronary arteries.
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| 6. |
- Janiec, Mikael, et al.
(author)
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No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit : a Swedish nationwide registry study
- 2018
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In: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 53:2, s. 448-454
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Coronary artery bypass grafting using saphenous vein grafts (SVGs) in addition to the left internal mammary artery (IMA) graft is vitiated by poor long-term patency of the vein grafts. Hypothetically, the increased use of arterial grafts could confer even better outcomes. Our goal was to evaluate results after coronary artery bypass grafting in Sweden, where arterial grafts were used as a second conduit.METHODS: Within the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we identified patients who had coronary artery bypass grafting from 2001 to 2015 using the IMA and the SVG, the radial artery (RA) or the additional IMA [bilateral IMA (BIMA)] as a second conduit. Deaths, postoperative incidence of coronary angiography and need for reintervention were recorded, and multivariable adjusted hazard ratios were calculated for different types of grafts.RESULTS: The study population comprised 45 319 cases of IMA + SVG, 1225 cases of IMA + RA and 1697 cases of BIMA. The mean follow-up time (SD) was 9.2 (4.2) years for IMA + SVG, 11.2 (4.0) years for IMA + RA grafts and 9.2 (5.2) years for the BIMA graft. The adjusted hazard ratio for death was (95% confidence interval) 1.06 (0.95-1.18) for IMA + RA and 1.21 (1.10-1.33) for BIMA grafts compared with IMA + SVG. The adjusted hazard ratio for the first angiographic examination was (95% confidence interval) 0.89 (0.78-1.01) for IMA + RA and 1.07 (0.96-1.20) for BIMA grafts. The adjusted hazard ratio for the need for reintervention was (95% confidence interval) 0.88 (0.74-1.04) for IMA + RA and 1.14 (0.98-1.32) for BIMA grafts.CONCLUSIONS: Patients who had arterial grafts as second conduits did not demonstrate a better outcome in any of the studied end-points. Radial artery grafts seem to be preferable to BIMA grafts as an alternative to an SVG.
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| 7. |
- Lindblom, Rickard P. F., et al.
(author)
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Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response
- 2015
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 12
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Journal article (peer-reviewed)abstract
- Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.
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| 8. |
- Lindblom, Rickard P. F., et al.
(author)
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Dissecting ventricular pseudoaneurysm after perimyocarditis : a case report
- 2015
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In: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 10
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Journal article (peer-reviewed)abstract
- Background: The current case describes the fast development of a pseudoaneurysm in a patient that presented with signs of systemic inflammation and generally deranged blood work. Case Presentation: The pseudoaneurysm appeared within one week of disease onset. The anatomic extent of the pseudoaneurysm was unusual, as it dissected intramurally beneath the septum, inferior to the right ventricle and had effect on the RV filling. The etiology could not be definitely defined, since in adults the most common cause for pseudoaneurysm development is recent myocardial infarction, but in this patient the coronary arteries were healthy. Instead it could have been a consequence of an aggressive perimyocarditis. Conclusions: Due to the unpredictable nature of pseudoaneurysms we advocate early contact with a center with cardiothoracic surgery expertise for rapid surgical intervention.
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| 9. |
- Lindblom, Rickard P F, et al.
(author)
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Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.
- 2013
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 10
-
Journal article (peer-reviewed)abstract
- BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection.METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains.RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury.CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.
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| 10. |
- Lindblom, Rickard P F, 1981-, et al.
(author)
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Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest
- 2018
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In: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 27:5, s. 1200-1211
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Journal article (peer-reviewed)abstract
- Background: Survivors of cardiac arrest often experience neurologic deficits. To date, treatment options are limited. Associated hyperglycemia is believed to further worsen the neurologic outcome. The aim with this study was to characterize expression pathways induced by hyperglycemia in conjunction with global brain ischemia.Methods: Pigs were randomized to high or normal glucose levels, as regulated by glucose and insulin infusions with target levels of 8.5-10 mM and 4-5.5 mM, respectively. The animals were subjected to 5-minute cardiac arrest followed by 8 minutes of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. Global expression profiling of the cortex using microarrays was performed in both groups.Results: A total of 102 genes differed in expression at P<.001 between the hyperglycemic and the normoglycemic pigs. Several of the most strongly differentially regulated genes were involved in transport and metabolism of glucose. Functional clustering using bioinformatics tools revealed enrichment of multiple biological processes, including membrane processes, ion transport, and glycoproteins.Conclusions: Hyperglycemia during cardiac arrest leads to differential early gene expression compared with normoglycemia. The functional relevance of these expressional changes cannot be deduced from the current study; however, the identified candidates have been linked to neuroprotective mechanisms and constitute interesting targets for further studies.
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| 11. |
- Lindblom, Rickard P F
(author)
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Impact of genetic variability on early immune reactions following nerve injury
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- Injury to the central nervous system (CNS) is frequently associated with significant morbidity, in worst case mortality. This in turn leads to considerable disease burden for the individual and also for society. The spectrum of conditions that cause damage to the CNS is wide and highly diverse, ranging from acute trauma to degenerative diseases that progress over decades. But in spite of the heterogeneity, there exist common aspects. For instance, there is often interplay between the immune and nervous systems in one stage or another of disease. Also, the genetic background of the individual influences both susceptibility to and severity of the disease. This thesis focuses on the early immune reactions that occur after CNS injury in rodents, based on the hypothesis that early immune reactions affect important downstream events, not least nerve cell death. In study I a large rat experimental cross F2(DAxPVG) was created from the inbred strains DA and PVG. The global transcriptome in the spinal cord was screened using microarrays five days after ventral root avulsion (VRA), a reproducible nerve injury model. In parallel, whole genome mapping was performed. The expression and genetic data was co-analyzed to identify gene regions regulating components of the complement system, in turn associated with loss of synapses. Lastly, we identified a link between the cholinergic and complement systems, which was confirmed in vitro. In study II, data from the F2(DAxPVG) cross was used to analyze regulation of complement receptors following injury. We found a strong cis-regulatory influence acting on the expression of complement receptor 2 (CR2), a receptor mostly associated with B cell functions, but with unknown role in the adult CNS. CR2 was up regulated on astrocytes and protected from injury induced synapse loss in rodents. Levels of CR2 were increased in the cerebrospinal fluid (CSF) of rats following injury, but also in the CSF of patients with multiple sclerosis as compared to controls, implicating a possible role for CR2 also in context of human disease. Traumatic brain injury (TBI) is one of the leading causes of death in the young population. Secondary events following initial injury contribute to the damage, but are not fully understood. In study III TBI was performed on DA and PVG rats and the ensuing injury processes analyzed at both the molecular and cellular levels using microarrays and flow cytometry. Large strain differences in complement activation and the size and composition of multiple immune cell populations were found. Complement was also found to label axons of injured neurons and the degree of complement expression correlated with the levels of neurofilament-light in CSF, a marker of axonal injury. C-type lectins (CLECs) are a group of immune molecules structurally similar to members of the complement family. Study I demonstrated several loci co-regulating the expression of complement and CLEC transcripts, thus providing a link between the two families. In study IV we examined the properties of a congenic rat strain, Aplec, which onto DA background has a very small genomic insert from PVG consisting of 7 CLEC genes. The Aplec rat displayed improved survival of motor neurons following VRA compared to DA, which in turn was associated with increased infiltration of T cells. This demonstrates that CLECs convey neuroprotection after nerve root injury, potentially through T cell pathways. These results provide insights into the molecular pathways regulating inflammation after mechanical nerve injuries, in turn of relevance for nerve injury-induced synaptic remodeling and neurodegeneration.
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| 12. |
- Lindblom, Rickard P F, et al.
(author)
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Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia
- 2017
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In: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 51:4, s. 773-781
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Prolonged global cerebral ischaemia leads to irreversible injury, often with lethal outcome. Brain injuries are partly caused by the uncontrolled reperfusion that occurs once the circulation is re-established. Recent animal experiments suggest that controlled reperfusion following lengthy ischaemia might prevent severe brain injury. This study aimed at further exploring cerebral alterations and outcome following prolonged global cerebral ischaemia and mechanically manipulated reperfusion.METHODS: Three groups of pigs were included; one sham operated (n = 3) and two that underwent 30-min global cerebral ischaemia. All vessels that supply the brain were isolated intrathoracically, after which they were occluded for 30 min in the ischaemic groups. In one of the ischaemic groups uncontrolled reperfusion was applied (URep, n = 6), i.e. normal circulation was restored 30 min after arrested cerebral circulation. The second ischaemic group received mechanical reperfusion (MRep, n = 6) with leucocyte-filtered blood at constant flow and pressure for 20 min using extracorporeal circulation following the 30-min ischaemia, after which normal blood flow resumed. All animals were monitored for 3 h after start of uncontrolled reperfusion. Haemodynamic parameters, arterial and sagittal sinus blood gases, cerebral oxygen extraction rates and intraparenchymal biomarkers using microdialysis were measured. Brain histology was performed post-mortem.RESULTS: Global brain ischaemia led to the same extent of severe morphological changes at the level of light microscopy in the two ischaemic experimental groups, regardless of reperfusion protocol. Furthermore, no significant differences were found between the URep and MRep groups regarding cerebral blood gases or microdialysis biomarkers.CONCLUSIONS: Mechanical reperfusion following the current protocol does not modify brain alterations caused by 30 min of arrested cerebral circulation.
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| 13. |
- Lindblom, Rickard P F, et al.
(author)
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Outcomes following the implementation of a quality control campaign to decrease sternal wound infections after coronary artery by-pass grafting
- 2015
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In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261 .- 1471-2261. ; 15
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Journal article (peer-reviewed)abstract
- BACKGROUND: Coronary artery by-pass grafting (CABG) remains the optimal strategy in achieving complete revascularization in patients with complex coronary artery disease. However, sternal wound infections (SWI), especially deep SWI are potentially severe complications to the surgery. At the department of cardiothoracic surgery in Uppsala University Hospital a gradual increase in all types of SWI occurred, which peaked in 2009. This prompted an in-depth revision of the whole surgical process. To monitor the frequency of post-operative infections all patients receive a questionnaire that enquires whether any treatment for wound infection has been carried out.METHODS: All patients operated with isolated CABG between start of 2006 and end of 2012 were included in the study. 1515 of 1642 patients answered and returned the questionnaire (92.3 %). The study period is divided into the time before the intervention program was implemented (2006-early 2010) and the time after the intervention (early 2010- end 2012). To assess whether potential differences in frequency of SWI were a consequence of change in the characteristics of the patient population rather than an effect of the intervention a retrospective assessment of medical records was performed, where multiple of the most known risk factors for developing SWI were studied.RESULTS: We noticed a clear decrease in the frequency of SWI after the intervention. This was not a consequence of a healthier population.CONCLUSIONS: Our results from implementing the intervention program are positive in that they reduce the number of SWI. As several changes in the perioperative care were introduced simultaneously we cannot deduce which is the most effective.
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| 14. |
- Lindblom, Rickard P F, 1981-, et al.
(author)
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Protein Profiling in Serum and Cerebrospinal Fluid Following Complex Surgery on the Thoracic Aorta Identifies Biological Markers of Neurologic Injury.
- 2018
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In: Journal of Cardiovascular Translational Research. - : Springer Science and Business Media LLC. - 1937-5387 .- 1937-5395. ; 11:6, s. 503-516
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Journal article (peer-reviewed)abstract
- Surgery on the arch or descending aorta is associated with significant risk of neurological complications. As a consequence of intubation and sedation, early neurologic injury may remain unnoticed. Biomarkers to aid in the initial diagnostics could prove of great value as immediate intervention is critical. Twenty-three patients operated in the thoracic aorta with significant risk of perioperative neurological injury were included. Cerebrospinal fluid (CSF) and serum were obtained preoperatively and in the first and second postoperative days and assessed with a panel of 92 neurological-related proteins. Three patients suffered spinal cord injury (SCI), eight delirium, and nine hallucinations. There were markers in both serum and CSF that differed between the affected and non-affected patients (SCI; IL6, GFAP, CSPG4, delirium; TR4, EZH2, hallucinations; NF1). The study identifies markers in serum and CSF that reflect the occurrence of neurologic insults following aortic surgery, which may aid in the care of these patients.
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| 15. |
- Lindblom, Rickard P. F., et al.
(author)
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Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central nervous system
- 2014
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In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 192:3, s. 1138-1153
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Journal article (peer-reviewed)abstract
- The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA × PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.
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| 16. |
- Lundström, Yasmin, et al.
(author)
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Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time
- 2019
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In: Applied immunohistochemistry & molecular morphology (Print). - 1541-2016 .- 1533-4058. ; 27:3, s. 238-245
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Journal article (peer-reviewed)abstract
- In this study, we have systematically assessed the influence of postmortem delay (PMD) and fixation time (FT) on the immunohistochemical (IHC) staining outcome. The IHC method is frequently applied on surgical and postmortem samples in diagnostics and research. To replicate the routine situation, brain tissues from pigs were exposed to either storage in a refrigerator (+8°C), that is, PMD (1 to 168 h), or fixed in 10% buffered formalin, that is, FT (18 to 94 d). Subsequently, the tissue was routinely processed into paraffin blocks to enable construction of tissue microarrays (TMA). Sections cut from the TMA blocks were stained applying 13 different antibodies directed against neuronal and glial antigens. Immunoreactivity applying 5 antibodies was influenced by prolonged PMD and applying 2 antibodies by prolonged FT. None of the staining outcomes related to the PMD or FT were predictable. Loss of TMA cores during processing was primarily influenced by pretreatment and by tissue characteristics (gray/white matter). The test model described here confirmed that these 2 variables, PMD and FT, indeed influence the IHC outcome. The PMD and FT are particularly of importance while assessing tissue samples obtained at autopsy. The result above is also of importance while comparing the IHC outcomes seen in the postmortem setting (various PMD/FT) with surgical samples or with IHC outcome seen in experimental animal setting (controlled PMD/FT). Thus, we suggest that the test model described here is considered when assessing the reliability of the IHC outcome when analyzing tissues with various characteristics.
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| 17. |
- Lytsy, Birgitta, 1968-, et al.
(author)
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Hygienic interventions to decrease deep sternal wound infections following coronary artery bypass grafting
- 2015
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In: Journal of Hospital Infection. - : Elsevier BV. - 0195-6701 .- 1532-2939. ; 91:4, s. 326-331
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Journal article (peer-reviewed)abstract
- BACKGROUND: The department of Cardiothoracic Surgery at Uppsala University Hospital has 25 beds in one to four patient rooms and an operating suite consisting of five operating rooms with ultraclean air. Around 700 open heart (250 isolated coronary artery bypass grafting, CABG) operations are performed annually. In 2009, the numbers of deep sternal wound infections (DSWIs) increased to unacceptable rates despite existing hygienic guidelines.AIM: To show how root cause analysis (RCA) followed by quality improvement interventions reduced the rate of DSWI after CABG surgery.METHODS: Only isolated CABG patients requiring surgical revision due to DSWI were included. Swabs and tissue biopsies were taken during surgical revision and analysed with standard methods. DSWIs were registered prospectively according to US Centers for Disease Control and Prevention definitions. RCA for infection was performed between September 2009 and April 2010. Interventions based on results of the RCA and on nationally recommended practices were concluded in April 2010, and thought to have taken full effect by July 1st, 2010. Air was actively sampled at ≤0.5m from the sternal incision.FINDINGS: DSWI incidence rates per CABG operations decreased from 5.1% pre intervention to 0.9% post intervention. Wound cultures pre intervention grew Staphylococcus aureus 27.1% and coagulase negative staphylococcus (CoNS) 47.1%, post intervention S. aureus 23.1% and CoNS 30.8%. Air counts did not exceed 5cfu/m(3).CONCLUSION: When the aetiology of an error is multifactorial, RCA engaging both the medical professions and the infection control team is a potential tool to map causes leading to adverse events such as healthcare-associated infections. A systematic quality improvement intervention based on the RCA may reduce the number of deep sternal wound infections after CABG surgery.
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| 18. |
- Tovedal, Thomas, et al.
(author)
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Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion
- 2017
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In: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 103:2, s. 610-616
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Journal article (peer-reviewed)abstract
- BACKGROUND: Perfusion strategies during aortic surgery usually comprise hypothermic circulatory arrest (HCA), often combined with selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion. Cerebral blood flow (CBF) is a fundamental parameter for which the optimal level has not been clearly defined. We sought to determine the CBF at a pump flow level of 6 mL/kg/min, previously shown likely to provide adequate SACP at 20°C in pigs.METHODS: Repeated positron emission tomography (PET) scans were used to quantify the CBF and glucose metabolism throughout HCA and SACP including cooling and rewarming. Eight pigs on cardiopulmonary bypass were assigned to either HCA alone (n = 4) or HCA+SACP (n = 4). The CBF was measured by repeated [(15)O]water PET scans from baseline to rewarming. The cerebral glucose metabolism was examined by [(18)F]fluorodeoxyglucose PET scans after rewarming to 37°C.RESULTS: Cooling to 20°C decreased the cortical CBF from 0.31 ± 0.06 at baseline to 0.10 ± 0.02 mL/cm(3)/min (p = 0.008). The CBF was maintained stable by SACP of 6 mL/kg/min during 45 minutes. After rewarming to 37°C, the mean CBF increased to 0.24 ± 0.07 mL/cm(3)/min, without significant differences between the groups at any time-point exclusive of the HCA period. The net cortical uptake (Ki) of [(18)F]fluorodeoxyglucose after rewarming showed no significant difference between the groups.CONCLUSIONS: Cooling autoregulated the CBF to 0.10 mL/cm(3)/min, and 45 minutes of SACP at 6 mL/kg/min maintained the CBF in the present model. Cerebral glucose metabolism after rewarming was similar in the study groups.
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- Vijayaraghavan, Swetha, et al.
(author)
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Regulated Extracellular Choline Acetyltransferase Activity : The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Journal article (peer-reviewed)abstract
- Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.
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