| 1. |
- Darreh-Shori, Taher, et al.
(författare)
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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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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:11, s. 2465-2481
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Even small aneurysms can bleed : a ruptured small idiopathic aneurysm of the internal thoracic artery
- 2013
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Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9293 .- 1569-9285. ; 17:3, s. 583-585
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Variability in C-type lectin receptors regulates neuropathic pain-like behavior after peripheral nerve injury
- 2014
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 10
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Graft failure and recurrence of symptoms after coronary artery bypass grafting
- 2018
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Ingår i: Scandinavian Cardiovascular Journal. - : TAYLOR & FRANCIS LTD. - 1401-7431 .- 1651-2006. ; 52:3, s. 113-119
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 53:2, s. 448-454
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094 .- 1742-2094. ; 12
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Dissecting ventricular pseudoaneurysm after perimyocarditis : a case report
- 2015
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Ingår i: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 10
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094 .- 1742-2094. ; 10
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest
- 2018
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 27:5, s. 1200-1211
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Tidskriftsartikel (refereegranskat)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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