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Lundström, Y., Lundström, P., Popova, S., Lindblom, R. P. .. & Alafuzoff, I. (2019). Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time. Applied immunohistochemistry & molecular morphology (Print), 27(3), 238-245
Open this publication in new window or tab >>Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time
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2019 (English)In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 27, no 3, p. 238-245Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
immunohistochemistry, tissue microarray, fixation time, postmortem delay
National Category
Other Basic Medicine Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-369701 (URN)10.1097/PAI.0000000000000658 (DOI)000462177700013 ()29912765 (PubMedID)
Funder
Hans-Gabriel och Alice Trolle-Wachtmeisters stiftelse för medicinsk forskning
Available from: 2018-12-16 Created: 2018-12-16 Last updated: 2019-04-24Bibliographically approved
Janiec, M., Dimberg, A., Nazari Shafti, T. Z., Lagerqvist, B. & Lindblom, R. P. (2018). Erratum to: "No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit. European Journal of Cardio-Thoracic Surgery, 53(5), Article ID 1098.
Open this publication in new window or tab >>Erratum to: "No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit
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2018 (English)In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 53, no 5, article id 1098Article in journal (Refereed) Published
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-369716 (URN)10.1093/ejcts/ezy123 (DOI)29534169 (PubMedID)
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-01-30Bibliographically approved
Janiec, M., Shafti, T. Z. N., Dimberg, A., Lagerqvist, B. & Lindblom, R. P. (2018). Graft failure and recurrence of symptoms after coronary artery bypass grafting. Scandinavian Cardiovascular Journal, 52(3), 113-119
Open this publication in new window or tab >>Graft failure and recurrence of symptoms after coronary artery bypass grafting
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2018 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, no 3, p. 113-119Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Coronary artery bypass grafting, graft failure, registry study
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-356335 (URN)10.1080/14017431.2018.1442930 (DOI)000432282000002 ()29508655 (PubMedID)
Available from: 2018-07-26 Created: 2018-07-26 Last updated: 2019-09-01Bibliographically approved
Lindblom, R. P., Molnar, M., Israelsson, C., Röjsäter, B., Wiklund, L. & Lennmyr, F. (2018). Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest. Journal of Stroke & Cerebrovascular Diseases, 27(5), 1200-1211
Open this publication in new window or tab >>Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest
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2018 (English)In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 27, no 5, p. 1200-1211Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Cerebral, ischemia-reperfusion, gene expression, glucose, hyperglycemia, microarray, pigs
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-351620 (URN)10.1016/j.jstrokecerebrovasdis.2017.11.036 (DOI)000428778400016 ()29306595 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-06-13Bibliographically approved
Janiec, M., Dimberg, A., Nazari Shafti, T. Z., Lagerqvist, B. & Lindblom, R. P. .. (2018). No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit: a Swedish nationwide registry study. European Journal of Cardio-Thoracic Surgery, 53(2), 448-454
Open this publication in new window or tab >>No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit: a Swedish nationwide registry study
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2018 (English)In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 53, no 2, p. 448-454Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
BIMA, Coronary artery bypass grafting (CABG), Radial artery, Registry study
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342951 (URN)10.1093/ejcts/ezx280 (DOI)000424256500023 ()28958083 (PubMedID)
Note

Correction in: European Journal of Cardio-Thoracic Surgery, Volume: 53, Issue: 5, Pages: 1098-1098, DOI: 10.1093/ejcts/ezy123

Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2019-09-01Bibliographically approved
Lindblom, R. P., Shen, Q., Axén, S., Landegren, U., Kamali-Moghaddam, M. & Thelin, S. (2018). Protein Profiling in Serum and Cerebrospinal Fluid Following Complex Surgery on the Thoracic Aorta Identifies Biological Markers of Neurologic Injury.. Journal of Cardiovascular Translational Research, 11(6), 503-516
Open this publication in new window or tab >>Protein Profiling in Serum and Cerebrospinal Fluid Following Complex Surgery on the Thoracic Aorta Identifies Biological Markers of Neurologic Injury.
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2018 (English)In: Journal of Cardiovascular Translational Research, ISSN 1937-5387, E-ISSN 1937-5395, Vol. 11, no 6, p. 503-516Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Biomarkers, Cardiovascular surgery, Neurologic injury, Thoracic aortic disease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-369702 (URN)10.1007/s12265-018-9835-8 (DOI)000453355000007 ()30367354 (PubMedID)
Available from: 2018-12-16 Created: 2018-12-16 Last updated: 2019-01-15Bibliographically approved
Tovedal, T., Lubberink, M., Morell, A., Estrada, S., Golla, S. S., Myrdal, G., . . . Lennmyr, F. (2017). Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion. Annals of Thoracic Surgery, 103(2), 610-616
Open this publication in new window or tab >>Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion
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2017 (English)In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 103, no 2, p. 610-616Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-302609 (URN)10.1016/j.athoracsur.2016.06.029 (DOI)000397165400067 ()27592601 (PubMedID)
Available from: 2016-09-07 Created: 2016-09-07 Last updated: 2018-09-03Bibliographically approved
Lindblom, R. P., Tovedal, T., Norlin, B., Hillered, L., Popova, S., Alafuzoff, I. & Thelin, S. (2017). Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia. European Journal of Cardio-Thoracic Surgery, 51(4), 773-781
Open this publication in new window or tab >>Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia
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2017 (English)In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 51, no 4, p. 773-781Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-315862 (URN)10.1093/ejcts/ezw367 (DOI)000398558800026 ()28007877 (PubMedID)
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-01-13Bibliographically approved
Lindblom, R., Aeinehband, S., Ström, M., Al Nimer, F., Sandholm, K., Khademi, M., . . . Ekdahl Nilsson, K. (2016). Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function. Clinical Immunology, 166, 89-95
Open this publication in new window or tab >>Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function
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2016 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 166, p. 89-95Article in journal (Refereed) Published
Abstract [en]

Besides its vital role in immunity, the complement system also contributes to the shaping of the synaptic circuitry of the brain. We recently described that soluble Complement Receptor 2 (sCR2) is part of the nerve injury response in rodents. We here study CR2 in context of multiple sclerosis (MS) and explore the molecular effects of CR2 on 0 activation. Significant increases in sCR2 levels were evident in cerebrospinal fluid (CSF) from both patients with relapsing remitting MS (n = 33; 6.2 ng/mL) and secondary-progressive MS (n = 9; 7.0 ng/mL) as compared to controls (n = 18; 4.1 ng/mL). Furthermore, CSF sCR2 levels correlated significantly both with CSF C3 and C1q as well as to a disease severity measure. In vitro, sCR2 inhibited the cleavage and down regulation of Cab to iC3b, suggesting that it exerts a modulatory role in complement activation downstream of C3. These results propose a novel function for CR2/sCR2 in human neuroinflammatory conditions.

Keywords
Complement Receptor 2; Complement system; Multiple sclerosis; Neurodegeneration; Neuroinflammation
National Category
Neurology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-285294 (URN)10.1016/j.clim.2016.04.003 (DOI)000378011500010 ()27085202 (PubMedID)
Funder
EU, European Research Council, LSHM-CT-2005-018637Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2019-01-29Bibliographically approved
Aeinehband, S., Lindblom, R. P., Al Nimer, F., Vijayaraghavan, S., Sandholm, K., Khademi, M., . . . Piehl, F. (2015). Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis. PLoS ONE, 10(4)
Open this publication in new window or tab >>Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-252175 (URN)10.1371/journal.pone.0122048 (DOI)000352139000074 ()25835709 (PubMedID)
Available from: 2015-05-06 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7913-4981

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