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- Needham, Edward J, et al.
(författare)
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Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.
- 2021
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 207:1, s. 90-100
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Tidskriftsartikel (refereegranskat)abstract
- Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
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| 5. |
- Thelin, J, et al.
(författare)
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The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia
- 2017
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 220:1, s. 124-136
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To date, the understanding and development of novel treatments for mental illness is hampered by inadequate animal models. For instance, it is unclear to what extent commonly used behavioural tests in animals can inform us on the mental and affective aspects of schizophrenia.METHODS: To link pathophysiological processes in an animal model to clinical findings, we have here utilized the recently developed Df(h15q13)/+ mouse model for detailed investigations of cortical neuronal engagement during pre-attentive processing of auditory information from two back-translational auditory paradigms. We also investigate if compromised putative fast-spiking interneurone (FSI) function can be restored through pharmacological intervention using the Kv3.1 channel opener RE1. Chronic multi-array electrodes in primary auditory cortex were used to record single cell firing from putative pyramidal and FSI in awake animals during processing of auditory sensory information.RESULTS: We find a decreased amplitude in the response to auditory stimuli and reduced recruitment of neurones to fast steady-state gamma oscillatory activity. These results resemble encephalography recordings in patients with schizophrenia. Furthermore, the probability of interneurones to fire with low interspike intervals during 80 Hz auditory stimulation was reduced in Df(h15q13)/+ mice, an effect that was partially reversed by the Kv3.1 channel modulator, RE1.CONCLUSIONS: This study offers insight into the consequences on a neuronal level of carrying the 15q13.3 microdeletion. Furthermore, it points to deficient functioning of interneurones as a potential pathophysiological mechanism in schizophrenia and suggests a therapeutic potential of Kv3.1 channel openers.
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| 8. |
- Berggård, T, et al.
(författare)
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Prothrombin, albumin and immunoglobulin A form covalent complexes with alpha1-microglobulin in human plasma
- 1997
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 245:3, s. 83-676
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Tidskriftsartikel (refereegranskat)abstract
- Molecules containing the 33-kDa plasma protein alpha1-microglobulin were isolated from human plasma by anti-(alpha1-microglobulin) affinity chromatography. Five major bands could be seen after electrophoretic separation of the alpha1-microglobulin-containing proteins under native conditions. Immunoblotting demonstrated alpha1-microglobulin in all five bands. Two of these have been described previously: free alpha1-microglobulin and alpha1-microglobulin complexed with IgA (IgA x alpha1-microglobulin). The other three bands were identified as prothrombin alpha1-microglobulin, albumin x alpha1-microglobulin and dimeric alpha1-microglobulin. Prothrombin x alpha1-microglobulin were 1:2 and 1:1 complexes which carried approximately 1% of total alpha1-microglobulin, had molecular masses of about 145 kDa and 110 kDa upon SDS/PAGE and dissociated completely to free alpha1-microglobulin and prothrombin (72 kDa) when reducing agents were added, suggesting that the complexes were stabilized by disulfide bonds. The alpha1-microglobulin molecules did not inhibit cleavage of prothrombin by factor Xa and were bound to the peptides which were released upon activation of prothrombin. Albumin x alpha1-microglobulin, corresponding to 7% of total plasma alpha1-microglobulin, was a mixture between 1:1 and 1:2 complexes, with masses upon SDS/PAGE of approximately 100 kDa and 135 kDa, respectively. Both these complexes dissociated only partially to free alpha1-microglobulin and albumin when reducing agents were added. The albumin x alpha1-microglobulin complexes carried a yellow-brown chromophore similar to free alpha1-microglobulin. The complex-binding to alpha1-microglobulin did not block the fatty-acid-binding ability of albumin. The plasma concentrations of albumin x alpha1-microglobulin and prothrombin x alpha1-microglobulin were estimated to 5.2 mg/l and 1.1 mg/l, respectively.
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| 9. |
- Edlmann, E, et al.
(författare)
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Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma: report of the internal pilot phase
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 5885-
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Tidskriftsartikel (refereegranskat)abstract
- The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.
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| 10. |
- Fletcher-Sandersjoo, A, et al.
(författare)
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Clinical Significance of Vascular Occlusive Events following Moderate-to-Severe Traumatic Brain Injury: An Observational Cohort Study
- 2022
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Ingår i: Seminars in thrombosis and hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 48:033, s. 301-308
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Tidskriftsartikel (refereegranskat)abstract
- Preventing hemorrhage progression is a potential therapeutic opportunity in traumatic brain injury (TBI) management, but its use has been limited by fear of provoking vascular occlusive events (VOEs). However, it is currently unclear whether VOE actually affects outcome in these patients. The aim of this study was to determine incidence, risk factors, and clinical significance of VOE in patients with moderate-to-severe TBI. A retrospective observational cohort study of adults (≥15 years) with moderate-to-severe TBI was performed. The presence of a VOE during hospitalization was noted from hospital charts and radiological reports. Functional outcome, using the Glasgow Outcome Scale (GOS), was assessed at 12 months posttrauma. Univariate and multivariate logistic regressions were used for endpoint assessment. In total, 848 patients were included, with a median admission Glasgow Coma Scale of 7. A VOE was detected in 54 (6.4%) patients, of which cerebral venous thrombosis was the most common (3.2%), followed by pulmonary embolism (1.7%) and deep vein thrombosis (1.3%). Length of ICU stay (p < 0.001), body weight (p = 0.002), and skull fracture (p = 0.004) were independent predictors of VOE. VOE development did not significantly impact 12-month GOS, even after adjusting for potential confounders using propensity score matching. In conclusion, VOE in moderate-to-severe TBI patients was relatively uncommon, and did not affect 12-month GOS. This suggests that the potential benefit of treating bleeding progression might outweigh the risks of VOE.
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