| 11. |
- Burguillos Garcia, Miguel, et al.
(författare)
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Caspase signalling controls microglia activation and neurotoxicity.
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 472, s. 214-319
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Tidskriftsartikel (refereegranskat)abstract
- Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
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| 12. |
- Ceberg, Crister, et al.
(författare)
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Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation.
- 2012
-
Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 57:24, s. 8377-8391
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Tidskriftsartikel (refereegranskat)abstract
- 75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.
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| 13. |
- Chen, Dongfeng, et al.
(författare)
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Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.
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| 14. |
- Chen, Dongfeng, et al.
(författare)
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Glioma Cell Proliferation Controlled by ERK Activity-Dependent Surface Expression of PDGFRA.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas.
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| 15. |
- Cronberg, Tobias, et al.
(författare)
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Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.
- 2011
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Ingår i: Neurology. - 1526-632X. ; 77:7, s. 623-630
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma. METHODS: Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died. RESULTS: Six of the 17 patients (35%) with NSE levels <33 μg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening. CONCLUSIONS: NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.
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| 16. |
- Dragancea, Irina, et al.
(författare)
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The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.
- 2013
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Ingår i: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 84:3, s. 337-342
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Brain injury is considered the main cause of death in patients who are hospitalized after cardiac arrest (CA). Induced hypothermia is recommended as neuroprotective treatment after (CA) but may affect prognostic parameters. We evaluated the effect of delayed neurological prognostication on the mode of death in hypothermia-treated CA-survivors. STUDY DESIGN: Retrospective study at a Swedish university hospital, analyzing all in-hospital and out-of-hospital CA-patients treated with hypothermia during a 5-year period. Cause of death was categorized as brain injury, cardiac disorder or other. Multimodal neurological prognostication and decision on level of care was performed in comatose patients 72hours after rewarming. Neurological function was evaluated by Cerebral Performance Categories scale (CPC). RESULTS: Among 162 patients, 76 survived to hospital discharge, 65 of whom had a good neurological outcome (CPC 1-2), and 11 were severely disabled (CPC 3). No patient was in vegetative state. The cause of death was classified as brain injury in 61 patients, cardiac disorder in 14 and other in 11. Four patients were declared brain dead and became organ donors. They were significantly younger (median 40 years) and with long time to ROSC. Active intensive care was withdrawn in 50 patients based on a statement of poor neurological prognosis at least 72h after rewarming. These patients died, mainly from respiratory complications, at a median 7 days after CA. CONCLUSION: Following induced hypothermia and delayed neurological prognostication, brain injury remains the main cause of death after CA. Most patients with a poor prognosis statement died within two weeks.
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| 17. |
- Elfving, Maria, et al.
(författare)
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Ectopic recurrence of a craniopharyngioma in a 15-year-old girl 9 years after surgery and conventional radiotherapy: case report.
- 2011
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Ingår i: Child's Nervous System. - : Springer Science and Business Media LLC. - 1433-0350 .- 0256-7040. ; 27, s. 845-851
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Tidskriftsartikel (refereegranskat)abstract
- This 15-year-old girl was operated due to an ectopic recurrence of a craniopharyngioma along the previous surgical route. She presented with a sellar craniopharyngioma at the age of 4 years and underwent a right subfrontal craniotomy. Two and a half years later she had a local recurrence in the sella that was resected along the same surgical route. Postoperative cranial radiotherapy was administered with 50 Gy divided into 28 fractions. Nine years later, magnetic resonance imaging (MRI) revealed a local recurrence within the sella together with a supraorbital cystic mass. Both tumors were surgically removed. Microscopic examination revealed recurrence of an adamantinous craniopharyngioma at both localisations. Histopathological preparations showed a higher MIB-1 index at the simultaneous recurrences in the sella and in the frontal lobe and also an elevated focal p53 expression, compared to previous operations, suggesting a transformation to a more aggressive tumor. This is the first case report of ectopic recurrence in a child that had received conventional radiotherapy of 50 Gy to the sella. Careful intra-operative procedure is probably crucial for preventing ectopic recurrences. The future will reveal if the transsphenoidal surgical route will put an end to ectopic tumor recurrence in patients with a craniopharyngioma.
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| 18. |
- Englund Dimitrova, Birgitta, 1946-, et al.
(författare)
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Retrospection in interpreting and translation: explaining the process?
- 2014
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Ingår i: Monografías de Traducción e Interpretación MonTi Special Issue (ed. R. Muñoz Martín). - Alicante : Universitat d'Alacant. - 1889-4178. ; 1:1, s. 177-200
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Tidskriftsartikel (refereegranskat)abstract
- For studying the processes involved in translation and in interpreting, retrospection is one of the few research methods equally suitable for both areas. At the first workshop on research methods in process-oriented research, in Graz in 2009, we presented the results of a pilot study of retrospection as a research method, published as Englund Dimitrova and Tiselius (2009). The study involved data from two groups (15 years of professional experience vs. no professional experience), each with 3+3 subjects (interpreter subjects vs. translator subjects, all with Swedish as their L1). The source text was a 10-minute plenary speech in English from the European Parliament, interpreted simultaneously into Swedish. For the translation data, the translator subjects translated the original European Parliament transcript of the speech, 1,093 words, writing in Translog. After the task, subjects did immediate retrospection. The first analysis of the data indicated that a challenge when using retrospection is that subjects tend to report having forgotten about some of their processes. In this paper we report an analysis of the process data in relation to the retrospective protocols. Our focus is on reported problems and the occurrences of problem indicators in the process. It was found that most reported problems are confirmed by the presence of problem indicators in the process. However, the majority of problem indicators found in the process do not correspond to any reported problem. Hence, the subjects’ problem reports can only explain a limited number of the potential problems in the process. The need for further research into retrospection as a research method in Translation Studies is pointed out.
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| 19. |
- Englund, Elisabet, et al.
(författare)
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Familial Lund frontotemporal dementia caused by C9ORF72 hexanucleotide expansion.
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580.
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) as an important clinical entity was rediscovered in Lund and Manchester in the early 1990s. Here we show that the large Lund pedigree with behavioral variant of frontotemporal dementia previously described with this disorder has an expansion in the recently described C9ORF72 locus on chromosome 9.
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| 20. |
- Gustafson, Lars, et al.
(författare)
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A factor analytic approach to symptom patterns in dementia.
- 2010
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Ingår i: International Journal of Alzheimer's Disease. - : Hindawi Limited. - 2090-0252 .- 2090-8024.
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Tidskriftsartikel (refereegranskat)abstract
- Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.
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