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  • 151.
    Högberg, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Stenbäck, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Engstrand Lilja, Heléne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Intestinal intraluminal glycerol and plasma I-FABP levels in preterm infants with necrotizing enterocolitis2016Inngår i: Clinics in Surgery, Vol. 1, nr 1085, s. 1-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Purpose: Necrotizing enterocolitis (NEC) is highly associated with prematurity and is characterized by bowel necrosis and multi-organ failure. There is a strong need for improved diagnostic methods to reduce the significant morbidity and mortality associated with NEC. The aim of this single centre prospective study was to investigate the possibility to detect early signs of NEC, by using rectal intraluminal microdialysis and plasma intestinal fatty acid binding protein (I-FABP) in preterm infants admitted to a level III neonatal intensive care unit.

    Methods: The study was performed on extremely preterm infants with a gestational age of less than 28 weeks. During a 4-week period after birth, rectal intraluminal microdialysate levels of glucose, lactate, pyruvate and glycerol were measured, and plasma was collected for I-FABP analysis. Infants not developing NEC served as controls.

     Results: Microdialysis revealed signs of intestinal hypoxic or ischemic damage and cell membrane degradation, with a marked increase of both intraluminal glycerol and plasma I-FABP in infants developing NEC, as well as in infants suffering from other complications. The microdialysate levels of glucose, lactate and pyruvate were too low to be evaluated in this setting. All infants tolerated the microdialysis well without any complications.

    Conclusion: Elevated levels of intraluminal glycerol and plasma I-FABP suggests mucosal cell membrane degradation and hypoxic or ischemic damage in preterm infants developing NEC, as well as in preterm infants suffering from other complications such as volvulus, sepsis or respiratory distress. However, it was not possible to predict development of NEC before clinical diagnosis using these markers. 

  • 152.
    Israelsson, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Bengtsson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Kylberg, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lewén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ebendal, Ted
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Distinct cellular patterns of upregulated chemokine expression supporting a prominent inflammatory role in traumatic brain injury2008Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 25, nr 8, s. 959-974Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cerebral gene expressions change in response to traumatic brain injury (TBI), and future trauma treatment may improve with increased knowledge about these regulations. We subjected C57BL/6J mice to injury by controlled cortical impact (CCI). At various time points post-injury, mRNA from neocortex and hippocampus was isolated, and transcriptional alterations studied using quantitative real-time polymerase chain reaction (PCR) and gene array analysis. Spatial distribution of enhanced expression was characterized by in situ hybridization. Products of the upregulated transcripts serve functions in a range of cellular mechanisms, including stress, inflammation and immune responses, and tissue remodeling. We also identified increased transcript levels characterizing reactive astrocytes, oligodendrocytes, and microglia, and furthermore, we demonstrated a novel pattern of scattered cell clusters expressing the chemokine Cxcl10. Notably, a sustained increase in integrin alpha X (Itgax), characterizing antigen-presenting dendritic cells, was found with the transcript located to similar cell clusters. In contrast, T-cell receptor alpha transcript showed only a modest increase. The induced P-selectin (Selp) expression level in endothelial cells, and chemokines from microglia, may guide perivascular accumulation of extravasating inflammatory monocytes differentiating into dendritic cells. In conclusion, our study shows that following TBI, secondary injury chiefly involves inflammatory processes and chemokine signaling, which comprise putative targets for pharmaceutical neuroprotection.

  • 153.
    Israelsson, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Bengtsson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Lobell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nilsson, Lars N. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kylberg, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Isaksson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wootz, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ebendal, Ted
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders2010Inngår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 31, nr 5, s. 852-863Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Traumatic brain injury (TBI) in the mouse results in the rapid appearance of scattered clusters of cells expressing the chemokine Cxcl10 in cortical and subcortical areas. To extend the observation of this unique pattern, we used neuropathological mouse models using quantitative reverse transcriptase-polymerase chain reaction, gene array analysis, in-situ hybridization and flow cytometry. As for TBI, cell clusters of 150–200 μm expressing Cxcl10 characterize the cerebral cortex of mice carrying a transgene encoding the Swedish mutation of amyloid precursor protein, a model of amyloid Alzheimer pathology. The same pattern was found in experimental autoimmune encephalomyelitis in mice modelling multiple sclerosis. In contrast, mice carrying a SOD1G93A mutant mimicking amyotrophic lateral sclerosis pathology lacked such cell clusters in the cerebral cortex, whereas clusters appeared in the brainstem and spinal cord. Mice homozygous for a null mutation of the Cxcl10 gene did not show detectable levels of Cxcl10 transcript after TBI, confirming the quantitative reverse transcriptase-polymerase chain reaction and in-situ hybridization signals. Moreover, unbiased microarray expression analysis showed that Cxcl10 was among 112 transcripts in the neocortex upregulated at least threefold in both TBI and ageing TgSwe mice, many of them involved in inflammation. The identity of the Cxcl10+ cells remains unclear but flow cytometry showed increased numbers of activated microglia/macrophages as well as myeloid dendritic cells in the TBI and experimental autoimmune encephalomyelitis models. It is concluded that the Cxcl10+ cells appear in the inflamed central nervous system and may represent a novel population of cells that it may be possible to target pharmacologically in a broad range of neurodegenerative conditions.

  • 154.
    Israelsson, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Flygt, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Astrand, Elaine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Kiwanuka, Olivia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Bengtsson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Altered expression of myelin-associated inhibitors and their receptors after traumatic brain injury in the mouse2014Inngår i: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 32, nr 5, s. 717-731Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.

  • 155.
    Israelsson, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Kylberg, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Bengtsson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ebendal, Ted
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Interacting Chemokine Signals Regulate Dendritic Cells in Acute Brain Injury2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 8, s. e104754-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brain trauma is known to activate inflammatory cells via various chemokine signals although their interactions remain to be characterized. Mice deficient in Ccl3, Ccr2 or Cxcl10 were compared with wildtype mice after controlled cortical impact injury. Expression of Ccl3 in wildtypes was rapidly upregulated in resident, regularly spaced reactive microglia. Ccl3-deficiency enhanced endothelial expression of platelet selectin and invasion of peripheral inflammatory cells. Appearance of Ccr2 transcripts, encoding the Ccl2 receptor, reflected invasion of lysozyme 2-expressing phagocytes and classical antigen-presenting dendritic cells expressing major histocompatibility complex class II. Ccr2 also directed clustered plasmacytoid dendritic cells positive for the T-cell attracting chemokine Cxcl10. A reduction in Ccr2 and dendritic cells was found in injured wildtype cortex after cyclophosphamide treatment resembling effects of Ccr2-deficiency. The findings demonstrate the feasibility to control inflammation in the injured brain by regulating chemokine-dependent pathways.

  • 156.
    Jansson, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Efficacy and safety of cefotaxime in combination with metronidazole for empirical treatment of brain abscess in clinical practice: a retrospective study of 66 consecutive cases2004Inngår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 23, nr 1, s. 7-14Artikkel i tidsskrift (Fagfellevurdert)
  • 157.
    Jiang, Yiwen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Olofsson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 4, s. 977-990Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 158.
    Jiltsova, Elena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Möttönen, Timo
    Fahlström, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Haapasalo, Joonas
    Tähtinen, Timo
    Peltola, Jukka
    Öhman, Juha
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kiekara, Tommi
    Lehtimäki, Kai
    Imaging of Anterior Nucleus of Thalamus Using 1.5T MRI for Deep Brain Stimulation Targeting in Refractory Epilepsy2016Inngår i: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 19, nr 8, s. 812-817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) is an evolving treatment option in refractory focal epilepsy. Due to poor visualization of ANT in traditional MRI sequences used for movement disorder surgery, targeting of ANT is mainly based on stereotactic atlas information. Sophisticated 3T MRI methods enable visualization of ANT, but 1.5T MRI is still preferred or more readily available in a large number of centers performing DBS.

    OBJECTIVE: In the present study, we sought to determine whether ANT could be adequately visualized at 1.5T MRI pre- and postoperatively using imaging techniques similar to the ones visualizing ANT in 3T MRI. A total of 15 MRI examinations with short tau inversion recovery (STIR) and T1-weighted magnetization prepared gradient echo (MPRAGE) images were performed to visualize ANT in nonepileptic subjects (n = 2), patients with vagus nerve stimulator (VNS) (n = 3), stereotactic MRI (n = 3), patients with ANT-DBS (n = 7).

    RESULTS: ANT was distinctly visualized in STIR and T1-weighted MPRAGE images in patients without implanted stimulators, with Leksell stereotactic frame and with fully implanted VNS. Postoperative 1.5T MRI was able to demonstrate some of the anatomical landmarks around ANT enabling assessment of electrode contact locations.

    CONCLUSIONS: The visualization of ANT is possible in preoperative 1.5T MRI enabling direct targeting of ANT all examined situations. The use of indirect targeting and its inherent potential for lead misplacement due to anatomical variation may be avoided using these MRI methods. Furthermore, postoperative MRI with STIR and T1-weighted MPRAGE images enable detailed postoperative assessment of contact locations.

  • 159.
    Johansson, Mats
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Cesarini, Kristina G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Contant, C F
    Persson, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Changes in intervention and outcome in elderly patients with subarachnoid hemorrhage.2001Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 32, nr 12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: The elderly constitute a significant and increasing proportion of the population. The aim of this investigation was to study time trends in clinical management and outcome in elderly patients with subarachnoid hemorrhage.

    METHODS: Two hundred eighty-one patients >/=65 years of age with aneurysmal subarachnoid hemorrhage who were accepted for treatment at the Uppsala University Hospital neurosurgery clinic during 1981 to 1998 were included. Hunt and Hess grades on admission, specific management components, and clinical outcomes were recorded. Three periods were compared: A, 1981 to 1986 (before neurointensive care); B, 1987 to 1992; and C, 1993 to 1998.

    RESULTS: The volume of elderly patients (>/=65 years of age) increased with time, especially patients >/=70 years of age. Furthermore the proportion of patients with more severe clinical conditions increased. A greater proportion of patients had a favorable outcome (A, 45%; B, 61%; C, 58%) despite older ages and more severe neurological and clinical conditions. In period C, Hunt and Hess I to II patients had a favorable outcome in 85% of cases compared with 64% in period A. This was achieved without any increase in the number of severely disabled patients.

    CONCLUSIONS: Elderly patients with subarachnoid hemorrhage can be treated successfully, and results are still improving. The introduction of neurointensive care may have contributed to the improved outcome without increasing the proportion of severely disabled patients. A defeatist attitude toward elderly patients with this otherwise devastating disease is not justified.

  • 160.
    Johansson, Mats
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Norbäck, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gál, Gyula
    Cesarini, Kristina G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Tovi, Metin
    Solander, Sten
    Contant, C F
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clinical outcome after endovascular coil embolization in elderly patients with subarachnoid hemorrhage.2004Inngår i: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 46, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Subarachnoid hemorrhage (SAH) is not an unusual disease in an elderly population. The clinical outcome has improved over time. It has been suggested that elderly SAH patients would benefit from endovascular aneurysm treatment. The aim of this study was to evaluate technical results and clinical outcome in a series of elderly SAH-patients treated with endovascular coil embolization. Sixty-two patients (> or = 65 years) presenting with aneurysmal SAH underwent early endovascular coil embolization at Uppsala University Hospital between September 1996 and December 2000. In all 62 cases included in the study, endovascular coil embolization was considered the first line of treatment. Admission variables, specific information on technical success, degree of occlusion and procedural complications, and outcome figures were recorded. Clinical grade on admission was Hunt and Hess (H&H) I-II in 39%, H&H III in 27% and H&H IV-V in 34% of the patients. The proportion of posterior circulation aneurysms was 24%. Coil embolization was successfully completed in 94%. The degree of occlusion of the treated aneurysm was complete occlusion in 56%, neck remnant in 21%, residual filling in 11%, other remnant in 5% and not treated in 6%. The rate of procedural complications was 11%. Outcome after 6 months was favorable in 41%, severe disability in 36% and poor in 22%. Favorable outcome was achieved in 57% of the H&H I-II patients, 47% of the H&H III patients and 17% of the H&H IV-V patients. Endovascular aneurysm treatment can be performed in elderly patients with SAH with a high level of technical success, acceptable aneurysm occlusion results, an acceptable rate of procedural complications and fair outcome results.

  • 161.
    Johnson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Pressure autoregulation of cerebral blood flow in traumatic brain injury and aneurysmal subarachnoid hemorrhage2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital.

    In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome.

    In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome.

    In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease.

    In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min).

    The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

    Delarbeid
    1. Favorable Outcome in Traumatic Brain Injury Patients With Impaired Cerebral Pressure Autoregulation When Treated at Low Cerebral Perfusion Pressure Levels
    Åpne denne publikasjonen i ny fane eller vindu >>Favorable Outcome in Traumatic Brain Injury Patients With Impaired Cerebral Pressure Autoregulation When Treated at Low Cerebral Perfusion Pressure Levels
    Vise andre…
    2011 (engelsk)Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 68, nr 3, s. 714-721Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Cerebral pressure autoregulation (CPA) is defined as the ability of the brain vasculature to maintain a constant blood flow over a range of different systemic blood pressures by means of contraction and dilatation. OBJECTIVE: To study CPA in relation to physiological parameters, treatment, and outcome in a series of traumatic brain injury patients. METHODS: In this prospective observational study, 44 male and 14 female patients (age, 15-72 years; mean, 38.7 years; Glasgow Coma Scale score, 4-13; median, 7) were analyzed. Patients were divided into groups on the basis of status of CPA (more pressure active vs more pressure passive) and level of cerebral perfusion pressure (CPP; low vs high CPP). The proportions of favorable outcome in the groups were assessed. Differences in physiological variables in the different groups were analyzed. RESULTS: Patients with more impaired CPA treated at CPP levels below median had a significantly higher proportion of favorable outcome compared with patients with more impaired CPA treated at CPP levels above median. No significant difference in outcome was seen between patients with more intact CPA when divided by level of CPP. In patients with more impaired CPA, CPP < 50 mm Hg and CPP < 60 mm Hg were associated with favorable outcome, whereas CPP > 70 mm Hg and CPP > 80 mm Hg were associated with unfavorable outcome. In patients with more intact CPA, no difference in physiological variables was seen between patients with favorable and unfavorable outcomes. CONCLUSION: Our results support that in traumatic brain injury patients with impaired CPA, CPP should not be elevated.

    Emneord
    Cerebral perfusion pressure, Cerebrovascular pressure autoregulation, Head injury, Outcome
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-148495 (URN)10.1227/NEU.0b013e3182077313 (DOI)000287242300043 ()21311298 (PubMedID)
    Tilgjengelig fra: 2011-03-07 Laget: 2011-03-07 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    2. Should the Neurointensive Care Management of Traumatic Brain Injury Patients be Individualized According to Autoregulation Status and Injury Subtype?
    Åpne denne publikasjonen i ny fane eller vindu >>Should the Neurointensive Care Management of Traumatic Brain Injury Patients be Individualized According to Autoregulation Status and Injury Subtype?
    Vise andre…
    2014 (engelsk)Inngår i: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 21, nr 2, s. 259-265Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The status of autoregulation is an important prognostic factor in traumatic brain injury (TBI), and is important to consider in the management of TBI patients. Pressure reactivity index (PRx) is a measure of autoregulation that has been thoroughly studied, but little is known about its variation in different subtypes of TBI. In this study, we examined the impact of PRx and cerebral perfusion pressure (CPP) on outcome in different TBI subtypes. 107 patients were retrospectively studied. Data on PRx, CPP, and outcome were collected from our database. The first CT scan was classified according to the Marshall classification system. Patients were assigned to "diffuse" (Marshall class: diffuse-1, diffuse-2, and diffuse-3) or "focal" (Marshall class: diffuse-4, evacuated mass lesion, and non-evacuated mass lesion) groups. 2 x 2 tables were constructed calculating the proportions of favorable/unfavorable outcome at different combinations of PRx and CPP. Low PRx was significantly associated with favorable outcome in the combined group (p = 0.002) and the diffuse group (p = 0.04), but not in the focal group (p = 0.06). In the focal group higher CPP values were associated with worse outcome (p = 0.02). In diffuse injury patients with disturbed autoregulation (PRx > 0.1), CPP > 70 mmHg was associated with better outcome (p = 0.03). TBI patients with diffuse injury may differ from those with mass lesions. In the latter higher levels of CPP may be harmful, possibly due to BBB disruption. In TBI patients with diffuse injury and disturbed autoregulation higher levels of CPP may be beneficial.

    Emneord
    Cerebral perfusion pressure, Cerebrovascular pressure autoregulation, Head injury, Outcome
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-236562 (URN)10.1007/s12028-014-9954-2 (DOI)000343132900013 ()24515639 (PubMedID)
    Tilgjengelig fra: 2014-11-20 Laget: 2014-11-19 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    3. Bedside Xenon-CT Shows Lower CBF in SAH Patients with Impaired CBF Pressure Autoregulation as Defined by Pressure Reactivity Index (PRx)
    Åpne denne publikasjonen i ny fane eller vindu >>Bedside Xenon-CT Shows Lower CBF in SAH Patients with Impaired CBF Pressure Autoregulation as Defined by Pressure Reactivity Index (PRx)
    Vise andre…
    2016 (engelsk)Inngår i: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 25, nr 1, s. 47-55Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Subarachnoid hemorrhage (SAH) is a disease with a high rate of unfavorable outcome, often related to delayed cerebral ischemia (DCI), i.e., ischemic injury that develops days-weeks after onset, with a multifactorial etiology. Disturbances in cerebral pressure autoregulation, the ability to maintain a steady cerebral blood flow (CBF), despite fluctuations in systemic blood pressure, have been suggested to play a role in the development of DCI. Pressure reactivity index (PRx) is a well-established measure of cerebral pressure autoregulation that has been used to study traumatic brain injury, but not extensively in SAH.

    OBJECTIVE: To study the relation between PRx and CBF in SAH patients, and to examine if PRx can be used to predict DCI.

    METHODS: Retrospective analysis of prospectively collected data. PRx was calculated as the correlation coefficient between mean arterial blood pressure (MABP) and intracranial pressure (ICP) in a 5 min moving window. CBF was measured using bedside Xenon-CT (Xe-CT). DCI was diagnosed clinically.

    RESULTS: 47 poor-grade mechanically ventilated patients were studied. Patients with disturbed pressure autoregulation (high PRx values) had lower CBF, as measured by bedside Xe-CT; both in the early (day 0-3) and late (day 4-14) acute phase of the disease. PRx did not differ significantly between patients who developed DCI or not.

    CONCLUSION: In mechanically ventilated and sedated SAH patients, high PRx (more disturbed CBF pressure autoregulation) is associated with low CBF, both day 0-3 and day 4-14 after onset. The role of PRx as a monitoring tool in SAH patients needs further studying.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-276116 (URN)10.1007/s12028-016-0240-3 (DOI)000380150700007 ()26842717 (PubMedID)
    Tilgjengelig fra: 2016-02-29 Laget: 2016-02-09 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    4. Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP
    Åpne denne publikasjonen i ny fane eller vindu >>Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP
    Vise andre…
    2017 (engelsk)Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, nr 6, s. 1065-1071Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background Cerebral pressure autoregulation can be quantified with the pressure reactivity index (PRx), based on the correlation between blood pressure and intracranial pressure. Using PRx optimal cerebral perfusion pressure (CPPopt) can be calculated, i.e., the level of CPP where autoregulation functions best. The relation between cerebral blood flow (CBF) and CPPopt has not been examined. The objective was to assess to which extent CPPopt can be calculated in SAH patients and to investigate CPPopt in relation to CBF.

    Methods Retrospective study of prospectively collected data. CBF was measured bedside with Xenon-enhanced CT (Xe-CT). The difference between actual CPP and CPPopt was calculated (CPPa dagger). Correlations between CPPa dagger and CBF parameters were calculated with Spearman's rank order correlation coefficient (rho). Separate calculations were done using all patients (day 0-14 after onset) as well as in two subgroups (day 0-3 and day 4-14).

    Results Eighty-two patients with 145 Xe-CT scans were studied. Automated calculation of CPPopt was possible in adjunct to 60% of the Xe-CT scans. Actual CPP < CPPopt was associated with higher numbers of low-flow regions (CBF < 10 ml/100 g/min) in both the early phase (day 0-3, n = 39, Spearman's rho = -0.38, p = 0.02) and late acute phase of the disease (day 4-14, n = 35, Spearman's rho = -0.39, p = 0.02). CPP level per se was not associated with CBF.

    Conclusions Calculation of CPPopt is possible in a majority of patients with severe SAH. Actual CPP below CPPopt is associated with low CBF.

    Emneord
    cerebral blood flow, autoregulation, CPP, subarachnoid haemorrhage
    HSV kategori
    Forskningsprogram
    Neurokirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-294191 (URN)10.1007/s00701-017-3139-7 (DOI)000401117700016 ()28361248 (PubMedID)
    Tilgjengelig fra: 2016-09-21 Laget: 2016-05-18 Sist oppdatert: 2017-06-13bibliografisk kontrollert
  • 162.
    Johnson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Engquist, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Howells, Tim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nilsson, Pelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lewén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rostami, Elham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Bedside Xenon-CT Shows Lower CBF in SAH Patients with Impaired CBF Pressure Autoregulation as Defined by Pressure Reactivity Index (PRx)2016Inngår i: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 25, nr 1, s. 47-55Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Subarachnoid hemorrhage (SAH) is a disease with a high rate of unfavorable outcome, often related to delayed cerebral ischemia (DCI), i.e., ischemic injury that develops days-weeks after onset, with a multifactorial etiology. Disturbances in cerebral pressure autoregulation, the ability to maintain a steady cerebral blood flow (CBF), despite fluctuations in systemic blood pressure, have been suggested to play a role in the development of DCI. Pressure reactivity index (PRx) is a well-established measure of cerebral pressure autoregulation that has been used to study traumatic brain injury, but not extensively in SAH.

    OBJECTIVE: To study the relation between PRx and CBF in SAH patients, and to examine if PRx can be used to predict DCI.

    METHODS: Retrospective analysis of prospectively collected data. PRx was calculated as the correlation coefficient between mean arterial blood pressure (MABP) and intracranial pressure (ICP) in a 5 min moving window. CBF was measured using bedside Xenon-CT (Xe-CT). DCI was diagnosed clinically.

    RESULTS: 47 poor-grade mechanically ventilated patients were studied. Patients with disturbed pressure autoregulation (high PRx values) had lower CBF, as measured by bedside Xe-CT; both in the early (day 0-3) and late (day 4-14) acute phase of the disease. PRx did not differ significantly between patients who developed DCI or not.

    CONCLUSION: In mechanically ventilated and sedated SAH patients, high PRx (more disturbed CBF pressure autoregulation) is associated with low CBF, both day 0-3 and day 4-14 after onset. The role of PRx as a monitoring tool in SAH patients needs further studying.

  • 163.
    Johnson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Engquist, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lewén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Howells, Tim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nilsson, Pelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rostami, Elham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP2017Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, nr 6, s. 1065-1071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Cerebral pressure autoregulation can be quantified with the pressure reactivity index (PRx), based on the correlation between blood pressure and intracranial pressure. Using PRx optimal cerebral perfusion pressure (CPPopt) can be calculated, i.e., the level of CPP where autoregulation functions best. The relation between cerebral blood flow (CBF) and CPPopt has not been examined. The objective was to assess to which extent CPPopt can be calculated in SAH patients and to investigate CPPopt in relation to CBF.

    Methods Retrospective study of prospectively collected data. CBF was measured bedside with Xenon-enhanced CT (Xe-CT). The difference between actual CPP and CPPopt was calculated (CPPa dagger). Correlations between CPPa dagger and CBF parameters were calculated with Spearman's rank order correlation coefficient (rho). Separate calculations were done using all patients (day 0-14 after onset) as well as in two subgroups (day 0-3 and day 4-14).

    Results Eighty-two patients with 145 Xe-CT scans were studied. Automated calculation of CPPopt was possible in adjunct to 60% of the Xe-CT scans. Actual CPP < CPPopt was associated with higher numbers of low-flow regions (CBF < 10 ml/100 g/min) in both the early phase (day 0-3, n = 39, Spearman's rho = -0.38, p = 0.02) and late acute phase of the disease (day 4-14, n = 35, Spearman's rho = -0.39, p = 0.02). CPP level per se was not associated with CBF.

    Conclusions Calculation of CPPopt is possible in a majority of patients with severe SAH. Actual CPP below CPPopt is associated with low CBF.

  • 164.
    Johnson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lewen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Howells, Tim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Should the Neurointensive Care Management of Traumatic Brain Injury Patients be Individualized According to Autoregulation Status and Injury Subtype?2014Inngår i: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 21, nr 2, s. 259-265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The status of autoregulation is an important prognostic factor in traumatic brain injury (TBI), and is important to consider in the management of TBI patients. Pressure reactivity index (PRx) is a measure of autoregulation that has been thoroughly studied, but little is known about its variation in different subtypes of TBI. In this study, we examined the impact of PRx and cerebral perfusion pressure (CPP) on outcome in different TBI subtypes. 107 patients were retrospectively studied. Data on PRx, CPP, and outcome were collected from our database. The first CT scan was classified according to the Marshall classification system. Patients were assigned to "diffuse" (Marshall class: diffuse-1, diffuse-2, and diffuse-3) or "focal" (Marshall class: diffuse-4, evacuated mass lesion, and non-evacuated mass lesion) groups. 2 x 2 tables were constructed calculating the proportions of favorable/unfavorable outcome at different combinations of PRx and CPP. Low PRx was significantly associated with favorable outcome in the combined group (p = 0.002) and the diffuse group (p = 0.04), but not in the focal group (p = 0.06). In the focal group higher CPP values were associated with worse outcome (p = 0.02). In diffuse injury patients with disturbed autoregulation (PRx > 0.1), CPP > 70 mmHg was associated with better outcome (p = 0.03). TBI patients with diffuse injury may differ from those with mass lesions. In the latter higher levels of CPP may be harmful, possibly due to BBB disruption. In TBI patients with diffuse injury and disturbed autoregulation higher levels of CPP may be beneficial.

  • 165.
    Johnson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nilsson, Pelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Howells, Tim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Favorable Outcome in Traumatic Brain Injury Patients With Impaired Cerebral Pressure Autoregulation When Treated at Low Cerebral Perfusion Pressure Levels2011Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 68, nr 3, s. 714-721Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Cerebral pressure autoregulation (CPA) is defined as the ability of the brain vasculature to maintain a constant blood flow over a range of different systemic blood pressures by means of contraction and dilatation. OBJECTIVE: To study CPA in relation to physiological parameters, treatment, and outcome in a series of traumatic brain injury patients. METHODS: In this prospective observational study, 44 male and 14 female patients (age, 15-72 years; mean, 38.7 years; Glasgow Coma Scale score, 4-13; median, 7) were analyzed. Patients were divided into groups on the basis of status of CPA (more pressure active vs more pressure passive) and level of cerebral perfusion pressure (CPP; low vs high CPP). The proportions of favorable outcome in the groups were assessed. Differences in physiological variables in the different groups were analyzed. RESULTS: Patients with more impaired CPA treated at CPP levels below median had a significantly higher proportion of favorable outcome compared with patients with more impaired CPA treated at CPP levels above median. No significant difference in outcome was seen between patients with more intact CPA when divided by level of CPP. In patients with more impaired CPA, CPP < 50 mm Hg and CPP < 60 mm Hg were associated with favorable outcome, whereas CPP > 70 mm Hg and CPP > 80 mm Hg were associated with unfavorable outcome. In patients with more intact CPA, no difference in physiological variables was seen between patients with favorable and unfavorable outcomes. CONCLUSION: Our results support that in traumatic brain injury patients with impaired CPA, CPP should not be elevated.

  • 166. Kenne, Ellinor
    et al.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lindbom, Lennart
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice2012Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Artikkel i tidsskrift (Annet vitenskapelig)
  • 167. Kenne, Ellinor
    et al.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lindbom, Lennart
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice2012Inngår i: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, s. 17-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear.

    Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data.

    Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury.

    Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice.

  • 168. Kocak, Oyku
    et al.
    Fridgeirsdottir, Gudrun Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Endogenous free radical production by NADPH oxidase 2 contributes to the secondary injury cascade after traumatic brain injury in mice2012Inngår i: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 26, nr 4-5, s. 503-504Artikkel i tidsskrift (Annet vitenskapelig)
  • 169.
    Kononenko, Olga
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stålhandske, Lada
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Zarelius, Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Lund Univ, Dept Clin Sci Neurosurg, Skane Univ Hosp, EA Blocket,4th Floor,Box 188, S-22100 Lund, Sweden.
    Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord2019Inngår i: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, nr 2, s. 87-96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf and Gap43 neuroplasticity genes in lumbar spinal cord.

    Approach/Methods: Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n=8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi- and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

    Results: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

    Conclusions: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

  • 170.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Lindqvist, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Pseudoparaproteinemia Detected by CE due to Omnipaque™ Infusion: A Case Report2007Inngår i: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 65, nr 11-12, s. 775-777Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serum or plasma protein electrophoresis is often performed in clinical laboratories to detect and monitor M-components. During the last decade, capillary electrophoresis (CE) has emerged as an interesting alternative to traditional analysis of serum, plasma and urine proteins by agarose gel electrophoresis. We here report a case of pseudoparaproteinemia detected by capillary electrophoresis after Omnipaque™ (iohexol) infusion in a patient with normal kidney function. It is important for the laboratories to be aware of this source of erroneous results and not misclassify it as monoclonal gammopathies.

  • 171.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Basma, Jaafar
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Krisht, Ali Fadl
    Epidural skull base approach for dural arteriovenous fistulas (DAVF) of the anterior and middle cranial fossa2014Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 156, nr 1, s. 93-95Artikkel i tidsskrift (Fagfellevurdert)
  • 172.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Fahlström, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Berntsson, Shala G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi. Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    A novel radiological classification system for cerebral gliomas: The Brain-Grid2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 1, artikkel-id e0211243Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Standard radiological/topographical classifications of gliomas often do not reflect the real extension of the tumor within the lobar-cortical anatomy. Furthermore, these systems do not provide information on the relationship between tumor growth and the subcortical white matter architecture. We propose the use of an anatomically standardized grid system (the Brain-Grid) to merge serial morphological magnetic resonance imaging (MRI) scans with a representative tractographic atlas. Two illustrative cases are presented to show the potential advantages of this classification system.

    METHODS: MRI scans of 39 patients (WHO grade II and III gliomas) were analyzed with a standardized grid created by intersecting longitudinal lines on the axial, sagittal, and coronal planes. The anatomical landmarks were chosen from an average brain, spatially normalized to the Montreal Neurological Institute (MNI) space and the Talairach space. Major white matter pathways were reconstructed with a deterministic tracking algorithm on a reference atlas and analyzed using the Brain-Grid system.

    RESULTS: In all, 48 brain grid voxels (areas defined by 3 coordinates, axial (A), coronal (C), sagittal (S) and numbers from 1 to 4) were delineated in each MRI sequence and on the tractographic atlas. The number of grid voxels infiltrated was consistent, also in the MNI space. The sub-cortical insula/basal ganglia (A3-C2-S2) and the fronto-insular region (A3-C2-S1) were most frequently involved. The inferior fronto-occipital fasciculus, anterior thalamic radiation, uncinate fasciculus, and external capsule were the most frequently associated pathways in both hemispheres.

    CONCLUSIONS: The Brain-Grid based classification system provides an accurate observational tool in all patients with suspected gliomas, based on the comparison of grid voxels on a morphological MRI and segmented white matter atlas. Important biological information on tumor kinetics including extension, speed, and preferential direction of progression can be observed and even predicted with this system. This novel classification can easily be applied to both prospective and retrospective cohorts of patients and increase our comprehension of glioma behavior.

  • 173.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hjortberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aldskogius, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    The Classical Pathways of Occipital Lobe Epileptic Propagation Revised in the Light of White Matter Dissection2015Inngår i: Behavioural Neurology, ISSN 0953-4180, E-ISSN 1875-8584, artikkel-id 872645Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The clinical evidences of variable epileptic propagation in occipital lobe epilepsy (OLE) have been demonstrated by several studies. However the exact localization of the epileptic focus sometimes represents a problem because of the rapid propagation to frontal, parietal, or temporal regions. Each white matter pathway close to the supposed initial focus can lead the propagation towards a specific direction, explaining the variable semiology of these rare epilepsy syndromes. Some new insights in occipital white matter anatomy are herein described by means of white matter dissection and compared to the classical epileptic patterns, mostly based on the central position of the primary visual cortex. The dissections showed a complex white matter architecture composed by vertical and longitudinal bundles, which are closely interconnected and segregated and are able to support specific high order functions with parallel bidirectional propagation of the electric signal. The same sublobar lesions may hyperactivate different white matter bundles reemphasizing the importance of the ictal semiology as a specific clinical demonstration of the subcortical networks recruited. Merging semiology, white matter anatomy, and electrophysiology may lead us to a better understanding of these complex syndromes and tailored therapeutic options based on individual white matter connectivity.

  • 174.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hjortberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aldskogius, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    The use of a cerebral perfusion and immersion-fixation process for subsequent white matter dissection2015Inngår i: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 253, s. 161-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The Klingler's method for white matter dissection revolutionized the study of deep cerebral anatomy. Although this technique made white matter dissection more feasible and widely used, it still presents some intrinsic limitations. New method: We evaluated the quality of different methods for specimen preparation based on an intra-carotidal formalin perfusion fixation process. Ten post-mortem human hemispheres were prepared with this method and dissected in a stepwise manner. Results: The homogeneous and rapid fixation of the brain allowed documentation of several fine additional anatomical details. Intra-cortical white matter terminations were described during the first stage of dissection on each specimen. No limitations were encountered during dissection of the major associative bundles. On the contrary, the quality of the fixation of the specimens made it possible to isolate them en bloc. One of the most complex and deep bundles (accumbo-frontal fasciculus) was dissected without technical limitations. Deep vascular structures were very well preserved and dissected within the white matter until their sub-millimetric terminations. Comparison with existing method: Short time for preparation, a more homogeneous fixation, no technical limitation for a detailed description of superficial and deep white matter anatomy, the possibility to dissect with a single technique the fibre organization and the white matter vascular architecture are the advantages reported with the perfusion fixation. Conclusion: These results provide encouraging data about the possibility to use a perfusion fixation process, which may help in improving the quality of white matter dissection for research, didactic purposes and surgical training.

  • 175.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rapid and Accurate MRI Segmentation of Peritumoral Brain Edema in Meningiomas2017Inngår i: Clinical neuroradiology, ISSN 1869-1447, Vol. 27, nr 2, s. 145-152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    The extent of peritumoral brain edema (PTBE) in meningiomas commonly affects the clinical outcome. Despite its importance, edema volume is usually highly inaccurately approximated to a spheroid shape. We tested the accuracy and the reproducibility of semiautomatic lesion management software for the analysis of PTBE in a homogeneous case series of surgically confirmed intracranial meningiomas.

    METHODS:

    PTBE volume was calculated on magnetic resonance images in 50 patients with intracranial meningiomas using commercial lesion management software (Vue PACS Livewire, Carestream, Rochester, NY, USA). Inter and intraobserver agreement evaluation and a comparison between manual volume calculation, the semiautomatic software and spheroid approximation were performed in 22 randomly selected patients.

    RESULTS:

    The calculation of edema volume was possible in all cases irrespective of the extent of the signal changes. The median time for each calculation was 3 min. Interobserver and intraobserver agreement confirmed the reproducibility of the method. Comparison with standard (fully manual) calculation confirmed the accuracy of this software.

    CONCLUSIONS:

    Our study showed a high level of reproducibility of this semiautomatic computational method for peritumoral brain edema. It is rapid and easy to use after relatively short training and is suitable for implementation in clinical practice.

  • 176.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Mårtensson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fredriksson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Hjortberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aldskogius, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study.2017Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, nr 1675, s. 102-115, artikkel-id S0006-8993(17)30386-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.

  • 177.
    Latini, Francesco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rethinking the standard trans-cortical approaches in the light of superficial white matter anatomy2015Inngår i: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, nr 12, s. 1906-1909Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    A better comprehension of the superficial white matter organization is important in order to minimize potential and avoidable damage to long or intermediate association fibre bundles during every step of a surgical approach. We recently proposed a technique for cadaver specimen preparation, which seems able to identify a more systematic organization of the superficial white matter terminations. Moreover, the use of the physiological intracranial vascular network for the fixation process allowed us to constantly show main vascular landmarks associated with white matter structures. Hence three examples of standard approaches to eloquent areas are herein reanalyzed starting from the first superficial layer. New insights into the possible surgical trajectories and subsequent quantitative damages of both vessels and white matter fibres can help readapt even the most standard and widely accepted approach trough the brain cortex. A more detailed study of these fine anatomical details may become in the near future a fundamental part of the neurosurgical training and the preoperative planning.

  • 178.
    Lenell, Samuel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nyholm, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lewen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Updated periodic evaluation of standardized neurointensive care shows that it is possible to maintain a high level of favorable outcome even with increasing mean age2015Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 157, nr 3, s. 417-425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Periodic evaluation of neurointensive care (NIC) is important. There is a risk that quality of daily care declines and there may also be unrecognized changes in patient characteristics and management. The aim of this work was to investigate the characteristics and outcome for traumatic brain injury (TBI) patients in the period 2008-2009 in comparison with 1996-1997 and to some extent also with earlier periods. TBI patients 16-79 years old admitted from 2008 to 2009 were selected for the study. Glasgow Coma Scale Motor score at admission (GCS M), radiology, surgery, and outcome (Glasgow Outcome Extended Scale) were collected from Uppsala Traumatic Brain Injury Register. The study included 148 patients (mean age, 45 years). Patients > 60 years old increased from 16 % 1996-1997 to 30 % 2008-2009 (p < 0.01). The proportion of GCS M 4-6 were similar, 92 vs. 93 % (NS). In 1996-1997 patients, 73 % had diffuse injury (Marshall classification) compared to 77 % for the 2008-2009 period (NS). More patients underwent surgery during 2008-2009 (43 %) compared to 1996-1997 (32 %, p < 0.05). Good recovery increased and mortality decreased substantially from 1980-1981 to 1987-1988 and to 1996-1997, but then the results were unchanged in the 2008-2009 period, with 73 % favorable outcome and 11 % mortality. Mortality increased in GCS M 6-4, from 2.8 % in 1996-1997 to 10 % in 2008-2009 (p < 0.05); most of the patients that died had aggravating factors, e.g., high age, malignancy. A large-proportion favorable outcome was maintained despite that patients > 60 years with poorer prognosis doubled, indicating that the quality of NIC has increased or at least is unchanged. More surgery may have contributed to maintaining the large proportion of favorable outcome. For future improvements, more knowledge about TBI management in the elderly is required.

  • 179.
    Lewén, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Dyhrfort, Philip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    A Dedicated 21-Plex Pea Panel For High-Sensitive Protein Biomarker Detection Using Micro-Dialysis In Traumatic Brain Injury2018Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, nr 16, s. A130-A130Artikkel i tidsskrift (Annet vitenskapelig)
  • 180.
    Li, Hao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Edin, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Hayashi, Hisamitsu
    Gifu Univ, Dept Otolaryngol, Gifu, Japan.
    Gudjonsson, Olafur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Danckwardt-Lillieström, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Rask-Andersen, Helge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Xia, Wei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface2017Inngår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 122, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cochlear implant (CI) is a successful device to restore hearing. Despite continuous development, frequency discrimination is poor in CI users due to an anatomical gap between the auditory neurons and CI electrode causing current spread and unspecific neural stimulation. One strategy to close this anatomical gap is guiding the growth of neuron dendrites closer to CI electrodes through targeted slow release of neurotrophins. Biodegradable calcium phosphate hollow nanospheres (CPHSs) were produced and their capacity for uptake and release of neurotrophins investigated using I-125-conjugated glia cell line-derived neurotrophic factor (GDNF). The CPHSs were coated onto CI electrodes and loaded with neurotrophins. Axon guidance effect of slow-released neurotrophins from the CPHSs was studied in an in vitro 3D culture model. CPHS coating bound and released GDNF with an association rate constant 6.3 x 10(3) M(-1)s(-1) and dissociation rate 2.6 x 10(-5) s(-1), respectively. Neurites from human vestibulocochlear ganglion explants found and established physical contact with the GDNF-loaded CPHS coating on the CI electrodes placed 0.7 mm away. Our results suggest that neurotrophin delivery through CPHS coating is a plausible way to close the anatomical gap between auditory neurons and electrodes. By overcoming this gap, selective neural activation and the fine hearing for CI users become possible.

  • 181.
    Libard, Sylwia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laurell, Katarina
    Umeå Univ, Dept Pharmacol & Clin Neurosci, Östersund.
    Cesarini, Kristina G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus2018Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, nr 4, s. 1451-1461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

  • 182.
    Libard, Sylwia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Popova, Svetlana N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kärjä, Vesa
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Pietiläinen, Timo
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Hämäläinen, Kirsi M
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Department of Neurosurgery, Uppsala University Hospital, Sweden.
    Bergqvist, Michael
    Department of radiation sciences, Umeå University, Sweden.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Zetterling, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Nilsson, Pelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Pfeifer, Susan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    de Ståhl, Teresita Diaz
    Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, s. e108861-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 183.
    Lindblom, Rickard P F
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Tovedal, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Norlin, Bo
    Uppsala Univ Hosp, Dept Cardiothorac Surg & Anesthesia, SE-75185 Uppsala, Sweden.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Popova, Svetlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Thelin, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia2017Inngår i: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 51, nr 4, s. 773-781Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 184.
    Lindholm, Tomas
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Helsa Foretagshalsovard Ostermalm, Stockholm, Sweden..
    Risling, Marten
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Carlstedt, Thomas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;UCL, Hammersmith Hosp, London WC1E 6BT, England.;Imperial Coll, London, England.;Soder Sjukhuset, Dept Hand Surg, Stockholm, Sweden.;Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden..
    Hammarberg, Henrik
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Soder Sjukhuset, Dept Hand Surg, Stockholm, Sweden.;Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden..
    Wallquist, Wilhelm
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Vasteras Gen Hosp, Dept Anesthesiol & Intens Care, Vasteras, Sweden..
    Cullheim, Staffan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Sköld, Mattias K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Expression of Semaphorins, Neuropilins, VEGF, and Tenascins in Rat and Human Primary Sensory Neurons after a Dorsal Root Injury2017Inngår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, artikkel-id 49Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dorsal root injury is a situation not expected to be followed by a strong regenerative growth, or growth of the injured axon into the central nervous system of the spinal cord, if the central axon of the dorsal root is injured but of strong regeneration if subjected to injury to the peripherally projecting axons. The clinical consequence of axonal injury is loss of sensation and may also lead to neuropathic pain. In this study, we have used in situ hybridization to examine the distribution of mRNAs for the neural guidance molecules semaphorin 3A (SEMA3A), semaphorin 3F (SEMA3F), and semaphorin 4F (SEMA4F), their receptors neuropilin 1 (NP1) and neuropilin 2 (NP2) but also for the neuropilin ligand vascular endothelial growth factor (VEGF) and Tenascin J1, an extracellular matrix molecule involved in axonal guidance, in rat dorsal root ganglia (DRG) after a unilateral dorsal rhizotomy (DRT) or sciatic nerve transcetion (SNT). The studied survival times were 1-365 days. The different forms of mRNAs were unevenly distributed between the different size classes of sensory nerve cells. The results show that mRNA for SEMA3A was diminished after trauma to the sensory nerve roots in rats. The SEMA3A receptor NP1, and SEMA3F receptor NP2, was significantly upregulated in the DRG neurons after DRT and SNT. SEMA4F was upregulated after a SNT. The expression of mRNA for VEGF in DRG neurons after DRT showed a significant upregulation that was high even a year after the injuries. These data suggest a role for the semaphorins, neuropilins, VEGF, and J1 in the reactions after dorsal root lesions.

  • 185.
    Ljunghill Hedberg, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Berglund, Sofia
    Wilske, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lewén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Winqvist, Ola
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Decreased T-lymphocyte response to T-cell-dependent vaccines after neurotrauma or neurosurgeryManuskript (preprint) (Annet vitenskapelig)
  • 186.
    Ljunghill Hedberg, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Pauksen, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Relationship between T-cell-dependent and T-cell-independent vaccines after neurotrauma; Can the response be predicted?Manuskript (preprint) (Annet vitenskapelig)
  • 187.
    Ljunghill Hedberg, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Pauksen, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Ronne-Engström, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lundberg, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Uppsala Univ, Infect Dis Sect, Dept Med Sci, Uppsala, Sweden..
    Johansson, Bjorn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rehabiliteringsmedicin. Uppsala Univ, Sect Rehabil Med, Dept Neurosci, Uppsala, Sweden..
    Kayhty, Helena
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Lower response to early T-cell-dependent vaccination after neurotrauma or neurosurgery in adults2015Inngår i: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 70, nr 6, s. 577-584Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Recent international guidelines recommend vaccination with a 13-valent pneumococcal conjugate vaccine to reduce the risk of meningitis after neurotrauma with cerebrospinal fluid leak. The antibody response and optimal time point for vaccination have not been established and because the risk of meningitis is at the highest shortly after trauma, early vaccination is preferable. This study aimed to investigate the antibody response and to ensure that central nervous system injury-induced immunodepression did not affect the response to a T-cell-dependent conjugate vaccine when administered shortly after the injury. Methods: So as not to interfere with routine pneumococcal vaccination, a conjugate vaccine against Haemophilus influenza type b (Hib) was chosen for the study. Thirty-three patients with basilar skull fracture and 23 patients undergoing transsphenoidal pituitary gland surgery were vaccinated within 10 days after trauma/surgery and 29 control patients at least three weeks after trauma/surgery. Sera were collected pre- and post-vaccination for analysis of anti-Hib concentration. Results: Four patients with post-vaccination target antibody concentration before vaccination were excluded from analysis. In the neurotrauma and neurosurgery groups 10/32 (31%) and 5/20 (25%) patients, respectively, were non-responders compared with 3/29 (10%) in the control group. Log(10) anti-Hib concentrations in the neurotrauma, neurosurgery and control groups were 1.52 +/- 0.15, 1.38 +/- 0.15 and 1.81 +/- 0.12 mu g/ml, respectively. Conclusions: The majority of the patients responded to vaccination. However, the number of responders was significantly decreased and antibody concentration significantly lower in patients vaccinated early after the trauma/surgery. Investigation of the pneumococcal conjugate vaccine response in neurotrauma patients is therefore urgent. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  • 188.
    Ljunghill Hedberg, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Pauksens, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Söderberg, Jessika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Johansson, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rehabiliteringsmedicin.
    Kayhty, Helena
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Pneumococcal polysaccharide vaccination administered early after neurotrauma or neurosurgery2017Inngår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 35, nr 6, s. 909-915Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Pneumococcal vaccination is recommended to lower the risk of posttraumatic meningitis, and early vaccination may be of importance. After both trauma and central nervous system injury, immune suppression may occur, which could affect T-cell function and the response to T-cell dependent vaccines. We therefore aimed to investigate the response to early vaccination with a T-cell independent pneumococcal polysaccharide vaccine (PPSV). Methods: Thirty-three patients with basilar skull fracture and 23 patients undergoing transsphenoidal pituitary gland surgery were vaccinated with PPSV within 10 days after neurotrauma or neurosurgery. Twenty-nine neurosurgical patients vaccinated >= 3 weeks after neurotrauma or neurosurgery served as controls. Serotype-specific anti-polysaccharide binding IgG antibody levels to serotypes 4, 6B, 9V, 14, 18C, 19F and 23F were determined by enzyme immunoassay. Results: The vaccination was safe and a highly significant antibody response was found against all serotypes in all groups (p < 0.001 for each of the serotypes). There were no differences between groups or in the group by time interaction in any of the serotypes. After early and late vaccination, protective levels were found in >80% for serotypes 9V, 14, 18C, 19F and 23F and in 70% and 50% for serotypes 6B and 4, respectively. Conclusion: Patients vaccinated with PPSV within 10 days after neurotrauma or neurosurgery respond similarly to those vaccinated after >= 3 weeks, indicating that PPSV can be administered early after neurotrauma or neurosurgery.

  • 189.
    Llano-Diez, Monica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Renaud, Guillaume
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Andersson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gonzales Marrero, Humberto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Cacciani, Nicola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Engquist, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Corpeno, Rebeca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Artemenko, Konstantin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading2012Inngår i: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, nr 5, s. R209-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

  • 190.
    Loov, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Nadadhur, Aishwarya Geeyarpuram
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Identification of Injury Specific Proteins in a Cell Culture Model of Traumatic Brain Injury2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 2, s. e55983-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The complicated secondary molecular and cellular mechanisms following traumatic brain injury (TBI) are still not fully understood. In the present study, we have used mass spectrometry to identify injury specific proteins in an in vitro model of TBI. A standardized injury was induced by scalpel cuts through a mixed cell culture of astrocytes, oligodendrocytes and neurons. Twenty-four hours after the injury, cell culture medium and whole-cell fractions were collected for analysis. We found 53 medium proteins and 46 cell fraction proteins that were specifically expressed after injury and the known function of these proteins was elucidated by an extensive literature survey. By using time-lapse microscopy and immunostainings we could link a large proportion of the proteins to specific cellular processes that occur in response to trauma; including cell death, proliferation, lamellipodia formation, axonal regeneration, actin remodeling, migration and inflammation. A high percentage of the proteins uniquely expressed in the medium after injury were actin-related proteins, which normally are situated intracellularly. We show that two of these, ezrin and moesin, are expressed by astrocytes both in the cell culture model and in mouse brain subjected to experimental TBI. Interestingly, we found many inflammation-related proteins, despite the fact that cells were present in the culture. This study contributes with important knowledge about the cellular responses after trauma and identifies several potential cell-specific biomarkers.

  • 191.
    Lord, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Englund, Hillevi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Söderberg, Linda
    Tucker, Stina
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gordon, Marcia
    Morgan, Dave
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ekholm Pettersson, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nilsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Amyloid-β protofibril levels correlate with spatial learning in Arctic Alzheimer’s disease transgenic mice2009Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, nr 4, s. 995-1006Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligomeric assemblies of amyloid-β (Aβ) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Aβ correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Aβ species have been shown to be neurotoxic, to interfere with learned behavior and to inhibit the maintenance of hippocampal long-term potentiation. The tg-ArcSwe model (i.e. transgenic mice with the Arctic and Swedish Alzheimer mutations) expresses elevated levels of Aβ protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these Aβ assemblies. In the present study, we estimated Aβ protofibril levels in the brain and cerebrospinal fluid of tg-ArcSwe mice, and also assessed their role with respect to cognitive functions. Protofibril levels, specifically measured with a sandwich ELISA, were found to be elevated in young tg-ArcSwe mice compared to several transgenic models lacking the Arctic mutation. In aged tg-ArcSwe mice with considerable plaque deposition, Aβ protofibrils were approximately 50% higher than in younger mice, whereas levels of total Aβ were exponentially increased. Young tg-ArcSwe mice showed deficits in spatial learning, and individual performances in the Morris water maze were correlated inversely with levels of Aβ protofibrils, but not with total Aβ levels. We conclude that Aβ protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extent than total Aβ. Our findings suggest that increased levels of Aβ protofibrils could result in spatial learning impairment.

  • 192.
    Lundin, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Stillesjö, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Nyberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rask-Andersen, Helge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Experiences from Auditory Brainstem Implantation (ABI) in four Paediatric Patients2016Inngår i: Cochlear Implants International, ISSN 1467-0100, E-ISSN 1754-7628Artikkel i tidsskrift (Fagfellevurdert)
  • 193.
    Lööv, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Cellular and Molecular Responses to Traumatic Brain Injury2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Traumatic brain injury (TBI) is a relatively unknown disease considering the tens of millions of people affected around the world each year. Many TBI patients die from their injuries and survivors often suffer from life-long disabilities. The primary injury initiates a variety of cellular and molecular processes that are both beneficial and detrimental for the brain, but that are not fully understood. The focus of this thesis has been to study the role of astrocytes in clearance of dead cells after TBI and to identify injury specific proteins that may function as biomarkers, by using cell cultures, animal models and in cerebrospinal fluid (CSF) from TBI patients.

    The result demonstrates a new function in that astrocytes, the most numerous cell type in the brain, engulf dead cells after injury both in cell cultures and in adult mice and thereby save neurons from contact-induced apoptosis. Astrocytes are effective phagocytes, but degrade the ingested dead cells very slowly. Moreover, astrocytes express the lysosome-alkalizing proteins Rab27a and Nox2 as well as major histocompatibility complex class II, the receptors on which antigens are being presented. By lowering the pH of the lysosomes with acidic nanoparticles, the degradation increases, but the astrocytes still remained less effective than macrophages. Taken together, the data indicates that the low acidification in astrocytes can preserve antigens and that astrocytes may be able to activate T cells.

    The expression and secretion of injury-specific proteins was studied in a cell culture model of TBI by separate mass spectrometry analysis of cells and medium. Interestingly, close to 30 % of the injury-specific proteins in medium are linked to actin, for example ezrin of the ezrin/radixin/moesin (ERM) protein family. Ezrin, but none of the other ERM proteins or actin, is actively secreted after injury. Extracellular ezrin also increases in CSF in response to experimental TBI in rats and is present in CSF from TBI patients, indicating that ezrin is a potential biomarker for TBI. 

    Delarbeid
    1. Engulfing Astrocytes Protect Neurons from Contact-Induced Apoptosis following Injury
    Åpne denne publikasjonen i ny fane eller vindu >>Engulfing Astrocytes Protect Neurons from Contact-Induced Apoptosis following Injury
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. e33090-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Clearing of dead cells is a fundamental process to limit tissue damage following brain injury. Engulfment has classically been believed to be performed by professional phagocytes, but recent data show that non-professional phagocytes are highly involved in the removal of cell corpses in various situations. The role of astrocytes in cell clearance following trauma has however not been studied in detail. We have found that astrocytes actively collect and engulf whole dead cells in an in vitro model of brain injury and thereby protect healthy neurons from bystander cell death. Time-lapse experiments showed that migrating neurons that come in contact with free-floating cell corpses induced apoptosis, while neurons that migrate through groups of dead cells, garnered by astrocytes, remain unaffected. Furthermore, apoptotic cells are present within astrocytes in the mouse brain following traumatic brain injury (TBI), indicating a possible role for astrocytes in engulfment of apoptotic cells in vivo. qRT-PCR analysis showed that members of both ced pathways and Megf8 are expressed in the cell culture, indicating their possible involvement in astrocytic engulfment. Moreover, addition of dead cells had a positive effect on the protein expression of MEGF10, an ortholog to CED1, known to initiate phagocytosis by binding to phosphatidylserine. Although cultured astrocytes have an immense capacity for engulfment, seemingly without adverse effects, the ingested material is stored rather than degraded. This finding might explain the multinuclear astrocytes that are found at the lesion site in patients with various brain disorders.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-175860 (URN)10.1371/journal.pone.0033090 (DOI)000304118900009 ()
    Tilgjengelig fra: 2012-06-13 Laget: 2012-06-13 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    2. Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification
    Åpne denne publikasjonen i ny fane eller vindu >>Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification
    2015 (engelsk)Inngår i: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 63, nr 11, s. 1997-2009Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Inefficient lysosomal degradation is central in the development of various brain disorders, but the underlying mechanisms and the involvement of different cell types remains elusive. We have previously shown that astrocytes effectively engulf dead cells, but then store, rather than degrade the ingested material. In the present study we identify reasons for the slow digestion and ways to accelerate degradation in primary astrocytes. Our results show that actin-rings surround the phagosomes for long periods of time, which physically inhibit the phago-lysosome fusion. Furthermore, astrocytes express high levels of Rab27a, a protein known to reduce the acidity of lysosomes by Nox2 recruitment, in order to preserve antigens for presentation. We found that Nox2 colocalizes with the ingested material, indicating that it may influence antigen processing also in astrocytes, as they express MHC class II. By inducing long-time acidification of astrocytic lysosomes using acidic nanoparticles, we could increase the digestion of astrocyte-ingested, dead cells. The degradation was, however, normalized over time, indicating that inhibitory pathways are up-regulated in response to the enhanced acidification.

    Emneord
    Phagocytosis, in vitro model, digestion, antigen presentation, Rab27a, Nox2, pHrodo, actin, Latrunculin
    HSV kategori
    Forskningsprogram
    Neurovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-215150 (URN)10.1002/glia.22873 (DOI)000361185000008 ()
    Forskningsfinansiär
    Magnus Bergvall Foundation
    Merknad

    Manuscript title: Degradation of Ingested Dead Cells in Phagocytic Astrocytes is Tightly Regulated, but can be Enhanced by Lysosomal Acidifcatio

    Tilgjengelig fra: 2014-01-11 Laget: 2014-01-11 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    3. Identification of Injury Specific Proteins in a Cell Culture Model of Traumatic Brain Injury
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of Injury Specific Proteins in a Cell Culture Model of Traumatic Brain Injury
    Vise andre…
    2013 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 2, s. e55983-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The complicated secondary molecular and cellular mechanisms following traumatic brain injury (TBI) are still not fully understood. In the present study, we have used mass spectrometry to identify injury specific proteins in an in vitro model of TBI. A standardized injury was induced by scalpel cuts through a mixed cell culture of astrocytes, oligodendrocytes and neurons. Twenty-four hours after the injury, cell culture medium and whole-cell fractions were collected for analysis. We found 53 medium proteins and 46 cell fraction proteins that were specifically expressed after injury and the known function of these proteins was elucidated by an extensive literature survey. By using time-lapse microscopy and immunostainings we could link a large proportion of the proteins to specific cellular processes that occur in response to trauma; including cell death, proliferation, lamellipodia formation, axonal regeneration, actin remodeling, migration and inflammation. A high percentage of the proteins uniquely expressed in the medium after injury were actin-related proteins, which normally are situated intracellularly. We show that two of these, ezrin and moesin, are expressed by astrocytes both in the cell culture model and in mouse brain subjected to experimental TBI. Interestingly, we found many inflammation-related proteins, despite the fact that cells were present in the culture. This study contributes with important knowledge about the cellular responses after trauma and identifies several potential cell-specific biomarkers.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-197400 (URN)10.1371/journal.pone.0055983 (DOI)000315157200097 ()
    Tilgjengelig fra: 2013-04-01 Laget: 2013-03-25 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    4. Extracellular Ezrin - a Novel Biomarker for Traumatic Brain Injury
    Åpne denne publikasjonen i ny fane eller vindu >>Extracellular Ezrin - a Novel Biomarker for Traumatic Brain Injury
    Vise andre…
    2015 (engelsk)Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 32, nr 4, s. 244-251Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Traumatic brain injury (TBI) is a heterogeneous disease, and the discovery of diagnostic and prognostic TBI biomarkers is highly desirable in order to individualize patient care. We have previously published a study in which we identified possible TBI biomarkers by mass spectrometry 24 h after injury in a cell culture model. Ezrin-radixin-moesin (ERM) proteins were found abundantly in the medium after trauma, and in the present study we have identified extracellular ezrin as a possible biomarker for brain trauma by analyzing cell culture medium from injured primary neurons and glia and by measuring ezrin in cerebrospinal fluid (CSF) from both rats and humans. Our results show that extracellular ezrin concentration was substantially increased in cell culture medium after injury, but that the intracellular expression of the protein remained stable over time. Controlled cortical impact injured rats showed an increased amount of ezrin in CSF at both day 3 and day 7 after trauma. Moreover, ezrin was present in all ventricular CSF samples from seven humans with severe TBI. In contrast to intracellular ezrin, which is distinctly activated following TBI, extracellular ezrin is nonphosphorylated. This is the first report of extracellular ERM proteins in human and experimental models of TBI, providing a scientific foundation for further assessment of ezrin as a potential biomarker.

    Emneord
    TBI, Moesin, Radixin, pERM, ERM, actin, extracellular proteins, astrocytes
    HSV kategori
    Forskningsprogram
    Neurovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-215151 (URN)10.1089/neu.2014.3517 (DOI)000349314900005 ()25087457 (PubMedID)
    Tilgjengelig fra: 2014-01-11 Laget: 2014-01-11 Sist oppdatert: 2018-01-11bibliografisk kontrollert
  • 194.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Molecular Mechanisms in Astrocytic Degradation2013Inngår i: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 61, nr S1, s. S81-S81Artikkel i tidsskrift (Annet vitenskapelig)
  • 195.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Fernqvist, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Walmsley, Adrian
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Erlansson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Neutralization of LINGO-1 during In Vitro Differentiation of Neural Stem Cells Results in Proliferation of Immature Neurons2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 1, s. e29771-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in βIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for βIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain.

  • 196.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ebendal, Ted
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Engulfing Astrocytes Protect Neurons from Contact-Induced Apoptosis following Injury2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. e33090-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Clearing of dead cells is a fundamental process to limit tissue damage following brain injury. Engulfment has classically been believed to be performed by professional phagocytes, but recent data show that non-professional phagocytes are highly involved in the removal of cell corpses in various situations. The role of astrocytes in cell clearance following trauma has however not been studied in detail. We have found that astrocytes actively collect and engulf whole dead cells in an in vitro model of brain injury and thereby protect healthy neurons from bystander cell death. Time-lapse experiments showed that migrating neurons that come in contact with free-floating cell corpses induced apoptosis, while neurons that migrate through groups of dead cells, garnered by astrocytes, remain unaffected. Furthermore, apoptotic cells are present within astrocytes in the mouse brain following traumatic brain injury (TBI), indicating a possible role for astrocytes in engulfment of apoptotic cells in vivo. qRT-PCR analysis showed that members of both ced pathways and Megf8 are expressed in the cell culture, indicating their possible involvement in astrocytic engulfment. Moreover, addition of dead cells had a positive effect on the protein expression of MEGF10, an ortholog to CED1, known to initiate phagocytosis by binding to phosphatidylserine. Although cultured astrocytes have an immense capacity for engulfment, seemingly without adverse effects, the ingested material is stored rather than degraded. This finding might explain the multinuclear astrocytes that are found at the lesion site in patients with various brain disorders.

  • 197.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Mitchell, Claire H.
    University of Pennsylvania.
    Simonsson, Martin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification2015Inngår i: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 63, nr 11, s. 1997-2009Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inefficient lysosomal degradation is central in the development of various brain disorders, but the underlying mechanisms and the involvement of different cell types remains elusive. We have previously shown that astrocytes effectively engulf dead cells, but then store, rather than degrade the ingested material. In the present study we identify reasons for the slow digestion and ways to accelerate degradation in primary astrocytes. Our results show that actin-rings surround the phagosomes for long periods of time, which physically inhibit the phago-lysosome fusion. Furthermore, astrocytes express high levels of Rab27a, a protein known to reduce the acidity of lysosomes by Nox2 recruitment, in order to preserve antigens for presentation. We found that Nox2 colocalizes with the ingested material, indicating that it may influence antigen processing also in astrocytes, as they express MHC class II. By inducing long-time acidification of astrocytic lysosomes using acidic nanoparticles, we could increase the digestion of astrocyte-ingested, dead cells. The degradation was, however, normalized over time, indicating that inhibitory pathways are up-regulated in response to the enhanced acidification.

  • 198.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nadadhur, Aishwarya
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Extracellular Ezrin - a Novel Biomarker for Traumatic Brain Injury2015Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 32, nr 4, s. 244-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Traumatic brain injury (TBI) is a heterogeneous disease, and the discovery of diagnostic and prognostic TBI biomarkers is highly desirable in order to individualize patient care. We have previously published a study in which we identified possible TBI biomarkers by mass spectrometry 24 h after injury in a cell culture model. Ezrin-radixin-moesin (ERM) proteins were found abundantly in the medium after trauma, and in the present study we have identified extracellular ezrin as a possible biomarker for brain trauma by analyzing cell culture medium from injured primary neurons and glia and by measuring ezrin in cerebrospinal fluid (CSF) from both rats and humans. Our results show that extracellular ezrin concentration was substantially increased in cell culture medium after injury, but that the intracellular expression of the protein remained stable over time. Controlled cortical impact injured rats showed an increased amount of ezrin in CSF at both day 3 and day 7 after trauma. Moreover, ezrin was present in all ventricular CSF samples from seven humans with severe TBI. In contrast to intracellular ezrin, which is distinctly activated following TBI, extracellular ezrin is nonphosphorylated. This is the first report of extracellular ERM proteins in human and experimental models of TBI, providing a scientific foundation for further assessment of ezrin as a potential biomarker.

  • 199.
    Lööv, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Identification of unique proteins after injury in a cell culture model of TBI2012Inngår i: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 26, nr 4-5, s. 487-488Artikkel i tidsskrift (Annet vitenskapelig)
  • 200.
    Magnusson, Kristina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hånell, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Bazov, Igor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clausen, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Zhou, Qin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nandrolone decanoate administration elevates hippocampal prodynorphin mRNA expression and impairs Morris water maze performance in male rats2009Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, nr 3, s. 189-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The misuse of anabolic androgenic steroids has in several reports been associated with effects resulting in altered behavior and cognition. This study used the Morris water maze task to investigate the effect of high doses of the anabolic androgenic steroid nandrolone on spatial learning and memory in male rats. The results on day two of the experiment and during the final probe trial indicated significant memory impairment compared with controls. The hippocampus, a brain region associated with cognitive function, was analyzed for mRNA expression of prodynorphin, the precursor of dynorphinergic peptides. The results indicated that the transcription levels of prodynorphin were significantly elevated in the animals treated with nandrolone compared with controls. Thus, the findings suggest that administration of nandrolone to male rats impairs memory function, possibly via dynorphinergic actions.

1234567 151 - 200 of 373
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