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Search Results: 1 - 10 of 730 matches for " Fredrik Piehl "
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Fine Mapping of Gene Regions Regulating Neurodegeneration
Maria Swanberg, Karin Harnesk, Mikael Str?m, Margarita Diez, Olle Lidman, Fredrik Piehl
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005906
Abstract: Background Damage to nerve cells and axons leading to neurodegeneration is a characteristic feature of many neurological diseases. The degree of genetic influence on susceptibility to axotomy-induced neuronal death has so far been unknown. We have examined two gene regions, Vra1 and Vra2, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains. Methodology/Principal Findings In this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVGav1 to reproduce linkage to Vra1 and to fine-map this region. By isolating the effect from Vra1 in congenic strains, we demonstrate that Vra1 significantly regulates the loss of motoneurons after avulsion. The regulatory effect mediated by Vra1 thus resides in a congenic fragment of 9 megabases. Furthermore, we have used the advanced intercross lines to give more support to Vra2, originally detected as a suggestive QTL. Conclusions/Significance The results demonstrated here show that naturally occurring allelic variations affect susceptibility to axotomy-induced nerve cell death. Vra1 and Vra2 represent the first quantitative trait loci regulating this phenotype that are characterized and fine mapped in an advanced intercross line. In addition, congenic strains provide experimental evidence for the Vra1 effect on the extent of injury-induced neurodegeneration. Identification of the underlying genetic variations will increase our understanding of the regulation and mechanisms of neurodegeneration.
Influence of Perineurial Cells and Toll-Like Receptors 2 and 9 on Herpes simplex Type 1 Entry to the Central Nervous System in Rat Encephalitis
Biborka Bereczky-Veress,Nada Abdelmagid,Fredrik Piehl,Tomas Bergstr?m,Tomas Olsson,Birgit Sk?ldenberg,Margarita Diez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012350
Abstract: Herpes simplex encephalitis (HSE) is a rare disease with high mortality and significant morbidity among survivors. We have previously shown that susceptibility to HSE was host-strain dependent, as severe, lethal HSE developed after injection of human Herpes simplex type 1 virus (HSV-1) into the whiskers area of DA rats, whereas PVG rats remained completely asymptomatic. In the present study we investigated the early immunokinetics in these strains to address the underlying molecular mechanisms for the observed difference. The virus distribution and the immunological responses were compared in the whiskers area, trigeminal ganglia and brain stem after 12 hours and the first four days following infection using immunohistochemistry and qRT-PCR. A conspicuous immunopathological finding was a strain-dependent difference in the spread of the HSV-1 virus to the trigeminal ganglia, only seen in DA rats already from 12 hpi. In the whiskers area infected perineurial cells were abundant in the susceptible DA strain after 2 dpi, whereas in the resistant PVG rats HSV-1 spread was confined only to the epineurium. In both strains activation of Iba1+/ED1+ phagocytic cells followed the distribution pattern of HSV-1 staining, which was visible already at 12 hours after infection. Notably, in PVG rats higher mRNA expression of Toll-like receptors (Tlr) -2 and -9, together with increased staining for Iba1/ED1 was detected in the whiskers area. In contrast, all other Tlr-pathway markers were expressed at higher levels in the susceptible DA rats. Our data demonstrate the novel observation that genetically encoded properties of the host nerve and perineurial cells, recruitment of phagocyting cells together with the low expression of Tlr2 and -9 in the periphery define the susceptibility to HSV-1 entry into the nervous system.
Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression
Jeppe Romme Christensen, Lars B?rnsen, Rikke Ratzer, Fredrik Piehl, Mohsen Khademi, Tomas Olsson, Per Soelberg S?rensen, Finn Sellebjerg
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057820
Abstract: Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.
The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis
Ellen Iacobaeus,Petra Amoudruz,Mikael Str?m,Mohsen Khademi,Lou Brundin,Jan Hillert,Ingrid Kockum,Vivianne Malmstr?m,Tomas Olsson,Emma Tham,Fredrik Piehl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019138
Abstract: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS.
Regulated Extracellular Choline Acetyltransferase Activity— The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway
Swetha Vijayaraghavan, Azadeh Karami, Shahin Aeinehband, Homira Behbahani, Alf Grandien, Bo Nilsson, Kristina N. Ekdahl, Rickard P. F. Lindblom, Fredrik Piehl, Taher Darreh-Shori
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065936
Abstract: Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer’s disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer’s disease and multiple sclerosis in particular.
Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers
Mohsen Khademi, Ann M. Dring, Jonathan D. Gilthorpe, Anna Wuolikainen, Faiez Al Nimer, Robert A. Harris, Magnus Andersson, Lou Brundin, Fredrik Piehl, Tomas Olsson, Anders Svenningsson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063172
Abstract: Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C–X–C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.
The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat
Nada Abdelmagid ,Biborka Bereczky-Veress,André Ortlieb Guerreiro-Cacais,Petra Bergman,Katarina M. Luhr,Tomas Bergstr?m,Birgit Sk?ldenberg,Fredrik Piehl,Tomas Olsson equal contributor,Margarita Diez equal contributor
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002753
Abstract: Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3–31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.
The Economics of Power Generation Technology Choice and Investment Timing in the Presence of Policy Uncertainty  [PDF]
Robert Lundmark, Fredrik Pettersson
Low Carbon Economy (LCE) , 2012, DOI: 10.4236/lce.2012.31001
Abstract: The purpose of this study is to analyze how market and policy uncertainties affect the general profitability of new investments in the power sector, and investigate the associated investment timing and technology choices. We develop an economic model for new investments in three competing energy technologies in the Swedish electric power sector. The model takes into account the policy impacts of the EU ETS and the Swedish green certificate scheme. By simulating and modeling policy effects through stochastic prices the results suggest that bio-fuelled power is the most profitable technology choice in the presence of existing policy instruments and under our assumptions. The likelihood of choosing gas power increases over time at the expense of wind power due to the relative capital requirement per unit of output for these technologies. Overall the results indicate that the economic incentives to postpone investments into the future are significant.
Teaching Anatomy in the Multimedia World—Using Digital Tools for Progressive Learning over Time  [PDF]
Marcus Granmo, Fredrik Bengtsson
Creative Education (CE) , 2015, DOI: 10.4236/ce.2015.611117
Abstract: In a cross-faculty project journalism students filmed anatomy briefings on a medical program. The material gave medical students free access to rehearse and repeat over time. The journalism students on their part practiced camera technique, directing and editing: It was an opportunity for students to help students. Following a quality evaluation of undergraduate studies at the Lund University medical faculty in 2011, we explored, developed, and implemented novel educational tools to meet students’ need in the multimedia world in which they operate. Incorporating complementary digital learning resources, in particular integration with mobile applications enabled us to meet students in their own world, thereby enhancing the learning process. We produced short video clips on specific anatomic themes, following the curriculum of the well-established anatomy course, and posted them online, allowing continuous rehearsal and repetition over time at a pace that suits individual students. Also, available to all semesters it provides free opportunities for repetition, reducing the risk of knowledge-loss between basic and clinical parts of the program. Besides the obvious benefits for students, the material gave teachers a clear view of the students’ curriculum. Thus, the material can be used for alternative, more interactive forms of examination. The paper describes the project, and the results from evaluations and integration with mobile technology.
Training practitioners in preparing systematic reviews: a cross-sectional survey of participants in the Australasian Cochrane Centre training program
Janet H Piehl, Sally Green, Chris Silagy
BMC Health Services Research , 2002, DOI: 10.1186/1472-6963-2-11
Abstract: Cross-sectional survey by email and facsimile of the 179 participants in Australasian Cochrane Centre training events between 1998 and 2000.Ninety-two participants responded to the survey (51 percent). Response rate of deliverable surveys was 82 percent (92/112). The remainder of the participants had invalid or no contact information on file. More than 75 percent of respondents felt that the current workshops met their needs for training. The most critical barriers to completion of a Cochrane review were: lack of time (80 percent), lack of financial support (36 percent), methodological problems (23 percent) and problems with group dynamics (10 percent).Strategies to protect reviewer time and increase the efficiency of the review process may increase the numbers of trained reviewers completing a systematic review.Increasing emphasis is being placed on evidence-based medicine. [1,2] The best evidence for treatment interventions comes from systematic reviews of randomised controlled trials, [3] however, systematic reviews with meta-analysis of published and unpublished data are time- and labour-intensive.A major player in the evidence-based medicine movement has been the Cochrane Collaboration, an international organisation committed to 'preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions.' [4] The Australasian Cochrane Centre is one of the component centres of the Cochrane Collaboration, providing ongoing training and support to people in the Australasian region who prepare systematic reviews that are subsequently published on the Cochrane Library. [5] The ultimate goal of the training program is to increase the number and quality of completed Cochrane reviews, and ensure that they are routinely updated.Currently, training occurs over two days, with the first day focusing on developing a protocol for a systematic review and the second, statistical analysis and interpretation of the review. Training s
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