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Search Results: 1 - 10 of 26259 matches for " Martin Ingelsson "
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The Grand Challenge of Cardiovascular Epidemiology: Turning the Tide
Erik Ingelsson
Frontiers in Cardiovascular Medicine , 2014, DOI: 10.3389/fcvm.2014.00002
The PPARGC1A Gly482Ser polymorphism is associated with left ventricular diastolic dysfunction in men
Erik Ingelsson, Louise Bennet, Martin Ridderstr?le, Marianne S?derstr?m, Lennart R?stam, Ulf Lindblad
BMC Cardiovascular Disorders , 2008, DOI: 10.1186/1471-2261-8-37
Abstract: The PPARGC1A Gly482Ser polymorphism was genotyped in a community-based cohort of 499 men and 533 women, who also underwent an echocardiographic examination to determine their left ventricular diastolic function. The association between the polymorphism and the presence of diastolic dysfunction was evaluated using logistic regression models.The Ser allele of the PPARGC1A Gly482Ser polymorphism was significantly associated with a lower risk of diastolic dysfunction in men, but not in women. In a model adjusting for potential confounders (age, body mass index, leisure time physical activity, hypertension and diabetes) the results were still significant and substantial (odds ratio 0.13, 95% confidence interval 0.03–0.54, p for trend = 0.004). The results were consistent in a series of models, and they imply a multiplicative, protective effect of the Ser allele, with lower risk of diastolic dysfunction for each copy of the allele.The Ser allele of the PPARGC1A Gly482Ser polymorphism was associated with decreased risk of diastolic left ventricular dysfunction in men, but not in women, in our large community-based sample. It was associated with a substantially decreased risk, even after adjustment for potential confounders. The clinical importance of the findings has to be established in further studies.Heart failure is one of the most common, costly, disabling and deadly diseases, with a lifetime risk of about 20% for a person aged 40 years [1]. Left ventricular systolic function is normal in about half of all heart failure patients [2-4], a condition often referred to as diastolic heart failure. No universally accepted measurement defining left ventricular diastolic dysfunction exists but Doppler-derived diastolic filling indexes have been used extensively [5-7]. Hypertension, diabetes and obesity are more important risk factors in patients with diastolic heart failure, as compared to heart failure patients with reduced left ventricular systolic function [3,4,8,9].Peroxi
Large Aggregates Are the Major Soluble Aβ Species in AD Brain Fractionated with Density Gradient Ultracentrifugation
Dag Sehlin, Hillevi Englund, Barbro Simu, Mikael Karlsson, Martin Ingelsson, Fredrik Nikolajeff, Lars Lannfelt, Frida Ekholm Pettersson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032014
Abstract: Soluble amyloid-β (Aβ) aggregates of various sizes, ranging from dimers to large protofibrils, have been associated with neurotoxicity and synaptic dysfunction in Alzheimer's Disease (AD). To investigate the properties of biologically relevant Aβ species, brain extracts from amyloid β protein precursor (AβPP) transgenic mice and AD patients as well as synthetic Aβ preparations were separated by size under native conditions with density gradient ultracentrifugation. The fractionated samples were then analyzed with atomic force microscopy (AFM), ELISA, and MTT cell viability assay. Based on AFM appearance and immunoreactivity to our protofibril selective antibody mAb158, synthetic Aβ42 was divided in four fractions, with large aggregates in fraction 1 and the smallest species in fraction 4. Synthetic Aβ aggregates from fractions 2 and 3 proved to be most toxic in an MTT assay. In AβPP transgenic mouse brain, the most abundant soluble Aβ species were found in fraction 2 and consisted mainly of Aβ40. Also in AD brains, Aβ was mainly found in fraction 2 but primarily as Aβ42. All biologically derived Aβ from fraction 2 was immunologically discriminated from smaller species with mAb158. Thus, the predominant species of biologically derived soluble Aβ, natively separated by density gradient ultracentrifugation, were found to match the size of the neurotoxic, 80–500 kDa synthetic Aβ protofibrils and were equally detected with mAb158.
Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer’s Disease
Gabriel Westman, Anna-Karin Lidehall, Peetra Magnusson, Martin Ingelsson, Lena Kilander, Lars Lannfelt, Olle Korsgren, Britt-Marie Eriksson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077921
Abstract: Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of na?ve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer’s disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of na?ve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.
Antibodies against Alpha-Synuclein Reduce Oligomerization in Living Cells
Thomas N?sstr?m, Susana Gon?alves, Charlotte Sahlin, Eva Nordstr?m, Valentina Screpanti Sundquist, Lars Lannfelt, Joakim Bergstr?m, Tiago F. Outeiro, Martin Ingelsson
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027230
Abstract: Recent research implicates soluble aggregated forms of α-synuclein as neurotoxic species with a central role in the pathogenesis of Parkinson's disease and related disorders. The pathway by which α-synuclein aggregates is believed to follow a step-wise pattern, in which dimers and smaller oligomers are initially formed. Here, we used H4 neuroglioma cells expressing α-synuclein fused to hemi:GFP constructs to study the effects of α-synuclein monoclonal antibodies on the early stages of aggregation, as quantified by Bimolecular Fluorescence Complementation assay. Widefield and confocal microscopy revealed that cells treated for 48 h with monoclonal antibodies internalized antibodies to various degrees. C-terminal and oligomer-selective α-synuclein antibodies reduced the extent of α-synuclein dimerization/oligomerization, as indicated by decreased GFP fluorescence signal. Furthermore, ELISA measurements on lysates and conditioned media from antibody treated cells displayed lower α-synuclein levels compared to untreated cells, suggesting increased protein turnover. Taken together, our results propose that extracellular administration of monoclonal antibodies can modify or inhibit early steps in the aggregation process of α-synuclein, thus providing further support for passive immunization against diseases with α-synuclein pathology.
Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease
Gabriel Westman, David Berglund, Johan Widén, Martin Ingelsson, Olle Korsgren, Lars Lannfelt, Dag Sehlin, Anna-Karin Lidehall, Britt-Marie Eriksson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096779
Abstract: Alzheimer’s disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.
Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain
Elin S. Blom,Yijing Wang,Lena Skoglund,Anita C. Hansson,Massimo Ubaldi,Anbarasu Lourdusamy,Wolfgang H. Sommer,Matthew Mielke,Bradley T. Hyman,Markus Heilig,Lars Lannfelt,Lars N. G. Nilsson,Martin Ingelsson
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/936580
Abstract: Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (<.05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide
Stephanie J. Soscia,James E. Kirby,Kevin J. Washicosky,Stephanie M. Tucker,Martin Ingelsson,Bradley Hyman,Mark A. Burton,Lee E. Goldstein,Scott Duong,Rudolph E. Tanzi,Robert D. Moir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009505
Abstract: The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities.
Common Familial Effects on Ischemic Stroke and Myocardial Infarction: A Prospective Population-Based Cohort Study
Katherine Kasiman,Cecilia Lundholm,Sven Sandin,P?r Sparén,Erik Ingelsson
Frontiers in Cardiovascular Medicine , 2014, DOI: 10.3389/fcvm.2014.00003
Abstract: Background: Recent genome-wide association studies suggest some overlap of genetic determinants of ischemic stroke (IS) and myocardial infarction (MI). This study aimed to assess shared familial risk between IS and MI in a large, population-wide cohort study.
Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer’s Disease Patients Alter Calcium Homeostasis
Fanny Rubio-Moscardo, Núria Setó-Salvia, Marta Pera, Mònica Bosch-Morató, Cristina Plata, Olivia Belbin, Gemma Gené, Oriol Dols-Icardo, Martin Ingelsson, Seppo Helisalmi, Hilkka Soininen, Mikko Hiltunen, Vilmantas Giedraitis, Lars Lannfelt, Ana Frank, MaJesús Bullido, Onofre Combarros, Pascual Sánchez-Juan, Mercè Boada, Lluís Tárraga, Pau Pastor, Jordi Pérez-Tur, Miquel Baquero, José L. Molinuevo, Raquel Sánchez-Valle, Pablo Fuentes-Prior, Juan Fortea, Rafael Blesa, Francisco J. Mu?oz, Alberto Lleó, Miguel A. Valverde, Jordi Clarimón
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074203
Abstract: Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ?-peptide (A?) production or A?-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical A? cascade.
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