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Search Results: 1 - 10 of 326017 matches for " Charlotte Mehlin S?rensen "
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Myocardial impulse propagation is impaired in right ventricular tissue of Zucker Diabetic Fatty (ZDF) rats
Kristine Boisen Olsen, Lene Nygaard Axelsen, Thomas Hartig Braunstein, Charlotte Mehlin Srensen, Claus B Andersen, Thorkil Ploug, Niels-Henrik Holstein-Rathlou, Morten Schak Nielsen
Cardiovascular Diabetology , 2013, DOI: 10.1186/1475-2840-12-19
Abstract: We used Zucker Diabetic Fatty (ZDF) rats, as a model of type 2 diabetes, and their lean controls Zucker Diabetic Lean (ZDL) rats to investigate CV and its response to the anti-arrhythmic peptide analogue AAP10. Gap junction remodeling was examined by immunofluorescence and western blotting. Cardiac histomorphometry was examined by Masson`s Trichrome staining and intracellular lipid accumulation was analyzed by Bodipy staining.CV was significantly slower in ZDF rats (56±1.9 cm/s) compared to non-diabetic controls (ZDL, 66±1.6 cm/s), but AAP10 did not affect CV in either group. The total amount of Connexin43 (C×43) was identical between ZDF and ZDL rats, but the amount of lateralized C×43 was significantly increased in ZDF rats (42±12 %) compared to ZDL rats (30±8%), p<0.04. Judged by electrophoretic mobility, C×43 phosphorylation was unchanged between ZDF and ZDL rats. Also, no differences in cardiomyocyte size or histomorphometry including fibrosis were observed between groups, but the volume of intracellular lipid droplets was 4.2 times higher in ZDF compared to ZDL rats (p<0.01).CV is reduced in type 2 diabetic ZDF rats. The CV disturbance may be partly explained by increased lateralization of C×43, but other factors are likely also involved. Our data indicates that lipotoxicity potentially may play a role in development of conduction disturbances and arrhythmias in type 2 diabetes.Diabetes is a major risk factor for sudden cardiac death and ventricular tachy-arrhythmias are suspected to be the predominant mechanism [1]. The prevalence of ventricular arrhythmias is increased in patients with diabetes and although ischemia is suspected to be an important trigger, the increased risk is independent of co-morbidities like coronary heart disease or heart failure [2,3].The electrocardiogram (ECG) of the diabetic heart is often characterized by a prolonged QT interval, reflecting an increase in action potential duration. In support of this, both the IKto- and delayed rec
Foveal Morphology Affects Self-Perceived Visual Function and Treatment Response in Neovascular Age-Related Macular Degeneration: A Cohort Study
Yousif Subhi, Gitte ?. Henningsen, Charlotte T. Larsen, Mette S. Srensen, Torben L. Srensen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091227
Abstract: Objectives To investigate the relationship between foveal morphology and self-perceived visual function in patients with neovascular age-related macular degeneration (AMD) and whether foveal characteristics are associated with Ranibizumab treatment response on the self-perceived visual function. Methods This prospective cohort study included patients with newly diagnosed neovascular AMD found eligible for treatment with Ranibizumab. Foveal morphology of both eyes was assessed using spectral-domain optical coherence tomography and all patients were interviewed using the 39-item National Eye Institute Visual Function Questionnaire (VFQ). Patients were re-interviewed 3 and 12 months after initiation of treatment with Ranibizumab. We evaluated foveal morphology at baseline in relation to VFQ scores at baseline and clinically meaningful changes in VFQ after 3 and 12 months. Results VFQ scores correlated with central foveal thickness, central foveal thickness of neuroretina (CFN), foveal RPE elevation, foveal integrity of the photoreceptor inner segment/outer segment junction (IS/OS), and external limiting membrane. In a multiple linear regression model, only best-corrected visual acuity of the better eye (p<0.001) and the IS/OS status in the better eye (p = 0.012) remained significant (Adjusted R2 = 0.418). Lower baseline VFQ and a baseline CFN within 170–270 μm in the better eye were both associated with a clinically meaningful increase in the VFQ scores after 3 and 12 months. An absent foveal IS/OS band in the better eye was associated with a clinically meaningful decrease in the VFQ scores at 12 months. Conclusions Foveal morphology in the better eye influences the self-perceived visual function in patients with neovascular AMD and possesses a predictive value for change in the self-perceived visual function at 3 and 12 months after initiation of treatment. These findings may help clinicians provide patients more individualized information of their disease and treatment prognosis from a patient-perceived point-of-view.
An improved PCR strategy for fast screening of specific and random integrations in rAAV-mediated gene targeted cell clones
Yonglun Luo, Lars Bolund, Charlotte B Srensen
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-246
Abstract: In this study, we have developed an improved PCR screening method, which can be used for fast screening of clones with unwanted random integration (RI) of the rAAV genome. This improved screening method includes four PCRs: a PCR for the selection gene (e.g. Neo-PCR), a PCR for targeted gene knockout (e.g. BRCA1-KO-PCR), and two generalized PCRs for random integration of the rAAV genome (5'-AAV-RI-PCR, and 3'-AAV-RI-PCR). We have shown that this screening method greatly facilitates the procedure of screening for BRCA1 (BReast CAncer susceptibility gene 1) targeted cell clones, eliminating cell clones with both BRCA1 knockout and random integration of the rAAV genome.This screening method has facilitated the screening of correct gene-targeted cells. As the AAV-RI-PCRs are generalized PCRs, this method can also be applied for screening of rAAV-mediated targeting of other genes.We have been using recombinant adeno-associated virus (rAAV)-mediated gene targeting to generate cloned pigs with specific gene knockout (KO) as models of human diseases [1]. However, screening for the pure gene knockout cell clones among the selection-positive cell clones can be difficult and hampers the applications of this technology. Primary fibroblasts are commonly used as target cells for gene targeting prior to cloning by somatic cell nuclear transfer. Unlike stem cells, these cells have a limited proliferation capacity rendering fast screening for knockout clones necessary. The standard screening strategy is based on PCR on cell lysates from cell clones (Figure 1A), and Southern blot analysis that requires long-term cultivation to obtain sufficient amounts of genomic DNA [1-3]. We have experienced that less than 50% of the selection-positive cell clones can be expanded sufficient for Southern blot screening when cultured in a normal growth medium (DMEM, +15%FCS, +P/S, +glutamine).In this study, we have developed an improved PCR screening method, which can be used for screening of clones w
Developing a generic, individualised adherence programme for chronic medication users
Herborg,Hanne; Haugb?lle,Lotte S.; Srensen,Lene; Rossing,Charlotte; Dam,Pernille;
Pharmacy Practice (Internet) , 2008, DOI: 10.4321/S1886-36552008000300006
Abstract: objective: the scope of this article is to describe the background for and content of an adherence counselling programme with a specific focus on an individualised, multi-dimensional adherence model for patients with a potential adherence problem (a so-called ?individualised systems model?). methods: an intervention programme based on who?s systems model for adherence was developed for implementation in primary health care and tested in a development project in danish pharmacies in 2004-2005 in three pharmacies and 4 gp practices by 27 patients. data were collected from the participants by registration forms, questionnaires, and focus groups. since the programme was to support patients in the self-management process regarding choice and implementation of medication treatment, various strategies were used and different theoretical assumptions and choices made prior to setting up the study. these strategies include distinguishing between different types of non-adherence, a model for stages of change, self-efficacy, narratives, motivating interviewing strategies and coaching techniques. these strategic and theoretical choices are described in the article. results: the strategies and theoretical reflections formed the platform for the creation of a counselling programme, which was tested in two forms, a basic and an extended version - provided by either a pharmaconomist or a pharmacist. the result section also describes a toolbox of instruments to enable pharmacy staff and gps to tailor a counselling programme for patients individually called ?safe and effective use of medicines?. besides, the results include a description of how the who-model is transformed into an individualised counselling model.
Consequences from use of reminiscence - a randomised intervention study in ten Danish nursing homes
Claire Gudex, Charlotte Horsted, Anders Jensen, Marianne Kjer, Jan Srensen
BMC Geriatrics , 2010, DOI: 10.1186/1471-2318-10-33
Abstract: In this randomised study, ten nursing homes were matched into two groups on the basis of location, type and size. In the period August 2006 - August 2007, staff in the Intervention Group were trained and supported in the use of reminiscence, involving individual and group sessions with residents as well as reminiscence boxes, posters and exhibitions. At baseline and again 6 and 12 months after the intervention start, data were collected on residents' cognitive level, agitated behaviour, general functioning and proxy-assessed quality of life, as well as on staff well-being and job satisfaction. Mixed linear modelling was used to analyse differences in outcome between the intervention and control groups.Project drop-out rates were 32% for residents and 38% for nursing staff. Most staff in the Intervention Group considered reminiscence a useful tool that improved their communication with residents, and that they would recommend to other nursing homes. There were no significant differences between residents in the Intervention and the Control Group in cognitive level, agitated behaviour or general functioning. Residents in the Intervention Group showed significant higher score at 6 months in quality of life subscale 'Response to surroundings', but there was no significant difference at 12 months.Positive effects of reminiscence were observed for all staff outcome measures, the only exception being SF-12 self-rated physical health. At 6 months after start of reminiscence, staff in the Intervention Group had significantly better scores than those in the Control Group for Personal accomplishment, Emotional exhaustion, Depersonalisation, 'Attitude towards individual contact with residents' and SF-12 self-rated mental health. At 12 months after start of reminiscence, staff in the Intervention Group had significantly better scores than those in the Control Group for Emotional exhaustion and 'Professional role and development'.The use of reminiscence appeared to have little lo
An update on targeted gene repair in mammalian cells: methods and mechanisms
Nanna M Jensen, Trine Dalsgaard, Maria Jakobsen, Roni R Nielsen, Charlotte B Srensen, Lars Bolund, Thomas G Jensen
Journal of Biomedical Science , 2011, DOI: 10.1186/1423-0127-18-10
Abstract: In the middle of the nineties, the field of targeted gene alteration (TGA) emerged as a possible method to correct diseases caused by single-base mutations [1,2]. Initially, the approach focused on stimulating the endogenous gene repair mechanisms using various single- or double-stranded oligonucleotides. These are complementary to part of the targeted gene except for one mismatched base specifically located at the site of the endogenous mutation. Upon cellular introduction these molecules will interact with the targeted gene sequence by different mechanisms. The mismatch is then recognized by components of the gene repair pathways, which subsequently can be stimulated to correct the mismatch by the use of the introduced targeting molecule [3-6].Using TGA, mutated genes can be targeted and corrected without interfering with the endogenous promoter as well as enhancer/silencer elements and reading frames [7]. Such an impact has otherwise been seen with certain aspects of gene therapy introducing a complete gene sequence including all its associated elements [8,9]. Several methods have been developed in order to optimize and effectively implement the TGA strategy in vitro as well as in vivo. These methods all constitute different structures of targeting molecules, pathways of integration and gene repair pathways stimulated, resulting in variable success rates [4,10-12].Mammalian cells utilize a variety of genetic repair pathways to ensure genomic stability of the genome. Understanding these pathways is essential for the further optimization of TGA [13-16]. A brief introduction to the pathways including their most central molecular factors is provided here (Figure 1). For detailed reviews see [17-23].The mismatch repair system (MMR) mainly corrects replication errors such as A-G and T-C mismatches [18]. It has been extensively studied both in prokaryotes and in mammalian cells, but for simplicity the following description will mainly focus on the mammalian homologues.T
Systematic Evaluation of the Metabolic to Mitogenic Potency Ratio for B10-Substituted Insulin Analogues
Tine Glendorf, Louise Knudsen, Carsten E. Stidsen, Bo F. Hansen, Anne Charlotte Hegelund, Anders R. Srensen, Erica Nishimura, Thomas Kjeldsen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029198
Abstract: Background Insulin analogues comprising acidic amino acid substitutions at position B10 have previously been shown to display increased mitogenic potencies compared to human insulin and the underlying molecular mechanisms have been subject to much scrutiny and debate. However, B10 is still an attractive position for amino acid substitutions given its important role in hexamer formation. The aim of this study was to investigate the relationships between the receptor binding properties as well as the metabolic and mitogenic potencies of a series of insulin analogues with different amino acid substitutions at position B10 and to identify a B10-substituted insulin analogue without an increased mitogenic to metabolic potency ratio. Methodology/Principal Findings A panel of ten singly-substituted B10 insulin analogues with different amino acid side chain characteristics were prepared and insulin receptor (both isoforms) and IGF-I receptor binding affinities using purified receptors, insulin receptor dissociation rates using BHK cells over-expressing the human insulin receptor, metabolic potencies by lipogenesis in isolated rat adipocytes, and mitogenic potencies using two different cell types predominantly expressing either the insulin or the IGF-I receptor were systematically investigated. Only analogues B10D and B10E with significantly increased insulin and IGF-I receptor affinities as well as decreased insulin receptor dissociation rates displayed enhanced mitogenic potencies in both cell types employed. For the remaining analogues with less pronounced changes in receptor affinities and insulin receptor dissociation rates, no apparent correlation between insulin receptor occupancy time and mitogenicity was observed. Conclusions/Significance Several B10-substituted insulin analogues devoid of disproportionate increases in mitogenic compared to metabolic potencies were identified. In the present study, receptor binding affinity rather than insulin receptor off-rate appears to be the major determinant of both metabolic and mitogenic potency. Our results also suggest that the increased mitogenic potency is attributable to both insulin and IGF-I receptor activation.
Absence of an Intron Splicing Silencer in Porcine Smn1 Intron 7 Confers Immunity to the Exon Skipping Mutation in Human SMN2
Thomas Koed Doktor, Lisbeth Dahl Schr?der, Henriette Skovgaard Andersen, Sabrina Br?ner, Anna Kitewska, Charlotte Brandt Srensen, Brage Storstein Andresen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098841
Abstract: Spinal Muscular Atrophy is caused by homozygous loss of SMN1. All patients retain at least one copy of SMN2 which produces an identical protein but at lower levels due to a silent mutation in exon 7 which results in predominant exclusion of the exon. Therapies targeting the splicing of SMN2 exon 7 have been in development for several years, and their efficacy has been measured using either in vitro cellular assays or in vivo small animal models such as mice. In this study we evaluated the potential for constructing a mini-pig animal model by introducing minimal changes in the endogenous porcine Smn1 gene to maintain the native genomic structure and regulation. We found that while a Smn2-like mutation can be introduced in the porcine Smn1 gene and can diminish the function of the ESE, it would not recapitulate the splicing pattern seen in human SMN2 due to absence of a functional ISS immediately downstream of exon 7. We investigated the ISS region and show here that the porcine ISS is inactive due to disruption of a proximal hnRNP A1 binding site, while a distal hnRNP A1 binding site remains functional but is unable to maintain the functionality of the ISS as a whole.
Feedback cooling of cantilever motion using a quantum point contact transducer
M. Montinaro,A. Mehlin,H. S. Solanki,P. Peddibhotla,S. Mack,D. D. Awschalom,M. Poggio
Physics , 2012, DOI: 10.1063/1.4754606
Abstract: We use a quantum point contact (QPC) as a displacement transducer to measure and control the low-temperature thermal motion of a nearby micromechanical cantilever. The QPC is included in an active feedback loop designed to cool the cantilever's fundamental mechanical mode, achieving a squashing of the QPC noise at high gain. The minimum achieved effective mode temperature of 0.2 K and the displacement resolution of 10^(-11) m/Hz^(1/2) are limited by the performance of the QPC as a one-dimensional conductor and by the cantilever-QPC capacitive coupling.
Comparison of Gene Expression and Genome-Wide DNA Methylation Profiling between Phenotypically Normal Cloned Pigs and Conventionally Bred Controls
Fei Gao, Yonglun Luo, Shengting Li, Jian Li, Lin Lin, Anders Lade Nielsen, Charlotte Brandt Srensen, Gábor Vajta, Jun Wang, Xiuqing Zhang, Yutao Du, Huanming Yang, Lars Bolund
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025901
Abstract: Animal breeding via Somatic Cell Nuclear Transfer (SCNT) has enormous potential in agriculture and biomedicine. However, concerns about whether SCNT animals are as healthy or epigenetically normal as conventionally bred ones are raised as the efficiency of cloning by SCNT is much lower than natural breeding or In-vitro fertilization (IVF). Thus, we have conducted a genome-wide gene expression and DNA methylation profiling between phenotypically normal cloned pigs and control pigs in two tissues (muscle and liver), using Affymetrix Porcine expression array as well as modified methylation-specific digital karyotyping (MMSDK) and Solexa sequencing technology. Typical tissue-specific differences with respect to both gene expression and DNA methylation were observed in muscle and liver from cloned as well as control pigs. Gene expression profiles were highly similar between cloned pigs and controls, though a small set of genes showed altered expression. Cloned pigs presented a more different pattern of DNA methylation in unique sequences in both tissues. Especially a small set of genomic sites had different DNA methylation status with a trend towards slightly increased methylation levels in cloned pigs. Molecular network analysis of the genes that contained such differential methylation loci revealed a significant network related to tissue development. In conclusion, our study showed that phenotypically normal cloned pigs were highly similar with normal breeding pigs in their gene expression, but moderate alteration in DNA methylation aspects still exists, especially in certain unique genomic regions.
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