Publications by authors named "Märit Jensen"

10 Publications

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Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial.

Front Neurol 2020 28;11:957. Epub 2020 Aug 28.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome. We performed a analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0-1 at 90 days. Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28-3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05-1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01-1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00-1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57-5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01-1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93-6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05-0.86]), while HI was not. Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.
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http://dx.doi.org/10.3389/fneur.2020.00957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483750PMC
August 2020

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency.

Int J Mol Sci 2020 Mar 9;21(5). Epub 2020 Mar 9.

German Centre for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT) mice and AGAT mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (, ), creatine metabolism (), cerebral myelination () and neuronal excitability (). While and showed regulation by hArg supplementation, and were creatine dependent. Additional regulated genes such as and need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of and . Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.
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http://dx.doi.org/10.3390/ijms21051865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084559PMC
March 2020

Analysis of L-arginine:glycine amidinotransferase-, creatine- and homoarginine-dependent gene regulation in the murine heart.

Sci Rep 2020 03 16;10(1):4821. Epub 2020 Mar 16.

University Heart and Vascular Centre Hamburg, Clinic for Cardiology, University Medical Centre Hamburg-Eppendorf, Hamburg, 20246, Germany.

L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Here, we report the first analysis of heart transcriptome variation using microarrays in an AGAT-deficient (AGAT) mouse model to evaluate AGAT-, creatine- and HA-dependent gene regulation. Our data revealed significant differences of gene expression between AGAT and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp2, Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc2, Ehd4, Hcn2, Hcn4, Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Using in silico analysis based on the GEO database we found that most of these candidate genes (Ctgf, Dsc2, Fbp2, Fgl2, Hcn2, Nppa)  revealed significant alterations in a WT mouse model of myocardial infarction underlining a pathophysiological relationship between AGAT metabolism and cardiovascular disease.
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http://dx.doi.org/10.1038/s41598-020-61638-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076046PMC
March 2020

Causes and Secondary Prevention of Acute Ischemic Stroke in Adults.

Hamostaseologie 2020 Feb 24;40(1):22-30. Epub 2019 Oct 24.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Stroke still remains a major cause of death and disability worldwide. Ischemic stroke is the most common type of stroke. Causes of ischemic stroke can be classified into large-artery atherosclerosis, cardiogenic embolism, small-vessel disease, stroke of other determined etiology, and stroke of undetermined etiology. Stroke causes in adults are mainly attributable to classical cardiovascular risk factors such as hypertension, diabetes, hypercholesterolemia, and smoking. In neuroimaging, stroke subtypes can be defined according to lesion localization and distribution (territorial infarct, lacunar infarct, hemodynamic infarct), which provide information as to the underlying etiology. Acute stroke management comprises rapid neurological assessment and rapid imaging to initiate effective reperfusion treatment with intravenous thrombolysis and mechanical thrombectomy. Stroke survivors are at increased risk of recurrent stroke. Therefore, diagnosis of the underlying cause and optimal secondary prevention is of importance. Pharmacologic secondary prevention includes antithrombotic therapy with antiplatelet drugs, oral anticoagulation, and treatment of vascular risk factors. Nonpharmacologic measures of secondary prevention comprise surgical or interventional revascularization of symptomatic carotid stenosis and interventional closure of patent foramen ovale.
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http://dx.doi.org/10.1055/s-0039-1700502DOI Listing
February 2020

Evidence for a centrosome-attracting body like structure in germ-soma segregation during early development, in the urochordate Oikopleura dioica.

BMC Dev Biol 2018 02 27;18(1). Epub 2018 Feb 27.

Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway.

Background: Germ cell formation has been investigated in sessile forms of tunicates. This process involves the release of a subset of maternal transcripts from the centrosome-attracting body (CAB) in the progenitor cells of the germ line. When germ-soma segregation is completed, CAB structures are missing from the newly formed primordial germ cells (PGCs). In free-swimming tunicates, knowledge about germ cell formation is lacking. In this investigation, comparative gene expression and electron microscopy studies were used to address germ cell formation in Oikopleura dioica (O. dioica).

Results: We found that the RNA localization pattern of pumilio (pum1) is similar to the pattern described for a subset of maternal transcripts marking the posterior end of ascidian embryos. Transcripts marking the posterior end are called postplasmic or posterior-end mark (PEM) transcripts. We found no localization of vasa (vas) transcripts to any sub-region within the germ-line precursor cells. Expression of vas4 was detected in the newly formed PGCs. Electron microscopy studies confirmed the presence of structures with similar morphology to CAB. In the same cytoplasmic compartment, we also identified pum1 transcripts and an epitope recognized by an antibody to histone H3 phosphorylated on serine 28.

Conclusions: Our findings support that a CAB-like structure participates in the segregation of maternal pum1 transcripts during germ-soma separation in O. dioica.
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http://dx.doi.org/10.1186/s12861-018-0165-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830320PMC
February 2018

Embryonic expression of endogenous retroviral RNAs in somatic tissues adjacent to the Oikopleura germline.

Nucleic Acids Res 2015 Apr 16;43(7):3701-11. Epub 2015 Mar 16.

Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, N-5008, Norway.

Selective pressure to maintain small genome size implies control of transposable elements, and most old classes of retrotransposons are indeed absent from the very compact genome of the tunicate Oikopleura dioica. Nonetheless, two families of retrotransposons are present, including the Tor elements. The gene organization within Tor elements is similar to that of LTR retrotransposons and retroviruses. In addition to gag and pol, many Tor elements carry a third gene encoding viral envelope-like proteins (Env) that may mediate infection. We show that the Tor family contains distinct classes of elements. In some classes, env mRNA is transcribed from the 5'LTR as in retroviruses. In others, env is transcribed from an additional promoter located downstream of the 5'LTR. Tor Env proteins are membrane-associated glycoproteins which exhibit some features of viral membrane fusion proteins. Whereas some elements are expressed in the adult testis, many others are specifically expressed in embryonic somatic cells adjacent to primordial germ cells. Such embryonic expression depends on determinants present in the Tor elements and not on their surrounding genomic environment. Our study shows that unusual modes of transcription and expression close to the germline may contribute to the proliferation of Tor elements.
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http://dx.doi.org/10.1093/nar/gkv169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402516PMC
April 2015

Plasticity of animal genome architecture unmasked by rapid evolution of a pelagic tunicate.

Science 2010 Dec 18;330(6009):1381-5. Epub 2010 Nov 18.

Commissariat à l'Énergie Atomique, Institut de Génomique, Genoscope, Evry, France.

Genomes of animals as different as sponges and humans show conservation of global architecture. Here we show that multiple genomic features including transposon diversity, developmental gene repertoire, physical gene order, and intron-exon organization are shattered in the tunicate Oikopleura, belonging to the sister group of vertebrates and retaining chordate morphology. Ancestral architecture of animal genomes can be deeply modified and may therefore be largely nonadaptive. This rapidly evolving animal lineage thus offers unique perspectives on the level of genome plasticity. It also illuminates issues as fundamental as the mechanisms of intron gain.
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http://dx.doi.org/10.1126/science.1194167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760481PMC
December 2010

Remodelling of the homeobox gene complement in the tunicate Oikopleura dioica.

Curr Biol 2005 Jan;15(1):R12-3

Sars Centre for Marine Molecular Biology, Bergen High Technology Centre, Thormoehlensgt. 55, 5008 Bergen, Norway.

Homeodomain transcription factors are involved in many developmental processes and have been intensely studied in a few model organisms, such as mouse, Drosophila and Caenorhabditis elegans. Homeobox genes fall into 10 classes (ANTP, PRD, POU, LIM, TALE, SIX, Cut, ZFH, HNF1, Prox) and 89 different families/groups, all of which are present in vertebrates. Additional groups may be uncovered by further genome annotation, particularly of complex vertebrate genomes. Eight of these groups have been found only in vertebrates, but not in the genome of the tunicate Ciona intestinalis. The other 81 groups of homeobox gene that have been detected in vertebrates so far probably appeared during the early evolution of bilaterians or earlier, as they are also present outside the chordates. How the homeobox genes evolved during and after the main radiation of the bilaterians remains poorly understood, as only a few animal genomes have been sequenced completely. However, drastic changes have occurred at least in the lineage of C. elegans , such as loss of several Hox genes and Hox cluster fragmentation . Here we report considerable alterations of the homeobox gene complement in the tunicate lineage.
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http://dx.doi.org/10.1016/j.cub.2004.12.010DOI Listing
January 2005

Hypervariable and highly divergent intron-exon organizations in the chordate Oikopleura dioica.

J Mol Evol 2004 Oct;59(4):448-57

Sars Centre for Marine Molecular Biology, Bergen High Technology Centre, Thormoehlensgt 55, 5020 Bergen, Norway.

Oikopleura dioica is a pelagic tunicate with a very small genome and a very short life cycle. In order to investigate the intron-exon organizations in Oikopleura, we have isolated and characterized ribosomal protein EF-1alpha, Hox, and alpha-tubulin genes. Their intron positions have been compared with those of the same genes from various invertebrates and vertebrates, including four species with entirely sequenced genomes. Oikopleura genes, like Caenorhabditis genes, have introns at a large number of nonconserved positions, which must originate from late insertions or intron sliding of ancient insertions. Both species exhibit hypervariable intron-exon organization within their alpha-tubulin gene family. This is due to localization of most nonconserved intron positions in single members of this gene family. The hypervariability and divergence of intron positions in Oikopleura and Caenorhabditis may be related to the predominance of short introns, the processing of which is not very dependent upon the exonic environment compared to large introns. Also, both species have an undermethylated genome, and the control of methylation-induced point mutations imposes a control on exon size, at least in vertebrate genes. That introns placed at such variable positions in Oikopleura or C. elegans may serve a specific purpose is not easy to infer from our current knowledge and hypotheses on intron functions. We propose that new introns are retained in species with very short life cycles, because illegitimate exchanges including gene conversion are repressed. We also speculate that introns placed at gene-specific positions may contribute to suppressing these exchanges and thereby favor their own persistence.
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http://dx.doi.org/10.1007/s00239-004-2636-5DOI Listing
October 2004

Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica.

Nature 2004 Sep;431(7004):67-71

Sars Centre for Marine Molecular Biology, Bergen High Technology Centre, Thormøhlensgaten 55, 5008 Bergen, Norway.

Tunicate embryos and larvae have small cell numbers and simple anatomical features in comparison with other chordates, including vertebrates. Although they branch near the base of chordate phylogenetic trees, their degree of divergence from the common chordate ancestor remains difficult to evaluate. Here we show that the tunicate Oikopleura dioica has a complement of nine Hox genes in which all central genes are lacking but a full vertebrate-like set of posterior genes is present. In contrast to all bilaterians studied so far, Hox genes are not clustered in the Oikopleura genome. Their expression occurs mostly in the tail, with some tissue preference, and a strong partition of expression domains in the nerve cord, in the notochord and in the muscle. In each tissue of the tail, the anteroposterior order of Hox gene expression evokes spatial collinearity, with several alterations. We propose a relationship between the Hox cluster breakdown, the separation of Hox expression domains, and a transition to a determinative mode of development.
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http://dx.doi.org/10.1038/nature02709DOI Listing
September 2004