Advancements in diagnostic and interventional radiology for stroke treatment:the path from trial to bedside through the pre-MR CLEAN, MR CLEAN, and MR CLEAN II eras

The stroke field is inevitably connected with imaging in which radiologists fulfill a central role. Our landmark MR CLEAN trial led to the implementation of baseline computed tomography angiography or magnetic resonance angiography in the acute stroke workup and subsequent endovascular treatment (EVT) for ischemic stroke patients with a large vessel occlusion in the anterior circulation, resulting in numerous patients worldwide currently being treated often successfully. A reversal of the pathophysiologic process behind an acute cerebrovascular event was made possible. Subsequently, in the MR CLEAN II trials, the clinical impact of both diagnostic and interventional radiologists remained a cornerstone of our research, which means value-based radiology. Within these MR CLEAN II trials, we proved that aspirin and heparin during EVT should be avoided due to increased symptomatic intracranial hemorrhage risk (MR CLEAN-MED). We concluded there is additional benefit of EVT in the 6-to-24-h window after stroke in the presence of good collaterals on baseline CTA (MR CLEAN-LATE). The impactful success of our stroke trials that changed many guidelines was mainly attributable to (1) the societal burden of the disease, with two thirds of patients dying or being independent at 3 months; (2) the fact that stroke is a common disease, (3) the relatively simple and pragmatic approach of the trials resembling real-world setting; (4) the acceleration of implementation in clinical practice facilitated by a structured approach to guideline development and conditional funding; and foremost (5) the excellent collaboration on a professional level between-disciplines, i.e., diagnostic radiologists, interventionalists, and neurologists. Critical relevance statement The MR CLEAN and MR CLEAN II trials have had tremendous impact on clinical practice, directly by more patients being treated with an effective intervention and indirectly through adoption of evidence-based guidelines. It is in this setting of stroke treatment that diagnostic and interventional radiologists have played a crucial role and created clinical impact.</p

The hydrogenosomes of Psalteriomonas lanterna

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The mitochondrial genomes of the ciliates Euplotes minuta and Euplotes crassus

Contains fulltext : 75729.pdf (publisher's version ) (Open Access)BACKGROUND: There are thousands of very diverse ciliate species from which only a handful mitochondrial genomes have been studied so far. These genomes are rather similar because the ciliates analysed (Tetrahymena spp. and Paramecium aurelia) are closely related. Here we study the mitochondrial genomes of the hypotrichous ciliates Euplotes minuta and Euplotes crassus. These ciliates are only distantly related to Tetrahymena spp. and Paramecium aurelia, but more closely related to Nyctotherus ovalis, which possesses a hydrogenosomal (mitochondrial) genome. RESULTS: The linear mitochondrial genomes of the hypotrichous ciliates Euplotes minuta and Euplotes crassus were sequenced and compared with the mitochondrial genomes of several Tetrahymena species, Paramecium aurelia and the partially sequenced mitochondrial genome of the anaerobic ciliate Nyctotherus ovalis. This study reports new features such as long 5'gene extensions of several mitochondrial genes, extremely long cox1 and cox2 open reading frames and a large repeat in the middle of the linear mitochondrial genome. The repeat separates the open reading frames into two blocks, each having a single direction of transcription, from the repeat towards the ends of the chromosome. Although the Euplotes mitochondrial gene content is almost identical to that of Paramecium and Tetrahymena, the order of the genes is completely different. In contrast, the 33273 bp (excluding the repeat region) piece of the mitochondrial genome that has been sequenced in both Euplotes species exhibits no difference in gene order. Unexpectedly, many of the mitochondrial genes of E. minuta encoding ribosomal proteins possess N-terminal extensions that are similar to mitochondrial targeting signals. CONCLUSION: The mitochondrial genomes of the hypotrichous ciliates Euplotes minuta and Euplotes crassus are rather different from the previously studied genomes. Many genes are extended in size compared to mitochondrial genes from other sources

The Organellar Genome and Metabolic Potential of the Hydrogen-Producing Mitochondrion of Nyctotherus ovalis

It is generally accepted that hydrogenosomes (hydrogen-producing organelles) evolved from a mitochondrial ancestor. However, until recently, only indirect evidence for this hypothesis was available. Here, we present the almost complete genome of the hydrogen-producing mitochondrion of the anaerobic ciliate Nyctotherus ovalis and show that, except for the notable absence of genes encoding electron transport chain components of Complexes III, IV, and V, it has a gene content similar to the mitochondrial genomes of aerobic ciliates. Analysis of the genome of the hydrogen-producing mitochondrion, in combination with that of more than 9,000 genomic DNA and cDNA sequences, allows a preliminary reconstruction of the organellar metabolism. The sequence data indicate that N. ovalis possesses hydrogen-producing mitochondria that have a truncated, two step (Complex I and II) electron transport chain that uses fumarate as electron acceptor. In addition, components of an extensive protein network for the metabolism of amino acids, defense against oxidative stress, mitochondrial protein synthesis, mitochondrial protein import and processing, and transport of metabolites across the mitochondrial membrane were identified. Genes for MPV17 and ACN9, two hypothetical proteins linked to mitochondrial disease in humans, were also found. The inferred metabolism is remarkably similar to the organellar metabolism of the phylogenetically distant anaerobic Stramenopile Blastocystis. Notably, the Blastocystis organelle and that of the related flagellate Proteromonas lacertae also lack genes encoding components of Complexes III, IV, and V. Thus, our data show that the hydrogenosomes of N. ovalis are highly specialized hydrogen-producing mitochondria

Periprocedural antithrombotic treatment during acute mechanical thrombectomy for ischemic stroke: A systematic review

Background: More than one-third of the patients with ischemic stroke caused by an intracranial large vessel occlusion do not recover to functional independence despite fast and successful recanalization by acute mechanical thrombectomy (MT). This may partially be explained by incomplete microvascular reperfusion. Some antithrombotics, e.g., antiplatelet agents and heparin, may be able to restore microvascular reperfusion. However, antithrombotics may also increase the risk of symptomatic intracranial hemorrhage (sICH). The aim of this review was to assess the potential safety and functional outcome of periprocedural antiplatelet or heparin use during acute MT for ischemic stroke. Methods: We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane for studies investigating the safety and functional outcome of periprocedural antiplatelet or heparin treatment during acute MT for ischemic stroke. The primary outcome was the risk for sICH. Secondary outcomes were functional independence after 3-6 months (modified Rankin Scale 0-2) and mortality within 6 months. Results: 837 studies were identified through the search, of which 19 studies were included. The sICH risks of the periprocedural use of antiplatelets ranged from 6 to 17%, and for heparin from 5 to 12%. Two of four studies reporting relative effects of the use of antithrombotics are pointing toward an increased risk of sICH. Among patients treated with antiplatelet agents, functional independence varied from 23 to 60% and mortality from 18 to 33%. For heparin, this was, respectively, 19-54% and 19-33%. The three studies presenting relative effects of antiplatelets on functional independence showed neutral effects. Both studies reporting relative effects of heparin on functional independence found it to increase this chance. Conclusion: Randomized controlled trials investigating the effect of periprocedural antithrombotic treatment in MT are lacking. Some observational studies report a slight increase in sICH risk, which may be acceptable because they also suggest a beneficial effect on functional outcome. Therefore, randomized controlled trials are warranted to address the question whether the potentially higher risk of sICH could be outweighed by improved functional outcome

Endovascular Treatment for Acute Ischemic Stroke in Patients on Oral Anticoagulants: Results from the MR CLEAN Registry

Background and Purpose - The use of oral anticoagulants (OAC) is considered a contra-indication for intravenous thrombolytics as acute treatment of ischemic stroke. However, little is known about the risks and benefits of endovascular treatment in patients on prior OAC. We aim to compare outcomes after endovascular treatment between patients with and without prior use of OAC. Methods - Data of patients with acute ischemic stroke caused by an intracranial anterior circulation occlusion, included in the nationwide, prospective, MR CLEAN Registry between March 2014 and November 2017, were analyzed. Outcomes of interest included symptomatic intracranial hemorrhage and functional outcome at 90 days (modified Rankin Scale score). Outcomes between groups were compared with (ordinal) logistic regression analyses, adjusted for prognostic factors. Results - Three thousand one hundred sixty-two patients were included in this study, of whom 502 (16%) used OAC. There was no significant difference in the occurrence of symptomatic intracranial hemorrhage between patients with and without prior OACs (5% versus 6%; adjusted odds ratio, 0.63 [95% CI, 0.38-1.06]). Patients on OACs had worse functional outcomes than patients without OACs (common odds ratio, 0.57 [95% CI, 0.47-0.66]). However, this observed difference in functional outcome disappeared after adjustment for prognostic factors (adjusted common odds ratio, 0.91 [95% CI, 0.74-1.13]). Conclusions - Prior OAC use in patients treated with endovascular treatment for ischemic stroke is not associated with an increased risk of symptomatic intracranial hemorrhage or worse functional outcome compared with no prior OAC use. Therefore, prior OAC use should not be a contra-indication for endovascular treatment

Comparison of norovirus genogroup I, II and IV seroprevalence among children in the Netherlands, 1963, 1983 and 2006

Noroviruses are a major cause of acute gastroenteritis worldwide and are a genetically diverse group of viruses. Since 2002, an increasing number of norovirus outbreaks have been reported globally, but it is not clear whether this increase has been caused by a higher awareness or reflects the emergence of new genogroup II genotype 4 (GII.4) variants. The hypothesis that norovirus prevalence has increased post-2002 and is related to the emergence of GII.4 is tested in this study. Sera collected from children aged <5 years of three Dutch cross-sectional population based cohorts in 1963, 1983 and 2006/2007 (n=143, n=130 and n=376, respectively) were tested for specific serum IgG by protein array using antigens to GII.4 and a range of other antigens representing norovirus GI, GII and GIV genotypes. The protein array was validated by paired sera of norovirus infected patients and supernatants of B-cell cultures with single epitope specificity. Evidence for norovirus infection was found to be common among Dutch children in each cohort, but the prevalence towards different genotypes changed over time. At the genogroup level, GI seroprevalence decreased significantly between 1963 and 2006/2007, while a significant increase of GII and, in particular, specific antibodies of the genotype GII.4 was detected in the 2006/2007 cohort. There were no children with only GII.4 antibodies in the 1963 cohort. This study shows that the high GII.4 norovirus incidence in very young children is a recent phenomenon. These findings are of importance for vaccine development and trials that are currently focusing mostly on GII.4 viruses

The [FeFe] hydrogenase of Nyctotherus ovalis has a chimeric origin

BACKGROUND: The hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis show how mitochondria can evolve into hydrogenosomes because they possess a mitochondrial genome and parts of an electron-transport chain on the one hand, and a hydrogenase on the other hand. The hydrogenase permits direct reoxidation of NADH because it consists of a [FeFe] hydrogenase module that is fused to two modules, which are homologous to the 24 kDa and the 51 kDa subunits of a mitochondrial complex I. RESULTS: The [FeFe] hydrogenase belongs to a clade of hydrogenases that are different from well-known eukaryotic hydrogenases. The 24 kDa and the 51 kDa modules are most closely related to homologous modules that function in bacterial [NiFe] hydrogenases. Paralogous, mitochondrial 24 kDa and 51 kDa modules function in the mitochondrial complex I in N. ovalis. The different hydrogenase modules have been fused to form a polyprotein that is targeted into the hydrogenosome. CONCLUSION: The hydrogenase and their associated modules have most likely been acquired by independent lateral gene transfer from different sources. This scenario for a concerted lateral gene transfer is in agreement with the evolution of the hydrogenosome from a genuine ciliate mitochondrion by evolutionary tinkering