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Find video protocols related to scientific articles indexed in Pubmed.
A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
Neurology
PUBLISHED: 11-02-2014
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We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.
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Shock management in acute myocardial infarction.
EuroIntervention
PUBLISHED: 09-27-2014
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This manuscript outlines the treatment of cardiogenic shock (CS) complicating acute myocardial infarction (AMI), focusing on new therapeutic strategies from the interventional cardiologist's perspective.
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Outcome in patients with left-sided native-valve infective endocarditis and isolated large vegetations.
Clin Cardiol
PUBLISHED: 08-25-2014
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In patients with left-sided native-valve infective endocarditis (IE), the risk of embolism is increased with a vegetation size ?10?mm. For this reason-according to guidelines-surgery may be considered in patients with isolated large vegetations (without any other indication for surgery). However, the value of surgery in this patient subset has never been systematically studied.
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Immediate multivessel percutaneous coronary intervention versus culprit lesion intervention in patients with acute myocardial infarction complicated by cardiogenic shock: results of the ALKK-PCI registry.
EuroIntervention
PUBLISHED: 08-20-2014
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Aims: Current guidelines recommend immediate multivessel percutaneous coronary intervention (PCI) in patients with cardiogenic shock, despite the lack of randomised trials. We sought to investigate the use and impact on outcome of multivessel PCI in current practice in cardiogenic shock in Germany. Methods and results: Between January 2008 and December 2011 a total of 735 consecutive patients with acute myocardial infarction, cardiogenic shock and multivessel coronary artery disease underwent immediate PCI in 41 hospitals in Germany. Of these, 173 (23.5%) patients were treated with immediate multivessel PCI. The acute success of PCI with respect to TIMI 3 flow did not differ between the groups (82.5% versus 79.6%). In-hospital mortality with multivessel PCI and culprit lesion PCI was 46.8% and 35.8%, respectively. In multivariate analysis multivessel PCI was associated with an increased mortality (odds ratio 1.5; 95% confidence interval 1.15-1.84). Conclusions: In current clinical practice in Germany multivessel PCI is used only in one quarter of patients with cardiogenic shock treated with primary PCI. We observed an adverse effect of immediate multivessel PCI. Therefore, a randomised trial is needed to determine the definitive role of multivessel PCI in cardiogenic shock.
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Effects of baseline coronary occlusion and diabetes mellitus in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
Am. J. Cardiol.
PUBLISHED: 07-30-2014
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Several studies have highlighted the prognostic role of preprocedural Thrombolysis In Myocardial Infarction (TIMI) flow in the infarct-related artery (IRA) in patients with ST-segment elevation myocardial infarction (STEMI). However, the impact of preprocedural IRA occlusion in patients with diabetes with STEMI has been insufficiently studied. The aim of this study was to evaluate the effects of baseline IRA occlusion and diabetic status in patients with STEMI who underwent primary percutaneous coronary intervention by using data from a pooled analysis of randomized trials comparing intracoronary with intravenous abciximab bolus administration. A total of 3,046 patients with STEMI who underwent primary percutaneous coronary intervention were included. Diabetes was present in 578 patients (19%). The primary outcome was mortality after a median follow-up period of 375 days. Secondary end points were reinfarction and stent thrombosis. In patients without diabetes, IRA occlusion versus no occlusion was not associated with increased rates of mortality (4.3% vs 2.7%, p = 0.051) and reinfarction (3.3% vs 2.5%, p = 0.33). Patients with diabetes with IRA occlusion compared with those without occlusion showed higher rates of mortality (10.6% vs 4.6%, p = 0.01) and reinfarction (5.6% vs 2.1%, p = 0.03). Baseline IRA occlusion increased the rate of stent thrombosis in the nondiabetic (2.1% vs 1.0%, p = 0.04) and diabetic (3.2% vs 0.8%, p = 0.05) cohorts. Interaction analysis demonstrated that the risk for death and reinfarction was significantly increased when diabetes and IRA occlusion occurred concomitantly. In conclusion, patients with STEMI with diabetes and baseline IRA occlusion had disproportionately higher rates of death and reinfarction. Preprocedural IRA occlusion increased the risk for stent thrombosis, irrespective of diabetic status.
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Frequency and significance of myocardial bridging and recurrent segment of the left anterior descending coronary artery in patients with takotsubo cardiomyopathy.
Am. J. Cardiol.
PUBLISHED: 07-30-2014
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Despite intensive research efforts, the causative mechanisms of takotsubo cardiomyopathy (TC) are still unknown. Recently, morphologic characteristics of the left anterior descending coronary artery (LAD) have been proposed as a potential pathophysiological substrate. Hence, the aim of the present study was to evaluate the prevalence of myocardial bridging and LAD recurrent segments in a large cohort of patients with TC. A total of 161 patients with TC were matched for age and gender with 161 controls without coronary artery or valvular heart disease. Myocardial bridging was diagnosed according to indirect signs in coronary angiography. Furthermore, the LAD was evaluated regarding parts of the vessel outreaching the left ventricular apex (LAD recurrent segment). The prevalence of myocardial bridging was similar in the TC and control groups (11.8% vs 6.8%, p = 0.18). Any part of the LAD outreaching the left ventricular apex was observed in 55.6% of patients with TC compared with 35.4% in the control population (p <0.001). Moreover, the LAD supplied ? 25% of the inferior myocardial wall in 21 patients with TC (13.1%), whereas patients in the control group did not show this pattern of coronary circulation at all (p <0.001). Patients with TC with typical apical ballooning compared with those with atypical ballooning patterns demonstrated a higher prevalence of myocardial bridging (p = 0.04) but not LAD recurrent segments (p = 0.28). In conclusion, the prevalence of myocardial bridging in patients with TC is low and comparable with that in a matched control group. In contrast, LAD recurrent segments are significantly more frequent in patients with TC.
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A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family.
Hum. Mol. Genet.
PUBLISHED: 06-20-2014
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Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53 Mb on Chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single-nucleotide polymorphism or exome sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephaly.
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Gender differences in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.
Clin Res Cardiol
PUBLISHED: 05-31-2014
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Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high mortality. Previous studies regarding gender-specific differences in CS are conflicting and there are insufficient data for the presence of gender-associated differences in the contemporary percutaneous coronary intervention era. Aim of this study was therefore to investigate gender-specific differences in a large cohort of AMI patients with CS undergoing contemporary treatment.
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Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy.
Epilepsia
PUBLISHED: 05-30-2014
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Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy-aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)-array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE.
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Mutation of POC1B in a severe syndromic retinal ciliopathy.
Hum. Mutat.
PUBLISHED: 05-28-2014
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We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.
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Prognosis after ST-elevation myocardial infarction: a study on cardiac magnetic resonance imaging versus clinical routine.
Trials
PUBLISHED: 05-21-2014
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This study aimed to evaluate the incremental prognostic value of infarct size, microvascular obstruction (MO), myocardial salvage index (MSI), and left ventricular ejection fraction (LV-EFCMR) assessed by cardiac magnetic resonance imaging (CMR) in comparison to traditional outcome markers in patients with ST-elevation myocardial infarction (STEMI) reperfused by primary percutaneous intervention (PCI).
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Incidence, characteristics and functional implications of cerebral embolic lesions after the MitraClip procedure.
EuroIntervention
PUBLISHED: 05-17-2014
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Aims: This study aimed to assess the incidence and impact of cerebral embolic events after the MitraClip procedure. Methods and results: Twenty-seven high-risk patients (logistic EuroSCORE I 25±15%) underwent the MitraClip procedure and cerebral diffusion-weighted magnetic resonance imaging (MRI) in median two days before and three days after the procedure. On the same day, neurocognitive function was assessed using the Montreal Cognitive Assessment (MoCA) questionnaire and thorough clinical examination. Comparison of pre- and post-interventional MRI showed that 23 of 27 patients (85.7%) had newly acquired microembolic lesions with in median three (interquartile range 1-9) new lesions per patient. Of these, three patients (11.1%) had lesions with diameter >5 mm. Patients with >3 new cerebral embolic lesions (n=13, 48%) had a lower post-interventional MoCA score in comparison to patients with ?3 embolic lesions (23.6±3.6 vs. 20.3±4.5; p=0.046) in univariate analysis. Multivariate stepwise regression analysis identified device time as an independent predictor of the number of post-procedural new lesions (p=0.003) and, for reduced post-interventional MoCA score, a low MoCA score at baseline (p<0.001). Conclusions: The MitraClip procedure results in new ischaemic cerebral lesions in the vast majority of patients. Preliminary data suggest that these lesions are clinically without significant impact on global cognitive function. Clinical trials.gov: NCT01288976.
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Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy.
Nat. Genet.
PUBLISHED: 05-09-2014
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Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.
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Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis.
Int. J. Cancer
PUBLISHED: 05-07-2014
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To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (?-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant.
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Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.
Nat. Genet.
PUBLISHED: 04-24-2014
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Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.
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Impact of long-term statin pretreatment on myocardial damage in ST elevation myocardial infarction (from the AIDA STEMI CMR Substudy).
Am. J. Cardiol.
PUBLISHED: 04-11-2014
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Nonrandomized studies suggested lower mortality rates with statin pretreatment in patients with acute ST elevation myocardial infarction (STEMI). However, clinical data are still inconclusive and the mechanisms of these presumed beneficial effects require further exploration. Cardiac magnetic resonance (CMR) imaging offers the possibility of studying a variety of markers of myocardial damage and reperfusion injury after myocardial infarction. The aim of this study was to assess a possible link of statin pretreatment with myocardial damage in acute STEMI. The multicenter Abciximab i.v. versus i.c. in ST-elevation Myocardial Infarction CMR substudy enrolled 795 consecutive patients with acute STEMI who underwent primary angioplasty within 12 hours of symptom onset. CMR studies assessing left ventricular ejection fraction, infarct size, microvascular obstruction, area at risk, and myocardial salvage index were performed in a median of 3 days after the clinical event. We performed a retrospective analysis to evaluate the impact of statin pretreatment on myocardial damage. Information on statin pretreatment was available in 791 of 795 patients (99%). Of these, 122 (15%) had long-term statin pretreatment. CMR results showed no significant differences in the area at risk, left ventricular ejection fraction, infarct size, microvascular obstruction, and myocardial salvage index between patients with and without statin pretreatment. Furthermore, no differences in short- and long-term outcomes could be observed. In conclusion, in this CMR study, statin pretreatment in patients with STEMI was not associated with lesser myocardial damage.
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Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients.
JACC Cardiovasc Imaging
PUBLISHED: 03-26-2014
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The aim of this study was to evaluate the value of microvascular obstruction (MO) and infarct size as a percentage of left ventricular mass (IS%LV), as measured by contrast-enhanced cardiac magnetic resonance, in predicting major cardiovascular adverse events (MACE) at 2 years in patients with ST-segment elevation myocardial infarction reperfused by primary percutaneous coronary intervention. Individual data from 1,025 patients were entered into the pooled analysis. MO was associated with the occurrence of MACE, defined as a composite of cardiac death, congestive heart failure, and myocardial re-infarction (adjusted hazard ratio: 3.74; 95% confidence interval: 2.21 to 6.34). IS%LV ?25% was not associated with MACE (adjusted hazard ratio: 0.90; 95% confidence interval: 0.59 to 1.37). The authors conclude that MO is an independent predictor of MACE and cardiac death, whereas IS%LV is not independently associated with MACE.
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Reprint of "Intra-aortic balloon counterpulsation--basic principles and clinical evidence".
Vascul. Pharmacol.
PUBLISHED: 03-18-2014
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Intra-aortic balloon pump (IABP) counterpulsation has been the most widely used left ventricular assist device for nearly five decades. Due to diastolic inflation and systolic deflation, coronary blood flow is increased and afterload decreased translating into augmentation of oxygen supply and lowering of oxygen demand. However, IABP may be associated with serious complications, including major bleeding, stroke, local and systemic infections and vascular complications. These might counterbalance the potential beneficial hemodynamic effects. In clinical routine, IABP is mainly used in high-risk patients with acute myocardial infarction, especially when complicated by cardiogenic shock. Further, prophylactic IABP use is frequently performed in patients at high risk for hemodynamic instability undergoing elective percutaneous coronary intervention or coronary artery bypass graft surgery. Current evidence, however, does not fully support routine use of IABP in these settings. This review focuses on the basic principles of IABP and discusses current evidence.
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Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.
Brain
PUBLISHED: 03-10-2014
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Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.
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Effect of aspiration thrombectomy on microvascular obstruction in NSTEMI patients: the TATORT-NSTEMI trial.
J. Am. Coll. Cardiol.
PUBLISHED: 03-03-2014
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Aspiration thrombectomy in ST-segment elevation myocardial infarction is recommended by current guidelines based on several randomized trials. There are no trials assessing thrombectomy in non-ST-segment elevation myocardial infarction (NSTEMI) patients.
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Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?
Am. J. Med. Genet. A
PUBLISHED: 03-01-2014
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We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.
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DEPDC5 mutations in genetic focal epilepsies of childhood.
Ann. Neurol.
PUBLISHED: 02-18-2014
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Recent studies reported DEPDC5 loss-of-function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n=11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes.
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Growth-differentiation factor 15 and osteoprotegerin in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the IABP-SHOCK II-trial.
Eur. J. Heart Fail.
PUBLISHED: 02-16-2014
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This study investigates the role of osteoprotegerin (OPG) and growth-differentiation factor 15 (GDF-15) as predictors of outcome in cardiogenic shock (CS) complicating acute myocardial infarction. The novel biomarkers OPG and GDF-15 have shown prognostic impact in various cardiovascular diseases including myocardial infarction. In acute myocardial infarction complicated by CS, the diagnostic and prognostic impact of these biomarkers has not been investigated yet. OPG and GDF-15 may have additional prognostic impact on early prognosis assessment, being potentially useful for decision-making in CS.
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Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.
Nat. Genet.
PUBLISHED: 02-13-2014
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Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
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Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction.
J. Am. Coll. Cardiol.
PUBLISHED: 02-11-2014
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Although the prognostic value of findings from cardiac magnetic resonance (CMR) imaging has been established in single-center center studies in patients with ST-segment elevation myocardial infarction (STEMI), a large multicenter investigation to evaluate the prognostic significance of myocardial damage and reperfusion injury is lacking.
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Association of upstream clopidogrel administration and myocardial reperfusion assessed by cardiac magnetic resonance imaging in patients with ST-elevation myocardial infarction.
Eur Heart J Acute Cardiovasc Care
PUBLISHED: 02-10-2014
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Current ST-elevation myocardial infarction (STEMI) guidelines recommend initiation of clopidogrel treatment as early as possible before angiography, based on pharmacokinetic and positive registry data. However, the mechanisms of the beneficial effect of clopidogrel pretreatment are unclear. Aim of this study was to investigate the impact of upstream clopidogrel on infarct size and microvascular obstruction (MO) assessed by cardiac magnetic resonance imaging (CMR) in STEMI patients.
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Intracoronary versus intravenous bolus abciximab administration in patients undergoing primary percutaneous coronary intervention with acute ST-elevation myocardial infarction: a pooled analysis of individual patient data from five randomised controlled trials.
EuroIntervention
PUBLISHED: 01-25-2014
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In recent years, intracoronary bolus abciximab has emerged as an alternative to the standard intravenous route in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The aim of the current study was to perform an individual patient-level pooled analysis of randomised trials, comparing intracoronary versus intravenous abciximab bolus use in STEMI patients undergoing primary PCI.
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Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease.
Am. J. Hum. Genet.
PUBLISHED: 01-07-2014
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Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
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Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome.
Cochrane Database Syst Rev
PUBLISHED: 01-04-2014
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The recently published German-Austrian S3 Guideline for the treatment of infarct related cardiogenic shock (CS) revealed a lack of evidence for all recommended therapeutic measures.
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The potential additional diagnostic value of assessing for pericardial effusion on cardiac magnetic resonance imaging in patients with suspected myocarditis.
Eur Heart J Cardiovasc Imaging
PUBLISHED: 12-29-2013
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The presence of pericardial effusion (PE) is considered to be suggestive of inflammation in suspected myocarditis. However, the incremental value of assessing for PE in addition to comprehensive cardiac magnetic resonance (CMR) imaging remains unclear.
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Intra-Aortic Balloon Counterpulsation - Basic Principles and Clinical Evidence.
Vascul. Pharmacol.
PUBLISHED: 12-11-2013
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Intra-aortic balloon-pump (IABP) counterpulsation has been the most widely used left ventricular assist device for nearly five decades. Due to diastolic inflation and systolic deflation, coronary blood flow is increased and afterload decreased translating into augmentation of oxygen supply and lowering of oxygen demand. However, IABP may be associated with serious complications, including major bleeding, stroke, local and systemic infections and vascular complications. These might counterbalance the potential beneficial hemodynamic effects. In clinical routine, IABP is mainly used in high-risk patients with acute myocardial infarction, especially when complicated by cardiogenic shock. Further, prophylactic IABP use is frequently performed in patients at high risk for hemodynamic instability undergoing elective percutaneous coronary intervention or coronary artery bypass graft surgery. Current evidence, however, does not fully support routine use of IABP in these settings. This review focuses on the basic principles of IABP and discusses current evidence.
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Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial.
Lancet
PUBLISHED: 09-03-2013
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In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefit only at extended follow-up. The present analysis therefore reports 6 and 12 month results.
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Intra-Aortic Balloon Pump (IABP) in cardiogenic shock.
Curr Opin Crit Care
PUBLISHED: 09-03-2013
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Despite developments in treatment of myocardial infarction, mortality rates in cardiogenic shock remain unacceptably high. Intra-aortic balloon pumping (IABP) is to date the most used device for hemodynamic support, but randomized evidence on survival benefit was lacking.
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Prognostic relevance of papillary muscle infarction in reperfused infarction as visualized by cardiovascular magnetic resonance.
Circ Cardiovasc Imaging
PUBLISHED: 08-23-2013
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Background- The prognostic significance of papillary muscle infarction (PapMI) on hard clinical outcomes has not been investigated in patients with reperfused ST-segment-elevation myocardial infarction. Noninvasive investigation by gadolinium-enhanced cardiac MRI enables the detection of PapMI with high spatial resolution. The aim of our study was (1) to assess the incidence, determinants, and clinical characteristics of PapMI in a large multicenter cohort of patients with ST-segment-elevation myocardial infarction and (2) to assess the prognostic significance of PapMI at 1-year follow-up. Methods and Results- We enrolled 738 patients with ST-segment-elevation myocardial infarction reperfused by primary angioplasty (<12 hours after symptom onset) in this cardiac MRI study at 8 centers. Cardiac MRI was completed within 1 week after infarction using a standardized protocol. Central core laboratory-masked analyses for the presence of PapMI were performed. The primary clinical end point of the study was the occurrence of major adverse cardiac events. PapMIs were detected in 104 patients (14%). The presence of PapMI was associated with larger infarcts (P<0.001), less myocardial salvage (P<0.001), impaired left ventricular function (P<0.001), and more pronounced reperfusion injury (P=0.02). Patients with PapMI had a significantly higher mortality (8 [7.7%] versus 12 [1.9%]) and major adverse cardiac events (21 [20.2%] versus 31 [4.9%]) rate at 12-month follow-up (P<0.001, respectively). PapMI was identified as a significant independent predictor of major adverse cardiac events (hazard ratio, 4.41 [confidence interval, 2.54-7.68]; P<0.001). Conclusions- The presence of PapMI is associated with decreased myocardial salvage, larger infarcts, and more pronounced reperfusion injury with subsequent significantly increased major adverse cardiac event rates. Consequently, our data underscore the importance of PapMI as a marker of poor outcome in patients with ST-segment-elevation myocardial infarction. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00712101.
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CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.
Hum. Mol. Genet.
PUBLISHED: 08-04-2013
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Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, reduction in the size of the cerebral cortex with otherwise grossly normal brain structure and variable intellectual disability. MCPH is caused by mutations of 11 different genes which code for proteins implicated in cell division and cell cycle regulation. We studied a consanguineous eight-generation family from Pakistan with ten microcephalic children using homozygosity mapping and found a new MCPH locus at HSA 7q21.11-q21.3. Sanger sequencing of the most relevant candidate genes in this region revealed a homozygous single nucleotide substitution c.589G>A in CDK6, which encodes cyclin-dependent kinase 6. The mutation changes a highly conserved alanine at position 197 into threonine (p.Ala197Thr). Post hoc whole-exome sequencing corroborated this mutations identification as the causal variant. CDK6 is an important protein for the control of the cell cycle and differentiation of various cell types. We show here for the first time that CDK6 associates with the centrosome during mitosis; however, this was not observed in patient fibroblasts. Moreover, the mutant primary fibroblasts exhibited supernumerary centrosomes, disorganized microtubules and mitotic spindles, an increased centrosome nucleus distance, reduced cell proliferation and impaired cell motility and polarity. Upon ectopic expression of the mutant protein and knockdown of CDK6 through shRNA, we noted similar effects. We propose that the identified CDK6 mutation leads to reduced cell proliferation and impairs the correct functioning of the centrosome in microtubule organization and its positioning near the nucleus which are key determinants during neurogenesis.
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A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.
Hum. Mol. Genet.
PUBLISHED: 08-01-2013
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Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.
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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Nat. Genet.
PUBLISHED: 07-18-2013
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Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fishers exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fishers exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
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A de novo gain-of-function mutation in SCN11A causes loss of pain perception.
Nat. Genet.
PUBLISHED: 05-22-2013
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The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.
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Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women.
Ann. Nutr. Metab.
PUBLISHED: 05-04-2013
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The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution.
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Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.
Am. J. Hum. Genet.
PUBLISHED: 04-30-2013
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Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.
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Thrombus Aspiration in ThrOmbus containing culpRiT lesions in Non-ST-Elevation Myocardial Infarction (TATORT-NSTEMI): study protocol for a randomized controlled trial.
Trials
PUBLISHED: 03-22-2013
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Current guidelines recommend thrombus aspiration in patients with ST-elevation myocardial infarction (STEMI); however, there are insufficient data to unequivocally support thrombectomy in patients with non-STEMI (NSTEMI).
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Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.
Am. J. Hum. Genet.
PUBLISHED: 03-19-2013
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Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.
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Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction.
Am. J. Hum. Genet.
PUBLISHED: 03-15-2013
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In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of ?-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.
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Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-11-2013
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Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.
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Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial.
Clin Res Cardiol
PUBLISHED: 03-09-2013
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Mild induced hypothermia (MIH) is indicated for comatose survivors of sudden cardiac arrest (SCA) to improve clinical outcome. In this study, we compared the efficacy of two different cooling devices for temperature management in SCA survivors.
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Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
Nat. Genet.
PUBLISHED: 03-01-2013
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Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ?) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
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Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.
J. Invest. Dermatol.
PUBLISHED: 02-25-2013
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The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.
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Effects of PPP1R1B (DARPP-32) Polymorphism on Feedback-Related Brain Potentials Across the Life Span.
Front Psychol
PUBLISHED: 02-07-2013
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Maximizing gains during probabilistic reinforcement learning requires the updating of choice - outcome expectations at the time when the feedback about a specific choice or action is given. Extant theories and evidence suggest that dopaminergic modulation plays a crucial role in reinforcement learning and the updating of choice - outcome expectations. Furthermore, recently a positive component of the event-related potential about 200?ms (P2) after feedback has been suggested to reflect such updating. The efficacy of dopaminergic modulation changes across the life span. However, to date investigations of age-related differences in feedback-related P2 during reinforcement learning are still scarce. The present study thus aims to investigate whether individual differences in the feedback-related P2 would be associated with polymorphic variations in a dopamine relevant gene PPP1R1B (also known as DARPP-32) and whether the genetic effect may differ between age groups. We observed larger P2 amplitudes in individuals carrying the genotype associated with higher dopamine receptor efficacy, i.e., a allele homozygotes of a single nucleotide polymorphism (rs907094) of the PPP1R1B gene. Moreover, this effect was more pronounced in children and older adults in comparison to adolescents and younger adults. Together, our findings indicate that polymorphic variations in a dopamine relevant gene are associated with individual differences in brain-evoked potentials of outcome updating and hint at the possibility that genotype effects on neurocognitive phenotypes may vary as a function of brain maturation and aging.
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Five-year clinical follow-up of a randomized comparison of a polymer-free sirolimus-eluting stent versus a polymer-based paclitaxel-eluting stent in patients with diabetes mellitus (LIPSIA Yukon trial).
Catheter Cardiovasc Interv
PUBLISHED: 02-04-2013
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The long-term performance of polymer-free stent systems in patients with diabetes mellitus has not been investigated extensively. This study reports long-term results of the LIPSIA Yukon trial which compared the polymer-free sirolimus-eluting Yukon Choice stent with the polymer-based paclitaxel-eluting Taxus Liberté stent in this subpopulation. At 9 months, the Yukon Choice stent failed to show non-inferiority in terms of the primary end point late lumen loss, while no significant difference in clinical outcome was detected.
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Comparison of bare-metal stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 10-year follow-up of a randomized trial.
JACC Cardiovasc Interv
PUBLISHED: 01-26-2013
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The aim of this prospective, randomized trial was to assess the 10-year long-term safety and effectiveness of percutaneous coronary intervention (PCI) and minimally invasive direct coronary artery bypass surgery (MIDCAB) for the treatment of proximal left anterior descending (LAD) lesions.
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Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial.
J. Am. Coll. Cardiol.
PUBLISHED: 01-08-2013
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The aim of the AIDA STEMI (Abciximab i.v. Versus i.c. in ST-elevation Myocardial Infarction) cardiac magnetic resonance (CMR) substudy was to investigate potential benefits of intracoronary versus intravenous abciximab bolus administration on infarct size and reperfusion injury in ST-segment elevation myocardial infarction.
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Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.
Hum. Mutat.
PUBLISHED: 01-07-2013
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The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders.
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Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-control study.
Nicotine Tob. Res.
PUBLISHED: 01-03-2013
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The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior.
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RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
PLoS ONE
PUBLISHED: 01-01-2013
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Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365?kb deletion affecting two untranslated 5-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.
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Optimal timing of invasive angiography in stable non-ST-elevation myocardial infarction: the Leipzig Immediate versus early and late PercutaneouS coronary Intervention triAl in NSTEMI (LIPSIA-NSTEMI Trial).
Eur. Heart J.
PUBLISHED: 11-21-2011
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The optimal timing of intervention in non-ST-elevation myocardial infarction (NSTEMI) remains uncertain. The aim of this multicentre trial was to assess whether an immediate invasive approach is superior to an early invasive or a selective invasive approach with respect to reduction of large infarction.
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Right ventricular injury in ST-elevation myocardial infarction: risk stratification by visualization of wall motion, edema, and delayed-enhancement cardiac magnetic resonance.
Circ Cardiovasc Imaging
PUBLISHED: 11-11-2011
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Patients with right ventricular injury (RVI) complicating ST-elevation myocardial infarction (STEMI) have impaired prognosis, but it is unclear which patients are at risk of developing RVI. Cardiac magnetic resonance can identify these patients and might add important information on risk stratification, prognosis, and treatment. Aims were to determine the predictors and the prognostic significance of RVI assessed by wall motion abnormalities, edema, myocardial salvage index, and delayed enhancement in acute reperfused STEMI.
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Sex differences in myocardial salvage and clinical outcome in patients with acute reperfused ST-elevation myocardial infarction: advances in cardiovascular imaging.
Circ Cardiovasc Imaging
PUBLISHED: 10-25-2011
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There is conflicting evidence regarding sex-based differences in myocardial salvage and clinical outcome in patients after ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate whether there are sex-associated differences in infarct characteristics (myocardial salvage, infarct size, microvascular obstruction) and clinical outcome in STEMI patients who are reperfused by primary angioplasty.
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Long-term prognostic value of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction.
Heart
PUBLISHED: 10-11-2011
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In acute myocardial infarction, cardiovascular magnetic resonance (CMR) allows for quantifying the extent of salvaged myocardium after reperfusion as a potential strong end point for clinical trials. The aim of this study was to investigate whether the early prognostic significance of myocardial salvage assessed by CMR is sustained at long-term clinical follow-up in patients with ST-elevation myocardial infarction (STEMI) undergoing primary angioplasty.
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Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial.
JAMA
PUBLISHED: 08-29-2011
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Intra-aortic balloon counterpulsation (IABC) is an adjunct to revascularization in patients with cardiogenic shock and reduces infarct size when placed prior to reperfusion in animal models.
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Assessment of mitral valve stenosis by helical MDCT: comparison with transthoracic doppler echocardiography and cardiac catheterization.
AJR Am J Roentgenol
PUBLISHED: 08-25-2011
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We evaluated the precision of helical MDCT for the quantification of mitral valve stenosis (MVS) compared with transthoracic echocardiography (TTE) and cardiac catheterization.
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Muscarinic Acetylcholine Receptor M3 Mutation Causes Urinary Bladder Disease and a Prune-Belly-like Syndrome.
Am. J. Hum. Genet.
PUBLISHED: 08-02-2011
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Urinary bladder malformations associated with bladder outlet obstruction are a frequent cause of progressive renal failure in children. We here describe a muscarinic acetylcholine receptor M3 (CHRM3) (1q41-q44) homozygous frameshift mutation in familial congenital bladder malformation associated with a prune-belly-like syndrome, defining an isolated gene defect underlying this sometimes devastating disease. CHRM3 encodes the M3 muscarinic acetylcholine receptor, which we show is present in developing renal epithelia and bladder muscle. These observations may imply that M3 has a role beyond its known contribution to detrusor contractions. This Mendelian disease caused by a muscarinic acetylcholine receptor mutation strikingly phenocopies Chrm3 null mutant mice.
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Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy.
JAMA
PUBLISHED: 07-21-2011
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Stress cardiomyopathy (SC) is a transient form of acute heart failure triggered by stressful events and associated with a distinctive left ventricular (LV) contraction pattern. Various aspects of its clinical profile have been described in small single-center populations, but larger, multicenter data sets have been lacking so far. Furthermore, it remains difficult to quickly establish diagnosis on admission.
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Platelet inhibition and GP IIb/IIIa receptor occupancy by intracoronary versus intravenous bolus administration of abciximab in patients with ST-elevation myocardial infarction.
Clin Res Cardiol
PUBLISHED: 07-14-2011
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In patients with ST-elevation myocardial infarction (STEMI), direct intracoronary bolus administration of the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is associated with a reduction in infarct size, better myocardial salvage, less microvascular obstruction and improved myocardial blush grade as compared to intravenous bolus injection, presumably caused by higher local drug concentrations leading to a more pronounced inhibition of platelet aggregation. We investigated whether there are differences in the degree of GP IIb/IIIa receptor occupancy and platelet inhibition in blood drawn from the coronary sinus (CS) shortly after intracoronary versus intravenous abciximab bolus administration.
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Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock.
Cochrane Database Syst Rev
PUBLISHED: 07-08-2011
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Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction.Although there is only limited evidence by randomised controlled trials, the current guidelines of the American Heart Association/American College of Cardiology and the European Society of Cardiology strongly recommend the use of the intra-aortic balloon counterpulsation in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations as also non-randomised trials and registry data.   
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Effect of carotid artery stenting on the release of S-100B and neurone-specific enolase.
Angiology
PUBLISHED: 05-21-2011
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Serum levels of S-100B and neurone-specific enolase (NSE) reflect cerebral injury in a variety of neurological conditions such as stroke, traumatic brain injury, and cardiac arrest. There are limited data on the release of S-100B and NSE following carotid artery stenting (CAS). In 22 patients undergoing CAS, serial blood samples for S-100B and NSE were collected before and 2, 4, and 6 to 8 hours after the procedure. A group of 20 patients with significant CAS undergoing purely diagnostic angiography served as controls. A significant increase in S-100B levels was observed 2 hours after the procedure in patients with CAS (P = .001) with a gradual decline over the next hours. In contrast, patients who underwent purely diagnostic angiography did not show significant changes in S-100B levels up to 8 hours after the procedure. Neither patients with CAS nor those undergoing diagnostic angiography displayed any significant changes in serial NSE levels.
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Cardiac magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute myocardial infarction.
Trials
PUBLISHED: 04-26-2011
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Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented.
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Prognostic value and determinants of a hypointense infarct core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation-myocardial infarction.
Circ Cardiovasc Imaging
PUBLISHED: 04-25-2011
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A hypointense core of infarcted myocardium in T2-weighted cardiovascular MRI (CMR) has been used as a noninvasive marker for intramyocardial hemorrhage. However, the clinical significance of such findings not yet been established. The aim of this study was to evaluate determinants and prognostic impact of a hypointense infarct core in T2-weighted CMR images, studied in patients after acute, reperfused ST-elevation-myocardial infarction.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.