Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

A 36-year-old man with a history of infantile strabismus presented with left ptosis, diplopia and bilateral distal leg paresthesias. He reported subjective fever, cough and myalgias which had developed 4 days earlier and resolved before presentation. Exam was notable for left mydriasis, mild ptosis and limited depression and adduction, consistent with a partial left oculomotor palsy. Abduction was limited bilaterally

We have cloned cDNA encoding a human transcription factor that belongs to the MEF2 (myocyte-specific enhancer-binding factor 2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family. This factor, which we have named MEF2C, binds specifically to the MEF2 element and activates transcription via this element.

Background and Purpose Impairments in CVR have been variably associated with increased risk of ischemic events and may stratify stroke risk in patients with high grade internal carotid artery (ICA) stenosis or occlusion. The purpose of this study is to perform a systematic review and meta-analysis to summarize the association of CVR impairment and stroke risk. Methods We performed a literature search evaluating the association of impairments in CVR with future stroke or transient ischemic attack (TIA) in patients with high grade ICA stenosis or occlusion. We included studies with a minimum of one year patient follow up with baseline CVR measures performed via any modality and primary outcome measures of stroke and/or TIA. A meta-analysis with assessment of study heterogeneity and publication bias was performed. Results were presented in a forest plot and summarized using a random-effects model. Results Thirteen studies met the inclusion criteria, representing a total of 1061 independent CVR tests in 991 unique patients with a mean follow up of 32.7 months. We found a significant positive relationship between impairment of CVR and development of stroke, with a pooled random effects odds ratio of 3.86 (95% CI, 1.99–7.48). Subset analysis showed that this association between CVR impairment and future risk of stroke/TIA remained significant regardless of ischemic outcome measure, symptomatic or asymptomatic disease, stenosis or occlusion, or CVR testing method. Conclusions CVR impairment is strongly associated with increased risk of ischemic events in carotid stenosis or occlusion and may be useful for stroke risk stratification.

The myocyte enhancer-binding factor 2 (MEF2) site is an essential element of many muscle-specific enhancers and promoters that binds nuclear proteins from muscle and brain. Recently, we have cloned a family of MEF2 transcription factors produced by two genes that, at the mRNA level, are broadly expressed and produce tissue-specific isoforms by posttranscriptional processes (Y.-T. Yu, R. E. Breitbart, L. B. Smoot, Y. Lee, V. Mahdavi, and B. Nadal-Ginard, Genes Dev. 6:1783Dev. 6: -1798Dev. 6: , 1992 Diverse cellular signals are involved in the induction of cell-type-specific genes that commit multipotent precursor cell lines to specific cell lineages. During the last decade, identification of factors responsible for the commitment of cells to a particular developmental fate has been one of the most productive aspects of developmental biology. The formation of skeletal muscle has proven to be a powerful model for the study of the mechanisms involved in both the production of cellular lineages as well as the establishment of the differentiated phenotype in vertebrates. Identification of the family of basic helix-loop-helix (bHLH) myogenic regulators (the MyoD family) as factors which can induce the myogenic program in a number of mesodermally derived cells has advanced our understanding of this process. The demonstration that they function as sequence-specific transcription factors, binding at the E-box present in many muscle enhancers and promoters, has become a paradigm for the analysis of cell determination and differentiation (16,38,50). However, despite the elegance and persuasiveness of the myogenesis model based on the MyoD family, it is clear that this family of regulators can neither be the exclusive myogenic determinants nor be wholly responsible for muscle-specific gene transcription. This is so because not all muscle-specific genes contain E-boxes, and even when they are present, they are not necessarily required for musclespecific gene regulation (4-7, 9, 18, 21, 25, 31, 36, 49, 53 Several families of transcription factors, in addition to the MyoD family of regulators, which mediate lineage determination and differentiation, such as the homeodomain (13) and MADS-box proteins (52), have been found to be expressed in muscle tissue. These factors have been proven to mediate lineage determination and differentiation in other systems and could provide new insights on the molecular mechanisms of myogenesis. In particular, the known homeotic function of MADS-box proteins in plants (11,26), together with their cooperative interaction with homeodomain proteins (23, 48), identifies them as candidates for evolutionarily conserved determinants of cell lineage. These interactions reveal a molecular strategy which through combinatorial mechanisms could generate a plethora of discrete signals necessary for the specification of a large number of different cell types by a limited number of factors.Recently, a new family of MADS-box transcription factors named the myocyte enhancer factor 2 (MEF2) genes have been identifi...

ContributionsMagdy Selim --organized the trial hypotheses, designed the trial, provided guidance about the data analysis and interpretation and presentation of the data, and drafted most of the sections of the manuscript. Lydia Foster --involved in the statistical analysis and data interpretation, and Contributed to the development and revisions to the manuscript. Claudia Moy --involved in the oversight of the trial conduct and progress Guohua Xi --organized the trial hypotheses, and provided critical revisions to the manuscript. MH, MJ, VS, and WC contributed to recruitment and randomization of trial participants, and provided critical revisions to the manuscript. LM and SG were involved in the design of the trial and provided critical revisions to the manuscript. Casey Norton --provided volumetric measurements of imaging data. Yuko Palesch --involved in the design of the study, statistical analysis and data interpretation, and provided critical revisions to the manuscript. Sharon yeatts --involved in the design of the study, statistical analysis and data interpretation, and contributed to the development and revisions to the manuscript. The idef investigators (see appendix) --contributed to the identification and, when eligible, randomization of trial participants. DECLARATION OF INTERESTSThis was an investigator-initiated study, funded by the NINDS (U01 NS074425). Deferoxamine Mesylate is a generic drug, and there was no commercial or industrial support for the trial. None of the authors has any competing interests related to the submitted work. MS reports grants from the NIH/NINDS (i-DEF) and the American Heart Association (outside the submitted work), and personal fees for serving on the advisory board of CSL Behring (outside the submitted work) during the conduct of the trial. SDY reports grant support from the NINDS, personal fees from Genentech and other fees from CR Bard Inc. (outside the submitted work) during the conduct of the study. SG, LDF, YP, and GX report grants from the NIH/NINDS. MDH reports personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada Ltd, grants from Covidien (Medtronic), grants from Boehringer-Ingleheim, grants from Stryker Inc., grants from Medtronic LLC, grants from NoNO Inc., (outside the submitted work); In addition, MDH has a patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent office Number: 62/086,077 and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software, is a director of the Canadian Federation of Neurological Sciences, a not-for-profit group and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and NINDS. LM, VS, WC, MJ, CM, and CN have nothing to disclose.

Background-Stroke is a major cause of disability and death. The Brain Attack Coalition has proposed establishment of primary and comprehensive stroke centers to provide appropriate care to stroke patients who require basic and more advanced interventions, respectively. Primary stroke centers have been designated by The Joint Commission since 2003, as well as by various states. The designation of comprehensive stroke centers (CSCs) is now being considered. To assist in this process, we propose a set of metrics and related data that CSCs should track to monitor the quality of care that they provide and to facilitate quality improvement. Methods and Results-We analyzed available guideline statements, reviews, and other literature to identify the major features that distinguish CSCs from primary stroke centers, drafted a set of metrics and related data elements to measure the key components of these aspects of stroke care, and then revised these through an iterative process to reach a consensus. We propose a set of metrics and related data elements that cover the major aspects of specialized care for patients with ischemic cerebrovascular disease and nontraumatic subarachnoid and intracerebral hemorrhages at CSCs. Conclusions-The metrics that we propose are intended to provide a framework for standardized data collection at CSCs to facilitate local quality improvement efforts and to allow for analysis of pooled data from different CSCs that may lead to development of national performance standards for CSCs in the future. (Stroke. 2011;42:849-877.)