Ischemic Stroke Severity and Mortality in Patients With and Without Atrial Fibrillation

Background Our objective was to investigate stroke severity and subsequent rate of mortality among patients with and without atrial fibrillation (AF). Contemporary data on stroke severity and prognosis in patients with AF are lacking. Methods and Results First‐time ischemic stroke patients from the Danish Stroke Registry (January 2005–December 2016) were included in an observational study. Patients with AF were matched 1:1 by sex, age, calendar year, and CHA2DS2‐VASc score with patients without AF. Stroke severity was determined by the Scandinavian Stroke Scale (0–58 points). The rate of death was estimated by Kaplan‐Meier plots and multivariable Cox regression. Among 86 458 identified patients with stroke, 17 205 had AF. After matching, 14 662 patients with AF and 14 662 patients without AF were included (51.8% women; median age, 79.6 years [25th–75th percentile, 71.8–86.0]). More patients with AF had very severe stroke (0–14 points) than patients without AF (13.7% versus 7.9%, P<0.01). The absolute rates of 30‐day and 1‐year mortality were significantly higher for patients with AF (12.1% and 28.4%, respectively) versus patients without AF (8.7% and 21.8%, respectively). This held true in adjusted models for 30‐day mortality (hazard ratio [HR], 1.40 [95% CI, 1.30–1.51]). However, this association became nonsignificant when additionally adjusting for stroke severity (HR, 1.10 [95% CI, 1.00–1.23]). AF was associated with a higher rate of 1‐year mortality (HR, 1.39 [95% CI, 1.32–1.46]), although it was mediated by stroke severity (HR, 1.15 [95% CI, 1.09–1.23], model including stroke severity). Conclusions In a contemporary nationwide cohort of patients with ischemic stroke, patients with AF had more severe strokes and higher mortality than patients without AF. The difference in mortality was mainly driven by stroke severity

MR-proADM as a Prognostic Marker in Patients With ST-Segment-Elevation Myocardial Infarction - DANAMI-3 (a Danish Study of Optimal Acute Treatment of Patients With STEMI) Substudy

Background Midregional proadrenomedullin ( MR ‐pro ADM ) has demonstrated prognostic potential after myocardial infarction ( MI ). Yet, the prognostic value of MR ‐pro ADM at admission has not been examined in patients with ST‐segment–elevation MI ( STEMI ). Methods and Results The aim of this substudy, DANAMI‐3 (The Danish Study of Optimal Acute Treatment of Patients with ST ‐segment–elevation myocardial infarction), was to examine the associations of admission concentrations of MR ‐pro ADM with short‐ and long‐term mortality and hospital admission for heart failure in patients with ST ‐segment–elevation myocardial infarction. Outcomes were assessed using Cox proportional hazard models and area under the curve using receiver operating characteristics. In total, 1122 patients were included. The median concentration of MR ‐pro ADM was 0.64 nmol/L (25th–75th percentiles, 0.53–0.79). Within 30 days 23 patients (2.0%) died and during a 3‐year follow‐up 80 (7.1%) died and 38 (3.4%) were admitted for heart failure. A doubling of MR ‐pro ADM was, in adjusted models, associated with an increased risk of 30‐day mortality (hazard ratio, 2.67; 95% confidence interval, 1.01–7.11; P =0.049), long‐term mortality (hazard ratio, 3.23; 95% confidence interval, 1.97–5.29; P &lt;0.0001), and heart failure (hazard ratio, 2.71; 95% confidence interval, 1.32–5.58; P =0.007). For 30‐day and 3‐year mortality, the area under the curve for MR ‐pro ADM was 0.77 and 0.78, respectively. For 3‐year mortality, area under the curve (0.84) of the adjusted model marginally changed (0.85; P =0.02) after addition of MR ‐pro ADM . Conclusions Elevation of admission MR ‐pro ADM was associated with long‐term mortality and heart failure, whereas the association with short‐term mortality was borderline significant. MR ‐pro ADM may be a marker of prognosis after ST‐segment–elevation myocardial infarction but does not seem to add substantial prognostic information to established clinical models. Clinical Trial Registration URL : http:/www.ClinicalTrials.gov /. Unique identifiers: NCT 01435408 and NCT 01960933. </jats:sec

The football is medicine plaform-scientific evidence, large-scale implementation of evidence-based concepts and future perspectives

The idea that football can be used as therapy and as a high-intensity and literally breath-taking training regime goes back centuries. To take one prominent example, the French philosopher Voltaire describes in the Book of Fate (1747), how a patient is cured by playing with a sacred football: “… full-blown and carefully covered with the softest Leather. You must kick this Bladder, Sir, once a Day about your Hall for a whole Hour together, with all the Vigour and Activity you possibly can”, “Ogul, upon making the first Experiment, was ready to expire for want of Breath”, “In short, our Doctor in about 8 days Time, performed an absolute Cure. His Patient was as brisk, active and gay, as One in the Bloom of his Youth.”1 Today, Voltaire and his main character, philosopher Zadig, have been proved right: Football is indeed a breath-taking activity and it can be used as therapy. Albeit today's recommendations suggest a lower training frequency, longer training periods and encourage group-based training, and say that any football can be applied

A Computational Approach to Understand In Vitro Alveolar Morphogenesis

Primary human alveolar type II (AT II) epithelial cells maintained in Matrigel cultures form alveolar-like cysts (ALCs) using a cytogenesis mechanism that is different from that of other studied epithelial cell types: neither proliferation nor death is involved. During ALC formation, AT II cells engage simultaneously in fundamentally different, but not fully characterized activities. Mechanisms enabling these activities and the roles they play during different process stages are virtually unknown. Identifying, characterizing, and understanding the activities and mechanisms are essential to achieving deeper insight into this fundamental feature of morphogenesis. That deeper insight is needed to answer important questions. When and how does an AT cell choose to switch from one activity to another? Why does it choose one action rather than another? We report obtaining plausible answers using a rigorous, multi-attribute modeling and simulation approach that leveraged earlier efforts by using new, agent and object-oriented capabilities. We discovered a set of cell-level operating principles that enabled in silico cells to self-organize and generate systemic cystogenesis phenomena that are quantitatively indistinguishable from those observed in vitro. Success required that the cell components be quasi-autonomous. As simulation time advances, each in silico cell autonomously updates its environment information to reclassify its condition. It then uses the axiomatic operating principles to execute just one action for each possible condition. The quasi-autonomous actions of individual in silico cells were sufficient for developing stable cyst-like structures. The results strengthen in silico to in vitro mappings at three levels: mechanisms, behaviors, and operating principles, thereby achieving a degree of validation and enabling answering the questions posed. We suggest that the in silico operating principles presented may have a biological counterpart and that a semiquantitative mapping exists between in silico causal events and in vitro causal events

Collective cell migration of smooth muscle and endothelial cells: impact of injury versus non-injury stimuli

BACKGROUND: Cell migration is a vital process for growth and repair. In vitro migration assays, utilized to study cell migration, often rely on physical scraping of a cell monolayer to induce cell migration. The physical act of scrape injury results in numerous factors stimulating cell migration - some injury-related, some solely due to gap creation and loss of contact inhibition. Eliminating the effects of cell injury would be useful to examine the relative contribution of injury versus other mechanisms to cell migration. Cell exclusion assays can tease out the effects of injury and have become a new avenue for migration studies. Here, we developed two simple non-injury techniques for cell exclusion: 1) a Pyrex® cylinder - for outward migration of cells and 2) a polydimethylsiloxane (PDMS) insert - for inward migration of cells. Utilizing these assays smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) migratory behavior was studied on both polystyrene and gelatin-coated surfaces. RESULTS: Differences in migratory behavior could be detected for both smooth muscle cells (SMCs) and endothelial cells (ECs) when utilizing injury versus non-injury assays. SMCs migrated faster than HUVECs when stimulated by injury in the scrape wound assay, with rates of 1.26 % per hour and 1.59 % per hour on polystyrene and gelatin surfaces, respectively. The fastest overall migration took place with HUVECs on a gelatin-coated surface, with the in-growth assay, at a rate of 2.05 % per hour. The slowest migration occurred with the same conditions but on a polystyrene surface at a rate of 0.33 % per hour. CONCLUSION: For SMCs, injury is a dominating factor in migration when compared to the two cell exclusion assays, regardless of the surface tested: polystyrene or gelatin. In contrast, the migrating surface, namely gelatin, was a dominating factor for HUVEC migration, providing an increase in cell migration over the polystyrene surface. Overall, the cell exclusion assays - the in-growth and out-growth assays, provide a means to determine pure migratory behavior of cells in comparison to migration confounded by cell wounding and injury.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Involvement of Girdin in the Determination of Cell Polarity during Cell Migration

Cell migration is a critical cellular process that determines embryonic development and the progression of human diseases. Therefore, cell- or context-specific mechanisms by which multiple promigratory proteins differentially regulate cell migration must be analyzed in detail. Girdin (girders of actin filaments) (also termed GIV, Gα-interacting vesicle associated protein) is an actin-binding protein that regulates migration of various cells such as endothelial cells, smooth muscle cells, neuroblasts, and cancer cells. Here we show that Girdin regulates the establishment of cell polarity, the deregulation of which may result in the disruption of directional cell migration. We found that Girdin interacts with Par-3, a scaffolding protein that is a component of the Par protein complex that has an established role in determining cell polarity. RNA interference-mediated depletion of Girdin leads to impaired polarization of fibroblasts and mammary epithelial cells in a way similar to that observed in Par-3-depleted cells. Accordingly, the expression of Par-3 mutants unable to interact with Girdin abrogates cell polarization in fibroblasts. Further biochemical analysis suggests that Girdin is present in the Par protein complex that includes Par-3, Par-6, and atypical protein kinase C. Considering previous reports showing the role of Girdin in the directional migration of neuroblasts, network formation of endothelial cells, and cancer invasion, these data may provide a specific mechanism by which Girdin regulates cell movement in biological contexts that require directional cell movement

Systematic Functional Analysis of Bicaudal-D Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD

Protein phosphorylation is involved in posttranslational control of essentially all biological processes. Using mass spectrometry, recent analyses of whole phosphoproteomes led to the identification of numerous new phosphorylation sites. However, the function of most of these sites remained unknown. We chose the Drosophila Bicaudal-D protein to estimate the importance of individual phosphorylation events. Being involved in different cellular processes, BicD is required for oocyte determination, for RNA transport during oogenesis and embryogenesis, and for photoreceptor nuclei migration in the developing eye. The numerous roles of BicD and the available evidence for functional importance of BicD phosphorylation led us to identify eight phosphorylation sites of BicD, and we tested a total of 14 identified and suspected phosphoserine residues for their functional importance in vivo in flies. Surprisingly, all these serines turned out to be dispensable for providing sufficient basal BicD activity for normal growth and development. However, in a genetically sensitized background where the BicDA40V protein variant provides only partial activity, serine 103 substitutions are not neutral anymore, but show surprising differences. The S103D substitution completely inactivates the protein, whereas S103A behaves neutral, and the S103F substitution, isolated in a genetic screen, restores BicDA40V function. Our results suggest that many BicD phosphorylation events may either be fortuitous or play a modulating function as shown for Ser103. Remarkably, amongst the Drosophila serines we found phosphorylated, Ser103 is the only one that is fully conserved in mammalian BicD