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Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.

Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (<18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (>18 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

We demonstrated neutron beam focusing and neutron imaging using axisymmetric optics, based on pairs of confocal ellipsoid and hyperboloid mirrors. Such systems, known as Wolter mirrors, are commonly used in x-ray telescopes. A system containing four nested Ni mirror pairs was implemented and tested by focusing a polychromatic neutron beam at the MIT Reactor and conducting an imaging experiment at HFIR. The major advantage of the Wolter mirrors is the possibility of nesting for large angular collection. Using nesting, the relatively short optics can be made comparable to focusing guides in flux collection capabilities. We discuss how such optics can be used as polychromatic lenses to improve the performance of small-angle-scattering, imaging, and other instruments at compact neutron sources., United States. Dept. of Energy. Office of Basic Energy Sciences (Award DE-FG02-09ER46556), National Science Foundation (U.S.) (Award DMR-0526754), United States. Dept. of Energy. Office of Basic Energy Sciences (Award DE-FG02-09ER46557)

An achromatic cold-neutron microscope with magnification 4 is demonstrated. The image-forming optics is composed of nested coaxial mirrors of full figures of revolution, so-called Wolter optics. The spatial resolution, field of view, and depth of focus are measured and found consistent with ray-tracing simulations. Methods of increasing the resolution and magnification are discussed, as well as the scientific case for the neutron microscope. In contrast to traditional pinhole-camera neutron imaging, the resolution of the microscope is determined by the mirrors rather than by the collimation of the beam, leading to possible dramatic improvements in the signal rate and resolution., United States. Dept. of Energy (Office of Basic Energy Sciences, Materials Sciences and Engineering under Award No. DE-FG02-09ER46556), United States. Dept. of Energy (Office of Basic Energy Sciences, Materials Sciences and Engineering under Award No. DE-FG02-09ER46557), United States. Dept. of Energy (interagency Agreement No. DE_AI01-01EE50660), National Institute of Standards and Technology (U.S.). Center for Neutron Research, National Institute of Standards and Technology (U.S.). Director’s Office, National Institute of Standards and Technology (U.S.). Radiation and Biomolecular Physics Division

Whole genome expression microarrays can be used to study gene expression in blood, which comes in part from leukocytes, immature platelets, and red blood cells. Since these cells are important in the pathogenesis of stroke, RNA provides an index of these cellular responses to stroke. Our studies in rats have shown specific gene expression changes 24 hours after ischemic stroke, hemorrhage, status epilepticus, hypoxia, hypoglycemia, global ischemia, and following brief focal ischemia that simulated transient ischemic attacks in humans. Human studies show gene expression changes following ischemic stroke. These gene profiles predict a second cohort with >90% sensitivity and specificity. Gene profiles for ischemic stroke caused by large-vessel atherosclerosis and cardioembolism have been described that predict a second cohort with >85% sensitivity and specificity. Atherosclerotic genes were associated with clotting, platelets, and monocytes, and cardioembolic genes were associated with inflammation, infection, and neutrophils. These gene profiles predicted the cause of stroke in 58% of cryptogenic patients. These studies will provide diagnostic, prognostic, and therapeutic markers, and will advance our understanding of stroke in humans. New techniques to measure all coding and noncoding RNAs along with alternatively spliced transcripts will markedly advance molecular studies of human stroke.

BackgroundTissue plasminogen activator (tPA) is known to have functions beyond fibrinolysis in acute ischemic stroke, such as blood brain barrier disruption. To further delineate tPA functions in the blood, we examined the gene expression profiles induced by tPA in a rat model of ischemic stroke.ResultstPA differentially expressed 929 genes in the blood of rats (p or= |1.2|). Genes identified had functions related to modulation of immune cells. tPA gene expression was found to be dependent on the reperfusion status of cerebral vasculature. The majority of genes regulated by tPA were different from genes regulated by ischemic stroke.ConclusionstPA modulates gene expression in the blood of rats involving immune cells in a manner that is dependent on the status of vascular reperfusion. These non-fibrinolytic activities of tPA in the blood serve to better understand tPA-related complications.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2008., Cataloged from PDF version of thesis., Includes bibliographical references (p. 69-72)., Small angle neutron scattering (SANS) is used to measure the density of water contained in 1-D cylindrical pores of a mesoporous silica material MCM-41-S. By being able to suppress the homogenous nucleation process inside the narrow pore, one can keep water in the liquid state down to at least 160 K. We observe a density minimum at 210±5 K. This is the first experimental evidence of the existence of the density minimum in supercooled water. We show that the results are consistent with the predictions of molecular dynamics simulations of supercooled bulk water. From a combined analysis of SANS data from both H20 and D20 hydrated samples, we determined the absolute value of the density of water in the 1-D confined geometry. We found that the average density of water inside the fully hydrated MCM-41-S is higher than that of the bulk water. Pore size and hydration level dependences of the density are also studied. The temperature derivative of the density shows a pronounced peak signaling the crossing of the Widom line and confirming the existence of a liquid-liquid critical point at an elevated pressure., by Dazhi Liu., Ph.D.