Key Points• Regulatory T cells are promoters of ischemic stroke by inducing dysfunction of the cerebral microvasculature. We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic antiinflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in IntroductionIschemic stroke induces a profound local inflammatory response involving various types of immune cells that transmigrate across the activated blood-brain barrier to invade the brain in a timed fashion. 1 Although previous research mainly focused on the role of innate immune cells, 2 recent evidence suggests that T cells, which belong to the adaptive immune system, also contribute critically to stroke development, especially in the early phase. 3 T cells have been identified in the postischemic brain as soon as 24 hours after reperfusion, 4 and Abs directed against vascular adhesion receptors expressed on the brain endothelium or leukocyte very late antigen-4 (VLA-4) expressed on lymphocytes inhibited T-cell transmigration and reduced tissue damage in models of stroke. 5 We and others showed recently that recombination activating gene (Rag1)-deficient mice, which lack functional T cells, are largely resistant against ischemic neurodegeneration. 6-8 T cellmediated brain damage became manifest by 24 hours after transient middle cerebral artery occlusion (tMCAO) and did not depend on antigen recognition or costimulation. 8 This clearly argues against TCR-driven mechanisms of tissue damage and suggests instead that T cells act detrimentally in ischemic stroke through antigenindependent pathways, at least during the early phase. Moreover, Rag1 Ϫ/Ϫ mice did not display a gross defect in thrombus formation after artificial vessel wall injury, which could easily explain the stroke protective phenotype in these animals. 8 Although the deleterious effects of T cells in stroke pathophysiology are well accepted, the functional relevance of the different T-cell subsets for stroke progression is less clear, as is their pathologic contribution at the different stages of cerebral ischemia (ie, acute versus chronic). Using adoptive cell transfer in Rag1 Ϫ/Ϫ mice, we could demonstrate that natural killer T cells (NKT cells) Submitted April 26, 2012; accepted October 27, 2012.Prepublished online as Blood First Edition paper, November 15, 2012; DOI 10.1182/blood-2012-04-426734. *C.K. and P.K. ...

Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. Highmolecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng Ϫ/Ϫ mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng Ϫ/Ϫ mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. (Blood. 2012;120(19): 4082-4092) IntroductionThe pathology of ischemic stroke is complex and involves a myriad of distinct molecular pathways and cellular interactions. Among these, progressive thrombus formation in the cerebral microvasculature is a key process that can cause secondary infarct growth despite successful recanalization of larger proximal brain vessels both under experimental conditions as well as in humans. 1,2 We recently identified the intrinsic coagulation cascade as a novel and safe antithrombotic target for the prevention and treatment of acute ischemic stroke. 3 Genetic depletion or pharmacologic blockade of coagulation factor XII (FXII), the origin of the intrinsic pathway, markedly reduced intracerebral thrombus formation and infarct growth in mice without increasing the risk of bleeding complications. 4,5 Clot formation was also significantly reduced in several in vitro models of thrombosis after FXII inhibition. 5 Current pathophysiologic concepts also emphasize the importance of inflammatory mechanisms in stroke. 6 The cerebral endothelium is activated early during the course of an ischemic event, leading to the up-regulation of cell adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the blood stream into the brain parenchyma. Those cells attracted from the periphery in concert with resident cell populations (endothelial cells, microglia) secrete an array of soluble immune mediators such as cytokines and chemokines that perpetuate the inflammatory response to cause direct or indirect ti...

We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.

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The compounds tetrakis(trimethylsilyl)methane C[Si(CH(3))(3)](4) (TC) and tetrakis(trimethylsilyl)silane Si[Si(CH(3))(3)](4) (TSi) have crystal structures with the molecules in a cubic closed-packed (c.c.p.) stacking. At room temperature both structures have space group Fm{\bar 3}m (Z = 4) with a = 13.5218 (1) Å, V = 2472.3 (1) Å(3) for TSi, and a = 12.8902 (2) Å, V = 2141.8 (1) Å(3) for TC. X-ray scattering data can be described by a molecule with approximately sixfold orientational disorder, ruling out a structure with free rotating molecules. Upon cooling, TSi exhibits a first-order phase transition at T(c) = 225 K, as is characterized by a jump of the lattice parameter of Deltaa = 0.182 Å and by an exothermal maximum in differential scanning calorimetry (DSC) with DeltaH = 11.7 kJ mol(-1) and DeltaS = 50.0 J mol(-1) K(-1). The structure of the low-temperature phase is refined against X-ray powder data measured at 200 K. It has space group P2(1)3 (Z = 4), a = 13.17158 (6) Å and V = 2285.15 (2) Å(3). The molecules are found to be ordered as a result of steric interactions between neighboring molecules, as is shown by analyzing distances between atoms and by calculations of the lattice energy in dependence on the orientations of the molecules. TC has a phase transition at T(c1) = 268 K, with Deltaa(1) = 0.065 Å, DeltaH(1) = 3.63 kJ mol(-1) and DeltaS(1) = 13.0 J mol(-1) K(-1). A second first-order phase transition occurs at T(c2) = 225 K, characterized by Deltaa(2) = 0.073 Å, DeltaH(2) = 6.9 kJ mol(-1) and DeltaS(2) = 30.0 J mol(-1) K(-1). The phase transition at higher temperature has not been reported previously. New NMR experiments show a small anomaly in the temperature dependence of the peak positions in NMR to occur at T(c2). Rietveld refinements were performed for the low-temperature phase measured at T = 150 K [space group P2(1)3, lattice parameter a = 12.609 (3) Å], and for the intermediate phase measured at T = 260 K [space group Pa{\bar 3}, lattice parameter a = 12.7876 (1) Å]. The low-temperature phase of TC is formed isostructural to the low-temperature phase of TSi. In the intermediate phase the molecules exhibit a twofold orientational disorder.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds—a vertebrate class of which some clades are cognitively on par with primates.

C MAS NMR experiments on solid L-tyrosine-ethylester with 13 C in low natural abundance and in fully 13 C enriched form are reported. The phenyl rings are found to undergo π flips with a rather low activation energy E a ) 50 ( 12 kJ mol -1 . In addition, the ester groups are afflicted by dynamic disorder at all temperatures accessible to MAS NMR experiments. Zero-quantum homonuclear 13 C recoupling experiments on fully 13 C enriched L-tyrosine-ethylester were carried out at low temperature. These experiments faithfully reproduce those molecular structural features, known from single-crystal X-ray diffraction, that are defined by shortrange 13 C-13 C interactions but fail to uniquely characterize the complete molecular conformation defined by intermediate-range 13 C-13 C interactions.

It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.