Campbell, B. C.V. et al. (2019) Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.ABSTRACT Background: CT-perfusion (CTP) and MRI may assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of ischaemic core and penumbra volumes were associated with functional outcomes and treatment effect.

Campbell, B. C. V. et al. (2018) Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data. Lancet Neurology, 17(1), pp. 47-53. (doi:10.1016/S1474-4422(17)30407-6) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/149670/ variables. An alternative approach using propensity-score stratification was also used. To account for between-trial variance we used mixed-effects modeling with a random effect for trial incorporated in all models. Bias was assessed using the Cochrane tool.Findings: Of 1764 patients in 7 trials, 871 were allocated to endovascular thrombectomy. After exclusion of 74 patients (72 who did not undergo the procedure and 2 with missing data on anaesthetic strategy), 236/797 (30%) of endovascular patients were treated under GA. At baseline, GA patients were younger and had shorter time to randomisation but similar pre-treatment clinical severity compared to non-GA. Endovascular thrombectomy improved functional outcome at 3 months versus standard care in both GA (adjusted common odds ratio (cOR) 1·52, 95%CI 1·09-2·11, p=0·014) and non-GA (adjusted cOR 2·33, 95%CI 1·75-3·10, p<0·001) patients. However, outcomes were significantly better for those treated under non-GA versus GA (covariate-adjusted cOR 1·53, 95%CI 1·14-2·04, p=0·004; propensitystratified cOR 1·44 95%CI 1·08-1·92, p=0·012). The risk of bias and variability among studies was assessed to be low.Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons. Funding:The HERMES collaboration was funded by an unrestricted grant from Medtronic to the University of Calgary. Research in contextEvidence before this study between abolition of the thrombectomy treatment effect in MR CLEAN and no effect in THRACE. Three single-centre randomised trials of general anaesthesia versus conscious sedation found either no difference in functional outcome between groups or a slight benefit of general anaesthesia. Added value of this studyThese data from contemporary, high quality randomised trials form the largest study to date of the association between general anesthesia and the benefit of endovascular thrombectomy versus standard care. We used two different approaches to adjust for baseline imbalances (multivariable logistic regression and propensity-score stratification). We found that GA for endovascular thrombectomy, as practiced in contemporary clinical care across a wide range of expert centres during the rand...

Morphine and the endogenous opioid peptide ␤-endorphin exert neuromodulatory as well as immunomodulatory effects, which are transduced by -opioid receptors. In this report we show that stimulation with interleukin-4 induces -opioid receptor transcripts in human primary blood cells (T cells and polymorphonuclear leukocytes), immune cell lines (Raji, U-937, and HMEC-1), and dendritic cells. In nonstimulated immune cells this gene is silent. In addition, receptor transcription is up-regulated by interleukin-4 in cultures of primary rat neurons. Transient transfection experiments in Raji and SH SY5Y neuronal cells with human and rat reporter gene constructs linked the interleukin-4 effect directly to cis-active receptor promoter elements located at nucleotide ؊997 on the human gene and nucleotide ؊727 on the rat gene. The interleukin-4 response elements function orientation independently. They bind STAT6 transcription factors as shown by electrophoretic mobility shift assays. In the human gene, a single nucleotide polymorphism within the interleukin-4 response element reduces the trans-activating potential of this element by 50%, which may affect the phenotype of persons carrying this variation. These findings provide a molecular basis for understanding bidirectional interactions between the opioid system and the immune system.Opioids are classically associated with phenomena such as analgesia, respiratory depression, and addiction. The effects of opioids are mediated by at least three different opioid receptors, termed , ␦, and , which belong to the G-protein-coupled membrane receptor family (1, 2). During the last years, evidence has accumulated showing that exogenous opiates like morphine and endogenous opioid peptides derived from the precursors proopiomelanocortin, proenkephalin, and prodynorphin have multiple immunomodulatory properties in addition to their classical functions as neuromodulators. It was stated that the endogenous opioid peptides would now be considered members of the cytokine family if they had been first discovered by immunologists (3). Elucidation of a broad bidirectional communication between the opioid system and the immune system strengthens this concept. Thus, morphine, the prototypical exogenous ligand for the receptor, is an immunosuppressive drug and is responsible for increased susceptibility of opioid addicts to infections (4 -8). Studies with -opioid receptor knockout mice emphasized the role of this receptor in immunosuppression (9). After chronic morphine treatment, these mice developed none of the symptoms characteristic of wild type mice, namely lymphoid organ atrophy, diminished CD4 ϩ / CD8 ϩ cell ratio and strongly reduced natural killer cell activity. In contrast, cytokines modulate the expression of opioid peptide genes and opioid receptor genes. For example, studies with IL-6 1 knockout mice revealed decreased levels of receptors in the brain compared with wild type animals, suggesting a positive regulation of this receptor by IL-6 in vivo (10). In vitro, up-regulation of ...

Stroke represents one of the leading causes of death and disability in Western countries, but despite intense research, only few options exist for the treatment of stroke-related infarction of brain tissue. In experimental stroke, cell therapy can partly reverse some behavioural deficits. However, the underlying mechanisms have remained unknown as most studies revealed only little, if any, evidence for neuronal replacement and the observed behavioural improvements appeared to be related rather to a graft-derived induction of a positive response in the remaining host tissue than to cell replacement by the graft itself. The present study was performed to test a murine embryonic stem cell (ESC)-based approach in rats subjected to endothelin-induced middle cerebral artery occlusion. Efficacy of cell therapy regarding graft survival, neuronal yield and diversity, and electrophysiological features of the grafted cells were tested after transplanting ESC-derived neural precursors into the infarct core and periphery of adult rats. Here, we show that grafted cells can survive, albeit not entirely, most probably as a consequence of an ongoing immune response, within the infarct core for up to 12 weeks after transplantation and that they differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. Most importantly, transplanted cells demonstrate characteristics of electrophysiologically functional neurons with voltage-gated sodium currents that enable these cells to fire action potentials. Additionally, during the first 7 weeks after transplantation we observed spontaneous excitatory post-synaptic currents in graft-derived cells indicating synaptic input. Thus, our observations show that ESC-based regenerative approaches may be successful in an acutely necrotic cellular environment.

Cerebral small vessel disease (CSVD) is associated with vessel wall changes, microbleeds, bloodbrain barrier (BBB) disturbances, and reduced cerebral blood flow (CBF). As spontaneously hypertensive stroke-prone rats (SHRSP) may be a valid model of some aspects of human CSVD, we aimed to identify whether those changes occur in definite temporal stages and whether there is an initial phenomenon beyond those common vascular alterations. Groups of 51 SHRSP were examined simultaneously by histologic (Hematoxylin-Eosin, IgG-Immunohistochemistry, vessel diameter measurement) and imaging methods (Magnetic Resonance Imaging, 201-ThalliumDiethyldithiocarbamate/99m-Technetium-HMPAO Single Photon Emission Computed Tomography conducted as pilot study) at different stages of age. Vascular pathology in SHRSP proceeds in definite stages, whereas an age-dependent accumulation of erythrocytes in capillaries and arterioles represents the homogeneous initial step of the disease. Erythrocyte accumulations are followed by BBB disturbances and microbleeds, both also increasing with age. Microthromboses, tissue infarctions with CBF reduction, and disturbed potassium uptake represent the final stage of vascular pathology in SHRSP. Erythrocyte accumulations-we parsimoniously interpreted as stases-without cerebral tissue damage represent the first step of vascular pathology in SHRSP. If that initial phenomenon could be identified in patients, these erythrocyte accumulations might be a promising target for implementing prophylactic and therapeutic strategies in human CSVD.

Cerebral small vessel disease (CSVD, cerebral microangiopathy) leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians.

Human induced pluripotent stem cells (hiPSCs) are a most appealing source for cell replacement therapy in acute brain lesions. We evaluated the potential of hiPSC therapy in stroke by transplanting hiPSC-derived neural progenitor cells (NPCs) into the postischemic striatum. Grafts received host tyrosine hydroxylase-positive afferents and contained developing interneurons and homotopic GABAergic medium spiny neurons that, with time, sent axons to the host substantia nigra. Grafting reversed stroke-induced somatosensory and motor deficits. Grafting also protected the host substantia nigra from the atrophy that follows disruption of reciprocal striatonigral connections. Graft innervation by tyrosine hydoxylase fibers, substantia nigra protection, and somatosensory functional recovery were early events, temporally dissociated from the slow maturation of GABAergic neurons in the grafts and innervation of substantia nigra. This suggests that grafted hiPSC-NPCs initially exert trophic effects on host brain structures, which precede integration and potential pathway reconstruction. We believe that transplantation of NPCs derived from hiPSCs can provide useful interventions to limit the functional consequences of stroke through both neuroprotective effects and reconstruction of impaired pathways.

Somatostatin mediates its diverse physiological effects through a family of five G-protein-coupled receptors (sst(1)-sst(5)); however, knowledge about the distribution of individual somatostatin receptor proteins in mammalian brain is incomplete. In the present study, we have examined the regional and subcellular distribution of the somatostatin receptor sst(4) in the rat CNS by raising anti-peptide antisera to the C-terminal tail of sst(4). The specificity of affinity-purified antibodies was demonstrated using immunofluorescent staining of HEK 293 cells stably transfected with an epitope-tagged sst(4) receptor. In Western blotting, the antiserum reacted specifically with a broad band in rat brain, which migrated at approximately 70 kDa before and approximately 50 kDa after enzymatic deglycosylation. sst(4)-Like immunoreactivity was most prominent in many forebrain regions, including the cerebral cortex, hippocampus, striatum, amygdala, and hypothalamus. Analysis at the electron microscopic level revealed that sst(4)-expressing neurons target this receptor preferentially to their somatodendritic domain. Like the sst(2A) receptor, sst(4)-immunoreactive dendrites were often closely apposed by somatostatin-14-containing fibers and terminals. However, unlike the sst(2A) receptor, sst(4) was not internalized in response to intracerebroventricular administration of somatostatin-14. After percussion trauma of the cortex, neuronal sst(4) receptors progressively declined at the sites of damage. This decline coincided with an induction of sst(4) expression in cells with a glial-like morphology. Together, this study provides the first description of the distribution of immunoreactive sst(4) receptor proteins in rat brain. We show that sst(4) is strictly somatodendritic and most likely functions in a postsynaptic manner. In addition, the sst(4) receptor may have a previously unappreciated function during the neuronal degeneration-regeneration process.