Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Reflections on the innovative city : examining three innovative locations in a knowledge bases framework

Abstract This paper combines three location-based cases with literature background focusing on knowledge bases and cities. The paper considers the regional context of the city of Helsinki and its surrounding area (HMA). Analyzed cases include three specific locations highlighting urban form, connectivity and knowledge-intensive production. Conceptually innovative cities are experiencing extensive change as they transform and change in order to become competitive providers of first class living for highly skilled global work-force. The integration of spatial characteristics into analyses of knowledge intensiveness of cities brings forth new theoretical openings for urban analysis setting platforms for open innovation and economy. The paper focuses on extensive material resources collected in numerous projects. The data gives more reliable picture of the knowledge-intensive locations compared to single interviews or survey studies. The total data includes work and education statistics, stakeholder interviews and observation field work. Provided reflections are classified according to key issues presented in urban studies and economic geography

Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome

Repair, regenerative and supportive therapies of the annulus fibrosus: achievements and challenges

Lumbar discectomy is a very effective therapy for neurological decompression in patients suffering from sciatica due to hernia nuclei pulposus. However, high recurrence rates and persisting post-operative low back pain in these patients require serious attention. In the past decade, tissue engineering strategies have been developed mainly targeted to the regeneration of the nucleus pulposus (NP) of the intervertebral disc. Accompanying techniques that deal with the damaged annulus fibrous are now increasingly recognised as mandatory in order to prevent re-herniation to increase the potential of NP repair and to confine NP replacement therapies. In the current review, the requirements, achievements and challenges in this quickly emerging field of research are discussed

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits

Effects of Acute Cytomegalovirus Infection on Rat Islet Allograft Survival

Transplantation of pancreatic islets is a promising therapy for the treatment of type 1 diabetes mellitus. However, long-term islet graft survival rates are still unsatisfactory low. In this study we investigated the role of cytomegalovirus (CMV) in islet allograft failure. STZ-diabetic rats received an allogenic islet graft in combination with either an acute CMV infection or control infection. A third group received ganciclovir treatment in addition to the CMV infection. Graft function was assessed by measuring basal blood glucose levels. After sacrifice, the islet grafts were retrieved for analysis of infection and leukocyte infiltration. CMV-infected recipients demonstrated accelerated islet graft failure compared to noninfected controls. CMV infection of the graft was only observed prior to complete graft failure. Quantification of the leukocyte infiltration demonstrated increased CD8(+) T-cell and NK cell infiltration in the CMV-infected grafts compared to the controls. This suggests that CMV infection accelerates immune-mediated graft destruction. Antiviral ganciclovir treatment did not prevent accelerated graft failure, despite effectively decreasing the grade of infection. Our data confirm the recently published CITR data, which state that CMV is an independent risk factor for failure of islet grafts. Also, our data demonstrate that new approaches for preventing virus-induced islet allograft failure may be required

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits