Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.

Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions

Proteoglycan Mimic of the Glycocalyx to Treat Endothelial Dysfunction

Patients with kidney failure usually undergo hemodialysis, a process by which toxins produced by the body are filtered from the blood, in order to survive. The preferred form for vascular access is called an arteriovenousfistula (AVF), a surgically created connection between an artery and vein that is utilized to undergo dialysis. However, AVFs have a failure rate of 50-60%. One of the contributions to AVF failure is endothelial cell dysfunction and loss of glycocalyx, which allows neutrophils and other native cells into the media of the vessel, which causes an inflammatory response. Our lab addresses endothelial dysfunction by mimicking the function of the glycocalyx to prevent transmigration of inflammatory cells and ultimately create a healthier vessel for hemodialysis. We have synthesized several glycocalyx mimics consisting of a dermatan sulfate backbone with multiple selectin and ICAM-binding peptides attached. Initial testing involved determining the ability of the variants to bind to inflamed endothelial cells. We also cultured human promyelocytic leukemia cells (HL60) and used retinoic acid to differentiate them into neutrophils. These cells would then test the glycocalyx mimics ability to prevent migration of neutrophils. Thus far, we have seen that the glycocalyx mimics binding to endothelial cells and that this binding is dependent upon the type of selectin and/or ICAM-binding peptides as well as how many peptides are present per dermatan sulfate backbone. We have also shown that proliferation occurs 10 days after seeding, and that rentinoic acid (RA) differentiates HL60 cells into neutrophils. We have developed a protocol for differentiation of HL60 cells to neutrophils, a promising set of glycocalyx mimics, and culturing method for HL60 cells

Children and young adults who received tracheostomies or were initiated on long-term ventilation in PICUs

Objectives: To characterize patients who received tracheostomies for airway compromise or were initiated on long-term ventilation for chronic respiratory failure in pediatric intensive care units (PICU), and to examine variation in the incidence of initiation, patient characteristics, and modalities across sites. Design: Retrospective cross-sectional analysis. Settings: Seventy three North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Performance System. Patients: PICU patients admitted between 2009 and 2011. Interventions: None. Measurements and Main Results: Among 115,437 PICU patients, 1.8% received a tracheostomy or were initiated on long-term ventilation; 1034 received a tracheostomy only, 717 were initiated on invasive ventilation (IV), and 381 were initiated on noninvasive ventilation (NIV). Ninety percent had substantial chronic conditions and comorbidities, including more than 50% with moderate or worse cerebral disability upon discharge. Seven percent were initiated after a catastrophic injury/event. Across sites, there was variation in incidence of tracheotomy and initiation of long-term ventilation, ranging 0–4.6%. There also was variation in patient characteristics, time to tracheotomy, number of extubations prior to tracheostomy, and the use of IV versus NIV. Conclusions: While the PICU incidence of initiation of tracheostomies and long-term ventilation was relatively uncommon, it suggests that thousands of children and young adults receive these interventions each year in North American PICUs. The majority of them have conditions and comorbidities that impose on-going care needs, beyond those required by artificial airways and long-term ventilation themselves

Financial phantasmagoria: corporate image-work in times of crisis

Our purpose in this article is to relate the real movements in the economy during 2008 to the ?image-work? of financial institutions. Over the period January?December 2008 we collected 241 separate advertisements from 61 financial institutions published in the Financial Times. Reading across the ensemble of advertisements for themes and evocative images provides an impression of the financial imaginaries created by these organizations as the global financial crisis unfolded. In using the term ?phantasmagoria? we move beyond its colloquial sense of a set of strange images designed to dazzle towards the more technical connotation used by Ranci�re (2004) who suggested that words and images can offer a trace of an overall determining set-up if they are torn from their obviousness so they become phantasmagoric figures. The key phantasmagoric figure we identify here is that of the financial institution as timeless, immortal and unchanging; a coherent and autonomous entity amongst other actors. This notion of uniqueness belies the commonality of thinking which precipitated the global financial crisis as well as the limited capacity for control of financial institutions in relation to market events. It also functions as a powerful naturalizing force, making it hard to question certain aspects of the recent period of ?capitalism in crisis?

The changing patterns of group politics in Britain

Two interpretations of ways in which group politics in Britain have presented challenges to democracy are reviewed: neo-corporatism or pluralistic stagnation and the rise of single issue interest groups. The disappearance of the first paradigm created a political space for the second to emerge. A three-phase model of group activity is developed: a phase centred around production interests, followed by the development of broadly based 'other regarding' groups, succeeded by fragmented, inner directed groups focusing on particular interests. Explanations of the decay of corporatism are reviewed. Single issue group activity has increased as party membership has declined and is facilitated by changes in traditional media and the development of the internet. Such groups can overload the policy-making process and frustrate depoliticisation. Debates about the constitution and governance have largely ignored these issues and there is need for a debate

Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma.

BACKGROUND: Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. METHODS: To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). RESULTS: Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically (Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. CONCLUSIONS: These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury