Construction of a large scale integrated map of macrophage pathogen recognition and effector systems

<p>Abstract</p> <p>Background</p> <p>In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.</p> <p>Results</p> <p>The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.</p> <p>Conclusions</p> <p>The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.</p

Skull thickening, paranasal sinus expansion, and sella turcica shrinkage from chronic intracranial hypotension

In children or young adults, the morphology of the skull can be altered by excessive drainage of CSF following placement of a ventriculoperitoneal (VP) shunt. In Sunken Eyes, Sagging Brain Syndrome, gradual enlargement of the orbital cavity occurs from low or negative intracranial pressure (ICP), leading to progressive bilateral enophthalmos. The authors report several heretofore unrecognized manifestations of this syndrome, which developed in a 29-year-old man with a history of VP shunt placement following a traumatic brain injury at the age of 9 years. Magnetic resonance imaging showed typical features of chronic intracranial hypotension, and lumbar puncture yielded an unrecordable subarachnoid opening pressure. The calvaria was twice its normal thickness, owing to contraction of the inner table. The paranasal sinuses were expanded, with aeration of the anterior clinoid processes, greater sphenoid wings, and temporal bones. The sella turcica showed a 50% reduction in cross-sectional area as compared with that in control subjects, resulting in partial extrusion of the pituitary gland. These new features broaden the spectrum of clinical findings associated with low ICP. Secondary installation of a valve to restore normal ICP is recommended to halt progression of these rare complications of VP shunt placement

Evaluation of a new model of care for people with complications of diabetic retinopathy: The EMERALD Study

Objectives: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent and life-long follow-up, have markedly increased hospital demands. Resulting delays in the evaluation/treatment of patients are leading to sight loss. Strategies to increase capacity of medical retina clinics are urgently needed. EMERALD tested diagnostic accuracy, acceptability and costs of a new health care pathway for people with previously treated DME/PDR. Design: Prospective, multicentric, case-referent, cross-sectional, diagnostic accuracy study, undertaken in 13 hospitals in the United Kingdom. Participants: Adults with type 1 or 2 diabetes and previously successfully treated DME/PDR who, at the time of enrolment, had active or inactive disease. Methods: A new health care pathway entailing multimodal imaging (spectral domain optical coherence tomography [SD-OCT] for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-wide-field fundus images [UWF] for PDR) interpreted by trained non-medical staff (ophthalmic graders) to detect re-activation of disease was compared with the current standard care (ophthalmologists face-to-face examination). Main Outcome Measures: Primary outcome: sensitivity of the new pathway. Secondary outcomes: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, with inadequate images/indeterminate findings. Results: The new pathway had sensitivity of 97% (95% confidence interval [CI] 92-99%) and specificity of 31% (95% CI 23-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS (85%, 95% CI 77-91%; 48%; 95% CI 41-56%, respectively) or UWF (83%, 95% CI 75-89%; 54%; 95% CI 46-61%, respectively) were comparable. For detection of high risk PDR sensitivity and specificity were higher when using UWF images (87%, 95% CI 78-93%; 49% 95% CI 42-56%, respectively for UWF, versus 80%, 95% CI 69-88%; 40% CI 34-47%, respectively, for 7-field ETDRS). Participants preferred ophthalmologist’s assessments; in their absence, wished immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard care, the new pathway could save £1,390/100 DME visits and between £461-£1,189/100 PDR visits. Conclusion: The new ophthalmic grader pathway has acceptable sensitivity and would release resources. Users’ suggestions should guide implementation.</p

The organisation of drug supply: South Asian criminal enterprise in the UK

This paper examines the structure and modus operandi of South Asian criminal organisations operating in the UK. It is based on empirical research conducted between 2005 and 2006 among prisoners sentenced for drug offences, a number of drug distributors operating in the market, and observers with a knowledge of the drugs business working for the police force or for rehabilitation services. First, the paper offers an overview of the debate on organised crime, and after a methodological note, the research findings are utilised to propose a typology. Hypotheses are formulated around the illicit drug enterprises involved in British markets. Finally, the implications for law enforcement with respect to these enterprises are discussed

Postrepression Activation of NF-κB Requires the Amino-Terminal Nuclear Export Signal Specific to IκBα

One of the most prominent NF-κB target genes in mammalian cells is the gene encoding one of its inhibitor proteins, IκBα. The increased synthesis of IκBα leads to postinduction repression of nuclear NF-κB activity. However, it is unknown why IκBα, among multiple IκB family members, is involved in this process and what significance this feedback regulation has beyond terminating NF-κB activity. Herein, we report an important IκBα-specific function dictated by its amino-terminal nuclear export sequence (N-NES). The IκBα N-NES is necessary for the postinduction export of nuclear NF-κB, which is a critical event in reestablishing a permissive condition for NF-κB to be rapidly reactivated. We show that although IκBα and another IκB member, IκBβ, can enter the nucleus and repress NF-κB DNA-binding activity during the postinduction phase, only IκBα allows the efficient export of nuclear NF-κB. Moreover, swapping the N-terminal region of IκBβ for the corresponding IκBα sequence is sufficient for the IκB chimera protein to export NF-κB similarly to IκBα during the postinduction state. Our findings provide a mechanistic explanation of why IκBα but not other IκB members is crucial for postrepression activation of NF-κB. We propose that this IκBα-specific function is important for certain physiological and pathological conditions where NF-κB needs to be rapidly reactivated