Structure of Complement Component C2a: Implications for Convertase Formation and Substrate Binding

SummaryC2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix α7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to “inside-out” signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix α7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases

Validation of ICD-10 codes shows intracranial venous thrombosis incidence to be higher than previously reported

Background: Intracranial venous thrombosis (ICVT) accounts for around 0.5% of all stroke cases. There have been no previously published studies of the International Classification of Diseases, Tenth Edition (ICD-10) validation for the identification of ICVT admissions in adults. Objective: The aims of this study were to validate and quantify the performance of the ICD-10 coding system for identifying cases of ICVT in adults and to derive an estimate of incidence. Method: Administrative data were collected for all patients admitted to a regional neurosciences centre over a 5-year period. We searched for the following ICD-10 codes at any position: G08.X (intracranial and intraspinal phlebitis and thrombophlebitis), I67.6 (non-pyogenic thrombosis of intracranial venous system), I63.6 (cerebral infarction due to cerebral venous thrombosis, non-pyogenic), O22.5 (cerebral venous thrombosis in pregnancy) and O87.3 (cerebral venous thrombosis in the puerperium). Results: Sixty-five admissions were identified by at least one of the relevant ICD-10 codes. The overall positive predictive value (PPV) for confirmed ICVT from all of the admissions combined was 92.3% (60 out of 65) with the results for each code as follows: G08.X 91.5% (54 of 59), O22.5 100% (4 of 4), I67.6 100% (1 of 1), I63.6 100% (1 of 1) and O87.3 100% (1 of 1). There were 40 unique cases of ICVT over a 5-year period giving an annual incidence of ICVT of 5 per million. Conclusions: All codes gave a high PPV. Implications for practice: As demonstrated in previous studies, the incidence of ICVT may be higher than previously thought

Late-onset epilepsy predicts stroke:Systematic review and meta-analysis

Objective: Late-onset epilepsy (LOE) is closely associated with cerebrovascular disease, acting as both a marker of cerebrovascular disease (CVD) and occurring as a direct consequence. Despite this, our understanding of LOE as a cerebrovascular phenomenon is in its infancy. LOE also appears to be a harbinger of dementia. Methods: A systematic review was performed to identify publications relating to LOE and identified observational studies, clinical studies, and radiological studies. Results: A meta-analysis of observational studies demonstrated that patients presenting with LOE experience an increased risk of subsequent stroke (weighted OR 3.88 (95% CI 2.76–5.46)). The additional studies demonstrated clinical and radiological evidence to support the premise that LOE is likely to reflect underlying cerebrovascular disease. Significance: Cerebrovascular disease risk factors convey increased risk of LOE and LOE can precede stroke and dementia, acting as an early marker for cerebrovascular risk. This may represent a potential point for intervention. There are a number of suggested mechanisms relating LOE to stroke; however, there is limited understanding of the natural history of LOE. Current data support the need for prospective research in order to understand the natural history of LOE and modify disease, in order to reduce the apparent sequelae of stroke and dementia

Immunomodulatory treatment for amyotrophic lateral sclerosis/ motor neuron disease (Protocol)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the efficacy and harms or adverse events of immunomodulatory therapies in people with ALS compared with a placebo, no additional treatment, or a standard-of-care protocol (with or without riluzole, edaravone, or both)

Hi4D-ADSIP 3-D dynamic facial articulation database

The face is an important medium used by humans to communicate, and facial articulation also reflects a person's emotional and awareness states, cognitive activity, personality or wellbeing. With the advances in 3-D imaging technology and ever increasing computing power, automatic analysis of facial articulation using 3-D sequences is becoming viable. This paper describes Hi4D-ADSIP — a comprehensive 3-D dynamic facial articulation database, containing scans with high spatial and temporal resolution. The database is designed not only to facilitate studies on facial expression analysis, but also to aid research into clinical diagnosis of facial dysfunctions. The database currently contains 3360 facial sequences captured from 80 healthy volunteers (control subjects) of various age, gender and ethnicity. The database has been validated using psychophysical experiments used to formally evaluate the accuracy of the recorded expressions. The results of baseline automatic facial expression recognition methods using Eigen- and Fisher-faces are also presented alongside some initial results obtained for clinical cases. This database is believed to be one of the most comprehensive repositories of facial 3-D dynamic articulations to date. The extension of this database is currently under construction aiming at building a comprehensive repository of representative facial dysfunctions exhibited by patients with stroke, Bell's palsy and Parkinson's disease

Outpatient neurology diagnostic coding: a proposed scheme for standardised implementation

Clinical coding uses a classification system to assign standard codes to clinical terms and so facilitates good clinical practice through audit, service design and research. However, despite clinical coding being mandatory for inpatient activity, this is often not so for outpatient services, where most neurological care is delivered. Recent reports by the UK National Neurosciences Advisory Group and NHS England's 'Getting It Right First Time' initiative recommend implementing outpatient coding. The UK currently has no standardised system for outpatient neurology diagnostic coding. However, most new attendances at general neurology clinics appear to be classifiable with a limited number of diagnostic terms. We present the rationale for diagnostic coding and its benefits, and the need for clinical engagement to develop a system that is pragmatic, quick and easy to use. We outline a scheme developed in the UK that could be used elsewhere.</p

Insomnia as a mediating therapeutic target for depressive symptoms: A sub-analysis of participant data from two large randomized controlled trials of a digital sleep intervention

Insomnia predicts the onset of depression, commonly co-presents with depression and often persists following depression remission. However, these conditions can be challenging to treat concurrently using depression-specific therapies. Cognitive behavioural therapy for insomnia may be an appropriate treatment to improve both insomnia and depressive symptoms. We examined the effects of a fully-automated digital cognitive behavioural therapy intervention for insomnia (Sleepio) on insomnia and depressive symptoms, and the mediating role of sleep improvement on depressive symptoms in participants from two randomized controlled trials of digital cognitiv