2016 International Orthoptic Congress Burian Lecture: folklore or evidence?

The theme of the 2016 Burian Lecture is how our understanding of strabismus has been changed by the research carried out in our laboratory in Reading over the years. Accommodation and convergence are fundamental to Orthoptics, but actual responses have often been very different to what we had expected. This paper outlines how our laboratory’s understanding of common issues such as normal development of accommodation and convergence, their linkage, intermittent strabismus, anisometropia, orthoptic exercises and risk factors for strabismus have changed. A new model of thinking about convergence and accommodation may help us to better understand and predict responses in our patients

Future asymptotic expansions of Bianchi VIII vacuum metrics

Bianchi VIII vacuum solutions to Einstein's equations are causally geodesically complete to the future, given an appropriate time orientation, and the objective of this article is to analyze the asymptotic behaviour of solutions in this time direction. For the Bianchi class A spacetimes, there is a formulation of the field equations that was presented in an article by Wainwright and Hsu, and in a previous article we analyzed the asymptotic behaviour of solutions in these variables. One objective of this paper is to give an asymptotic expansion for the metric. Furthermore, we relate this expansion to the topology of the compactified spatial hypersurfaces of homogeneity. The compactified spatial hypersurfaces have the topology of Seifert fibred spaces and we prove that in the case of NUT Bianchi VIII spacetimes, the length of a circle fibre converges to a positive constant but that in the case of general Bianchi VIII solutions, the length tends to infinity at a rate we determine.Comment: 50 pages, no figures. Erronous definition of Seifert fibred spaces correcte

Blocking glycosphingolipid production alters autophagy in osteoclasts and improves myeloma bone disease

Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss

Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment

Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling

Future geodesic completeness of some spatially homogeneous solutions of the vacuum Einstein equations in higher dimensions

It is known that all spatially homogeneous solutions of the vacuum Einstein equations in four dimensions which exist for an infinite proper time towards the future are future geodesically complete. This paper investigates whether the analogous statement holds in higher dimensions. A positive answer to this question is obtained for a large class of models which can be studied with the help of Kaluza-Klein reduction to solutions of the Einstein-scalar field equations in four dimensions. The proof of this result makes use of a criterion for geodesic completeness which is applicable to more general spatially homogeneous models.Comment: 18 page

927-37 Is Coronary Revascularization Complete Therapy for Secondary Prevention of Ischemic Cardiac Arrest?

Coronary revascularization has been suggested assole therapy for secondary prevention of sudden cardiac arrest associated with ischemia. Among 412 consecutive patients receiving an implantable defibrillator (ICD), 23 (6%) were identified as: sudden cardiac arrest survivors, noninducible with programmed stimulation, unstable angina or ischemia on a functional study, and underwent successful coronary revascularization. In follow-up, 10 (43%) of the 23 patients received ICD shocks (8±8 per patient, range: 1–22) shocks) and 9/10 had syncope/presyncope associated with at least one ICD discharge.Clinical Characteristics:ICD firings (n=10)*No ICD firings (n=13)*Follow-up (months)39±1331±21Age (years)63±763±12Male gender89Mean left ventricular ejection fraction (%)36±1040±14Previous history of a myocardial infarction1010Presence of a left ventricular aneurysm41Q-wave infarction pattern on electrocardiogram75Sudden cardiac arrest presenting with exertion, angina, or CPK elevation88Mean number of vessels with coronary disease2.2±0.823±0.9Mean severity of coronary stenosis (%)87±1888±16Coronary revascularization considered complete710β-blocker therapy55Antiarrhythmic therapy812*p value>0.05No clinical characteristic was statistically different between patients with and without ICD shocks. In conclusion, coronary revascularization alone may be inadequate therapy for survivors of sudden cardiac arrest associated with ischemia who are noninducible with programmed stimulation, and clinical variables cannot predict which patients are likely to experience recurrent malignant ventricular arrhythmias. Therefore, ICD therapy should be considered in these patients

Pathways between childhood victimization and psychosis-like symptoms in the ALSPAC Birth Cohort

Background: Several large population-based studies have demonstrated associations between adverse childhood experiences and later development of psychotic symptoms. However, little attention has been paid to the mechanisms involved in this pathway and the few existing studies have relied on cross-sectional assessments. Methods: Prospective data on 6692 children from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) were used to address this issue. Mothers reported on children’s exposure to harsh parenting and domestic violence in early childhood, and children self-reported on bullying victimization prior to 8.5 years. Presence of children’s anxiety at 10 years and their depressive symptoms at 9 and 11 years were ascertained from mothers, and children completed assessments of self-esteem and locus of control at 8.5 years. Children were interviewed regarding psychotic symptoms at a mean age of 12.9 years. Multiple mediation analysis was performed to examine direct and indirect effects of each childhood adversity on psychotic symptoms. Results: The association between harsh parenting and psychotic symptoms was fully mediated by anxiety, depressive symptoms, external locus of control, and low self-esteem. Bullying victimization and exposure to domestic violence had their associations with psychotic symptoms partially mediated by anxiety, depression, locus of control, and self-esteem. Similar results were obtained following adjustment for a range of confounders and when analyses were conducted for boys and girls separately. Conclusions: These findings tentatively suggest that specific cognitive and affective difficulties in childhood could be targeted to minimize the likelihood of adolescents exposed to early trauma from developing psychotic symptoms

927-37 Is Coronary Revascularization Complete Therapy for Secondary Prevention of Ischemic Cardiac Arrest?

Coronary revascularization has been suggested assole therapy for secondary prevention of sudden cardiac arrest associated with ischemia. Among 412 consecutive patients receiving an implantable defibrillator (ICD), 23 (6%) were identified as: sudden cardiac arrest survivors, noninducible with programmed stimulation, unstable angina or ischemia on a functional study, and underwent successful coronary revascularization. In follow-up, 10 (43%) of the 23 patients received ICD shocks (8±8 per patient, range: 1–22) shocks) and 9/10 had syncope/presyncope associated with at least one ICD discharge.Clinical Characteristics:ICD firings (n=10)*No ICD firings (n=13)*Follow-up (months)39±1331±21Age (years)63±763±12Male gender89Mean left ventricular ejection fraction (%)36±1040±14Previous history of a myocardial infarction1010Presence of a left ventricular aneurysm41Q-wave infarction pattern on electrocardiogram75Sudden cardiac arrest presenting with exertion, angina, or CPK elevation88Mean number of vessels with coronary disease2.2±0.823±0.9Mean severity of coronary stenosis (%)87±1888±16Coronary revascularization considered complete710β-blocker therapy55Antiarrhythmic therapy812*p value>0.05No clinical characteristic was statistically different between patients with and without ICD shocks. In conclusion, coronary revascularization alone may be inadequate therapy for survivors of sudden cardiac arrest associated with ischemia who are noninducible with programmed stimulation, and clinical variables cannot predict which patients are likely to experience recurrent malignant ventricular arrhythmias. Therefore, ICD therapy should be considered in these patients

Parental separation/divorce in childhood and partnership outcomes at age 30

Their critiques centre around two general issues: (1) the choice of research design used to test the research hypothesis; and (2) the selection and analysis of data. We address these issues

Homogeneous Plane-wave Spacetimes and their Stability

We consider the stability of spatially homogeneous plane-wave spacetimes. We carry out a full analysis for plane-wave spacetimes in (4+1) dimensions, and find there are two cases to consider; what we call non-exceptional and exceptional. In the non-exceptional case the plane waves are stable to (spatially homogeneous) vacuum perturbations as well as a restricted set of matter perturbations. In the exceptional case we always find an instability. Also we consider the Milne universe in arbitrary dimensions and find it is also stable provided the strong energy condition is satisfied. This implies that there exists an open set of stable plane-wave solutions in arbitrary dimensions.Comment: 15 pages, no figures; minor changes, new references, to appear in CQ