Management of Orbital and Periorbital Venous Malformation

BackgroundTo review our management of common venous malformation (VM) affecting the orbit and/or periorbital area.MethodsConsecutive patients with orbital and/or periorbital VM were identified from our vascular anomalies database. Demographic details of the patients, anatomic site(s) affected, symptoms and signs, presence of a family history of VM, and types of treatment(s) were collected, supplemented by chart review.ResultsA total of 24 patients’ age 1–68 (mean, 30) years with orbital and/or periorbital VM presented with cosmetic concerns (n = 17, 71%), distensibility (n = 15, 63%), pain (n = 9, 38%), diplopia (n = 4, 17%), and spontaneous thrombosis (n = 1, 8%). The VM caused globe dystopia (n = 13, 54%), enophthalmos (n = 6, 25%), proptosis (n = 3, 12%), exotropia (n = 3, 12%), and pseudoptosis with visual obstruction (n = 3, 13%). A total of 11 (46%) patients were managed conservatively. 13 (54%) patients underwent active treatment. Ethanol sclerotherapy (ES) was performed in six patients with extensive facial VM associated with orbital/periorbital involvement, resulting in symptomatic improvement in five patients, one of whom developed skin necrosis and another patient developed reduced infraorbital nerve sensation. Surgery was performed for localized lesion (n = 3, 23%), for extensive lesions (n = 4, 31%) and as an adjunct to ES (n = 6, 46%) resulting in symptomatic improvement in all patients. One patient required correction of lower lid ectropion.ConclusionOrbital and/or periorbital VMs are heterogeneous, and management needs to be individualized. Surgery is used for localized lesions aiming for complete excision, as a debulking procedure for extensive orbital/periorbital VM when ES was not possible, or following ES for extensive facial VM with orbital and/or periorbital involvement

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

A BURST-BAUS consensus document for best practice in the conduct of scrotal exploration for suspected testicular torsion : the Finding consensus for orchIdopeXy In Torsion (FIX-IT) study

Acknowledgements The authors would like to thank Jacqueline Emkes and Rachel Jury for their contribution to our protocol development with respect to patient and public involvement. Similarly, the authors would like to thank Dr Matthew Coward, Department of Urology, University of North Carolina, and Dr Selcuk Sarikaya, Department of Urology, University of Ankara, for their international perspectives and input to our study protocol. We would like to acknowledge the BAUS Trustees for allowing this collaboration. Unrelated to this work, The BURST Research Collaborative would like to acknowledge funding from the BJUI, the Urology Foundation, Ferring Pharmaceuticals Ltd, Rosetrees Trust and Action Bladder Cancer UK. Veeru Kasivisvanathan is an Academic Clinical Lecturer funded by the United Kingdom National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. PubMed Indexed Collaborative Authors: Matthew Coward, Selcuk Sarikaya, Jacqueline Emkes, Rachel Jury. Research Funding Department of Health National Institute for Health Research National Institute for Health Research Rosetrees Trust Ferring Pharmaceuticals Urology Foundation University of North CarolinaPeer reviewedPublisher PD

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 x 0.39 x 1.0 mm³) 7.0T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P 3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans

A Modular BAM Complex in the Outer Membrane of the α-Proteobacterium Caulobacter crescentus

Mitochondria are organelles derived from an intracellular α-proteobacterium. The biogenesis of mitochondria relies on the assembly of β-barrel proteins into the mitochondrial outer membrane, a process inherited from the bacterial ancestor. Caulobacter crescentus is an α-proteobacterium, and the BAM (β-barrel assembly machinery) complex was purified and characterized from this model organism. Like the mitochondrial sorting and assembly machinery complex, we find the BAM complex to be modular in nature. A ∼150 kDa core BAM complex containing BamA, BamB, BamD, and BamE associates with additional modules in the outer membrane. One of these modules, Pal, is a lipoprotein that provides a means for anchorage to the peptidoglycan layer of the cell wall. We suggest the modular design of the BAM complex facilitates access to substrates from the protein translocase in the inner membrane

Global circulation patterns of seasonal influenza viruses vary with antigenic drift.

Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.T.B. was supported by a Newton International Fellowship from the Royal Society and through NIH U54 GM111274. S.R. was supported by MRC (UK, Project MR/J008761/1), Wellcome Trust (UK, Project 093488/Z/10/Z), Fogarty International Centre (USA, R01 TW008246‐01), DHS (USA, RAPIDD program), NIGMS (USA, MIDAS U01 GM110721‐01) and NIHR (UK, Health Protection Research Unit funding). The Melbourne WHO Collaborating Centre for Reference and Research on Influenza was supported by the Australian Government Department of Health and thanks N. Komadina and Y.‐M. Deng. The Atlanta WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza was supported by the U.S. Department of 13 Health and Human Services. NIV thanks A.C. Mishra, M. Chawla‐Sarkar, A.M. Abraham, D. Biswas, S. Shrikhande, AnuKumar B, and A. Jain. Influenza surveillance in India was expanded, in part, through US Cooperative Agreements (5U50C1024407 and U51IP000333) and by the Indian Council of Medical Research. M.A.S. was supported through NSF DMS 1264153 and NIH R01 AI 107034. Work of the WHO Collaborating Centre for Reference and Research on Influenza at the MRC National Institute for Medical Research was supported by U117512723. P.L., A.R. & M.A.S were supported by EU Seventh Framework Programme [FP7/2007‐2013] under Grant Agreement no. 278433-­‐PREDEMICS and ERC Grant agreement no. 260864. C.A.R. was supported by a University Research Fellowship from the Royal Society.This is the author accepted manuscript. It is currently under infinite embargo pending publication of the final version

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development