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Neovascularization is a hallmark pathology of numerous retinal diseases from diabetic retinopathy (DR) to age-related related macular degeneration (AMD). Over the past 2 decades, the rise of anti-VEGF based medications for neovascular eye conditions has revolutionized the treatment paradigm for patients and preserved the vision of millions. With any form of therapy however, there remain pitfalls and areas for improved interventions. Here, we succinctly present some current views on treatment options for patients with retinal and choroidal neovascularization. We also highlight some of the most promising therapeutic strategies currently being developed and where these therapies may fit with the current clinical standard of care. [ABSTRACT FROM AUTHOR]

Purpose: Paediatric Epilepsy surgery in the UK has recently been centralised in order to improve expertise and quality of service available to children. Video EEG monitoring or telemetry is a highly specialised and a crucial component of the pre-surgical evaluation. Although many Epilepsy Monitoring Units work to certain standards, there is no national or international guideline for paediatric video telemetry.Methods: Due to lack of evidence we used a modified Delphi process utilizing the clinical and academic expertise of the clinical neurophysiology sub-specialty group of Children's Epilepsy Surgical Service (CESS) centres in England and Wales. This process consisted of the following stages I: Identification of the consensus working group, II: Identification of key areas for guidelines, III: Consensus practice points and IV: Final review. Statements that gained consensus (median score of either 4 or 5 using a five-point Likerttype scale) were included in the guideline.Results: Two rounds of feedback and amendments were undertaken. The consensus guidelines includes the following topics: referral pathways, neurophysiological equipment standards, standards of recording techniques, with specific emphasis on safety of video EEG monitoring both with and without drug withdrawal, a protocol for testing patient's behaviours, data storage and guidelines for writing factual reports and conclusions. All statements developed received a median score of 5 and were adopted by the group.Conclusion: Using a modified Delphi process we were able to develop universally-accepted video EEG guidelines for the UK CESS. Although these recommendations have been specifically developed for the pre-surgical evaluation of children with epilepsy, it is assumed that most components are transferable to any paediatric video EEG monitoring setting. [ABSTRACT FROM AUTHOR]

In this study we describe a previously unreported function for NFκB2, an NFκB family transcription factor, in antiviral immunity. NFκB2 is induced in response to poly(I:C), a mimic of viral dsRNA. Poly(I:C), acting via TLR3, induces p52-dependent transactivation of a reporter gene in a manner that requires the kinase activity of IκB kinase ∈ (IKK∈) and the transactivating potential of RelA/p65. We identify a novel NFκB2 binding site in the promoter of the transcription factor Sp1 that is required for Sp1 gene transcription activated by poly(I:C).We show that Sp1 is required for IL-15 induction by both poly(I:C) and respiratory syncytial virus, a response that also requires NFκB2 and IKK∈. Our study identifies NFκB2 as a target for IKK∈ in antiviral immunity and describes, for the first time, a role for NFκB2 in the regulation of gene expression in response to viral infection. [ABSTRACT FROM AUTHOR]

Abstract: This column provides a country by country analysis of the latest legal developments, cases and issues relevant to the IT, media and telecommunications industries in key jurisdictions across the Asia-Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Abstract: This column provides a country by country analysis of the latest legal developments, cases and issues relevant to the IT, media and telecommunications'' industries in key jurisdictions across the Asia-Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Abstract: This column provides a country by country analysis of the latest legal developments, cases and issues relevant to the IT, media and telecommunications'' industries in key jurisdictions across the Asia Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Abstract: The increasing reliance on technology as a means of conducting cross-border businesses has spurred on the development of data protection and privacy laws in many countries across the globe. In Asia, however, many countries today still have no or extremely limited data protection laws. Cultural attitudes towards the concept of autonomy and the well-established right of certain governments to monitor and scrutinise its people in certain countries have been partly to blame. However, in order to remain economically viable, the businesses and government of these countries must be able to provide protections which are at least similar to those afforded by the data protection laws of their business counterparts. This article examines the effectiveness and relevance of the APEC Privacy Framework and the state of the data protection laws in eight Asia-Pacific countries today. [Copyright &y& Elsevier]

Abstract: This column provides a country-by-country snapshot of the latest legal developments, cases and issues relevant to the IT, media and telecommunications'' industries in key jurisdictions across the Asia Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Toll-like receptors (TLRs) are a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. TLR7 and TLR8 sense single-stranded RNA from viruses or host ribonucleoproteins and synthetic imidazoquino-lines such as R848, whereas TLR9 senses unmethylated CpG motifs in viral and bacterial DNA and in host DNA. Here we report the endogenous interaction between Brutons's tyrosine kinase (Btk) and human TLR8 and TLR9 in the monocytic cell line THP1. We also show that R848, single-stranded RNA, and CpGB-DNA activate Btk in THP1 cells as shown by phosphorylation of the tyrosine 223 residue of Btk and also by increased autokinase activity. We demonstrate that Btk is required for NFKB activation, participating in the pathway to increased phosphorylation of p65 on serine 536 activated by TLR8 and TLR9. Finally we demonstrate that peripheral blood mononuclear cells from patients with X-linked agammaglobulinaemia (XLA) that have dysfunctional Btk are impaired in the induction of interleukin-6 by CpGB-DNA. This study therefore establishes Btk as a key signaling molecule that interacts with and acts downstream of TLR8 and TLR9. Lack of functioning Btk in XLA patients downstream of TLR8 and TLR9 might explain the susceptibility of XLA patients to viral infections. [ABSTRACT FROM AUTHOR]

Abstract: This column provides a country by country snapshot of the latest legal developments, cases and issues relevant to the IT, media and telecommunications industries in key jurisdictions across the Asia Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Abstract: This new column provides a country-by-country snapshot of the latest legal developments, cases and issues relevant to the IT, media and telecommunications industries in key jurisdictions across the Asia Pacific region. The articles appearing in this column are intended to serve as ‘alerts’ and are not submitted as detailed analyses of cases or legal developments. [Copyright &y& Elsevier]

Background & Aims: We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinflammatory cytokines. Methods: We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, and IL-6) was measured by enzyme-linked immunosorbent assay. Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale. Results: IBS patients showed significantly (P < .017) higher baseline TNF-α, IL-1β, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients, whereas constipation-predominant IBS patients showed increased LPS-induced IL-1β levels compared with HCs. Baseline TNF-α and LPS-induced TNF-α and IL-6 levels were significantly higher in patients reporting more than 3 bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-α production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS. Conclusions: Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety. [Copyright &y& Elsevier]

Abstract: Toll-like receptors (TLRs) are key components of the innate immune system, functioning as pattern recognition receptors that recognise a wide range of microbial pathogens. TLRs represent a primary line of defence against invading pathogens in mammals, plants and insects. Recognition of microbial components by TLRs triggers a cascade of cellular signals that culminates in the activation of NFκB which leads to inflammatory gene expression and clearance of the infectious agent. The history of NFκB began with the TLR4 ligand lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, since this was the stimulus first used to activate NFκB in pre-B-cells. However, since those early days it has been a circuitous route, made possible by drawing on information provided by many different fields, that has led us not only to the discovery of TLRs but also to an understanding of the complex pathways that lead from TLR ligation to NFκB activation. In this review we will summarize the current knowledge of TLR-mediated NFκB activation, and also the recent discoveries that subtle differences in κB binding sequences and NFκB dimer formation result in specific gene expression profiles. [Copyright &y& Elsevier]

Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor κB (NFκB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFκB-dependent reporter gene expression but not IκBα degradation. Transient transfection of HEK293 cells with Btk had no effect on NFκB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IκBα degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFκB. [ABSTRACT FROM AUTHOR]

Focuses on the identification of the Toll-like receptor family as binding protein for intracellular protein tyrosine kinase, Bruton's tyrosine kinase (BTK). Requirement for the presence of Toll/interleukin receptor domain for interaction; Role of BTK in lipoposaccharide signal transduction; Increase of the level of tyrosine phosphorylation.

Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology. • TLR2 activates the alternative complement pathway • TLR2 signaling triggers sub-lytic MAC formation on retinal pigment epithelial cells • TLR2 deficiency reduces oxidative stress-induced C3 and MAC in the outer retina • TLR2 blockade protects photoreceptors and RPE from oxidative stress-induced cell death Oxidative stress and complement deposition are common to many retinal degenerative diseases. Mulfaul et al. demonstrate that TLR2 blockade protects against photoreceptor neuronal cell death and RPE fragmentation in experimental models of oxidative stress-induced retinal degeneration and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology. [ABSTRACT FROM AUTHOR]

Purpose: Catheterisation can be an uncomfortable and traumatic procedure for some children. HPS are in an ideal position to provide preparation and distraction for this procedure during urodynamics. Entonox is recognised as an effective treatment during uncomfortable or painful procedures (Kanagasundaram et al. Arch Dis Child 2001; 84: 492 - 495). We explore and discuss the administration and patient experience of entonox by a trained and assessed HPS during urodynamics. Material and Methods: HPS have specialised skills to prepare, relax and support patients undergoing traumatic and painful procedures. Administration of entonox by our HPS was considered to be a unique but beneficial extended skill to complement current practice. Training was provided and assessments by competencies were undertaken by the pain specialist team under the guidance of the head of pharmacy. Results: Over a ten month period thirty five patients (aged 5-17 years) used entonox administered by the HPS during urodynamics. Thirty four children and young people thought that entonox helped them to relax resulting in the catheterisation experience being pain free. Thirty four children and young people reported that they would use entonox again. One patient was unable to use the entonox due to his learning difficulties which limited his mastery of the correct breathing technique when using entonox. Conclusions: HPS administration of entonox for catheterisation has had a positive impact. It has improved the time efficiency and cost effectiveness of the service. The number of patients requiring general anaesthetic for catheterisation has been reduced. Most importantly positive feedback from patients has demonstrated a positive impact on quality of care. [Copyright &y& Elsevier]

PURPOSE: To report the impact and tolerability of PTNS and the effect on the child''s reported quality of life. MATERIAL AND METHODS: Prospective data from 8 children (M:F 1:7; mean age 12 years 3 months) with OAB demonstrated on urodynamics. PTNS was performed weekly for 30 minutes over 12 weeks. Symptoms (voiding diary, dry pie chart) objective measures (uriflow, post void residual (PVR), needle pain score, urge score, PinQ score) and child''s thoughts about the experience were recorded. RESULTS: The number of days per week of incontinence ranged from 2-7 (mean 4 days) two had nocturnal enuresis (NE), one sporadic NE, none had faecal incontinence. Seven had urge/frequency and 2 had a history of symptomatic UTI within last 6 months. Four of the eight children with incontinence became dry, 1 significantly improved. Three children had no improvement 2/3 had recurrent UTI. Noninvasive uriflow and PVR were not statistically significant before and after treatment. Pre-treatment patient age, sex and frequency of wetting were not predictive of outcome. PinQ score changed demonstrating an improvement in QoL. Pain scores were low or absent in all children. Qualitative themes included improved confidence and positive fun experiences. There were no reported side effects or adverse events. CONCLUSIONS: PTNS for children that have failed previous standard treatments is safe and well tolerated. It is not reported as painful and improvement in continence was reflected in QoL score for most children. Weekly treatments impact on family life and some families had difficulties meeting this commitment. Long term outcome data collection is in progress. [Copyright &y& Elsevier]

There is limited evidence on the risk of in-flight transmission of SARS-CoV-2. This study estimated the extent of in-flight SARS-CoV-2 transmission on international flights arriving in Ireland during December 2020. This was a cross-sectional analysis. National surveillance data identified all notified cases of COVID-19 who were infectious while travelling on international flights to Ireland during December 2020. Close contacts of cases were tested for SARS-CoV-2, and the results were collated to estimate the pooled secondary attack rate across all flights. Laboratory and epidemiological data were obtained from the Health Service Executive Covid Care Tracker, a national database of COVID-19 cases in Ireland. A total of 165 infectious cases of COVID-19 were identified on 134 incoming flights; 40.0% were symptomatic on board. There were 2099 flight close contacts identified, of whom 40.9% had results of a SARS-CoV-2 polymerase chain reaction test within 14 days of arrival. The pooled secondary attack rate for these contacts was 7.0% and was higher among those on flights of ≥5-hour duration (P = 0.008). More than half (59.1%) of close contacts had no SARS-CoV-2 test result recorded; the reasons included incorrect or absent contact details (26.5%) and no response when contacted (17.8%). In this national study investigating transmission of SARS-CoV-2 from international flights arriving into Ireland, the pooled secondary attack rate was 7.0%. International travel is likely to have contributed to the third wave of SARS-CoV-2 infections in Ireland in early 2021. Application of non-pharmaceutical interventions remains central to mitigating the risk of in-flight transmission. [ABSTRACT FROM AUTHOR]

Abstract: Polyunsaturated fatty acids (PUFA) can modulate the immune response, however the mechanism by which they exert this effect remains unclear. Previous studies have clearly demonstrated that the cis-9, trans-11 isomer of conjugated linoleic acid (c9,t11-CLA), found predominantly in beef and dairy products, can modulate the response of immune cells to the toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). This study aimed to investigate further the mechanism by which these effects are mediated. Treatment of macrophages with c9,t11-CLA significantly decreased CD14 expression and partially blocked its association with lipid rafts following stimulation with LPS. Furthermore the c9,t11-CLA isomer inhibited both nuclear factor-κB (NF-κB) and IRF3 activation following TLR4 ligation while eicosapentaenoic acid (EPA) only suppressed NF-κB activation. Given that the ability of LPS to activate IRF3 downstream of TLR4 depends on internalisation of the TLR4 complex and involves CD14, we examined TLR4 endocytosis. Indeed the internalisation of TLR4 to early endosomes following activation with LPS was markedly inhibited in c9,t11-CLA treated cells. These effects were not seen with the n-3 fatty acid, EPA, which was used as a comparison. Our data demonstrates that c9,t11-CLA inhibits IRF3 activation via its effects on CD14 expression and localisation. This results in a decrease in the endocytosis of TLR4 which is necessary for IRF3 activation, revealing a novel mechanism by which this PUFA exerts its anti-inflammatory effects. [Copyright &y& Elsevier]

IL-10 is a potent anti-inflammatory cytokine that is crucial for down-regulating pro-inflammatory genes, which are induced by Toll-like receptor (TLR) signaling. In this study, we have examined whether modulation of microRNAs plays a role in the inhibitory effect of IL-10 on TLR4 signaling. Analyzing microRNAs known to be induced by TLR4, we found that IL-10 could inhibit the expression of miR-155 in response to lipopolysaccharide but had no effect on miR-21 or miR-146a. IL-10 inhibited miR-155 transcription from the BIC gene in a STAT3-dependent manner. This inhibitory effect of IL-10 on miR-155 led to an increase in the expression of the miR-155 target, SHIP1. This is the first example of IL-10 playing a role in microRNA function and suggests that through its inhibitory effect on miR- 155, IL-10 has the ability to promote anti-inflammatory gene expression. [ABSTRACT FROM AUTHOR]

Members of the Toll-like receptor (TLR) family are essential players in activating the host innate immune response against infectious microorganisms. All TLRs signal through Toll/interleukin 1 receptor domain-containing adapter proteins. MyD88 adapter-like (Mal) is one such adapter that specifically is involved in TLR2 and TLR4 signaling. When overexpressed we have found that Mal undergoes tyrosine phosphorylation. Three possible phospho-accepting tyrosines were identified at positions 86, 106, and 187, and two mutant forms of Mal in which tyrosines 86 and 187 were mutated to phenylalanine acted as dominant negative inhibitors of NF-κB activation by lipopolysaccharide (LPS). Activation of THP-1 monocytic cells with the TLR4 agonist LPS and the TLR2 agonist macrophage-activating lipopeptide-2 induced phosphorylation of Mal on tyrosine residues. We found that the Bruton's tyrosine kinase (Btk) inhibitor LFM-A13 could block the endogenous phosphorylation of Mal on tyrosine in cells treated with macrophage-activating lipopeptide-2 or LPS. Furthermore, Btk immunoprecipitated from THP-1 cells activated by LPS could phosphorylate Mal. Our study therefore provides the first demonstration of the key role of Mal phosphorylation on tyrosine during signaling by TLR2 and TLR4 and identifies a novel function for Btk as the kinase involved. [ABSTRACT FROM AUTHOR]