Altered Patterns of Fungal Keratitis at a London Ophthalmic Referral Hospital: An Eight-Year Retrospective Observational Study.

PURPOSE: In previous studies of fungal keratitis (FK) from temperate countries, yeasts were the predominant isolates, with ocular surface disease (OSD) being the leading risk factor. Since the 2005-2006 outbreak of contact lens (CL)-associated Fusarium keratitis, there may have been a rise in CL-associated filamentary FK in the United Kingdom. This retrospective case series investigated the patterns of FK from 2007 to 2014. We compared these to 1994-2006 data from the same hospital. DESIGN: Retrospective observational study. METHODS: All cases of FK presenting to Moorfields Eye Hospital between 2007 and 2014 were identified. The definition of FK was either a fungal organism isolated by culture or fungal structures identified by light microscopy (LM) of scrape material, histopathology, or in vivo corneal confocal microscopy (IVCM). Main outcome measure was cases of FK per year. RESULTS: A total of 112 patients had confirmed FK. Median age was 47.2 years. Between 2007 and 2014, there was an increase in annual numbers of FK (Poisson regression, P = .0001). FK was confirmed using various modalities: 79 (70.5%) by positive culture, 16 (14.3%) by LM, and 61 (54.5%) by IVCM. Seventy-eight patients (69.6%) were diagnosed with filamentary fungus alone, 28 (25%) with yeast alone, and 6 (5.4%) with mixed filamentary and yeast infections. This represents an increase in the proportion of filamentary fungal infections from the pre-2007 data. Filamentary fungal and yeast infections were associated with CL use and OSD, respectively. CONCLUSIONS: The number of FK cases has increased. This increase is due to CL-associated filamentary FK. Clinicians should be aware of these changes, which warrant epidemiologic investigations to identify modifiable risk factors

Rapid transport of East Asian pollution to the deep tropics

Abstract. Anthropogenic emissions from East Asia have increased over recent decades, and under the prevailing westerly winds, these increases have led to changes in atmospheric composition as far afield as North America. Here we show that, during Northern Hemisphere (NH) winter, pollution originating in East Asia also directly affects atmospheric composition in the deep tropics. We present observations of marked intra-seasonal variability in the anthropogenic tracer perchloroethene (C2Cl4) collected at two locations in Borneo during the NH winter of 2008/09. We use the NAME trajectory model to show that the observed enhancements in C2Cl4 mixing ratio are caused by rapid meridional transport, in the form of "cold surges", from the relatively polluted East Asian land mass. In these events air masses can move across > 30° of latitude in 4 days. We then present data from the Monitoring Atmospheric Composition and Climate reanalysis which suggests that air masses high in C2Cl4 may also contain levels of the pollutants carbon monoxide and ozone that are approximately double the typical "background" levels in Borneo. Convection in Southeast Asia can be enhanced by cold surges, and further trajectory calculations indicate that the polluted air masses can subsequently be lifted to the tropical upper troposphere. This suggests a potentially important connection between mid-latitude pollution sources and the very low stratosphere. This work was supported by a NERC consortium grant to the OP3 team, by NCAS, by the European Commission through the SCOUT-O3 project (505390-GOCECF2004), though the ERC ACCI project, Project No 267760, and by NERC western Pacific grant number NE/F020341/1 and NERC CAST grant number NE/J006246/1. M. J. Ashfold thanks NERC for a research studentship. A. D. Robinson acknowledges NERC for their support through small grant project NE/D008085/1. N. R. P. Harris is supported by a NERC Advanced Research Fellowship. We thank the Sabah Foundation, Danum Valley Field Centre and the Royal Society (Glen Reynolds) for field site support. This is paper number X of the Royal Society’s South East Asian Rainforest Research Programme. We are grateful for use of data provided by the MACC-II project, funded by the European Union under the 7th Framework Programme. We also acknowledge use of the NAME atmospheric dispersion model and associated NWP meteorological data sets made available to us by the Met O ce. We acknowledge the significant storage resources and analysis facilities made available to us on JASMIN by STFC CEDA along with the corresponding support teams.This is the published version. It first appeared at: http://www.atmos-chem-phys-discuss.net/14/30705/2014/acpd-14-30705-2014.html

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury.

Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction

Effects of metal-contaminated soils on the accumulation of heavy metals in gotu kola (Centella asiatica) and the potential health risks: a study in Peninsular Malaysia

Centella asiatica is a commonly used medicinal plant in Malaysia. As heavy metal accumulation in medicinal plants which are highly consumed by human is a serious issue, thus the assessment of heavy metals in C. asiatica is important for the safety of consumers. In this study, the heavy metal accumulation in C. asiatica and the potential health risks were investigated. Samples of C. asiatica and surface soils were collected from nine different sites around Peninsular Malaysia. The concentration of six heavy metals namely Cd, Cu, Ni, Fe, Pb and Zn were determined by air-acetylene flame atomic absorption spectrophotometer (AAS). The degree of anthropogenic influence was assessed by calculating the enrichment factor (EF) and index of geoaccumulation (Igeo). The heavy metal uptake into the plant was estimated through the calculation of translocation factor (TF), bioconcentration factor (BCF) and correlation study. Estimated daily intakes (EDI) and target hazard quotients (THQ) were used to determine the potential health risk of consuming C. asiatica. The results showed that the overall surface soil was polluted by Cd, Cu and Pb, while the uptake of Zn and Ni by the plants was high. The value of EDI and THQ showed that the potential of Pb toxicity in C. asiatica was high as well. As heavy metal accumulation was confirmed in C. asiatica, daily consumption of the plant derived from polluted sites in Malaysia was not recommended

Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans

Background: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms ( SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort ( 1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF- II levels. Results: Both offspring's and mother's H19 2992C> T SNP genotypes showed associations with offspring birthweight ( P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels ( P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype ( P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight ( P = 0.04) and higher cord blood IGF-II levels ( P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies ( P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight ( P = 0.04) and with mother's glucose levels ( P = 0.01) in first pregnancies. Conclusion: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants

Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study

Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma. Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months. Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype. Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability. Funding: GlaxoSmithKline and UK Medical Research Council

Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.

OBJECTIVES: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities. RESULTS: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis. CONCLUSIONS: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms

Factors associated with self-care activities among adults in the United Kingdom: a systematic review

Background: The Government has promoted self-care. Our aim was to review evidence about who uses self-tests and other self-care activities (over-the-counter medicine, private sector,complementary and alternative medicine (CAM), home blood pressure monitors). Methods: During April 2007, relevant bibliographic databases (Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Applied Social Sciences Index and Abstracts, PsycINFO,British Nursing Index, Allied and Complementary Medicine Database, Sociological Abstracts, International Bibliography of the Social Sciences, Arthritis and Complementary Medicine Database, Complementary and Alternative Medicine and Pain Database) were searched, and potentially relevant studies were reviewed against eligibility criteria. Studies were included if they were published during the last 15 years and identified factors, reasons or characteristics associated with a relevant activity among UK adults. Two independent reviewers used proformas to assess the quality of eligible studies. Results: 206 potentially relevant papers were identified, 157 were excluded, and 49 papers related to 46 studies were included: 37 studies were, or used data from questionnaire surveys, 36 had quality scores of five or more out of 10, and 27 were about CAM. Available evidence suggests that users of CAM and over-the-counter medicine are female, middle-aged, affluent and/or educated with some measure of poor health, and that people who use the private sector are affluent and/or educated. Conclusion: People who engage in these activities are likely to be affluent. Targeted promotion may, therefore, be needed to ensure that use is equitable. People who use some activities also appear to have poorer measures of health than non-users or people attending conventional services. It is, therefore, also important to ensure that self-care is not used as a second choice for people who have not had their needs met by conventional service

Long-term halocarbon observations from a coastal and an inland site in Sabah, Malaysian Borneo

Abstract. Short-lived halocarbons are believed to have important sources in the tropics, where rapid vertical transport could provide a significant source to the stratosphere. In this study, quasi-continuous measurements of short-lived halocarbons are reported for two tropical sites in Sabah (Malaysian Borneo), one coastal and one inland (rainforest). We present the observations for C2Cl4, CHBr3, CH2Br2* (actually ~80% CH2Br2 and ~20% CHBrCl2) and CH3I from November 2008 to January 2010 made using our μDirac gas chromatographs with electron capture detection (GC-ECD). We focus on the first 15 months of observations, showing over one annual cycle for each compound and therefore adding significantly to the few limited-duration observational studies that have been conducted thus far in southeast Asia. The main feature in the C2Cl4 behaviour at both sites is its annual cycle, with the winter months being influenced by northerly flow with higher concentrations, typical of the Northern Hemisphere, and with the summer months influenced by southerly flow and lower concentrations representative of the Southern Hemisphere. No such clear annual cycle is seen for CHBr3, CH2Br2* or CH3I. The baseline values for CHBr3 and CH2Br2* are similar at the coastal (overall median: CHBr3 1.7 ppt, CH2Br2* 1.4 ppt) and inland sites (CHBr3 1.6 ppt, CH2Br2* 1.1 ppt), but periods with elevated values are seen at the coast (overall 95th percentile: CHBr3 4.4 ppt, CH2Br2ast 1.9 ppt), presumably resulting from the stronger influence of coastal emissions. Overall median bromine values from [CHBr3 × 3] + [CH2Br2* × 2] are 8.0 ppt at the coast and 6.8 ppt inland. The median values reported here are largely consistent with other limited tropical data and imply that southeast Asia generally is not, as has been suggested, a hot spot for emissions of these compounds. These baseline values are consistent with the most recent emissions found for southeast Asia using the p-TOMCAT (Toulouse Off-line Model of Chemistry And Transport) model. CH3I, which is only observed at the coastal site, is the shortest-lived compound measured in this study, and the observed atmospheric variations reflect this, with high variability throughout the study period. This work was supported by a NERC consortium grant to the OP3 team, by NCAS, by the European Commission through the SCOUT-O3 project (505390-GOCE-CF2004) and by NERC western Pacific grant number NE/F020341/1 and NERC CAST grant number NE/J006246/1. L. M. O’Brien and M. J. Ashfold thank NERC for research studentships. A. D. Robinson acknowledges NERC for their support through small grant project NE/D008085/1. N. R. P. Harris is supported by a NERC Advanced Research Fellowship. We thank the Sabah Foundation, Danum Valley Field Centre and the Royal Society (Glen Reynolds) for field site support. The research leading to these results has received funding from the European Union’s Seventh Framework Programme FP7/2007–2013 under grant agreement no. 226224 – SHIVA. We thank David Oram and Stephen Humphrey at UEA for their assistance in checking the calibration of our Aculife cylinder in May 2009. This is paper number 626 of the Royal Society’s South East Asian Rainforest Research Programme.This is the final published version. It first appeared at http://www.atmos-chem-phys.net/14/8369/2014/acp-14-8369-2014.html

Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization.

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment