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Purpose To describe the clinical course of acute syphilitic posterior placoid chorioretinitis (ASPPC) in the preplacoid stage, placoid stage, and after treatment with penicillin. Method A retrospective case report of serial multimodal imaging and electrophysiology studies of a patient with ASPPC, with 18 months of follow-up. Results A 47-year-old man presented with bilateral panuveitis. The patient defaulted follow-up and returned when his vision deteriorated. Tests for neurosyphilis and retroviral disease were positive, and treatment was initiated. The earliest change on serial optical coherence tomography was loss of the signal from the reflective band corresponding to the ellipsoid zone. In the placoid stage, there was nodular thickening of the retinal pigment epithelium. The ellipsoid zone signals reappeared after treatment. Fundus fluorescein angiogram at presentation showed peripapillary vasculitis and disk leakage; indocyanine green angiography revealed multiple hypofluorescent spots in the peripapillary region and posterior pole that was not visible clinically. The angiographic abnormalities resolved after treatment. Electrophysiology demonstrated bilateral maculopathy and reduction of both a- and b-waves from dark-adapted and light-adapted responses at presentation. The b-waves (inner retina) recovered partially with treatment. Conclusion To the best of our knowledge, this is the first case report of the multimodal imaging and electrophysiology findings in a patient with acute syphilitic posterior placoid chorioretinitis, before the development of the classic placoid lesion. Improvement of structural and functional pathology after systemic treatment is demonstrated.

Although acute organophosphate (OP) pesticide poisoning is associated with the risk cardiovascular diseases (CVD), the association between chronic occupational OP pesticide exposure and CVD risk is limited. We investigated serum high-sensitivity C-reactive protein (hs-CRP) levels and QTc intervals in 45 agricultural workers who were chronically exposed to OP pesticides and 45 non-exposed subjects. Serum hs-CRP level was determined by enzyme-linked immunosorbent assay (ELISA) and a level >1.0 mg/l was regarded as CVD risk. The QT interval was measured by routine 12-lead Electrocardiogram (ECG) with Lead II rhythm, and QTc was calculated. The median value of the serum hs-CRP level [1.20 (0.67-2.38) vs 0.74 (0.41-1.17) mg/l, P

These recommendations are synthesized from international references coupled with expert advice from endocrinologists and doctors caring for patients with COVID-19, to help guide physicians in Myanmar in managing persons with diabetes who are admitted.

IntroductionAgeing is associated with a multitude of healthcare issues including dementia, depression, frailty, morbidity associated with chronic disease and high healthcare utilisation. With Singapore’s population projected to age significantly over the next two decades, it has become increasingly important to understand the disease burden and etiological process among older adults. The Community Health and Intergenerational study aims to holistically examine ageing in place by investigating the resilience and vulnerability factors of the ageing process in the biological, psychological and social domains within the environment.Methods and analysisUsing a cohort multiple randomised controlled trial design, comprehensive health profiles of community-dwelling older adults will be collected. The objective is to recruit 1000 participants (aged 60–99 years) living in the western region of Singapore within a period of 3 years (2018–2020). Assessments include basic sociodemographic, physical health and function (cardiac, oral and blood profiles and visual function), cognitive functioning, daily functioning, physical fitness, emotional state, free-flowing speech, sleep quality, social connectedness, caregiver burden, intergenerational communication, quality of life, life satisfaction, attitudes to ageing and gratitude and compassion. Results from the cohort will enable future studies to identify at-risk groups and develop interventions to improve the physical and mental health and quality of life of older adults.Ethics and disseminationApproval of the cohort study by the National University of Singapore Institutional Review Board (NUS-IRB Reference code: H-17-047) was obtained on 12 October 2017. Written consent will be obtained from all participants. Findings from the cohort study will be disseminated by publication of peer-reviewed manuscripts, presentations at scientific meetings and conferences with local stakeholders.

Purpose. To identify systemic factors that may influence the response to anti-VEGF therapy in patients with diabetic macular edema (DME). Methods. 35 patients undergoing anti-VEGF injections for centre-involving DME were studied in this prospective observational study. The primary outcome was change in macular thickness one month after treatment, measured using spectral-domain optical coherence tomography (OCT). At baseline, information on various systemic factors was collected including glycosylated hemoglobin (HbA1c), serum VEGF levels, lipid profile and markers of renal function, and blood pressure. Thirty-three of the 35 patients were included in this study. Nonparametric statistical tests were used for the analysis of the data in view of the nonnormal distribution of the outcome variables. Multivariate analysis was performed using logistic regression. Stata 12.1 software was used for the analysis. Main Outcome Measures. Reduction in macular central subfield thickness (on spectral-domain OCT) and change in logMAR visual acuity at one month after injection. Results. Lower HbA1c levels (7% or less) were significantly associated with greater reduction in central macular subfield thickness at one month after injection of bevacizumab or ranibizumab on both univariate analysis (p=0.012) and multivariate analysis (p=0.042). Conclusions. Better glycemic control is associated with a greater reduction in central macular thickness after the first injection of bevacizumab or ranibizumab in diabetic macular edema. Patients with high levels of HbA1c and poor response to anti-VEGF may benefit from strict control of their blood glucose.

// Christine C. Dobson 1, 2 , Thet Naing 1 , Shawn T. Beug 1 , Mame D. Faye 1 , Janelle Chabot 1 , Martin St-Jean 1 , Danielle E. Walker 1 , Eric C. LaCasse 1 , David F. Stojdl 1, 3 , Robert G. Korneluk 1, 3 , Martin Holcik 1, 4 1 Molecular Biomedicine Program, Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada 3 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada 4 Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada Correspondence to: Martin Holcik, email: martin@arc.cheo.ca Keywords: rhabdomyosarcoma, Smac mimetic, oncolytic virus, immunotherapy Received: June 20, 2016 Accepted: November 23, 2016 Published: December 10, 2016 ABSTRACT Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo . Indeed, we show that innate immune stimuli (oncolytic virus (VSVΔ51-GFP), interferon γ (IFNγ), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVΔ51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers.

Genome-wide association studies for plasma triglycerides and hepatic steatosis identified a risk locus on chromosome 8q24 close to the TRIB1 gene, encoding Tribbles Pseudokinase 1 (TRIB1). In previous studies conducted in murine models, hepatic over-expression of Trib1 was shown to increase fatty acid oxidation and decrease triglyceride synthesis whereas Trib1 knockdown mice exhibited hypertriglyceridemia. Here we have examined the impact of TRIB1 suppression in human and mouse hepatocytes. Examination of a panel of lipid regulator transcripts revealed species-specific effects, prompting us to focus on human models for the remainder of the study. Acute knockdown of TRIB1 in human primary hepatocytes resulted in decreased expression of MTTP and APOB, required for very low density lipoprotein (VLDL) assembly although particle secretion was not significantly affected. A parallel analysis performed in HepG2 revealed reduced MTTP, but not APOB, protein as a result of TRIB1 suppression. Global gene expression changes of human primary hepatocytes upon TRIB1 suppression were analyzed by clustering algorithms and found to be consistent with dysregulation of several pathways fundamental to liver function, including altered CEBPA and B transcript levels and impaired glucose handling. Indeed, TRIB1 expression in HepG2 cells was found to be inversely proportional to glucose concentration. Lastly TRIB1 downregulation in primary hepatocytes was associated with suppression of the HNF4A axis. In HepG2 cells, TRIB1 suppression resulted in reduced HNF4A protein levels while HNF4A suppression increased TRIB1 expression. Taken together these studies reveal an important role for TRIB1 in human hepatocyte biology.

We have recently proposed a slit coater method for printable liquid crystal (LC) devices. In this method, the LC/reactive mesogen (RM) mixture was directly coated uniaxially onto the substrate surface by shear flow between the slit nozzle and the substrate, and the liquid crystalline molecules were anchored by in situ photopolymerisation of RM monomers. In this study, the dependence of electro-optical properties and device parameters of LC sample cells fabricated by the slit coater on ultraviolet (UV) exposure dosage was investigated. Moreover, effects of UV exposure dosage and thermal annealing on the azimuthal anchoring energy of LC sample cells fabricated by the slit coater are presented.

The TRIB1 locus (8q24.13) is a novel locus identified and replicated by several genome-wide association studies for associations with plasma triglycerides, apolipoprotein B and coronary artery disease. The TRIB1 protein product, tribbles-like protein 1 (Trib1), regulates MAPK activity. MAP kinases transduce a large variety of external signals, leading to a wide range of cellular responses, including growth, differentiation, inflammation and apoptosis. Importantly, Trib1 has been shown to regulate hepatic lipogenesis and very low density lipoprotein production. Despite the relevance of hepatocyte Trib1 to lipid metabolism and atherosclerosis, little is known about the mechanisms regulating Trib1 itself. Here, we identify the mitochondria axis as a regulator of Trib1. Treatment of HepG2 cells with a short pulse of a low oligomycin concentration led to a potent and prolonged increase in the Trib1 mRNA, an effect that was shared with other mitochondria stressors. HuH7 cells as well murine hepatocytes were also responsive albeit to a weaker extent. The upregulation appeared largely independent of reactive oxygen species generation or metabolic stress and was mainly under transcriptional control, with ERK1/2 playing an important regulating role in the process. While the presence of the Trib1 protein could be inferred, attempts to correlate the increased mRNA to changes in protein level were unsuccessful due to the lack of recognizable Trib1 signal. Our data enrich the current paradigm of Trib1 as an activator of the MAPK pathway by uncovering a role for MAPK in regulating Trib1.

Background The TRIB 1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid‐associated single nucleotide polymorphisms ( SNP s), identified by genome‐wide association studies, are located ≈30 kb downstream from TRIB 1, suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNP s at the TRIB 1 locus and plasma lipid traits. Methods and Results Characterization of the risk locus reveals that it encompasses a gene, TRIB1 ‐associated locus ( TRIBAL ), composed of a well‐conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high‐density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome‐wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus ( eQTL ) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions These studies demonstrate an interplay between a novel locus, TRIBAL, and TRIB1 . TRIBAL is located in the genome‐wide association studies identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression, and associates with plasma triglyceride concentrations.

Pathogenic bacteria secrete various virulence factors, including toxins, lipases and proteases that allow them to infect, breakdown and colonize host tissue. Among various modes of action that the pathogenic bacteria use to damage the host, pore formation (by pore forming toxins (PFTs)) and lipid hydrolysis (by phospholipases) modes are common in damaging the eukaryotic cell membrane. PFTs in their monomeric form are extracellular diffusible and able to form hydrophilic pores in cell membrane while phospholipases cleaves and hydrolyzes the ester bonds of most phospholipids in cell membrane. Both modes of action cause uncontrolled permeation of ions and molecules across cell membrane, leading to cell death by apoptosis or necrosis. In this work, the toxins secreted by two clinically important human pathogens, methicillin susceptible Staphylococcus aureus (MSSA476) and Pseudomonas aeruginosa (PAO1) were studied via their interaction with a planar tethered bilayer lipid membrane (pTBLM) using surface plasmon resonance spectroscopy (SPR) and electrochemical impedance spectroscopy (EIS). Detection and discrimination is based on lipid-loss (lipid hydrolysis by phospholipases) or non lipid-loss (pore formation by PFTs) from pTBLM upon interaction with supernatant of pathogenic bacteria. Using EIS and SPR, it is demonstrated that major toxins of S. auerus are PFTs while most of toxin associated with P. aeruginosa are more lipid damaging lipolytic enzymes. Such a format might have future utility as a simple assay for measuring the presence membrane lytic virulence factors in clinical samples.

We report a case of a 70-year-old farmer admitted for viper bite who presented with bilateral hyphema and angle closure attack. He was managed conservatively with topical steroids and cycloplegics. He responded well and was discharged after 2 weeks.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2, 119 patients with exudative AMD and 5, 691 controls, with independent replication in 4, 226 patients and 10, 289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10[-22]). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17mmoll-1 (P=5.82 × 10[-21]) in East Asians (n=7, 102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10[-18]), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10[-11]) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10[-8]). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature., 加齢黄斑変性の発症に関わるアジア人特有の遺伝子変異を発見. 京都大学プレスリリース. 2015-02-05., Updated 30 March 2015. [Corrigendum] doi:10.1038/ncomms7817

A new methodology for detecting the microbiological state of a wound dressing in terms of its colonization with pathogenic bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa has been developed. Here we report how stabilized lipid vesicles containing self-quenched carboxyfluorescein dye are sensitive to lysis only by toxins/virulence factors from P. aeruginosa and S. aureus but not by a non-toxic Escherichia coli species. The development of the stabilized vesicles is discussed and their response to detergent (triton), bacterial toxin (α-hemolysin) and lipases (phospholipase A 2). Finally, fabrics with stabilized vesicles attached via plasma deposited maleic anhydride coupling are shown visibly responding to S. aureus (MSSA 476) and P. aeruginosa (PAO1) but not E. coli DH5α in a prototype dressing. Refereed/Peer-reviewed

Common intronic SNPs in the human fat mass and obesity associated (FTO) gene are strongly associated with body mass index (BMI). In mouse models, inactivation of the Fto gene results in a lean phenotype, whereas overexpression of Fto leads to increased food intake and obesity. The latter finding suggests that copy number variants at the FTO locus might be associated with extremes of adiposity. To address this question, we searched for rare, private or de novo copy number variation in a cohort of 985 obese and 869 lean subjects of European ancestry drawn from the extremes of the BMI distribution, genotyped on Affymetrix 6.0 arrays. A ∼680 kb duplication, confirmed by real-time PCR and G-to-FISH analyses, was observed between ∼rs11859825 and rs9932411 in a 68-year-old male with severe obesity. The duplicated region on chromosome 16 spans the entire genome-wide association studies risk locus for obesity, and further encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene. Affected family members exhibit a unique obesity phenotype, characterized by increased fat distribution in the shoulders and neck with a significantly increased neck circumference. This phenotype was accompanied by increased peripheral blood expression of RBL2 with no alteration in expression of FTO or other genes in the region. No other duplications or deletions in this region were identified in the cohort of obese and lean individuals or in a further survey of 4778 individuals, suggesting that large rare copy number variants surrounding the FTO gene are not a frequent cause of obesity.

Pathogenic bacteria secrete various virulence factors that can directly interact with the outer lipid bilayer membrane of eukaryotic cells, inducing cell death by apoptosis or necrosis. Such virulence factors account for much of the toxic action associated with bacterial infection; therefore the detection of such proteins could provide a methodology for sensing/detection of pathogenic bacteria in, for example, food or human tissue. Detection and identification of pathogenic bacteria by conventional methods such as plating and counting in laboratory is expensive and time consuming. With growing concerns over emergence and re-emergence of pathogenic bacteria with high resistant to current antibiotics, there is a potential need for effective detection of pathogenic toxins in-vitro. This paper presents the application of tethered bilayer lipid membrane (TBLM) as a sensing platform for the detection of the clinically relevant pathogenic bacterial, Staphylococcus aureus MSSA 476 and Pseudomonas aeruginosa PAO1 via their secreted virulence factors, using electrochemical impedance spectroscopy (EIS). A non-pathogenic strain of bacteria, E. coli DH5α was used as a control. A clear difference in the impedance of the TBLM for the pathogenic vs. non-pathogenic species was observed. Keywords: Pathogenic bacteria, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Pore-forming toxins, Electrochemical impedance spectroscopy

We have recently reported on a method that utilizes a slit coater as a novel liquid crystal alignment technique. We carried out this study under two ultraviolet (UV) irradiation conditions, viz., (i) UV irradiation from the side of a glass substrate (exposure type 1) and (ii) UV irradiation from the side of the air–liquid crystal interface (exposure type 2), and investigated the electro-optical characteristics and azimuthal anchoring energy of liquid crystal sample cells performed under these two UV irradiation conditions.

29 male patients (14 from Taunggyi, 6 from Rangoon and 9 from Tharrawaddy in Burma) were treated simultaneously with 200 mg artemether (Single intramuscular dose), 1500 mg sulfadoxine and 75 mg [corrected] pyrimethamine (orally). The mean parasite clearance time was 106.7 +/- 48.7 h. Side effects were few and self-limiting. 13 of 29 patients had recrudescences before day 28; as all the patients were living in towns, reinfection was unlikely. This parasite clearance time was longer than that in patients treated with artemether alone (600 mg total dose), and the recrudescence rate was higher. This drug combination is not recommended for patients in areas where sulfadoxine/pyrimethamine resistance is already established.