Interventions for preventing ophthalmia neonatorum.

BACKGROUND: Ophthalmia neonatorum is an infection of the eyes in newborns that can lead to blindness, particularly if the infection is caused by Neisseria gonorrhoeae. Antiseptic or antibiotic medication is dispensed into the eyes of newborns, or dispensed systemically, soon after delivery to prevent neonatal conjunctivitis and potential vision impairment. OBJECTIVES: 1. To determine if any type of systemic or topical eye medication is better than placebo or no prophylaxis in preventing ophthalmia neonatorum. 2. To determine if any one systemic or topical eye medication is better than any other medication in preventing ophthalmia neonatorum. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers, date of last search 4 October 2019. We also searched references of included studies and contacted pharmaceutical companies.  SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of any topical, systemic, or combination medical interventions used to prevent ophthalmia neonatorum in newborns compared with placebo, no prophylaxis, or with each other. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Outcomes were: blindness or any adverse visual outcome at 12 months, conjunctivitis at 1 month (gonococcal (GC), chlamydial (CC), bacterial (BC), any aetiology (ACAE), or unknown aetiology (CUE)), and adverse effects.  MAIN RESULTS: We included 30 trials with a total of 79,198 neonates. Eighteen studies were conducted in high-income settings (the USA, Europe, Israel, Canada), and 12 were conducted in low- and middle-income settings (Africa, Iran, China, Indonesia, Mexico). Fifteen of the 30 studies were quasi-randomised. We judged every study to be at high risk of bias in at least one domain. Ten studies included a comparison arm with no prophylaxis. There were 14 different prophylactic regimens and 12 different medications in the 30 included studies. Any prophylaxis compared to no prophylaxis  Unless otherwise indicated, the following evidence comes from studies assessing one or more of the following interventions: tetracycline 1%, erythromycin 0.5%, povidone-iodine 2.5%, silver nitrate 1%. None of the studies reported data on the primary outcomes: blindness or any adverse visual outcome at any time point. There was only very low-certainty evidence on the risk of GC with prophylaxis (4/5340 newborns) compared to no prophylaxis (5/2889) at one month (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.24 to 2.65, 3 studies). Low-certainty evidence suggested there may be little or no difference in effect on CC (RR 0.96, 95% CI 0.57 to 1.61, 4874 newborns, 2 studies) and BC (RR 0.84, 95% CI 0.37 to 1.93, 3685 newborns, 2 studies). Moderate-certainty evidence suggested a probable reduction in risk of ACAE at one month (RR 0.65, 95% 0.54 to 0.78, 9666 newborns, 8 studies assessing tetracycline 1%, erythromycin 0.5%, povidone-iodine 2.5%, silver nitrate 1%, colostrum, bacitracin-phenacaine ointment). There was only very low-certainty evidence on CUE  (RR 1.75, 95% CI 0.37 to 8.28, 330 newborns, 1 study). Very low-certainty evidence on adverse effects suggested no increased nasolacrimal duct obstruction (RR 0.93, 95% CI 0.68 to 1.28, 404 newborns, 1 study of erythromycin 0.5% and silver nitrate 1%) and no increased keratitis (single study of 40 newborns assessing silver nitrate 1% with no events).    Any prophylaxis compared to another prophylaxis Overall, evidence comparing different interventions did not suggest any consistently superior intervention. However, most of this evidence was of low-certainty and was extremely limited. AUTHORS' CONCLUSIONS: There are no data on whether prophylaxis for ophthalmia neonatorum prevents serious outcomes such as blindness or any adverse visual outcome. Moderate-certainty evidence suggests that the use of prophylaxis may lead to a reduction in the incidence of ACAE in newborns but the evidence for effect on GC, CC or BC was less certain. Comparison of individual interventions did not suggest any consistently superior intervention, but data were limited. A trial comparing tetracycline, povidone-iodine (single administration), and chloramphenicol for GC and CC could potentially provide the community with an effective, universally applicable prophylaxis against ophthalmia neonatorum.

High resolution crystal structures of human kynurenine aminotransferase-I bound to PLP cofactor, and in complex with aminooxyacetate.

In this study, we report two high-resolution structures of the pyridoxal 5' phosphate (PLP)-dependent enzyme kynurenine aminotransferase-I (KAT-I). One is the native structure with the cofactor in the PLP form bound to Lys247 with the highest resolution yet available for KAT-I at 1.28 Å resolution, and the other with the general PLP-dependent aminotransferase inhibitor, aminooxyacetate (AOAA) covalently bound to the cofactor at 1.54 Å. Only small conformational differences are observed in the vicinity of the aldimine (oxime) linkage with which the PLP forms the Schiff base with Lys247 in the 1.28 Å resolution native structure, in comparison to other native PLP-bound structures. We also report the inhibition of KAT-1 by AOAA and aminooxy-phenylpropionic acid (AOPP), with IC50s of 13.1 and 5.7 µM, respectively. The crystal structure of the enzyme in complex with the inhibitor AOAA revealed that the cofactor is the PLP form with the external aldimine linkage. The location of this oxime with the PLP, which forms in place of the native internal aldimine linkage of PLP of the native KAT-I, is away from the position of the native internal aldimine, with the free Lys247 substantially retaining the orientation of the native structure. Tyr101, at the active site, was observed in two conformations in both structures.

Ianthellamide A, a selective kynurenine-3-hydroxylase inhibitor from the Australian marine sponge Ianthella quadrangulata.

Ianthellamide A (1), a novel octopamine derivative, was isolated from the Australian marine sponge Ianthella quadrangulata. Compound 1 selectively inhibited the activity of kynurenine 3-hydroxylase with an IC(50) value of 1.5 µM. It also significantly increased the level of endogenous kynurenic acid in rat brain and hence has the potential as a neuroprotective agent in the treatment of neurodegenerative disorders.

Effects of acute postoperative pain on catecholamine plasma levels, hemodynamic parameters, and cardiac autonomic control.

Postoperative pain is often stated to be a significant contributor to a sympathetic stress response after surgery. However, hardly any evidence has been published to support this assumption. Hence it was the aim of this trial to investigate the relationship between postoperative pain and hemodynamic, endocrine, and autonomic parameters. A total of 85 postoperative patients in the recovery room were repeatedly asked to rate their pain on a numeric rating scale (NRS). Concurrently, the parameters of heart rate variability (HRV) were analysed, and mean arterial pressure (MAP), heart rate (HR) and respiration rate (RR) were recorded. Pain was categorized into no, mild, moderate, and severe. Blood samples were taken for epinephrine (EPI) and norepinephrine (NE) plasma level assessment at the time of recovery room admission and discharge, and each time pain was found decreased in categorized severity. A total of 239 pain readings were obtained. None of the investigated parameters correlated with NRS scores. NE was higher at NRS 5 to 10 vs. NRS 0 to 4 (mean [SEM]: 1009 [73] pg/mL vs. 872 [65] pg/mL; P<0.01). This was also found for MAP, but not for EPI or the parameters of HRV, HR, and RR. In contrast to common belief, the severity of postoperative pain does not appear to be associated with the degree of sympathetic stress response after surgery, and other factors such as surgical trauma may be more important. Importantly, the absence of signs of sympathetic stimulation cannot be seen as a guarantee for the absence of significant pain.

Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I.

Herein we report 6-ethoxy-6-oxo-5-(2-phenylhydrazono) hexanoic acid and 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives as synthetically accessible leads for human kynurenine aminotransferase-I (KAT-I) inhibitors. In total, 12 compounds were synthesized and their biological activities were determined using the HPLC-UV based KAT-I inhibition assay. Of the 12 compounds synthesized, 10 were found to inhibit human KAT-I and the most active compound was found to be 5-(2-(4-chlorophenyl) hydrazono)-6-ethoxy-6-oxohexanoic acid (9a) with an IC(50) of 19.8 µM.

Kynurenine is an endothelium-derived relaxing factor produced during inflammation.

Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.

Characterization of the kynurenine pathway in human neurons.

The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

Preliminary evidence for a link between schizophrenia and NMDA-glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1).

Preliminary investigations, studying gene expression and biochemical activities of enzymes d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1), revealed elevated cerebellar KAT-1 and DAAO activities in post-mortem brain samples from schizophrenic versus normal individuals. In addition, we have identified a transcript of DAAO, which was expressed in significantly higher quantities in the diseased cerebellum but not detected in the parietal cortex where DAAO activity is absent.

Djinn Lite: a tool for customised gene transcript modelling, annotation-data enrichment and exploration.

BACKGROUND: There is an ever increasing rate of data made available on genetic variation, transcriptomes and proteomes. Similarly, a growing variety of bioinformatic programs are becoming available from many diverse sources, designed to identify a myriad of sequence patterns considered to have potential biological importance within inter-genic regions, genes, transcripts, and proteins. However, biologists require easy to use, uncomplicated tools to integrate this information, visualise and print gene annotations. Integrating this information usually requires considerable informatics skills, and comprehensive knowledge of the data format to make full use of this information. Tools are needed to explore gene model variants by allowing users the ability to create alternative transcript models using novel combinations of exons not necessarily represented in current database deposits of mRNA/cDNA sequences. RESULTS: Djinn Lite is designed to be an intuitive program for storing and visually exploring of custom annotations relating to a eukaryotic gene sequence and its modelled gene products. In particular, it is helpful in developing hypothesis regarding alternate splicing of transcripts by allowing the construction of model transcripts and inspection of their resulting translations. It facilitates the ability to view a gene and its gene products in one synchronised graphical view, allowing one to drill down into sequence related data. Colour highlighting of selected sequences and added annotations further supports exploration, visualisation of sequence regions and motifs known or predicted to be biologically significant. CONCLUSION: Gene annotating remains an ongoing and challenging task that will continue as gene structures, gene transcription repertoires, disease loci, protein products and their interactions become more precisely defined. Djinn Lite offers an accessible interface to help accumulate, enrich, and individualize sequence annotations relating to a gene, its transcripts and translations. The mechanism of transcript definition and creation, and subsequent navigation and exploration of features, are very intuitive and demand only a short learning curve. Ultimately, Djinn Lite can form the basis for providing valuable clues to plan new experiments, providing storage of sequences and annotations for dedication to customised projects. The application is appropriate for Windows 98-ME-2000-XP-2003 operating systems.

Inhibition of indoleamine 2,3-dioxygenase activity in IFN-gamma stimulated astroglioma cells decreases intracellular NAD levels.

Astroglia provide essential metabolic and neurotropic support to cells within the CNS and participate in the cellular immune response with microglia/macrophages following activation by the pro-inflammatory cytokine IFN-gamma. Activation of glial cells results in local oxidative stress and induction of a number of proteins including the enzyme indoleamine 2,3-dioxygenase (IDO). As a rate-limiting enzyme, IDO regulates tryptophan catabolism via the kynurenine pathway producing a series of metabolic precursors (some of which are neurotoxic) before complete oxidation to the essential pyridine nucleotide NAD. Inhibition of this pathway may therefore prove therapeutic in neuroinflammatory disease by reducing production of cell toxins. However, kynurenine metabolism may also be cytoprotective through de novo synthesis of cellular NAD levels. We investigated the hypothesis that IDO activity is directly involved in maintenance of intracellular [NAD] in activated astroglial cells through control of de novo synthesis. Exposure to IFN-gamma increased IDO activity from 7+/-1 nmol to 129+/-11 nmol kynurenine/hr/mg protein. Inhibition of IDO activity with either 6-chloro-D-tryptophan (competitive inhibition), or 3-ethoxy beta-carboline (non-competitive inhibition) resulted in a dose-dependent decrease in IDO activity that correlated directly with decreasing [NAD] (R(2)=0.92 and 0.81, respectively). These results support the hypothesis that one important consequence of increasing IDO activity in astroglial cells during inflammation is to maintain NAD levels through de novo synthesis from tryptophan. Inhibition of kynurenine pathway metabolism under these conditions may significantly decrease cell viability and CNS functions unless alternate precursors for NAD synthesis are available.

Extraction and chromatography-mass spectrometric analysis of the active principles from selected Chinese herbs and other medicinal plants.

Medicinal herbs have a long history of use in the practice of traditional Chinese medicine and a substantial body of evidence has, over recent decades, demonstrated a range of important pharmacological properties. Western biomedical researchers are examining not only the efficacy of the traditional herbal products but, through the use of a range of bioassays and analytical techniques, are developing improved methods to isolate and characterize active components. This review briefly describes the different extraction methodologies used in the preparation of herbal extracts and reviews the utility of chromatography-mass spectrometry for the analysis of their active components. In particular, applications of gas or liquid chromatography with mass spectrometry for the isolation and characterization of active components of ginseng are critically assessed. The analysis of toxic substances from herb extracts with mass spectrometric techniques is also discussed along with the potential for mass spectrometric methods to investigate the proteomics of herbal extracts.

A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are the most extensively used animal model for genetic hypertension, increased stroke damage, and insulin resistance syndromes; however, the identification of target genes has proved difficult. SHR show elevated sympathetic nerve activity, and stimulation of the central blood pressure control centers with glutamate or nicotine results in exaggerated blood pressure responses, effects that appear to be genetically determined. Kynurenic acid, a competitive glutamate antagonist and a non-competitive nicotinic antagonist, can be synthesized in the brain by the enzyme kynurenine aminotransferase-1 (KAT-1). We have previously shown that KAT-1 activity is significantly reduced in SHR compared with normotensive Wistar Kyoto rats (WKY). Here we show that KAT-1 contains a missense mutation, E61G, in all the strains of SHR examined but not in any of the WKY or outbred strains. Previous studies on F2 rats from a cross of stroke-prone SHR and WKY have shown a suggestive level of linkage between elevated blood pressure and the KAT-1 locus on chromosome 3. In addition, the mutant enzyme expressed in Escherichia coli displays altered kinetics. This mutation may explain the enhanced sensitivity to glutamate and nicotine seen in SHR that may be related to an underlying mechanism of hypertension and increased sensitivity to stroke.