Intoksikacija nafazolin kapima za nos u djece

Naphazoline, a sympathomimetic and an imidazoline derivative, is used as 0.05-0.1% solution for local decongestion of the nasal and ocular mucosa. In excessive dosage, or if ingested by accident, may cause depression of the central nervous system (disturbances of consciousness progressing to coma), hypothermia, bradycardia and sweating. These naphazoline effects are particularly strongly pronounced in children. Anglo-Saxon pharmacotherapy excludes the application of naphazoline nasal drops in children younger than six years, whereas the Croatian pharmacotherapeutic literature (and practice) allows its use even in infancy. At the Kantrida Paediatric Clinic, Clinical Hospital Centre in Rijeka, 11 children with signs of intoxication with naphazoline nasal drops were hospitalized from 1990 to 1992. The symptoms pertaining to the central nervous system i.e. disturbances of consciousness in the form of somnolence were dearly marked in all children. Some children developed skin pallor, bradycardia, bradypnoea and hypothermia. Resolution occurred within 24 hours and the findings relumed to normal values. Clinical picture followed by rapid resolution and normal findings, with a personal history of drug taking, is a safe indication for diagnosis. There are several reasons to account for intoxication (drops difficult to use with children, containers inadequate for proper dosage), but the major factor is the age of the patient - all hospitalized children were younger than six years. It is pointed out that administration of naphazoline drops at an early age is not advisable.Nafazolin je simpatomimetik, derivat imidazolina, a primjenjuje se kao 0,05-0,1 % otopina za lokalnu dekongestiju sluznice oka i nosa. Predoziran ili slučajno uzet peroralno može uzrokovati depresiju središnjeg živčanog sustava (poremećaje svijesti sve do kome) te hipotermiju, bradikardiju i znojenje. Navedeni učinci nafazolina napose su izraženi u djece. Anglosaksonska farmakoterapija isključuje primjenu nafazolina u djece do šest godina starosti doćim naša farmakoterapijska literature (a i praksa) dopušta njegovu uporabu već od dojenačke dobi. Na Klinici za dječje bolesti Kantrida Kliničkog bolničkog centra u Rijeci, u razdoblju od 1990. do 1992. godine hospitalizirano je 11-ero djece sa znacima trovanja nafazolin kapima za nos. U sve djece bili su izraženi simptomi poremećaja središnjeg živčanog sustava i to poremećaji svijest u vidu somnolencije. U neke djece pridruženo je bilo i bljedilo kože, bradikardija, bradipneja i hipotermija. Oporavak je u sve djece uslijedio unutar 24 sata, a učinjenom obradom dobiveni su uredni nalazi. Klinička slika s brzim oporavkom i urednim nalazima uz anamnestički podatak o uzimanju lijeka siguran je putokaz k dijagnozi. Razloga koji su doveli do otrovanja ima više (otežano ukapavanje djeci neadekvatna ambalaža za ispravno doziranje) no svakako je najistaknutiji faktor uzrast. Sva hospitalizirana djeca bila su naime mlađa od šest godina. Zaključuje se da u ovoj starosnoj skupini nije uputno primjenjivati nafazolin kapi. Farmaceutsku industriju valja upozoriti na neke osobitosti dječje dobi koja postavlja specifične zahtjeve za oblikom i ambalažom ljekovitog pripravka, a domaću farmakoterapijsku literaturu obogatiti ovim spoznajama

Label-free electrochemical monitoring of DNA ligase activity

This study presents a simple, label-free electrochemical technique for the monitoring of DNA ligase activity. DNA ligases are enzymes that catalyze joining of breaks in the backbone of DNA and are of significant scientific interest due to their essential nature in DNA metabolism and their importance to a range of molecular biological methodologies. The electrochemical behavior of DNA at mercury and some amalgam electrodes is strongly influenced by its backbone structure, allowing a perfect discrimination between DNA molecules containing or lacking free ends. This variation in electrochemical behavior has been utilized previously for a sensitive detection of DNA damage involving the sugar-phosphate backbone breakage. Here we show that the same principle can be utilized for monitoring of a reverse process, i.e., the repair of strand breaks by action of the DNA ligases. We demonstrate applications of the electrochemical technique for a distinction between ligatable and unligatable breaks in plasmid DNA using T4 DNA ligase, as well as for studies of the DNA backbone-joining activity in recombinant fragments of E. coli DNA ligase

The role of ADP-ribosylation in regulating DNA interstrand crosslink repair

ADP-ribosylation by ADP-ribosyltransferases (ARTs) has a well-established role in DNA strand break repair by promoting enrichment of repair factors at damage sites through ADP-ribose interaction domains. Here we exploit the simple eukaryote Dictyostelium to uncover a role for ADP-ribosylation in regulating DNA interstrand crosslink repair and redundancy of this pathway with non-homologous end-joining (NHEJ). In silico searches identify a protein that contains a permutated macrodomain (Aprataxin/APLF-and-PNKP-Like protein; APL). Structural analysis reveals permutated macrodomains retain features associated with ADP-ribose interactions and APL is capable of binding poly-ADP-ribose through its macrodomain. APL is enriched in chromatin in response to cisplatin, an agent that induces DNA interstrand crosslinks (ICLs). This is dependent on the macrodomain of APL, and the ART Adprt2, indicating a role for ADP-ribosylation in the cellular response to cisplatin. Although adprt2− cells are sensitive to cisplatin, ADP-ribosylation is evident in these cells due to redundant signalling by the DSB-responsive ART Adprt1a, promoting NHEJ-mediated repair. These data implicate ADP-ribosylation in DNA ICL repair and identify NHEJ can function to resolve this form of DNA damage in the absence of Adprt2

A critical review of the formation of mono- and dicarboxylated metabolic intermediates of alkylphenol polyethoxylates during wastewater treatment and their environmental significance

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Taylor & Francis.Alkylphenoxyacetic acids, the metabolic biodegradation products of alkylphenol ethoxylates, are commonly found in wastewaters and sewage effluents. These persistent hydrophilic derivatives possess intrinsic estrogenic activity, which can mimic natural hormones. Their concentrations increase through the sewage treatment works as a result of biodegradation and biotransformation, and when discharged can disrupt endocrine function in fish. These acidic metabolites represent the dominant alkylphenolic compounds found in wastewater effluent and their presence is cause for concern as, potentially, through further biotransformation and biodegradation, they can act as sources of nonylphenol, which is toxic and estrogenic. The authors aim to assess the mechanisms of formation as well as elimination of alkylphenoxyacetic acids within conventional sewage treatment works with the emphasis on the activated sludge process. In addition, they evaluate the various factors influencing their degradation and formation in laboratory scale and full-scale systems. The environmental implications of these compounds are considered, as is the need for tertiary treatment processes for their removal

Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal

Poly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry. Bio-organic Synthesi

ERCC6L2 mitigates replication stress and promotes centromere stability

Structurally complex genomic regions, such as centromeres, are inherently difficult to duplicate. The mechanism behind centromere inheritance is not well understood, and one of the key questions relates to the reassembly of centromeric chromatin following DNA replication. Here, we define ERCC6L2 as a key regulator of this process. ERCC6L2 accumulates at centromeres and promotes deposition of core centromeric factors. Interestingly, ERCC6L2−/− cells show unrestrained replication of centromeric DNA, likely caused by the erosion of centromeric chromatin. Beyond centromeres, ERCC6L2 facilitates replication at genomic repeats and non-canonical DNA structures. Notably, ERCC6L2 interacts with the DNA-clamp PCNA through an atypical peptide, presented here in a co-crystal structure. Finally, ERCC6L2 also restricts DNA end resection, acting independently of the 53BP1-REV7-Shieldin complex. We propose a mechanistic model, which reconciles seemingly distinct functions of ERCC6L2 in DNA repair and DNA replication. These findings provide a molecular context for studies linking ERCC6L2 to human disease

The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase

Post-translational modification of proteins by poly(ADP-ribosyl)ation regulates many cellular pathways that are critical for genome stability, including DNA repair, chromatin structure, mitosis and apoptosis1. Poly(ADP-ribose) (PAR) is composed of repeating ADP-ribose units linked via a unique glycosidic ribose–ribose bond, and is synthesized from NAD by PAR polymerases1, 2. PAR glycohydrolase (PARG) is the only protein capable of specific hydrolysis of the ribose–ribose bonds present in PAR chains; its deficiency leads to cell death3, 4. Here we show that filamentous fungi and a number of bacteria possess a divergent form of PARG that has all the main characteristics of the human PARG enzyme. We present the first PARG crystal structure (derived from the bacterium Thermomonospora curvata), which reveals that the PARG catalytic domain is a distant member of the ubiquitous ADP-ribose-binding macrodomain family5, 6. High-resolution structures of T. curvata PARG in complexes with ADP-ribose and the PARG inhibitor ADP-HPD, complemented by biochemical studies, allow us to propose a model for PAR binding and catalysis by PARG. The insights into the PARG structure and catalytic mechanism should greatly improve our understanding of how PARG activity controls reversible protein poly(ADP-ribosyl)ation and potentially of how the defects in this regulation are linked to human disease

Influence of operating parameters on the biodegradation of steroid estrogens and nonylphenolic compounds during biological wastewater treatment processes

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Environmental Science & Technology, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/es901612v.This study investigated operational factors influencing the removal of steroid estrogens and nonylphenolic compounds in two sewage treatment works, one a nitrifying/denitrifying activated sludge plant and the other a nitrifying/denitrifying activated sludge plant with phosphorus removal. Removal efficiencies of >90% for steroid estrogens and for longer chain nonylphenol ethoxylates (NP4−12EO) were observed at both works, which had equal sludge ages of 13 days. However, the biological activity in terms of milligrams of estrogen removed per day per tonne of biomass was found to be 50−60% more efficient in the nitrifying/denitrifying activated sludge works compared to the works which additionally incorporated phosphorus removal. A temperature reduction of 6 °C had no impact on the removal of free estrogens, but removal of the conjugated estrone-3-sulfate was reduced by 20%. The apparent biomass sorption (LogKp) values were greater in the nitrifying/denitrifying works than those in the nitrifying/denitrifying works with phosphorus removal for both steroid estrogens and nonylphenolic compounds possibly indicating a different cell surface structure and therefore microbial population. The difference in biological activity (mg tonne−1 d−1) identified in this study, of up to seven times, suggests that there is the potential for enhancing the removal of estrogens and nonylphenols if more detailed knowledge of the factors responsible for these differences can be identified and maximized, thus potentially improving the quality of receiving waters.Public Utilities Board (Singapore), Anglian Water Ltd, Severn Trent Water Ltd, Thames Water Utilities Ltd, United Utilities 393 Plc and Yorkshire Water Services

PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

This is the final version. Available on open access from the American Association for the Advancement of Science via the DOI in this recordData availability: The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (92) partner repository with the dataset identifier PXD043452.PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. We show that PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a marked increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and antiviral PARP13, and displays specific cellular phenotypes. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated antiviral response.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustOxford University Challenge Seed FundEdward Penley Abraham Research FundOvarian Cancer Research AllianceResearch Council of NorwaySwedish Research CouncilMedical Research Council (MRC)Novo Nordisk Foundation Center for Protein ResearchDanish Council of Independent ResearchDanish Cancer Societ

Stress-Induced PARP Activation Mediates Recruitment of Drosophila Mi-2 to Promote Heat Shock Gene Expression

Eukaryotic cells respond to genomic and environmental stresses, such as DNA damage and heat shock (HS), with the synthesis of poly-[ADP-ribose] (PAR) at specific chromatin regions, such as DNA breaks or HS genes, by PAR polymerases (PARP). Little is known about the role of this modification during cellular stress responses. We show here that the nucleosome remodeler dMi-2 is recruited to active HS genes in a PARP–dependent manner. dMi-2 binds PAR suggesting that this physical interaction is important for recruitment. Indeed, a dMi-2 mutant unable to bind PAR does not localise to active HS loci in vivo. We have identified several dMi-2 regions which bind PAR independently in vitro, including the chromodomains and regions near the N-terminus containing motifs rich in K and R residues. Moreover, upon HS gene activation, dMi-2 associates with nascent HS gene transcripts, and its catalytic activity is required for efficient transcription and co-transcriptional RNA processing. RNA and PAR compete for dMi-2 binding in vitro, suggesting a two step process for dMi-2 association with active HS genes: initial recruitment to the locus via PAR interaction, followed by binding to nascent RNA transcripts. We suggest that stress-induced chromatin PARylation serves to rapidly attract factors that are required for an efficient and timely transcriptional response