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Author(s): Nicolai Haase [sup.1], Sisse Rye Ostrowski [sup.2], Jørn Wetterslev [sup.3], Theis Lange [sup.4], Morten Hylander Møller [sup.1] [sup.5], Hamid Tousi [sup.6], Morten Steensen [sup.1] [sup.7], Frank Pott [sup.5], Peter [...], Purpose To investigate the association between consecutively measured thromboelastographic (TEG) tracings and outcome in patients with severe sepsis. Methods Multicentre prospective observational study in a subgroup of the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial (NCT00962156) comparing hydroxyethyl starch (HES) 130/0.42 vs. Ringer's acetate for fluid resuscitation in severe sepsis. TEG (standard and functional fibrinogen) was measured consecutively for 5 days, and clinical data including bleeding and death was retrieved from the trial database. Statistical analyses included Cox regression with time-dependent covariates and joint modelling techniques. Results Of 267 eligible patients, we analysed 260 patients with TEG data. At 90 days, 68 (26 %) had bled and 139 (53 %) had died. For all TEG variables, hypocoagulability according to the reference range was significantly associated with increased risk of death. In a linear model, hazard ratios for death were 6.03 (95 % confidence interval, 1.64-22.17) for increased clot formation speed, 1.10 (1.04-1.16) for decreased angle, 1.09 (1.05-1.14) for decreased clot strength and 1.12 (1.06-1.18) for decreased fibrinogen contribution to clot strength (functional fibrinogen MA), showing that deterioration towards hypocoagulability in any TEG variable significantly increased the risk of death. Patients treated with HES had lower functional fibrinogen MA than those treated Ringer's acetate, which significantly increased the risk of subsequent bleeding [HR 2.43 (1.16-5.07)] and possibly explained the excess bleeding with HES in the 6S trial. Conclusions In our cohort of patients with severe sepsis, progressive hypocoagulability defined by TEG variables was associated with increased risk of death and increased risk of bleeding.

Chlorinated phenol derivatives are highly toxic xenobiotics; their concentration of in environmental objects is to be controlled. Di- and polychlorophenols (PCP) appear the most toxic [1, 2]. The maximal acceptable [...], A selective and highly selective procedure is presented for the determination of the systematic class of polychlorophenols (PCP) by gas chromatography with electron capture detection (ECD) upon derivatization with monochloroacetic anhydride. The relative intensity of the analytical signal (in comparison to simple acetates) is increased 8-9 times for dichlorophenols and 2.5-4 times for trichlorophenols; for tetra- and pentochlorophenols, the enhancement coefficient is 1.5-2. The stage of PCP derivatization is studied by GC/MS; the mass spectra of tri- and tetrachlorophenol monochloroacetates were recorded for the first time. The limits of determination were 0.005-0.016 µg/L (RSD 6-7%), and the upper limit of the detected concentrations was 0.050-0.160 µg/L (RSD 3-4%). Key words: gas chromatography, polychlorophenols, monochloroacetic anhydride DOI: 10.1134/S1061934810100060

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.03.018 Byline: Hyunkyung Jeong (1), Florian Then (1), Thomas J. Melia (3), Joseph R. Mazzulli (1), Libin Cui (1), Jeffrey N. Savas (4)(5), Cindy Voisine (2), Paolo Paganetti (6), Naoko Tanese (4), Anne C. Hart (2), Ai Yamamoto (7), Dimitri Krainc (1) Keywords: MOLNEURO Abstract: Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy. Author Affiliation: (1) Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA (2) Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA (3) Department of Cell Biology, Yale University, New Haven, CT 06519, USA (4) Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA (5) NYU and NIH Graduate Partnership Program in Structural Biology, New York University School of Medicine, New York, NY 10016, USA (6) Novartis Pharma AG, NIBR Basel, Neuroscience Discovery, CH-4002 Basel, Switzerland (7) Department of Neurology, College of Physician and Surgeons, Columbia University, New York, NY 10032, USA Article History: Received 11 February 2008; Revised 13 October 2008; Accepted 11 March 2009 Article Note: (miscellaneous) Published: April 2, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.06.018 Byline: Qing Li (1), Hui Zhou (1), Hugo Wurtele (2), Brian Davies (1), Bruce Horazdovsky (1), Alain Verreault (2), Zhiguo Zhang (1) Keywords: DNA Abstract: Chromatin assembly factor 1 (CAF-1) and Rtt106 participate in the deposition of newly synthesized histones onto replicating DNA to form nucleosomes. This process is critical for the maintenance of genome stability and inheritance of functionally specialized chromatin structures in proliferating cells. However, the molecular functions of the acetylation of newly synthesized histones in this DNA replication-coupled nucleosome assembly pathway remain enigmatic. Here we show that histone H3 acetylated at lysine 56 (H3K56Ac) is incorporated onto replicating DNA and, by increasing the binding affinity of CAF-1 and Rtt106 for histone H3, H3K56Ac enhances the ability of these histone chaperones to assemble DNA into nucleosomes. Genetic analysis indicates that H3K56Ac acts in a nonredundant manner with the acetylation of the N-terminal residues of H3 and H4 in nucleosome assembly. These results reveal a mechanism by which H3K56Ac regulates replication-coupled nucleosome assembly mediated by CAF-1 and Rtt106. Author Affiliation: (1) Department of Biochemistry and Molecular Biology, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USA (2) Institute for Research in Immunology and Cancer (IRIC), Departement de Pathologie et Biologie Cellulaire, PO Box 6128 Succursale Centre-Ville, Montreal, Qc, Canada H3C 3J7 Article History: Received 22 December 2007; Revised 6 April 2008; Accepted 9 June 2008 Article Note: (miscellaneous) Published: July 24, 2008

One of the strategies to prevent insulin resistance is to reduce circulating free fatty acids (FFA). The aim of this study is to assess the effect of an oral lactulose load on fatty acid metabolism in overweight subjects. Eight overweight subjects received a primed constant intravenous infusion of [1-[sup.13]C]acetate and of [1,1,2,3,3-[sup.2][H.sub.5]]glycerol for 9 h. After 3 h of tracer infusion, patients ingested 30 g lactulose, or saline solution. Arterialized blood samples were collected every 20 min. Basal plasma concentrations of acetate were similar before and between oral treatments as well as glycerol and FFA concentrations. Plasma acetate turnover was 11.4 [+ or -] 2.4 vs. 10.7 [+ or -] 1.4 [micro]mol * [kg.sup.-1] * [min.sup.-2 ][not significant (NS)], and plasma glycerol turnover was 3.8 [+ or -] 0.4 vs. 4.8 [+ or -] 1.9 [micro]mol * [kg.sup.-1] * [min.sup.-1] (NS). After lactulose ingestion, acetate concentration increased twofold and then decreased to baseline. Acetate turnover rate increased to 15.5 [+ or -] 2.2 [micro]mol * [kg.sup.-1] * [min.sup.1] after lactulose treatment, whereas it was unchanged after saline treatment (10.3 [+ or -] 2.2 [micro]mol * [kg.sup.-1] * [min.sup.-1], p [less than or equal to] 0.0001). In contrast, FFA concentrations decreased significantly after lactulose ingestion and then increased slowly. Glycerol turnover decreased after lactulose ingestion compared with saline, 2.8 [+ or -] 0.4 vs. 3.5 [+ or -] 0.3 [micro]mol * [kg.sup.-1] * [min.sup.-1] (p [less than or equal to] 0.05). A significant negative correlation was found between glycerol and acetate turnover after lactulose treatments (r = -0.78, P [less than or equal to] 0.02). These results showed in overweight subjects a short-term decrease in FFA level and glycerol turnover after lactulose ingestion related to a decrease of lipolysis in close relationship with an increase of acetate production. stable isotopes; acetate; turnover; obesity; lipolysis; nonabsorbable carbohydrates

Abstract -- Two simple and sensitive spectrophotometric procedures are proposed for the determination of roxatidine in pure form and in tablets. Both methods are based on the charge transfer complexation [...]