A quotation is a handy thing to have about, saving one the trouble of thinking for oneself… A.A. Milne While reading through recent issues of Anaesthesia, I have found myself mildly bemused by the inclusion of contemporary or historical quotations at the start of some of the editorials. Although occasionally integral to the opinions presented, they usually seem to be a decorative affectation, and I suspected that their frequency has been increasing. So I examined the incidence of opening quotations in 150 consecutive Anaesthesia editorials up to September 2017. I discovered musings from Voltaire 1 and Tolstoy 2, William Osler 3, Atul Gawande 4, and even Michael Jordan 5, The Beatles 6 and Spiderman's uncle 1! Henry Ford put in a particularly strong showing, supplying three quotations to three editorials over the time period 7-9. The inclusion of literary, musical or intellectual quotes appears more prevalent within the last year in particular. Up to and including September 2016, 11/113 (10%) editorials carried quotations; this rose to 9/37 (24%) editorials in the subsequent year. Does this finding suggest more recent efforts to include them by authors, editors, or both? Does their inclusion represent ‘publication bias’, by improving authors' chances of publication? Whether this effect is replicated in the Correspondence section remains to be seen. Editor's reply We've actually carried two quotes by Voltaire 1, 10.

Finding a cure for Alzheimer's disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.

As the nation's nuclear energy laboratory, Idaho National Laboratory brings together talented people and specialized nuclear research capability to accomplish our mission. This edition of the Nuclear Fuels and Materials Division Spotlight provides an overview of some of our recent accomplishments in research and capability development. These accomplishments include: • The first identification of silver and palladium migrating through the SiC layer in TRISO fuel • A description of irradiation assisted stress corrosion testing capabilities that support commercial light water reactor life extension • Results of high-temperature safety testing on coated particle fuels irradiated in the ATR • New methods for testing the integrity of irradiated plate-type reactor fuel • Description of a 'Smart Fuel' concept that wirelessly provides real time information about changes in nuclear fuel properties and operating conditions • Development and testing of ultrasonic transducers and real-time flux sensors for use inside reactor cores, and • An example of a capsule irradiation test. Throughout Spotlight, you'll find examples of productive partnerships with academia, industry, and government agencies that deliver high-impact outcomes. The work conducted at Idaho National Laboratory helps to spur innovation in nuclear energy applications that drive economic growth and energy security. We appreciate your interest in our work here at INL, and hope that you find this issue informative.

The deleterious role of metal ions in Alzheimer's disease has inspired the study of various metal chelators. We previously showed the synthesis and in vitro activity of several bidentate hydroxypyridinone compounds, including 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (1), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (2), and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (3). While the focus has been on the Cu(II) ion, the other biorelevant metals, Zn(II) and Fe(III) have been largely neglected. Herein, we report the synthesis of Zn(II) and Fe(III) complexes of ligands 1, 2, and 3, and their characterization by infrared (IR) spectroscopy, high resolution mass spectrometry (HR-MS), elemental analysis, and NMR, where applicable. Solid state structures of Zn(1)2, Fe(1)3, and Cu(3)2 are analyzed with X-ray crystallography. The cytotoxicity of pro-ligands 1, 2, and 3, and the three metal complexes of 2 are examined in a neuronal cell line to determine the effect of metal chelation on toxicity of the compounds.

Metal ions have been implicated in several neurodegenerative diseases, including Alzheimer's disease, as their dyshomeostasis may lead to production of reactive oxygen species as well as increased toxicity of amyloid protein aggregates. In this work, we present design and synthesis of three novel multifunctional hydroxypyridinone ligands, HL11, HL12, and HL13, bearing benzothiazole and benzoxazole functionalities. We study the ability of these compounds to bind metal ions Cu(ii), Zn(ii), and Fe(iii), as well as their antioxidant activity and cytotoxicity. Additionally, we determine the pro-ligands' (compounds prior to chelation) propensity to target amyloid protein. Through these studies we determine the effect of combining amyloid- and metal-binding functionalities within the HPO scaffold on different aspects of AD pathology.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone(HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(beta-Dglucopyranosyloxy)-1-[4-(4-[I-125] iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([I-125]-GL(7)) was shown to cross the blood-brain barrier using an in situ rat brain perfusion technique.

Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, (1)H and (13)C NMR spectroscopy, and in one case by X-ray crystallography. The Cu(2+) complex of a novel 3-hydroxy-4-pyridinone was synthesized and characterized by IR and X-ray crystallography, showing the ability of these compounds to chelate potentially toxic metal ions. An MTT cytotoxicity assay of a selected glycosylated compound showed a relatively low toxicity of IC(50) = 570 +/- 90 microM in a human breast cancer cell line. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.beta-glucosidase, and for one compound k(cat) and K(m) were determined to be 19.8 s(-1) and 1.52 mM, respectively. Trolox Equivalent Antioxidant Capacity (TEAC) values were determined for the free pyridinones, indicating the good antioxidant properties of these compounds. Metal-Abeta(1-40) aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands.

The tetrahydrosalens N,N'-bis(2-hydroxybenzyl)-ethane-1,2-diamine ((2)(1)), N,N'-bis(2-hydroxybenzyl)-(-)-1,2-cyclohexane-(1R,2R)-diamine ((2)(2)), N,N'-bis(2-hydroxybenzyl)-N,N'-dimethyl-ethane-1,2-diamine ((2)(3)), N,N'-bis(2-hydroxybenzyl)-N,N'-dibenzyl-ethane-1,2-diamine ((2)(4)), and N,N'-bis(2-(4-tert-butyl)hydroxybenzyl)-ethane-1,2-diamine ((2)(5)), as well as their prodrug glycosylated forms, (1-5), have been prepared and evaluated in vitro for their potential use as Alzheimer's disease (AD) therapeutics. Dysfunctional interactions of metal ions, especially those of Cu, Zn, and Fe, with the amyloid-beta (Abeta) peptide are hypothesised to play an important role in the aetiology of AD, and disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy. Tetrahydrosalens such as (2)(1-5) have a significant affinity for metal ions, and thus should be able to compete with the Abeta peptide for Cu, Zn, and Fe in the brain. This activity was assayed in vitrovia a turbidity assay; (2)(1) and (2)(3) were found to attenuate Abeta(1-40) aggregation after exposure to Cu(2+) and Zn(2+). In addition, (2)(1-5) were determined to be potent antioxidants on the basis of an in vitro antioxidant assay. (1-5) were prepared as metal binding prodrugs; glycosylation is intended to prevent systemic metal binding, improve solubility, and enhance brain uptake. Enzymatic (beta-glucosidase) deprotection of the carbohydrate moieties was facile, with the exception of (4), demonstrating the general feasibility of this prodrug approach. Finally, a representative prodrug, (3), was determined to be non-toxic over a large concentration range in a cell viability assay.

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Selective design modifications of specifically substituted 3-hydroxy-4(1H)-pyridinones show possibly advantageous ring freedom while maintaining metal-binding ability and antioxidant capacity, moving toward an efficient potential treatment for Alzheimer's disease.

Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-beta (A beta) peptide are hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to direct effects on A beta aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) in the brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurable disease. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5-beta-D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5-beta-D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided by UV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bonding between the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have an important stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1 displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduce Zn2+- and Cu2+- induced Abeta1-40 aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.

Angewandte ChemieVolume 119, Issue 10 p. 1746-1748 Zuschrift Combating Alzheimer's Disease With Multifunctional Molecules Designed for Metal Passivation† Harvey Schugar Prof., Harvey Schugar Prof. [email protected] Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854-8087, USA, Fax: (+1) 732-445-5312Search for more papers by this authorDavid E. Green Dr., David E. Green Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorMeryn L. Bowen, Meryn L. Bowen Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorLauren E. Scott, Lauren E. Scott Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorTim Storr Dr., Tim Storr Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorKarin Böhmerle, Karin Böhmerle Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorFancy Thomas, Fancy Thomas Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorDavid D. Allen Prof., David D. Allen Prof. Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorPaul R. Lockman Prof., Paul R. Lockman Prof. Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorMichael Merkel Dr., Michael Merkel Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorKatherine H. Thompson Dr., Katherine H. Thompson Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorChris Orvig Prof., Chris Orvig Prof. [email protected] Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this author Harvey Schugar Prof., Harvey Schugar Prof. [email protected] Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854-8087, USA, Fax: (+1) 732-445-5312Search for more papers by this authorDavid E. Green Dr., David E. Green Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorMeryn L. Bowen, Meryn L. Bowen Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorLauren E. Scott, Lauren E. Scott Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorTim Storr Dr., Tim Storr Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorKarin Böhmerle, Karin Böhmerle Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorFancy Thomas, Fancy Thomas Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorDavid D. Allen Prof., David D. Allen Prof. Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorPaul R. Lockman Prof., Paul R. Lockman Prof. Texas Tech University Health Sciences Center, School of Pharmacy, 1300 Coulter, Suite 112, Amarillo, TX 79106, USASearch for more papers by this authorMichael Merkel Dr., Michael Merkel Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorKatherine H. Thompson Dr., Katherine H. Thompson Dr. Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this authorChris Orvig Prof., Chris Orvig Prof. [email protected] Department of Chemistry, The University of British Columbia, 2106 Main Mall, Vancouver, BC V6T 1Z1, Canada, Fax: (+1) 604-822-2847Search for more papers by this author First published: 19 February 2007 https://doi.org/10.1002/ange.200603866Citations: 17 † This work was supported by the Natural Sciences and Engineering Research Council (NSERC) and the Canadian Institutes of Health Research (CIHR). The authors wish to thank Profs. D. Devine and C. Overall for allowing us to use their turbidometric assay facilities in the Centre for Blood Research, University of British Columbia; Prof. S. G. Withers for supplying Abg, and technical assistance in the glycosidase enzyme assays; Drs. Mike Adam and Jianming Liu at TRIUMF for assistance with radiolabeling and supply of Na125I; and MDS Nordion, Inc. for Na123I. L.E.S. is the recipient of an Alzheimer Society of Canada Fellowship, T.S. of an NSERC Postgraduate Scholarship, and M.M. of a Feodor Lynen fellowship. Read the full textAboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Ein trifunktioneller Ansatz: 3-Hydroxy-4-pyridinone mit antioxidativ wirkenden Phenolresten wurden für eine bessere Blut-Hirn-Gängigkeit zusätzlich mit Glucosylgruppen funktionalisiert (siehe Bild; R=Ph, 4-HOC6H4). Abspaltung der Kohlenhydratgruppe im Gehirn mit Glycosidase ergibt die reinen Liganden, die besonders Kupfer und Zink stark komplexieren. Die Verbindungen sind mögliche Prodrugs für die Behandlung neurodegenerativer Störungen wie Alzheimer. Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2007/z603866_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1 1aA. I. 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Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. ReferencesRelatedInformation

BACKGROUND:BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (dx5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity.PATIENTS AND METHODS:Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified.RESULTS:Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m(2)/day. The 0.15-mg/m(2) dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m(2)/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation.CONCLUSIONS:The MTD and RD of diflomotecan administered according to a dx5 repeated three weekly are 0.15 and 0.125 mg/m(2)/day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.

Background Between 1937 and 1991, Capper Pass and Sons Limited operated a tin smelter complex in North Humberside, UK, at which employees were potentially exposed to a number of substances, including lead, arsenic, cadmium and natural series radionuclides. Decommissioning and site clearance continued until 1995. Between 1967 and 1995 the company was a subsidiary of Rio Tinto plc.Aims The aim was to identify any significant excess, or deficits, in mortality among former employees that might be attributable to factors associated with occupation.Methods We defined a cohort of 1462 males who had been employed for at least 12 months between 1/11/1967 and 28/7/1995, followed-up through to 31/12/2001. The mortality of the cohort was compared against that expected for both national and regional populations.Results Mortality from all causes and all cancers did not differ from that expected. Mortality from ischaemic heart disease showed a deficit and mortality from lung cancer showed a statistically significant excess. Mortality from smoking related diseases other than lung cancer showed a non-significant deficit.Conclusions The pattern of lung cancer mortality is consistent with the hypothesis that the risk of lung cancer has been enhanced by occupational exposure to one or more carcinogens, the effect of which diminishes with time since exposure. The deficit in ischaemic heart disease may be attributed to a protective effect from manual labour. The results provide no evidence for attribution of other excess or deficits in mortality to factors associated with employment.

From a database of a quarter of a million births in Cumbria during 1950-89, 10 363 children have been positively linked to paternal employment at the Sellafield nuclear installation in West Cumbria at, or before, the conception of the child, 9256 of these children being associated with paternal preconceptional radiation exposure. The doses of external whole-body radiation received by fathers prior to conception have been estimated from annual recorded doses, and the detailed distributions of these preconceptional doses are presented. The collective paternal total preconceptional dose is 539 person-Sv, a mean individual preconceptional dose per paternally exposed child of 58 mSv. The number of serious hereditary effects predicted to be induced by this collective dose among these first generation children is less than two, and these will not be discernible against the much larger number of background cases. There is no evidence of an excess of hereditary disorders in the immediate vicinity of Sellafield, although comprehensive studies have not, as yet, been carried out. The suggestion advanced by Gardner et al. (1990) that paternal preconceptional irradiation is sufficient to account for the excess of childhood leukaemia cases in the West Cumbrian Village of Seascale is highly unlikely to be correct because, inter alia, of the absence of a comparable excess among children born outside Seascale who are associated with the great majority (93%) of the collective paternal preconceptional dose.