A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Thyroid-Disrupting Chemicals: Interpreting Upstream Biomarkers of Adverse Outcomes

Background There is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health. Objectives We review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals. Data sources We drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies. Data synthesis THs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the “normal” range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms. Conclusions Individuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes

Toksični učinci olova u profesionalno izložene indijske obitelji

This article describes an entire family manufacturing lead acid batteries who all suffered from lead poisoning. The family of five lived in a house, part of which had been used for various stages of battery production for 14 years. Open space was used for drying batteries. They all drank water from a well located on the premises. Evaluation of biomarkers of lead exposure and/or effect revealed alarming blood lead levels [(3.92±0.94) µmol L-1], 50 % reduction in the activity of δ-aminolevulinic acid dehydratase [(24.67±5.12) U L-1] and an increase in zinc protoporphyrin [(1228±480) µg L-1]. Liver function tests showed an increase in serum alkaline phosphatase [(170.41±41.82) U L-1]. All other liver function test parameters were normal. Renal function tests showed an increase in serum uric acid [(515.81±86.29) µmol L-1] while urea and creatinine were normal. Serum calcium was low [(1.90±0.42) mmol L-1 in women and (2.09±0.12) mmol L-1 in men], while blood pressure was high in the head of the family and his wife and normal in children. Lead concentration in well water was estimated to 180 µg L-1. The family was referred to the National Referral Centre for Lead Poisoning in India, were they were received treatment and were informed about the hazards of lead poisoning. A follow up three months later showed a slight decrease in blood lead levels and a significant increase in haemoglobin. These findings can be attributed to behavioural changes adopted by the family, even though they continued producing lead batteries.Olovo je sveprisutni metal s mnogo namjena, a čovječanstvo ga rabi već više od 6000 godina. Danas je olovo među najrasprostranjenijim toksinima u okolišu, a drugi je na popisu toksičnih metala, odmah iza arsena. Mnogi još nisu svjesni njegova toksičnoga djelovanja te se i dalje izlažu olovu. Ovdje je opisana obitelj koja proizvodi olovne akumulatore i koja je pretrpjela trovanje olovom zahvaljujući svojoj neobaviještenosti. Ova peteročlana obitelj živjela je u jednome kućanstvu čiji je dio namijenjen različitim fazama proizvodnje akumulatora već 14 godina. Akumulatori su se sušili na otvorenome. Na imanju je bio i bunar s pitkom vodom. Mjerenja biopokazatelja izloženosti olovu i njegova djelovanja u svih pet članova obitelji dovela su do alarmantnoga saznanja o razinama olova u krvi [(3,92±0,94) µmol L-1], 50 %-tnom padu aktivnosti dehidrataze δ-aminolevulinske kiseline [(24,67±5,12) U L-1] te povišenom cinkovu protoporfirinu [(1228±480) µg L-1]. Jetrene probe otkrile su povišene razine alkalne fosfataze u serumu [(170,41±41,82) U L-1]. Ostali su parametri jetrene funkcije bili normalni. Testovi funkcije bubrega otkrili su povišene razine mokraćne kiseline u serumu [(515,81±86,29) µmol L-1], dok su razine ureje i kreatinina bile normalne. Također je zabilježen pad razina kalcija u serumu [(1,90±0,42) mmol L-1 u žena te (2,09±0,12) mmol L-1 u muškaraca]. Povišeni krvni tlak zamijećen je u glave obitelji i njegove supruge, dok je u djece bio normalan. Koncentracija olova u bunarskoj vodi bila je izrazito visoka, prema procjeni 180 µg L-1. Obitelj je upućena u indijski Državni referalni centar za otrovanje olovom (National Referral Centre for Lead Poisoning) gdje je primila lijekove i bila upoznata s činjenicama vezanim uz otrovanje olovom. Tromjesečno je praćenje pokazalo blagi pad razina olova u krvi te značajan porast hemoglobina. Ovi se nalazi mogu pripisati promjenama u ponašanju obitelji, bez obzira na to što je nastavila proizvoditi akumulatore

Metabolism and Toxicity of Thioacetamide and Thioacetamide SOxide in Rat Hepatocytes

“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3002719The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification

Covalent Modification of Lipids and Proteins in Rat Hepatocytes, and In Vitro, by Thioacetamide Metabolites

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3001658Thioacetamide (TA) is a well-known hepatotoxin in rats. Acute doses cause centrilobular necrosis and hyperbilirubinemia while chronic administration leads to biliary hyperplasia and cholangiocarcinoma. Its acute toxicity requires its oxidation to a stable S-oxide (TASO) that is oxidized further to a highly reactive S,S-dioxide (TASO2). To explore possible parallels between the metabolism, covalent binding and toxicity of TA and thiobenzamide (TB) we exposed freshly isolated rat hepatocytes to [14C]-TASO or [13C2D3]-TASO. TLC analysis of the cellular lipids showed a single major spot of radioactivity that mass spectral analysis showed to consist of N-acetimidoyl PE lipids having the same side chain composition as the PE fraction from untreated cells; no carbons or hydrogens from TASO were incorporated into the fatty acyl chains. Many cellular proteins contained N-acetyl- or N-acetimidoyl lysine residues in a 3:1 ratio (details to be reported separately). We also oxidized TASO with hydrogen peroxide in the presence of dipalmitoyl phosphatidylenthanolamine (DPPE) or lysozyme. Lysozyme was covalently modified at five of its six lysine side chains; only acetamide-type adducts were formed. DPPE in liposomes also gave only amide-type adducts, even when the reaction was carried out in tetrahydrofuran with only 10% water added. The exclusive formation of N-acetimidoyl PE in hepatocytes means that the concentration or activity of water must be extremely low in the region where TASO2 is formed, whereas at least some of the TASO2 can hydrolyze to acetylsulfinic acid before it reacts with cellular proteins. The requirement for two sequential oxidations to produce a reactive metabolite is unusual, but it is even more unusual that a reactive metabolite would react with water to form a new compound that retains a high degree of chemical reactivity toward biological nucleophiles. The possible contribution of lipid modification to the hepatotoxicity of TA/TASO remains to be determined

An evidence-based recommendation on bed head elevation for mechanically ventilated patients

A semi-upright position in ventilated patients is recommended to prevent ventilator-associated pneumonia (VAP) and is one of the components in the Ventilator Bundle of the Institute for Health Care Improvement. This recommendation, however, is not an evidence-based one.status: publishe

It's about time: A synthesis of changing phenology in the Gulf of Maine ecosystem

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Staudinger, M. D., Mills, K. E., Stamieszkin, K., Record, N. R., Hudak, C. A., Allyn, A., Diamond, A., Friedland, K. D., Golet, W., Henderson, M. E., Hernandez, C. M., Huntington, T. G., Ji, R., Johnson, C. L., Johnson, D. S., Jordaan, A., Kocik, J., Li, Y., Liebman, M., Nichols, O. C., Pendleton, D., Richards, R. A., Robben, T., Thomas, A. C., Walsh, H. J., & Yakola, K. It's about time: A synthesis of changing phenology in the Gulf of Maine ecosystem. Fisheries Oceanography, 28(5), (2019): 532-566, doi: 10.1111/fog.12429.The timing of recurring biological and seasonal environmental events is changing on a global scale relative to temperature and other climate drivers. This study considers the Gulf of Maine ecosystem, a region of high social and ecological importance in the Northwest Atlantic Ocean and synthesizes current knowledge of (a) key seasonal processes, patterns, and events; (b) direct evidence for shifts in timing; (c) implications of phenological responses for linked ecological‐human systems; and (d) potential phenology‐focused adaptation strategies and actions. Twenty studies demonstrated shifts in timing of regional marine organisms and seasonal environmental events. The most common response was earlier timing, observed in spring onset, spring and winter hydrology, zooplankton abundance, occurrence of several larval fishes, and diadromous fish migrations. Later timing was documented for fall onset, reproduction and fledging in Atlantic puffins, spring and fall phytoplankton blooms, and occurrence of additional larval fishes. Changes in event duration generally increased and were detected in zooplankton peak abundance, early life history periods of macro‐invertebrates, and lobster fishery landings. Reduced duration was observed in winter–spring ice‐affected stream flows. Two studies projected phenological changes, both finding diapause duration would decrease in zooplankton under future climate scenarios. Phenological responses were species‐specific and varied depending on the environmental driver, spatial, and temporal scales evaluated. Overall, a wide range of baseline phenology and relevant modeling studies exist, yet surprisingly few document long‐term shifts. Results reveal a need for increased emphasis on phenological shifts in the Gulf of Maine and identify opportunities for future research and consideration of phenological changes in adaptation efforts.This work was supported by the Department of the Interior Northeast Climate Adaptation Science Center (G14AC00441) for MDS, AJ, and KY; the National Science Foundation's Coastal SEES Program (OCE‐1325484) for KEM, ACT, MEH, and AA; the National Aeronautics and Space Administration (NNX16 AG59G) for ACT, KEM, NRR, and KSS; the USGS Climate Research and Development Program for TGH; National Science & Engineering Research Council of Canada, University of New Brunswick, Environment Canada, Sir James Dunn Wildlife Research Centre, and New Brunswick Wildlife Trust Fund for AD. We also thank the Regional Association for Research on the Gulf of Maine for support, and the Gulf of Maine Research Institute for hosting and providing in kind resources for a two day in‐person workshop in August 2016. We greatly appreciate contributions from K. Alexander, G. Calandrino, C. Feurt, I. Mlsna, N. Rebuck, J. Seavey, and J. Sun for helping shape the initial scope of the manuscript. We thank J. Weltzin and two anonymous reviewers for their constructive comments. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the views of the Northeast Climate Adaptation Science Center, U.S. Geological Survey, National Oceanographic and Atmospheric Administration, Fisheries and Oceans Canada or the US Environmental Protection Agency. This manuscript is submitted for publication with the understanding that the United States Government is authorized to reproduce and distribute reprints for Governmental purposes. None of the authors have conflicts of interest to declare in association with the contents of this manuscript

Improved adherence with once-daily versus twice-daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study

Background Poor adherence with prescribed asthma medication is a major barrier to positive treatment outcomes. This study was designed to determine the effect of a once-daily administration of mometasone furoate administered via a dry powder inhaler (MF-DPI) on treatment adherence compared with a twice-daily administration. Methods This was a 12-week open-label study designed to mimic an actual clinical setting in patients ≥12 years old with mild-to-moderate persistent asthma. Patients were randomized to receive MF-DPI 400 μg once-daily in the evening or MF-DPI 200 μg twice-daily. Adherence was assessed primarily using the number of actual administered doses reported from the device counter divided by the number of scheduled doses. Self-reports were also used to determine adherence. Health-related quality of life, healthcare resource utilization, and days missed from work or school were also reported. Results 1233 patients were randomized. The mean adherence rates, as measured by the automatic dose counter, were significantly better (P < 0.001) with MF-DPI 400 μg once-daily in the evening (93.3%) than with MF-DPI 200 μg twice-daily (89.5%). Mean adherence rates based on self-reports were also significantly better (P < 0.001) with MF-DPI 400 μg QD PM (97.2%) than with MF-DPI 200 μg twice-daily (95.3%). Adherence rates were lower in adolescents (12-17 years old). Health-related quality of life improved by 20% in patients using MF-DPI once-daily in the evening and by 14% in patients using MF-DPI twice-daily. Very few (<8%) patients missed work/school. Conclusion Mean adherence rates were greater with a once-daily dosing regimen of MF-DPI than with a twice-daily dosing regimen. This trial was completed prior to the ISMJE requirements for trial registration