Ефективність рофлуміласту у хворих на хронічне обструктивне захворювання легень із ожирінням

Хронічне обструктивне захворювання легень (ХОЗЛ) – проблема, актуальність якої в усьому світі стрімко зростає. ХОЗЛ є четвертою провідною причиною смерті в світі, являє собою важливу проблему охорони здоров'я [19]. Розуміння проблеми ХОЗЛ значно змінилося за останнє десятиліття. Зараз це не просто обмеження швидкості повітряного потоку, а складний і гетерогенний стан зі значними позалегеневими проявами, які включають в себе хвороби серцево-судинної системи, дисфункцію скелетних м'язів, і діабет [27]. Особливої актуальності набуває проблема асоціації ХОЗЛ та ожиріння, яке є складовою метаболічного синдрому (МС) і стало проблемою нашого часу. Зв'язок між МС та ХОЗЛ спостерігається в декількох довготривалих і одномоментних дослідженнях, а також синдром був визначений як незалежний фактор ризику для погіршення респіраторних симптомів, збільшення порушення функції легень, легеневої гіпертензії та бронхіальної астми [3]. 50% пацієнтів з ХОЗЛ мають один або декілька компонентів МС [2]. Одним із актуальних аспектів проблеми поєднання ХОЗЛ та МС є розроблення обґрунтованої патогенетичної терапії. Залишається відкритим питання про лікування ХОЗЛ на тлі МС (глюкокортикостероїдні гормони сприяють підвищенню артеріального тиску та рівня глюкози в крові) [16, 44]. Є дані про сприятливу дію на рівень глюкози інгібітору фосфодіестерази-4 [ФДЕ-4] — рофлуміласту [9]. Встановлено, що даний препарат зменшує вираженість порушення толерантності до глюкози [34]. На тлі лікування рофлуміластом, відзначається зниження маси тіла у пацієнтів з ожирінням, поліпшення глікемічного профілю у хворих на цукровий діабет 2-го типу [70]. За даними подвійного сліпого, рандомізованого дослідження [17] лікування рофлуміластом призводило до значного зниження ваги (-2.0 кг з рофлуміластом, проти 0,1 кг з плацебо), індексу маси тіла (ІМТ) (-0,73 кг/м² з рофлуміластом, проти 0,03 кг/м² з плацебо). Застосування рофлуміласту покращує показники oб’єму фoрсoванoгo видиху за першу секунду (ОФВ1) та позитивно впливає на інші показники функції легень у порівнянні з плацебо [7]. Позитивна дія рофлуміласту на функцію легень пов'язана зі значним зменшенням ваги пацієнтів, в першу чергу за рахунок втрати жирової маси [6]. Мета нашої роботи дослідити ефективність рофлуміласту у хворих на хронічне обструктивне захворювання легень із ожирінням

Ion Mobility Spectrometry in Food Analysis: Principles, Current Applications and Future Trends

In the last decade, ion mobility spectrometry (IMS) has reemerged as an analytical separation technique, especially due to the commercialization of ion mobility mass spectrometers. Its applicability has been extended beyond classical applications such as the determination of chemical warfare agents and nowadays it is widely used for the characterization of biomolecules (e.g., proteins, glycans, lipids, etc.) and, more recently, of small molecules (e.g., metabolites, xenobiotics, etc.). Following this trend, the interest in this technique is growing among researchers from different fields including food science. Several advantages are attributed to IMS when integrated in traditional liquid chromatography (LC) and gas chromatography (GC) mass spectrometry (MS) workflows: (1) it improves method selectivity by providing an additional separation dimension that allows the separation of isobaric and isomeric compounds; (2) it increases method sensitivity by isolating the compounds of interest from background noise; (3) and it provides complementary information to mass spectra and retention time, the so-called collision cross section (CCS), so compounds can be identified with more confidence, either in targeted or non-targeted approaches. In this context, the number of applications focused on food analysis has increased exponentially in the last few years. This review provides an overview of the current status of IMS technology and its applicability in different areas of food analysis (i.e., food composition, process control, authentication, adulteration and safety).M.H.-M. was granted a postdoctoral fellowship (University Research Plan, Program “Perfeccionamiento de doctores en el extranjero 2017”) by the University of Granada (Spain)

First insights into serum metabolomics of trenbolone/estradiol implanted bovines; screening model to predict hormone-treated and control animals’ status

International audienceThe use of anabolic agents in livestock production is a subject of much concern. Although prohibited for more than 20&nbsp;years within the EU, growth promoting practices are still widely suspected. To meet the current challenges for detecting illicit practices, ‘omics’ strategies have recently been demonstrated as important new investigative tools. These investigations, based on the observation of physiological disturbances, mainly in urine, demonstrated the possibility to monitor biomarkers enabling high throughput determination of animal status in terms of hormonal treatment. In this context, serum was investigated for the first time as an alternative and potential complementary sample type. A metabolomic approach based on liquid chromatography coupled to high resolution mass spectrometry, was exploited in order to, highlight metabolic perturbations in serum of Revalor-XS® (trenbolone acetate/estradiol) implanted bovines. Univariate and multivariate statistical analyses were carried out to establish descriptive and predictive models. These models enabled the discrimination of anabolised from control animals, and highlighted a number of metabolites which contributed the most in the observed discrimination. Further, a screening model combining a set of selected markers intensities was generated and it successfuly classified animals according to their status, up to 4&nbsp;weeks post Revalor-XS® implant. This research indicates, for the first time, that serum metabolomics has an important role in screening to detect for anabolic misuse in bovines.</p

Dioxin-like, non-dioxin like PCB and PCDD/F contamination in European eel (Anguilla anguilla) from the Loire estuarine continuum: spatial and biological variabilities

To characterize the eel contamination by dioxin-like (dl) and non dioxin-like (ndl) PCBs and PCDD/Fs, 62 eels from the Loire estuary (France) were analyzed. PCB contamination significantly increased from glass eel stage (3.7 ±1.9 and 15.2±4.2 ng.g-1 dw) to other life stages (for yellow eels: 62.8±34.4 and 381.8±181.8 ng.g-1 dw; for silver eels: 93.7±56.3 and 463.2±244.6 ng.g-1 dw respectively for dl and ndl PCB). An inter-site variability based on PCB levels and fingerprints was observed between the three studied sites. The glass eel pattern was mainly characterized by the less chlorinated PCBs contrarily to the other eels, underlying a different bioaccumulation pathway. Overall, eels from this estuary showed an intermediate contamination level compared to other international/national areas. However, more than 60% of studied silver eels displayed WHO2005 PCDD/F and dl-PCB TEQ values higher than the recommended level of 10 pg.g-1 ww. This statement indicates a potential exposure to PCBs through eel consumption, especially with silver individuals, and could potentially lead to damages for the eel population

Fate and Complex Pathogenic Effects of Dioxins and Polychlorinated Biphenyls in Obese Subjects before and after Drastic Weight Loss

BACKGROUND: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear. OBJECTIVES: We characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters. METHODS: Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women. RESULTS: POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6-12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index. CONCLUSIONS: POP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden

Coupling Complete Blood Count and Steroidomics to Track Low Doses Administration of Recombinant Growth Hormone: An Anti-Doping Perspective

Growth Hormone (GH) under its human recombinant homologue (rhGH), may be abused by athletes to take advantage of its well-known anabolic and lipolytic properties; hence it is prohibited in sports by the World Anti-Doping Agency. Due to the rapid turnover of rhGH, anti-doping screening tests have turned to monitor two endocrine biomarkers (IGF-I and P-III-NP), but unfortunately, they show population-wise variability, limiting the identification rate of rhGH users. Previous studies have evidenced the numerous effects of GH on human physiology, especially in hematopoiesis and steroidogenesis. In this work, aiming to discover novel physiological rhGH biomarkers, we analyzed the complete blood count and the steroidomics profile of healthy, physically active, young males treated either with EPO + rhGH or EPO + placebo. The time-trends of these two physiological routes have been analyzed through geometric trajectory analysis (GTA) and OPLS-DA. Individuals supplemented with micro-doses of rhGH exhibited different leukopoietic and steroidal profiles compared to the control population, suggesting a role of the rhGH in both pathways. In the article, hypotheses on the observed differences are discussed according to the most recent literature and compared to results in animal models. The use of leukopoietic and steroidal biomarkers together with endocrine biomarkers (IGF-1 and P-III-NP) allows to correctly classify over 98% of samples with no false positives, miss-classifying only one single sample (false negative) over a total of 56; a promising result, if compared to the current rhGH detection strategies

Alternative (backdoor) androgen production and masculinization in the human fetus

Funding: The study was supported by the following grants: Chief Scientist Office (Scottish Executive, CZG/4/742) (PAF and PJOS) (http://www.cso.scot.nhs.uk/funding-2/); NHS Grampian Endowments 08/02 (PAF and PJOS) and 15/1/010 (PAF, PF, US, and PJOS) (https://www.nhsgcharities.com/); the Glasgow Children’s Hospital Research Charity Research Fund, YRSS/PHD/2016/05 (NW, MB, PJOS, and PAF) (http://www.glasgowchildrenshospitalcharity.org/research/glasgow-childrens-hospital-charity-research-fund); the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 212885 (PAF) (https://ec.europa.eu/research/fp7/index_en.cfm); Medical Research Council Grants MR/L010011/1 (PAF and PJOS) and MR/K501335/1 (MB, PAF, and PJOS) (https://mrc.ukri.org/); and the Kronprinsessan Lovisas Foundation, “Stiftelsen Gunvor och Josef Anérs,” the “Stiftelsen Jane och Dan Olssons,” and the “Stiftelsen Tornspiran” (KS and OS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling

STUDY QUESTION How does maternal cigarette smoking disturb development of the human fetal ovary?&lt;p&gt;&lt;/p&gt; SUMMARY ANSWER Maternal smoking increases fetal estrogen titres and dysregulates several developmental processes in the fetal ovary.&lt;p&gt;&lt;/p&gt; WHAT IS KNOWN ALREADY Exposure to maternal cigarette smoking during gestation reduces human fetal ovarian cell numbers, germ cell proliferation and subsequent adult fecundity.&lt;p&gt;&lt;/p&gt; STUDY DESIGN, SIZE, DURATION The effects of maternal cigarette smoking on the second trimester human fetal ovary, fetal endocrine signalling and fetal chemical burden were studied. A total of 105 fetuses were studied, 56 from mothers who smoked during pregnancy and 49 from those who did not.&lt;p&gt;&lt;/p&gt; PARTICIPANTS/MATERIALS, SETTING METHODS Ovary, liver and plasma samples were collected from electively terminated, normally progressing, second trimester human fetuses. Circulating fetal hormones, levels of 73 fetal ovarian transcripts, protein localization, density of oocytes/primordial follicles and levels of 16 polycyclic aromatic hydrocarbons (PAHs) in the fetal liver were determined.&lt;p&gt;&lt;/p&gt; MAIN RESULTS AND THE ROLE OF CHANCE Circulating fetal estrogen levels were very high and were increased by maternal smoking (ANOVA, P = 0.055–0.004 versus control). Smoke exposure also dysregulated (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.046–0.023) four fetal ovarian genes (cytochrome P450 scc [CYP11A1], NOBOX oogenesis homeobox [NOBOX], activator of apoptosis harakiri [HRK], nuclear receptor subfamily 2, group E, member 1 [NR2E1]), shifted the ovarian Inhibin βA/inhibin α ratio (NHBA/INHA) transcript ratio in favour of activin (ANOVA, P = 0.049 versus control) and reduced the proportion of dominant-negative estrogen receptor 2 (ERβ: ESR2) isoforms in half the exposed fetuses. PAHs, ligands for the aryl hydrocarbon receptor (AHR), were increased nearly 6-fold by maternal smoking (ANOVA, P = 0.011 versus control). A fifth transcript, COUP transcription factor 1 (nuclear receptor subfamily 2, group F, member 1: NR2F1, which contains multiple AHR-binding sites), was both significantly increased (ANOVA, P = 0.026 versus control) and dysregulated by (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.021) maternal smoking. NR2F1 is associated with repression of FSHR expression and smoke-exposed ovaries failed to show the normal increase in FSHR expression during the second trimester. There was a significantly higher number of DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4) VASA-positive (ANOVA, P = 0.016 versus control), but not POU domain, class 1, transcription factor 1 (POU5F1) OCT3/4-positive, oocytes in smoke-exposed fetuses and this matched with a significantly higher number of primordial follicles (ANOVA, P = 0.024 versus control).&lt;p&gt;&lt;/p&gt; LIMITATIONS, REASONS FOR CAUTION The effects of maternal smoking on establishment of the maximum fetal primordial follicle pool cannot be reliably studied in our population since the process is not completed until 28 weeks of gestation and normal fetuses older than 21 weeks of gestation are not available for study. Our data suggest that some fetal ovaries are affected by smoke exposure while others are not, indicating that additional studies, with larger numbers, may show more significant effects.&lt;p&gt;&lt;/p&gt; WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to chemicals in cigarette smoke is known to lead to reduced fecundity in women. Our study suggests, for the first time, that this occurs via mechanisms involving activation of AHR, disruption of inhibin/activin and estrogen signalling, increased exposure to estrogen and dysregulation of multiple molecular pathways in the exposed human fetal ovary. Our data also suggest that alterations in the ESR2 positive and dominant negative isoforms may be associated with reduced sensitivity of some fetuses to increased estrogens and maternal smoking