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

Residues of synthetic hormones in pork, Madagascar

In Madagascar, little information is available on drug residues in animal products. Official veterinary services have been recently informed about the misuse of human injectable contraceptives in pig farms. Farmers and local animal health workers have been suspected of treating pigs for growth promotion and of using human progestins, especially medroxyprogesterone acetate (MPA), as a chemical alternative method for castration of sows that are then fattened before culling. Indeed, MPA may arrest the onset of farrowing and induce post-lactational anestrus in sows. Because the use of synthetic hormones in pig husbandry is consid¬ered a fraud by the Malagasy legislation, an exploratory study was carried out to confirm these suspicions and investigate the main molecules concerned. We investigated 80 pigs slaughtered in seven Malagasy abattoirs and raised in eight (out of 22) Malagasy regions (i) to confirm the contamination of carcasses by anabolic hormones by liquid chromatography coupled to mass spectrometry (LC-MS/MS), (ii) to identify the concerned molecules, and (iii) to explore consumers' exposure to hormone residues. Only adult sows were sampled con¬sidering that chemical castration with progestogens was the most common hypothesis of misuse of synthetic hormones in the field. The screening of the 80 kidney-fat samples did not reveal residues of progestogens other than MPA. MPA-positive samples were detected in 10 out of 15 districts (66.7%), and in all eight surveyed regions except one (87.5%), Diana Region in Northern Madagascar. Our results revealed heavy contamination of pork products by synthetic hormone residues; its prevalence was high considering that such residues are not supposed to occur accord¬ing to the Malagasy legislation. Investigations by Malagasy vet¬erinary services revealed that farmers and animal health workers purchased syringes of progestogens (Confiance™, Pfizer). These low-price progestins are easily available in private local dispen-saries and basic health centers (public sector). Without any control, farmers can easily administer MPA to pigs. It has thus become urgent to launch public-awareness campaigns and improve control within the sectors of animal production and public health over the entire country. (Résumé d'auteur

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

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?<p></p> SUMMARY ANSWER Maternal smoking increases fetal estrogen titres and dysregulates several developmental processes in the fetal ovary.<p></p> WHAT IS KNOWN ALREADY Exposure to maternal cigarette smoking during gestation reduces human fetal ovarian cell numbers, germ cell proliferation and subsequent adult fecundity.<p></p> 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.<p></p> 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.<p></p> 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).<p></p> 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.<p></p> 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

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

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)

Comparative study of low- versus high-resolution liquid chromatography-mass spectrometric strategies for measuring perfluorinated contaminants in fish

International audiencePerfluorinated compounds (PFCs) are usually monitored by high performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on triple quadrupole instruments. Although not yet widely implemented in the field, high resolution mass spectrometry (HRMS) today appears as a valuable alternative for these halogenated chemicals due to their significant mass defect. Indeed, this second approach offers a way to cope with particular matrix effects caused by co-eluting and isobaric interferences affecting the measurement of some PFCs in fish. The present study has compared three different LC-MS related instruments and various signal acquisition modes, from low resolution full scan and selected ion monitoring (SIM) mode on triple quadrupole (QqQ) instrument to high resolution full scan or product ion scan mode on orbital trap (LTQ-Orbitrap) or quadrupole-time-of-flight (Q-TOF) devices. Performances have been compared for 7 model compounds belonging to 7 PFCs sub-classes (perfluoralkylsulfonate, perfluoroalkylcarboxylate, perfluoroalkylsulfinate, perfluoroalkyl-sulfonamide, fluorotelomer saturated acid, fluorotelomer unsaturated acid and perfluoroalkylphosphonic acid). Low resolution MS/MS was found to be unsurprisingly reliable for extended multiresidues monitoring. However, the high stability of PFCs leads to a relatively poor and non-specific fragmentation pathway in MS/MS. In addition, biliary acid interfering compounds (e.g. taurochenodeoxycholic acid), that where encountered in the present case in fish samples but that may be present in other biological samples, were found particularly disturbing in low resolution MS/MS. Indeed, these interferences presented the same retention time and diagnostic signals as PFOS, leading to a possible overestimation of the PFOS quantification in LC-MS/MS. On the other hand, high resolution MS and MS/MS (LTQ-Orbitrap and Q-TOF) provided better results in terms of signal specificity and sensitivity. For instance, the estimated limits of detection (LOD) reached for PFOS on QqQ, Q-TOF and LTQ-Orbitrap instruments were 3.8, 0.7 and 0.5 pg injected, respectively

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

Detection of bromochloro alkanes in indoor dust using a novel CP-Seeker data integration tool

Bromochloro alkanes (BCAs) have been manufactured for use as flame retardants for decades and preliminary environmental risk screening suggests they are likely to behave similarly to polychlorinated alkanes (PCAs), subclasses of which are restricted as Stockholm Convention Persistent Organic Pollutants (POPs). BCAs have rarely been studied in the environment, though some evidence suggests they may migrate from treated-consumer materials into indoor dust, resulting in human exposure via inadvertent ingestion. In this study, BCA-C14 mixture standards were synthesized and used to validate an analytical method. This method relies on chloride-enhanced liquid chromatography-electrospray ionization-Orbitrap-high resolution mass spectrometry (LC-ESI-Orbitrap-HRMS) and a novel CP-Seeker integration software package for homologue detection and integration. Dust sample preparation via ultrasonic extraction, acidified silica clean-up and fractionation on neutral silica cartridges was found to be suitable for BCAs, with absolute recovery of individual homologues averaging 66 to 78% and coefficients of variation $\le$10% in replicated spiking experiments (n=3). In addition, a total of 59 indoor dust samples from six countries including Australia (n=10), Belgium (n=10), Colombia (n=10), Japan (n=10), Thailand (n=10) and the United States of America (n=9) were analysed for BCAs. BCAs were detected in seven samples from the USA, with carbon chain lengths of C8, C10, C12, C14, C16, C18, C24 to C28, C30 and C31 observed overall, though not detected in samples from any other countries. Bromination of detected homologues in the indoor dust samples ranged from Br1-4 as well as Br7, while chlorine numbers ranged from Cl2-11. BCA-C18 were the most frequently detected, observed in each of the USA samples, while the most prevalent halogenation degrees were homologues of Br2 and Cl4-5. Broad estimations of BCA concentrations in the dust samples indicated that levels may approach those of other flame retardants in at least some instances. These findings suggest that development of quantification strategies and further investigation of environmental occurrence and health implications are needed