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Laurent O.,Laboratoire Detude Et Of Recherche En Santepublique | Benichou J.,French Institute of Health and Medical Research | Pedrono G.,SEPIA Sante | Segala C.,SEPIA Sante | And 5 more authors.
Environnement, Risques et Sante | Year: 2012

It is increasingly suspected that the health impact of air pollution may be greater among socioeconomically disadvantaged populations than among those who are better off. However, health impact assessments of air pollution generally do not take socioeconomic status into account. In this paper, we propose an approach to the quantitative estimation of the short-term impacts of environmental risk factors such as air pollution among socioeconomically contrasted populations. We do so through an illustrative case study of ambient air pollution and emergency calls for asthma attacks in Strasbourg (France). Next, we discuss the potential advantages of this approach as well as its current limitations, and then look at the research needs that must be addressed to improve its applicability. Among these, the most urgent appear to be the needs for improved exposure estimates and for large-scale epidemiological studies that use harmonized methods to investigate the modification by socioeconomic status and other factors of the effects of air pollution. Case-crossover designs offer promising perspectives for that purpose, especially as more accurate and individualized estimates of air pollution exposure become available for epidemiological studies.

All animal experimentation in this study was approved and performed according to the standards of the animal ethics committee at Imperial College London and to UK Home Office regulations (ASPA 1986). C57Bl/6 mice were purchased from Harlan UK Ltd; Col2.3–GFP, Col2.3–CFP18, nestin–GFP and mTmG25 mice were bred and housed at Imperial College London. For imaging experiments, female Col2.3–GFP and nestin–GFP mice >8 weeks old were used. osterix–CreGFP mice were provided by A. McMahon and backcrossed over eight generations into NSG mice and maintained at the Francis Crick Institute, Cancer Research UK26. Equal proportions of male and female osterix–CreGFP mice aged 11–14 weeks were used. T-ALL was generated as previously described27. Briefly, timed matings were established between C57Bl/6 mice and embryos harvested at E14.5. Single-cell suspensions were prepared from whole fetal livers isolated from the embryos. Suspensions were cultured in IL-3, IL-6, and stem cell factor conditioned media with 20% FCS for 3 days. Lin-xE cells were transfected by calcium phosphate with MigR1 plasmids containing either DsRed only or DsRed with NotchICNΔRamΔP as described previously28. We also used GFP-tagged plasmids when required. Supernatants containing recombinant retrovirus were removed and spun by centrifugation onto non-tissue-culture-treated plates coated with 15 μg/ml retronectin (Takara Clontech, CA). Fetal liver cells were cultured in the presence of virus for 3 days and transduction was assessed by flow cytometry. Primary lethally irradiated recipient mice (two doses of 5.5 Gy administered greater than three hours apart) were transplanted with 1 × 106 DsRed+ fetal liver cells by intravenous injection into the tail vein. Recipient mice were maintained on baytril-treated water to prevent infection for >6 weeks post-transplantation. Cohorts of reconstituted mice were the result of three independent fetal liver isolations and three independent transfections. Transformation of Notch-transduced non-malignant cells is highly heterogeneous in vivo, with onset of primary disease ranging from 6–25 weeks28 (Extended Data Fig. 1). More than 4 weeks post-reconstitution, peripheral blood was isolated from mice, red blood cells were lysed, and successful reconstitution determined by presence of DsRed+ cells. Mice reconstituted with NotchICNΔRamΔP-transduced fetal livers were monitored daily for signs of leukaemia onset or other signs of ill health. Mice were euthanized when any one or a combination of the following signs were observed: hunched posture, laboured breathing, weight loss, enlarged lymph nodes and/or spleen, peripheral white blood cell cellularity of 13 × 109 per litre or greater. No experiment exceeded the tumour burden approved by the Home Office and Imperial College ethics committee. Peripheral lymphoid organs were analysed by flow cytometry for DsRed or GFP, CXCR4, CD3, CD4 and CD8 expression. All FACS data was collected on a Fortessa flow cytometer (BD Biosciences, CA). Secondary recipients were sub-lethally irradiated (two doses of 3 Gy administered greater than three hours apart) and injected with 10,000 thawed, Ficoll purified T-ALL blasts and monitored as described earlier. In selected cases 10,000 secondary T-ALL cells were transplanted into tertiary recipients. For therapy experiments, mice were injected i.v. daily with 15 mg/kg dexamethasone sodium phosphate29, 30 (Sellekchem, MA) alone, 0.15 mg/kg vincristine sulfate salt (Sigma) alone or with a combination of 15 mg/kg dexamethasone, 0.15 mg/kg vincristine and 1,000 IU/kg l-asparaginase (medac; obtained from the Imperial College Healthcare NHS Trust Pharmacy). Reconstitution with MigR1 DsRed-transduced cells yields <50% chimaerism. For this reason, analysis of healthy BM cells by microscopy is inaccurate. Therefore, to obtain >95% chimaerism of healthy, red fluorescent BM to be used for imaging control experiments, whole BM mononuclear cells were isolated from femurs, hips and tibia of mTmG donor mice, suspended in phosphate balanced salt solution and administered intravenously to recipient mice at a dose of 2 × 106 cells/mouse. Recipient Col2.3–GFP or C57Bl/6 mice had been lethally irradiated (two doses of 5.5 Gy irradiation greater than 3 h apart) immediately before the transplant, and were maintained on baytril-treated water to prevent infection >6 weeks post-transplantation. Intravital microscopy was performed using a Leica SP5 and a Zeiss LSM 780 upright confocal microscope with a motorized stage. The SP5 was fitted with the following lasers: Argon, 546, 633 and a tunable infrared multiphoton laser (Spectraphysics Mai Tai 690-1020). The Zeiss LSM 780 was fitted with the following lasers: Argon, 561, 633 and a tunable infrared multiphoton laser (Spectraphysics Mai Tai DeepSee 690-1040). Signal was visualized with a Leica HCX IRAPO L ×25 water immersion lens (0.95 N.A) and a W Plan-Apochromat ×20 DIC water immersion lens (1.0 N.A). Collagen bone second harmonic generation signal and GFP and CFP signals were generated through excitation at 840 and 870 nm and detected with external detectors. Internal detectors were used to collect DsRed and Cy5 signal (and on some occasions, GFP). Prior to surgery, mice were administered analgesia with buprenorphine (0.1 mg/kg intraperitoneally (i.p.)). Anaesthesia was induced in mice with 4% isoflurane mixed with pure oxygen. This was gradually reduced to approximately 1% as anaesthesia stabilized. Surgery to attach the headpiece was then performed as described previously16. Large three-dimensional ‘tile scans’ of the entire BM cavity space were acquired by stitching adjacent, high-resolution z-stack images using a surgically implanted imaging window that ensures steady positioning of mice on the microscope. The calvarium has been demonstrated to be equivalent to the long bones such as the femur with regards to haematopoietic stem cell frequency, function and localization14, 22, and is the only BM compartment that allows longitudinal imaging through minimally invasive surgery16, 31. Blood vessels were highlighted by i.v. injection of 50 μl of 8 mg/ml 500 kDa Cy5-Dextran (Nanocs, MA). Cy5-Dextran was re-injected every 1–2 h to maintain blood vessel signal and cross reference for registration of blood vessel data in time-lapse analysis. For repeated imaging, protective intrasite gel (Smith & Nephew) was applied to the imaging window to preserve the bone integrity and prevent scar formation. The window was bandaged, and mice were allowed to recover from anaesthesia. Owing to the lock-and-key mechanism of the imaging window16, mice could then be re-anaesthetized and accurately repositioned on the microscope stage and the same BM areas re-imaged. After each imaging, analgesia was administered via oral buprenorphine in raspberry jelly at a dose of approximately 0.8 mg/kg. Microscopy data was processed using multiple platforms. Tile scans were stitched using Leica Application Systems (LAS; Leica Microsystems, Germany) and ZEN black (Zeiss, Germany) softwares. Raw data were visualized and processed using Fiji/Image J. Simulated data was prepared using FIJI macros to create, and overlay z-stack images on original tile-scan data. Using the internal random number algorithm, spheres matching the size of T-ALL cells (11–15 μm) were placed at random x,y,z coordinates. Simulated data FIJI macro is available on request. Automated cell segmentation, distance and volume measurements were performed in Definiens (Definiens Developer 64, Germany) using local heterogeneity segmentation32 to isolate osteoblast and nestin cells as well as vasculature, and a combination of seed detection algorithm and morphological growing and shrinking operations to detect leukaemia cells. Definiens rulesets for these functions are available upon request. Distance measurements from this segmentation were performed as described previously32. Cell tracking was performed using Imaris (Bitplane, Switzerland) and the FIJI plugin MTrackJ. For accuracy in cell tracking data, videos were registered when required before using four-dimensional data protocols implemented in Fiji33. Three-dimensional data rendering and measurement of cell division distances were performed in Volocity (Perkin Elmer, MA) and Definiens (Definiens Developer 64, Germany). T-ALL samples were harvested from bone marrow and FACS sorted based on fluorescent protein expression (DsRed or GFP) unless infiltration of bone marrow was complete. Control samples for microarray were prepared by FACS sorting for splenic CD4+ T cells, CD8+ T cells and CD4+CD8+ thymocytes from 8–14-week female C57Bl/6 mice. RNA was purified from samples using the Qiagen RNeasy mini kit (Netherlands) as per the manufacturer’s instructions. Purified RNA was prepared for hybridization using the Genechip WT Plus reagent kit (Affymetrix, CA) as per the manufacturer’s instructions and hybridized with genechip Mouse gene 2.0 ST array (Affymetrix, CA) by the MRC Genomics Facility (Imperial College London). Analysis was performed using R version 3.1.1. Data were normalized and summarized to ‘core’ level using the RMA method from the oligo package (version 1.30.0)34. Annotation was downloaded from the Affymetrix NetAffx Query website. Differential expression was determined using limma version 3.22.7 (ref. 35). Genes with Benjamini–Hochberg-adjusted P value < 0.05 and absolute log-fold-change >1 were deemed significant. Heatmaps of gene expression were generated with pheatmap package version 1.0.2. Primary human T-ALL samples were obtained from Barts Hospital (London) after informed consent via a protocol approved by the East London Research Ethics Committee and carried out in accordance with the principles of the Helsinki declaration (see Supplementary Table 2 for details), before treatment being administered to the patients. Primary cells from two distinct patients were immunophenotyped, and CD45+/CD7+/CD4−/low/CD8−/low cells sorted and infused i.v. in non-conditioned osterix–CreGFP/NOD/SCID/γ recipient mice. Primary xenograft transplantation was assessed via peripheral blood sampling and/or BM aspiration. BM and spleen-derived primary xenografts were infused i.v. in non-conditioned NOD/SCID/γ secondary recipient mice for therapy experiments. Intravital imaging was performed as described earlier. Human T-ALL cells were labelled by injecting 10 μg of PE-conjugated human CD45 antibody (clone HI30, Biolegend) 15–30 min before the imaging session. For dexamethasone therapy experiments, mice were treated with daily injections of 15 mg/kg i.v.30. Number of human T-ALL cells in therapy experiments was quantified using reference beads as described previously36. Hips and tibias were harvested and post-fixed overnight in periodate-lysine-paraformaldehyde fixative, at 4 °C. Bones were then washed with 0.1 M phosphate buffer, cryoprotected in sucrose (10–30% gradient), for 48 h, frozen in optimal cutting temperature compound (TissueTek) and stored at −80 °C. Sections were cut in a Leica Cryostat, using the Cryojane tape transfer system (Leica Microsystems) and stored at −80 °C. For staining, slides were re-hydrated in PBS, permeabilized in 0.1% Triton X-100, blocked in 5% goat serum and incubated with primary antibodies overnight, at 4 °C. After washing in PBS, slides were incubated with secondary antibodies, counter-stained with DAPI (Invitrogen), washed in 0.1% Triton X-100 and mounted using Prolong Diamond antifade (Invitrogen). The following antibodies were used: Alexa Fluor 647 mouse anti-Ki-67 (B56, BD Biosciences, 1:50), PE-conjugated human CD45 antibody (HI30, BD Biosciences, 1:100), rabbit anti-cleaved caspase-3 (Asp175, Cell Signaling, 1:100), goat anti-rabbit IgG Alexa Fluor 633 (Life Technologies, 1:400). TUNEL labelling was performed to detect apoptotic cells, according to the manufacturer’s instructions (DeadEnd Colorimetric TUNEL System, Promega). Images were obtained using a Zeiss LSM 780 upright confocal/two-photon combined microscope and analysed using Fiji/ImageJ. Cell counting was performed manually using the FIJI plugin Cell Counter. BM from human T-ALL xenotransplanted, untreated and treated mice was harvested and stained with DAPI (Invitrogen) and FITC mouse anti-Ki-67 set (BD Biosciences), according to the manufacturer’s instructions. Cells were analysed by flow cytometry and absolute numbers were obtained using reference beads as described previously36. T-ALL engraftment and infiltration was confirmed via peripheral blood sampling and/or tibia puncture. Once mice presented with signs of ill health (as described earlier), mice were euthanized and bones were digested with a DNase I/Collagenase (Sigma) solution. The total number of Osx–GFP+ cells was assessed by flow cytometry analysis using counting beads (CountBright, Life Technologies). Samples were obtained from patients after informed consent had been obtained, under full ethical approval by the Peter MacCallum Cancer Centre Human Research Ethics Committee. De-waxed human trephine biopsy sections (3 μM) were stained with osteocalcin antibody (Abcam ab93876, Cambridge), counterstained and mounted for viewing. All areas of each section were monitored for visible osteoblasts. The sample size required for the experiments was estimated based on the results of preliminary data. Blinding or randomization for animal experiments were not necessary due to the nature of the experiments. Statistical differences between the means of two data groups was determined by using two-tailed unpaired Student’s t-test, and P values < 0.05 were considered significant. Multiple group comparisons were performed using ANOVA with a Bonferroni correction, P values < 0.05 were considered significant.

Carnevale C.,University of Brescia | Finzi G.,University of Brescia | Pederzoli A.,University of Brescia | Turrini E.,University of Brescia | And 13 more authors.
Science of the Total Environment | Year: 2014

When designing air pollution reduction policies, regional decision makers face a limited budget to choose the most efficient measures which will have impacts on several pollutants in different ways. RIAT+ is a regional integrated assessment tool that supports the policy maker in this selection of the optimal emission reduction technologies, to improve air quality at minimum costs. In this paper, this tool is formalized and applied to the specific case of a French region (Alsace), to illustrate how focusing on one single pollutant may exacerbate problems related to other pollutants, on top of conflicts related to budget allocation. In our case, results are shown for possible trade-offs between NO2 and O3 control policies. The paper suggests an approach to prioritize policy maker objectives when planning air pollution policies at regional scale. © 2014 Elsevier B.V.

PubMed | Polytechnic of Milan, ASPA, European Commission - Joint Research Center Ispra, University of Strasbourg and 3 more.
Type: | Journal: The Science of the total environment | Year: 2014

When designing air pollution reduction policies, regional decision makers face a limited budget to choose the most efficient measures which will have impacts on several pollutants in different ways. RIAT+ is a regional integrated assessment tool that supports the policy maker in this selection of the optimal emission reduction technologies, to improve air quality at minimum costs. In this paper, this tool is formalized and applied to the specific case of a French region (Alsace), to illustrate how focusing on one single pollutant may exacerbate problems related to other pollutants, on top of conflicts related to budget allocation. In our case, results are shown for possible trade-offs between NO2 and O3 control policies. The paper suggests an approach to prioritize policy maker objectives when planning air pollution policies at regional scale.

Favez O.,INERIS | Petit J.-E.,INERIS | Petit J.-E.,French Climate and Environment Sciences Laboratory | Bessagnet B.,INERIS | And 20 more authors.
Pollution Atmospherique | Year: 2012

This paper aims at gaining an insight into the PM10 daily threshold (50 ug/m3) exceedances measured by French regional air quality monitoring networks for the last four years. As almost three quarter of these exceedances happens to occur between November and April, we focus here on such winter (broadly speaking) pollution episodes. The deployment of monitoring devices allowing for a proper account of semi-volatile material within PM10 was achieved concomitantly to the development particulate pollution episodes largely influenced by ammonium nitrate (which is semi-volatile) in March-April 2007. Since then, such pollution events are frequently observed at this period of the year, notably due to stable meteorological conditions favoring the condensation of semi-volatile material into the particulate phase along with the resumption of manure spreading, which constitutes a major source of ammonium nitrate gaseous precursors (at least at some points of the year). Such pollution events, which are also related to combustion emissions (among which mobile sources) are typically preceded, from November to February, by frequent daily threshold exceedances with potentially significant influences of biomass burning (e.g. residential wood burning). The winter period is also impacted by long range transport episodes, corresponding notably to increases of ammonium sulfate relative abundances within PM10. Moreover, as traffic sites are generally the first ones showing PM10 exceedances due the increment of direct emissions and resuspension processes, mobile sources are also considered as a major target for action plans. Finally, it is underlined that the occurrence of daily threshold exceedances is highly influenced by meteorological conditions, so that the yearly number of these exceedances shows well-marked inter-annual variations, with 2009 and 2011 (and 2012, but not shown here) being significantly more polluted than 2008 and 2010. The on-going development of efficient forecasting systems still suffer lacks of detailed emission inventories and strong knowledge on the physical and chemical transformation processes of particles and their gaseous precursors within the boundary layer.

News Article | December 15, 2016

Who’s the ideal candidate for liposuction? It really depends on where you are getting your information from and what your expectations are for your results. Trevor Schmidt PA-C, the owner and liposuction expert at MyShape Lipo has a very liberal view on this subject, which he discusses in his live interview on the FOX 5 More Show. The American Society of Plastic Surgeons (ASPS) claims the best lipo candidates are “Adults within 30% of their ideal weight who have firm, elastic skin and good muscle tone.” By this definition, you should be near your ideal weight in order to get your fat removed through liposuction. Unfortunately, this eliminates nearly all the people that actually want liposuction to remove their unwanted fat. Schmidt believes that anyone who has excess fat that they want removed and has realistic expectations is a good candidate for liposuction. “I remove fat for a living, who am I to tell someone that they have too much fat for me to remove,” says Schmidt. “If they understand and have realistic expectations, then I think they are a good candidate for lipo.” According the the Center for Disease Control and Prevention, “2 out of 3 adults are considered overweight and 1 in 3 adults is considered obese.” So by the definition of the ideal candidate by ASPS, nearly 2/3 of the adult population who struggle with fat are eliminated as candidates. “It’s absurd to tell someone who struggles with their accumulation of fat, that they are not a good candidate to get their fat removed,” says Schmidt. “We have had amazing, life changing results with treating larger individuals. The more fat we can remove, the bigger the change the patient will experience.” Tina Gray was not an ideal candidate in that she was overweight and she is approaching her 60’s. Despite this, she was able to achieve very good results from liposuction. In a single procedure she was able to reduce her waist by 4 inches and eliminate the part of her belly that folds over. She also reduced her inner thighs by 2 inches each and eliminated the rubbing she experienced. “I’m ecstatic, my belly is nearly flat and I am able to fit into clothes that were previously too small,” says Tina. “I feel so much more confident, I wish I would have done this sooner.” At MyShape Lipo, most of their patients are not the “ideal candidate” set forth by ASPA. Instead they remove large volumes of fat to offer dramatic results for those that have bigger problems and have struggled with diet and exercise. Their patients are expecting to get significantly smaller. Most of the larger patients are expecting only to look better in their clothes as opposed to getting into a bathing suit or showing off their belly. Many already have irregularities or loose skin and are not expecting these issues to completely go away. These people are looking for improvement, not perfection and they are happy with a significant reduction is size. In the case of Tina, she had a substantial reduction in her belly. In fact the fold of loose skin and fat in the front of her belly has retracted and disappeared completely. She’s been able to fit into her clothes better and experienced improvements in her functionality. Hygiene is easier now that her belly doesn't fold over. “I’ve actually found that our larger patients tend to be much happier with their results,” says Schmidt. “Their improvement goes far beyond cosmetic results including functionality, mobility and confidence.” MyShape Lipo is a Liposuction and Fat Transfer specialty clinic located in Las Vegas, NV. Trevor Schmidt PA-C, the owner and liposuction specialist has performed over 15,000 liposuction procedures on all shapes, sizes and ages of individuals. He has the experience to get the most dramatic, smoothest and most consistent results for his patients. They offer free Body Shape Analysis, Call Now 702-818-5476. View their photo gallery online at

Bentayeb M.,French Institute for Public Health Surveillance InVS | Stempfelet M.,French Institute for Public Health Surveillance InVS | Wagner V.,French Institute for Public Health Surveillance InVS | Zins M.,University of Versailles | And 14 more authors.
Atmospheric Environment | Year: 2014

Introduction: Exposure to air pollution has been associated to mortality and morbidity in numerous studies. However, few studies assessed retrospectively long-term exposure at a fine spatial scale. Aims: To contribute to the assessment of long-term exposure to air pollution of participants from the French GAZEL cohort, we estimated atmospheric PM10, PM2.5, NO2, SO2, C6H6 and O3 levels at 2km resolution over France, from 1989 to 2008. Methods: The spatiotemporal concentrations of selected air pollutants were estimated at a fine scale by combining (1) the CHIMERE chemistry-transport model (2) mesh refinement and (3) data assimilation with geostatistical analyzes. Assimilated concentrations were assigned to participants according to their residential zip codes, taking into account residential history. Results: Despite a decreasing trend in concentrations for all pollutant concentrations, levels remained high in some French regions, especially for PM, NO2 and O3.Annual median concentrations at the cohort participants' zip code of PM10, PM2.5, NO2 and O3 were decreased from 1989 to 2008 by 27%, 29%, 40% and 16%, respectively. The largest decreases occurred for SO2 (86%) and C6H6 (85%).Validation showed high correlations between observations and final modeled data (R above 0.75 in 2007) for PM10, NO2 and O3. Conclusion: The modeling process enabled us to assess air pollution over 20 years (1989-2008) at a fine-geographical scale, with acceptable agreement being found between observations and models for all pollutants. © 2014 Elsevier Ltd.

Ten years after their implementation, the Alsatian prefectorial orders concerning emergency measures applied in case of exceedance of alert thresholds for ozone, nitrogen dioxide and, a pioneer feature of the French region, the PM, required an update. In 2007, the ASPA was mandated by the Bas-Rhin and the Haut-Rhin Prefectures to define and assess new emergency measures. The Alsatian emissions inventory first identified the activity sectors which would be potentially targeted by the measures, and then calculated the associated emission reductions. In association with the transportation agency, 3 scenarios were retained for concentration simulation: limitation of the speed limit at 70 km/h on freeways and major urban roads, alternated traffic in towns, and a combination of both measures. Then, an integrated modelling chain, including the CHIMERE and ADMS-Urban models, was allowed to simulate, for the three scenarios, the variation of ozone during the heat wave of 2003, and the variation of nitrogen dioxide and the PM during wintry episodes, for the cities of Strasbourg, Colmar and Mulhouse. Finally, the urban cartographies of the impact of the scenarios on the concentrations were crossed with the georeferenced residence data to estimate the population affected by threshold exceedances in each case. A weak impact was obtained for speed limit reduction, while it was significant for the alternated traffic; for the PM, the concentrations fell about 10 μg/m 3 and the population exposed to threshold exceedance fell by a factor 4; for nitrogen dioxide, the concentrations were lowered by several dozen μg/m 3 and the exposed population fell by a factor 2; whereas for ozone, we noted a slight increase in the concentration and the exposed population. At the same time as the implementation of the newly developed emergency measures, the evolution of knowledge and modelling shows that it would be technically justified to differentiate the measures, pollutant by pollutant. © 2011 INRETS et Springer-Verlag France.

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