Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
ABSTRACT: BACKGROUND: Climate change poses unprecedented challenges, ranging from global and local policy challenges to personal and social action. Heat-related deaths are largely preventable, but interventions for the most vulnerable populations need improvement. Therefore, the prior identification of high risk areas at the community level is required to better inform planning and prevention. We aimed to demonstrate a simple and flexible conceptual framework relying upon satellite thermal data and other digital data with the goal of easily reproducing this framework in a variety of urban configurations. RESULTS: The study area encompasses Rennes, a medium-sized French city. A Landsat ETM + image (60 m resolution) acquired during a localized heatwave (June 2001) was used to estimate land surface temperature (LST) and derive a hazard index. A land-use regression model was performed to predict the LST. Vulnerability was assessed through census data describing four dimensions (socio-economic status, extreme age, population density and building obsolescence). Then, hazard and vulnerability indices were combined to deliver a heatwave health risk index. The LST patterns were quite heterogeneous, reflecting the land cover mosaic inside the city boundary, with hotspots of elevated temperature mainly observed in the city center. A spatial error regression model was highly predictive of the spatial variation in the LST (R2 = 0.87) and was parsimonious. Three land cover descriptors (NDVI, vegetation and water fractions) were negatively linked with the LST. A sensitivity analysis (based on an image acquired on July 2000) yielded similar results. Southern areas exhibited the most vulnerability, although some pockets of higher vulnerability were observed northeast and west of the city. The heatwave health risk map showed evidence of infra-city spatial clustering, with the highest risks observed in a north--south central band. Another sensitivity analysis gave a very high correlation between 2000 and 2001 risk indices (r = 0.98, p < 10-12). CONCLUSIONS: Building on previous work, we developed a reproducible method that can provide guidance for local planners in developing more efficient climate impact adaptations. We recommend, however, using the health risk index together with hazard and vulnerability indices to implement tailored programs because exposure to heat and vulnerability do not require the same prevention strategies.
ISSN: 1476-072X

inserm-00762303
http://www.hal.inserm.fr/inserm-00762303
http://www.hal.inserm.fr/inserm-00762303/document
http://www.hal.inserm.fr/inserm-00762303/file/1476-072X-11-38.pdf
DOI : 10.1186/1476-072X-11-38

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: End-Stage renal disease (ESRD) causes considerable morbidity and mortality, and significantly alterspatients’ quality of life. There are very few published data on this problem in the French Overseas territories. Thedevelopment of a registry on end stage renal disease in French Guiana in 2011 allowed to describe the magnitudeof this problem in the region for the first time.Methods: Using data from the French Renal Epidemiology and Information Network registry (R.E.I.N). Descriptivestatistics on quantitative and qualitative variables in the registry were performed on prevalent cases and incidentcases in 2011, 2012 and 2013.Results: French Guiana has one of the highest ESRD prevalence and incidence in France. The two main causes ofESRD were hypertensive and diabetic nephropathies. The French Guianese population had a different demographicprofile (younger, more women, more migrants) than in mainland France. Most patients had at least one comorbidity,predominantly (95.3%) hypertension. In French Guiana dialysis was initiated in emergency for 71.3% of patients versus33% in France (p < 0.001).Conclusion: These first results give important public health information: i) End stage renal disease has a very highprevalence relative to mainland France ii) Patients have a different demographic profile and enter care late in thecourse of their renal disease. These data are closer to what is observed in the Caribbean or in Latin America than inMainland France.
ISSN: 1471-2369

inserm-01567222
http://www.hal.inserm.fr/inserm-01567222
http://www.hal.inserm.fr/inserm-01567222/document
http://www.hal.inserm.fr/inserm-01567222/file/2017%2C%20Rochemont%20-%20End%20stage%20renal%20disease.pdf
DOI : 10.1186/s12882-017-0614-6

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Hepatocellular carcinoma (HCC) is a particularly severe disease characterized by a high rate of recurrence and death even after surgical resection. Molecular characterization of HCC helps refine prognosis and may facilitate the development of improved therapy. Phosphatidylinositol 4-kinases have recently been identified as cellular factors associated with cancer. Also, phosphatidylinositol 4-kinase type IIIα (PI4KA) is necessary for the propagation of the hepatitis C virus, a major etiological factor for HCC. METHODS: Reverse transcription, quantitative real-time PCR was used to assay PI4KA mRNA. The expression levels were investigated both in a collection of molecularly and clinically characterized hepatic tissues from 344 patients with diverse liver diseases and in human hepatocyte cell lines whose proliferative and differentiation status was controlled by specific culture conditions. Analytical microarray data for 60 HCC and six normal liver tissue samples were exploited to study correlations between PI4KA mRNA levels and cell proliferation markers in vivo. Postoperative disease-specific survival and time to recurrence in a set of 214 patients with HCC were studied by univariate and multivariate analyses. RESULTS: PI4KA mRNA was more abundant in HCC than normal healthy tissues. This upregulation correlated significantly with both poor differentiation and the active proliferation rate in HCC. These associations were confirmed with in vitro models. Moreover, patients with HCC who had been treated by surgical resection and had higher PI4KA mRNA concentrations in their tumor tissue exhibited a higher risk of tumor recurrence (median time: 20 months versus 49 months, P = 0.0012) and shorter disease-specific survival (first quartile time: 16 months versus 48 months, P = 0.0004). Finally, the abundance of PI4KA mRNA proved to be an independent prognostic marker of survival for cases of HCC (hazard ratio = 2.36, P = 0.0064). CONCLUSIONS: PI4KA mRNA could be used as a new molecular marker to improve established prognostic models for HCC. These findings also indicate possible new lines of research for the development of innovative therapeutic approaches targeting PI4KA.
ISSN: 1471-2407

inserm-00934294
http://www.hal.inserm.fr/inserm-00934294
http://www.hal.inserm.fr/inserm-00934294/document
http://www.hal.inserm.fr/inserm-00934294/file/1471-2407-14-7.pdf
DOI : 10.1186/1471-2407-14-7

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: The evaluation of geographical healthcare accessibility in residential areas provides crucial information to public policy. Traditional methods - such as Physician Population Ratios (PPR) or shortest travel time - offer only a one-dimensional view of accessibility. This paper developed an improved indicator: the Index of Spatial Accessibility (ISA) to measure geographical healthcare accessibility at the smallest available infra-urban level, that is, the Ilot Regroupe pour des Indicateurs Statistiques. Methods: This study was carried out in the department of Nord, France. Healthcare professionals are geolocalized using postal addresses available on the French state health insurance website. ISA is derived from an Enhanced Two-Step Floating Catchment Area (E2FCA). We have constructed a catchment for each healthcare provider, by taking into account residential building centroids, car travel time as calculated by Google Maps and the edge effect. Principal Component Analyses (PCA) were used to build a composite ISA to describe the global accessibility of different kinds of health professionals. Results: We applied our method to studying geographical healthcare accessibility for pregnant women, by selecting three types of healthcare provider: general practitioners, gynecologists and midwives. A total of 3587 healthcare providers are potentially able to provide care for inhabitants of the department of Nord. On average there are 92 general practitioners, 22 midwives and 21 gynecologists per 100,000 residents. The composite ISA for the three types of healthcare provider is 39 per 100,000 residents. A comparative analysis between ISA and physician-population ratios indicates that ISA represents a more even distribution whereas the physician-population ratios show an 'all-or-nothing' approach. Conclusion: ISA is a multidimensional and improved measure, which combines the volume of services relative to population size with the proximity of services relative to the population's location, available at the smallest feasible geographical scale. It could guide policy makers towards highlighting critical areas in need of more healthcare providers, and these areas should be earmarked for further knowledge-based policy making.
ISSN: 1475-9276

hal-01359567
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359567
DOI : 10.1186/s12939-016-0411-z
PUBMED : 27485740

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
The natural history of pulmonary Langerhans cell histiocytosis (PLCH) has been unclear due to the absence of prospective studies. The rate of patients who experience an early progression of their disease is unknown. Additionally, conflicting effects of smoking cessation on the outcome of PLCH have been reported. In this prospective, multicentre study, 58 consecutive patients with newly diagnosed PLCH were comprehensively evaluated over a two-year period. Our objectives were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes. Lung function deterioration was defined as a decrease of at least 15% in FEV1 and/or FVC and/or DLCO, compared with baseline values. At each visit, smoking status was recorded based on the patients' self-reports and urinary cotinine measurements that were blinded for the patients. The cumulative incidence of lung function outcomes over time was estimated using the non-parametric Kaplan-Meier method. Multivariate Cox models with time-dependent covariates were used to calculate the hazards ratios of the lung function deterioration associated with smoking status with adjustment for potential confounders. The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV1 and DLCO, and 9% for FVC). In the multivariate analysis, smoking status and PaO2 at inclusion were the only factors associated with the risk of lung function deterioration. The patients' smoking statuses markedly changed over time. Only 20% of the patients quit using tobacco for the entire study period. Nevertheless, being a non-smoker was associated with a decreased risk of subsequent lung function deterioration, even after adjustment for baseline predictive factors. By serial lung computed tomography, the extent of cystic lesions increased in only 11% of patients. Serial lung function evaluation on a three- to six-month basis is essential for the follow-up of patients with recently diagnosed PLCH to identify those who experience an early progression of their disease. These patients are highly addicted to tobacco, and robust efforts should be undertaken to include them in smoking cessation programs. ClinicalTrials.gov: No: NCT01225601 .
ISSN: 1750-1172

hal-01146047
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146047
PUBMED : 25887097
DOI : 10.1186/s13023-015-0249-2

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
UNLABELLED: ABSTRACT: BACKGROUND: Evidence of a dose-response relationship between prenatal exposure to methylmercury (MeHg) and neurodevelopmental consequences in terms of IQ reduction, makes it possible to evaluate the economic consequences of MeHg exposures. OBJECTIVE: To perform an economic evaluation of annual national benefits of reduction of the prenatal MeHg exposure in France. METHODS: We used data on hair-Hg concentrations in French women of childbearing age (18-45 years) from a national sample of 126 women and from two studies conducted in coastal regions (n = 161and n = 503). A linear dose response function with a slope of 0.465 IQ point reduction per μg/g increase in hair-Hg concentration was used, along with a log transformation of the exposure scale, where a doubling of exposure was associated with a loss of 1.5 IQ points. The costs calculations utilized an updated estimate of €2008 17,363 per IQ point decrement, with three hypothetical exposure cut-off points (hair-Hg of 0.58, 1.0, and 2.5 μg/g). RESULTS: Because of higher exposure levels of women in coastal communities, the annual economic impacts based on these data were greater than those using the national data, i.e. € 1.62 billion (national), and € 3.02 billion and € 2.51 billion (regional), respectively, with the linear model, and € 5.46 billion (national), and € 9.13 billion and € 8.17 billion (regional), with the log model, for exposures above 0.58 μg/g. CONCLUSIONS: These results emphasize that efforts to reduce MeHg exposures would have high social benefits by preventing the serious and lifelong consequences of neurodevelopmental deficits in children.
ISSN: 1476-069X

inserm-00769338
http://www.hal.inserm.fr/inserm-00769338
http://www.hal.inserm.fr/inserm-00769338/document
http://www.hal.inserm.fr/inserm-00769338/file/1476-069X-11-53.pdf
DOI : 10.1186/1476-069X-11-53

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Reliable molecular typing tools are required for a better understanding of the molecular epidemiology of Plasmodium vivax. The genes msp3a and msp1_block5 are highly polymorphic and have been used as markers in many P. vivax population studies. These markers were used to assess the genetic diversity of P. vivax strains from French Guiana (South America) and to develop a molecular typing protocol. METHODS: A total of 120 blood samples from 109 patients (including 10 patients suffered from more than one malaria episode, samples were collected during each episode) with P. vivax infection were genotyped. All samples were analysed by msp3a PCR-RFLP and msp1_b5 gene sequencing was performed on 57 samples. Genotyping protocol applied to distinguish between new infection or relapse from heterologus hypnozoites and treatment failure or relapse from homologus hypnozoites was based on analysing first msp3a by PCR-RFLP and secondly, only if the genotypes of the two samples are identical, on sequencing the msp1_b5 gene. RESULTS: msp3a alleles of three sizes were amplified by PCR: types A, B and C. Eleven different genotypes were identified among the 109 samples analysed by msp3a PCR-RFLP. In 13.8% of cases, a mixed genotype infection was observed. The sequence of msp1_b5 gene revealed 22 unique genotypes and 12.3% of cases with mixed infection. In the 57 samples analysed by both methods, 45 genotypes were found and 21% were mixed. Among ten patients with two or three malaria episodes, the protocol allowed to identify five new infections or relapses from heterologous hypnozoites and six treatment failures of relapses from homologous hypnozoites. CONCLUSION: The study showed a high diversity of msp3a and msp1_b5 genetic markers among P. vivax strains in French Guiana with a low polyclonal infection rate. These results indicated that the P. vivax genotyping protocol presented has a good discrimination power and can be used in clinical drug trials or epidemiological studies.
ISSN: 1475-2875

pasteur-00590981
https://hal-riip.archives-ouvertes.fr/pasteur-00590981
DOI : 10.1186/1475-2875-8-40
PUBMED : 19284592

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: The Hippo pathway regulates growth rate and organ size in fly and mouse, notably through control of cell proliferation. Molecular interactions at the heart of this pathway are known to have originated in the unicellular ancestry of metazoans. They notably involve a cascade of phosphorylations triggered by the kinase Hippo, with sub‑ sequent nuclear to cytoplasmic shift of Yorkie localisation, preventing its binding to the transcription factor Scalloped, thereby silencing proliferation genes. There are few comparative expression data of Hippo pathway genes in non‑ model animal species and notably none in non‑bilaterian phyla.Results: All core Hippo pathway genes could be retrieved from the ctenophore Pleurobrachia pileus and the hydro‑ zoan cnidarian Clytia hemisphaerica, with the important exception of Yorkie in ctenophore. Expression study of the Hippo, Salvador and Scalloped genes in tentacle " cellular conveyor belts " of these two organisms revealed striking differences. In P. pileus, their transcripts were detected in areas where undifferentiated progenitors intensely prolifer‑ ate and where expression of cyclins B and D was also seen. In C. hemisphaerica, these three genes and Yorkie are expressed not only in the proliferating but also in the differentiation zone of the tentacle bulb and in mature tentacle cells. However, using an antibody designed against the C. hemiphaerica Yorkie protein, we show in two distinct cell lineages of the medusa that Yorkie localisation is predominantly nuclear in areas of active cell proliferation and mainly cytoplasmic elsewhere.Conclusions: This is the first evidence of nucleocytoplasmic Yorkie shift in association with the arrest of cell prolifera‑ tion in a cnidarian, strongly evoking the cell division‑promoting role of this protein and its inhibition by the activated Hippo pathway in bilaterian models. Our results furthermore highlight important differences in terms of deployment and regulation of Hippo pathway genes between cnidarians and ctenophores.
ISSN: 2041-9139

Droits : http://creativecommons.org/licenses/by/
hal-01286578
http://hal.upmc.fr/hal-01286578
http://hal.upmc.fr/hal-01286578/document
http://hal.upmc.fr/hal-01286578/file/comparative.pdf
DOI : 10.1186/s13227-016-0041-y

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: Increasingly, similarity networks are being used for evolutionary analyses of molecular datasets. These networks are very useful, in particular for the analysis of gene sharing, lateral gene transfer and for the detection of distant homologs. Currently, such analyses require some computer programming skills due to the limited availability of user-friendly freely distributed software. Consequently, although appealing, the construction and analyses of these networks remain less familiar to biologists than do phylogenetic approaches. Results: In order to ease the use of similarity networks in the community of evolutionary biologists, we introduce a software program, EGN, that runs under Linux or MacOSX. EGN automates the reconstruction of gene and genome networks from nucleic and proteic sequences. EGN also implements statistics describing genetic diversity in these samples, for various user-defined thresholds of similarities. In the interest of studying the complexity of evolutionary processes affecting microbial evolution, we applied EGN to a dataset of 571,044 proteic sequences from the three domains of life and from mobile elements. We observed that, in Borrelia, plasmids play a different role than in most other eubacteria. Rather than being genetic couriers involved in lateral gene transfer, Borrelia's plasmids and their genes act as private genetic goods, that contribute to the creation of genetic diversity within their parasitic hosts. Conclusion: EGN can be used for constructing, analyzing, and mining molecular datasets in evolutionary studies. The program can help increase our knowledge of the processes through which genes from distinct sources and/or from multiple genomes co-evolve in lineages of cellular organisms.
ISSN: 1471-2148

hal-01544799
https://hal.archives-ouvertes.fr/hal-01544799
DOI : 10.1186/1471-2148-13-146

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
ABSTRACT: Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question.
ISSN: 1476-069X

inserm-00785248
http://www.hal.inserm.fr/inserm-00785248
http://www.hal.inserm.fr/inserm-00785248/document
http://www.hal.inserm.fr/inserm-00785248/file/1476-069X-12-8.pdf
DOI : 10.1186/1476-069X-12-8

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Malaria is a major public health problem in French Guiana, where Plasmodium vivax has become the dominant malaria species since 2000. As in others endemic areas, it is important to specify the pattern of vivax malaria relapses and to try to discriminate efficiently re-infections from relapses. METHODS: This study was conducted in children born between January 1, 2001 and December 31, 2008 in Camopi, an Amerindian village located in the Amazon forest (n = 325), using an open cohort design. Primary and secondary attack rates of P. vivax were calculated using survival analysis. With the difference between the primary and secondary rates, this study aimed to estimate indirectly P. vivax relapse rate and evaluate its time evolution. RESULTS: Of the 1042 malaria attacks recorded, 689 (66%) were due to P. vivax (without mixed infection). One hundred and fifty one children had their primary attack with P. vivax and 106 had their two first attacks with P. vivax. In the absence of primaquine treatment, it was shown that P. vivax relapses mainly occurred during the first three months after the first attack. Thirty percent of children never had a relapse, 42% had a relapse before the first month after primary attack, 59% before the second month and 63% before the third month. CONCLUSION: This study confirmed that the relapse pattern in Camopi was compatible with the pattern described for the P. vivax Chesson (tropical) strain. In addition, due to the relapse rate time evolution, a simple arbitrary classification rule could be constructed: before 90 days after the primary attack, the secondary attack is a relapse; after 90 days, it is a re-infection. Adapted management of malaria cases based on these results could be devised.
ISSN: 1475-2875

inserm-00663913
http://www.hal.inserm.fr/inserm-00663913
http://www.hal.inserm.fr/inserm-00663913/document
http://www.hal.inserm.fr/inserm-00663913/file/1475-2875-8-278.pdf
DOI : 10.1186/1475-2875-8-278

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: The relative scarcity of Copia retrotransposons has been recently characterized in metazoans in comparison with the other superfamilies of LTR elements. Furthermore, Copia retrotransposons have often a particular dynamics that results in a highly predominant single clade of elements within a large host taxon, such as the GalEa-like retrotransposons in crustaceans. Taking advantage of the skyrocketing amount of genomic data available for fungi, we carried out the first large-scale comparative genomic analysis of the Copia clades in filamentous ascomycetes.Results: Screening 30 completely sequenced genomes allowed us to identify more than 2500 Copia copies with conserved LTR, which are distributed in 138 families. Their characterization revealed that fungal Copia diversity is much broader than previously thought with at least 27 clades, 23 of which likely correspond to new ones. While the Copia copy number is low in most species, the two clades GalEa and FunCo1 are widely distributed and highly dominate Copia content as they both account for 80% of the detected sequences.Conclusions: In Fungi, GalEa retrotransposons are restricted to Pezizomycotina in which they can make up an outstandingly high proportion of the genome (up to 10% in Cenococcum geophilum). At last, we revealed that fungal GalEa elements structurally differ from all other Copia elements with an absence of Primer Binding Site. These elements however harbor a Conserved Hairpin Site which is probably essential for their transposition.sequences.
ISSN: 1471-2164

Droits : http://creativecommons.org/licenses/by/
hal-01529914
http://hal.upmc.fr/hal-01529914
http://hal.upmc.fr/hal-01529914/document
http://hal.upmc.fr/hal-01529914/file/art_10.1186_s12864-017-3795-2.pdf
DOI : 10.1186/s12864-017-3795-2

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
A major requirement for malaria elimination is the development of transmission-blocking interventions. In vitro transmission-blocking bioassays currently mostly rely on the use of very few Plasmodium falciparum reference laboratory strains isolated decades ago. To fill a piece of the gap between laboratory experimental models and natural systems, the purpose of this work was to determine if culture-adapted field isolates of P. falciparum are suitable for in vitro transmission-blocking bioassays targeting functional maturity of male gametocytes: exflagellation. Plasmodium falciparum isolates were adapted to in vitro culture before being used for in vitro gametocyte production. Maturation was assessed by microscopic observation of gametocyte morphology over time of culture and the functional viability of male gametocytes was assessed by microscopic counting of exflagellating gametocytes. Suitability for in vitro exflagellation-blocking bioassays was determined using dihydroartemisinin and methylene blue. In vitro gametocyte production was achieved using two isolates from French Guiana and two isolates from Cambodia. Functional maturity of male gametocytes was assessed by exflagellation observations and all four isolates could be used in exflagellation-blocking bioassays with adequate response to methylene blue and dihydroartemisinin. This work shows that in vitro culture-adapted P. falciparum field isolates of different genetic background, from South America and Southeast Asia, can successfully be used for bioassays targeting the male gametocyte to gamete transition, exflagellation.
ISSN: 1475-2875

Droits : http://creativecommons.org/licenses/by/
pasteur-01182753
https://hal-pasteur.archives-ouvertes.fr/pasteur-01182753
https://hal-pasteur.archives-ouvertes.fr/pasteur-01182753/document
https://hal-pasteur.archives-ouvertes.fr/pasteur-01182753/file/LeBas%20et%202015%20version%20publie%20%281%29.pdf
DOI : 10.1186/s12936-015-0752-x

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: The Ras/Raf/MEK/ERK signaling pathway is involved in essential cell processes and it is abnormally activated in similar to 30 % of cancers and cognitive disorders. Two ERK isoforms have been described, ERK1 and ERK2; ERK2 being regarded by many as essential due to the embryonic lethality of ERK2 knock-out mice, whereas mice lacking ERK1 are viable and fertile. The controversial question of why we have two ERKs and whether they have differential functions or display functional redundancy has not yet been resolved. Results: To investigate this question we used a novel approach based on comparing the evolution of ERK isoforms' sequences and protein expression across vertebrates. We gathered and cloned erk1 and erk2 coding sequences and we examined protein expression of isoforms in brain extracts in all major clades of vertebrate evolution. For the first time, we measured each isoforms' relative protein level in phylogenetically distant animals using anti-phospho antibodies targeting active ERKs. We demonstrate that squamates (lizards, snakes and geckos), despite having both genes, do not express ERK2 protein whereas other tetrapods either do not express ERK1 protein or have lost the erk1 gene. To demonstrate the unexpected squamates' lack of ERK2 expression, we targeted each ERK isoform in lizard primary fibroblasts by specific siRNA-mediated knockdown. We also found that undetectable expression of ERK2 in lizard is compensated by a greater strength of lizard's erk1 promoter. Finally, phylogenetic analysis revealed that ERK1 amino acids sequences evolve faster than ERK2' s likely due to genomic factors, including a large difference in gene size, rather than from functional differences since amino acids essential for function are kept invariant. Conclusions: ERK isoforms appeared by a single gene duplication at the onset of vertebrate evolution at least 400 Mya. Our results demonstrate that tetrapods can live by expressing either one or both ERK isoforms, supporting the notion that ERK1/2 act interchangeably. Substrate recognition sites and catalytic cleft are nearly invariant in all vertebrate ERKs further suggesting functional redundancy. We suggest that future ERK research should shift towards understanding the role and regulation of total ERK quantity, especially in light of newly described erk2 gene amplification identified in tumors.
ISSN: 1471-2148

hal-01546165
https://hal.archives-ouvertes.fr/hal-01546165
DOI : 10.1186/s12862-015-0450-x

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
IntroductionFever is associated with a poor outcome in severely brain-injured patients, and its control is one of the therapies used in this condition. But, fever suppression may promote infection, and severely brain-injured patients are frequently exposed to infectious diseases, particularly ventilator-associated pneumonia (VAP). Therefore, we designed a study to explore the role of a fever control protocol in VAP development during neuro-intensive care.MethodsAn observational study was performed on severely brain-injured patients hospitalized in a university ICU. The primary goal was to assess whether fever control was a risk factor for VAP in a prospective cohort in which a fever control protocol was applied and in a historical control group. Moreover, the density of VAP incidence was compared between the two groups. The statistical analysis was based on a competing risk model multivariate analysis.ResultsThe study included 189 brain-injured patients (intervention group, n¿=¿98, and historical control group, n¿=¿91). The use of a fever control protocol was an independent risk factor for VAP (hazard ratio 2.73, 95% confidence interval [1.38, 5.38; P¿=¿0.005]). There was a significant increase in the incidence of VAP in patients treated with a fever control protocol (26.1 versus 12.5 VAP cases per 1000 days of mechanical ventilation). In cases in which a fever control protocol was applied for >3 days, we observed a higher rate of VAP in comparison with the rate among patients treated for ¿3 days.ConclusionFever control in brain-injured patients was a major risk factor for VAP occurrence, particularly when applied for >3 days.
ISSN: 1364-8535

hal-01118640
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118640
PUBMED : 25498970
DOI : 10.1186/s13054-014-0689-4
PUBMEDCENTRAL : PMC4279880

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Environmental exposures, including dietary contaminants, may influence the developing immune system. This study assesses the association between maternal pre-parturition consumption of seafood and wheeze, eczema, and food allergy in preschool children. Fish and shellfish were studied separately as they differ according to their levels of omega-3 polyunsaturated fatty acids (which have anti-allergic properties) and their levels of contaminants. METHODS: The PELAGIE cohort included 3421 women recruited at the beginning of pregnancy. Maternal fish and shellfish intake was measured at inclusion by a food frequency questionnaire. Wheeze, eczema, and food allergy were evaluated by a questionnaire completed by the mother when the child was 2 years old (n = 1500). Examination of the associations between seafood intake and outcomes took major confounders into account. Complementary sensitivity analyses with multiple imputation enabled us to handle missing data, due mostly to attrition. RESULTS: Moderate maternal pre-parturition fish intake (1 to 4 times a month) was, at borderline significance, associated with a lower risk of wheeze (adjusted OR = 0.69 (0.45-1.05)) before age 2, compared with low intake (< once/month). This result was not, however, consistent: after multiple imputation, the adjusted OR was 0.86 (0.63-1.17). Shellfish intake at least once a month was associated with a higher risk of food allergy before age 2 (adjusted OR = 1.62 (1.11-2.37)) compared to low or no intake (< once/month). Multiple imputation confirmed this association (adjusted OR = 1.52 (1.05-2.21)). CONCLUSIONS: This study suggests that maternal pre-parturition shellfish consumption may increase the risk of food allergy. Further large-scale epidemiologic studies are needed to corroborate these results, identify the contaminants or components of shellfish responsible for the effects observed, determine the persistence of the associations seen at age 2, and investigate potential associations with health effects observable at later ages, such as allergic asthma.
ISSN: 1476-069X

Droits : info:eu-repo/semantics/OpenAccess
inserm-00926282
http://www.hal.inserm.fr/inserm-00926282
http://www.hal.inserm.fr/inserm-00926282/document
http://www.hal.inserm.fr/inserm-00926282/file/1476-069X-12-102.pdf
DOI : 10.1186/1476-069X-12-102

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: The orphan receptors COUP-TF (chicken ovalbumin upstream promoter transcription factor) I and II are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis. The involvement of COUP-TFs in cancer development has recently been suggested by several studies but remains poorly understood. METHODS: MCF-7 breast cancer cells overexpressing COUP-TFI and human breast tumors were used to investigate the role of COUP-TFI in the regulation of CXCL12/CXCR4 signaling axis in relation to cell growth and migration. We used Immunofluorescence, western-blot, RT-PCR, Formaldehyde-assisted Isolation of Regulatory Elements (FAIRE) assays, as well as cell proliferation and migration assays. RESULTS: Previously, we showed that COUP-TFI expression is enhanced in breast cancer compared to normal tissue. Here, we report that the CXCL12/CXCR4 signaling pathway, a crucial pathway in cell growth and migration, is an endogenous target of COUP-TFI in breast cancer cells. The overexpression of COUP-TFI in MCF-7 cells inhibits the expression of the chemokine CXCL12 and markedly enhances the expression of its receptor, CXCR4. Our results demonstrate that the modification of CXCL12/CXCR4 expression by COUP-TFI is mediated by the activation of epithelial growth factor (EGF) and the EGF receptor. Furthermore, we provide evidence that these effects of COUP-TFI increase the growth and motility of MCF-7 cells in response to CXCL12. Cell migration toward a CXCL12 gradient was inhibited by AMD3100, a specific antagonist of CXCR4, or in the presence of excess CXCL12 in the cell culture medium. The expression profiles of CXCR4, CXCR7, CXCL12, and COUP-TFI mRNA in 82 breast tumors and control non-tumor samples were measured using real-time PCR. CXCR4 expression was found to be significantly increased in the tumors and correlated with the tumor grade, whereas the expression of CXCL12 was significantly decreased in the tumors compared with the healthy samples. Significantly higher COUP-TFI mRNA expression was also detected in grade 1 tumors. CONCLUSIONS: Together, our mechanistic in vitro assays and in vivo results suggest that a reduction in chemokine CXCL12 expression, with an enhancement of CXCR4 expression, provoked by COUP-TFI, could be associated with an increase in the invasive potential of breast cancer cells.
ISSN: 1471-2407

hal-01024753
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753/file/1471-2407-14-407.pdf
DOI : 10.1186/1471-2407-14-407

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
UNLABELLED: ABSTRACT: BACKGROUND: Malaria remains a major health problem in French Guiana, with a mean of 3800 cases each year. A previous study in Camopi, an Amerindian village on the Oyapock River, highlighted the major contribution of environmental features to the incidence of malaria attacks. We propose a method for the objective selection of the best multivariate peridomestic landscape characterisation that maximises the chances of identifying relationships between environmental features and malaria incidence, statistically significant and meaningful from an epidemiological point of view. METHODS: A land-cover map, the hydrological network and the geolocalised inhabited houses were used to characterise the peridomestic landscape in eleven discoid buffers with radii of 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000 metres. Buffer-based landscape characterisations were first compared in terms of their capacity to discriminate between sites within the geographic space and of their effective multidimensionality in variable space. The Akaike information criterion (AIC) was then used to select the landscape model best explaining the incidences of P. vivax and P. falciparum malaria. Finally, we calculated Pearson correlation coefficients for the relationships between environmental variables and malaria incidence, by species, for the more relevant buffers. RESULTS: The optimal buffers for environmental characterisation had radii of 100 m around houses for P. vivax and 400 m around houses for P. falciparum. The incidence of P. falciparum malaria seemed to be more strongly linked to environmental features than that of P. vivax malaria, within these buffers. The incidence of P. falciparum malaria in children was strongly correlated with proportions of bare soil (r = -0.69), land under high vegetation (r = 0.68) and primary forest (r = 0.54), landscape division (r = 0.48) and the number of inhabited houses (r = -0.60). The incidence of P. vivax malaria was associated only with landscape division (r = 0.49). CONCLUSIONS: The proposed methodology provides a simple and general framework for objective characterisation of the landscape to account for field observations. The use of this method enabled us to identify different optimal observation horizons around houses, depending on the Plasmodium species considered, and to demonstrate significant correlations between environmental features and the incidence of malaria.
ISSN: 1476-072X

inserm-00674075
http://www.hal.inserm.fr/inserm-00674075
http://www.hal.inserm.fr/inserm-00674075/document
http://www.hal.inserm.fr/inserm-00674075/file/1476-072X-10-65.pdf
DOI : 10.1186/1476-072X-10-65

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Although widely used, area-based deprivation indices remain sensitive to urban-rural differences as such indices are usually standardised around typical urban values. There is, therefore, a need to determine to what extent available deprivation indices can be used legitimately over both urban and rural areas. METHODS: This study was carried out in Brittany, France, a relatively affluent region that contains deep rural areas. Among the 1,736 residential census block groups (IRIS) composing the Brittany region, 1,005 (57.9%) are rural. Four deprivation indices were calculated: two scores (Carstairs and Townsend) developed in the UK and two more recent French measures (Havard and Rey). Two standardisation levels were considered: all of the IRIS and only the urban IRIS of the region. Internal validity (Kappa coefficients and entropy values) and external validity (relationship with colorectal cancer screening [CCS] attendance) were investigated. RESULTS: Regardless of the deprivation measure used, wealthy areas are mostly clustered in the West and at the outskirts of major towns. Carstairs and Rey scores stand out by all evaluation criteria, capturing both urban and rural deprivation. High levels of agreements were found across standardisation levels (κ = 0.96). The distributions of deprivation scores were balanced across urban and rural areas, and high Shannon entropy values were observed in the capital city (≥0.93). Similar and significant negative trends were observed between CCS attendance and both deprivation indices, independent of the degree of urbanisation. CONCLUSIONS: These results provide support, despite potential sociological objections, for the use of a compromise index that would facilitate comparisons and interpretations across urban and rural locations in public health research.
ISSN: 1476-072X

hal-01063904
https://hal.archives-ouvertes.fr/hal-01063904
https://hal.archives-ouvertes.fr/hal-01063904/document
https://hal.archives-ouvertes.fr/hal-01063904/file/1476-072X-13-22.pdf
PUBMED : 24929662

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: The TGF-β transforming growth factor is the most pleiotropic cytokine controlling a broad range of cellular responses that include proliferation, differentiation and apoptosis. The context-dependent multifunctional nature of TGF-β is associated with complex signaling pathways. Differential models describe the dynamics of the TGF-β canonical pathway, but modeling the non-canonical networks constitutes a major challenge. Here, we propose a qualitative approach to explore all TGF-β-dependent signaling pathways. RESULTS: Using a new formalism, CADBIOM, which is based on guarded transitions and includes temporal parameters, we have built the first discrete model of TGF-β signaling networks by automatically integrating the 137 human signaling maps from the Pathway Interaction Database into a single unified dynamic model. Temporal property-checking analyses of 15934 trajectories that regulate 145 TGF-β target genes reveal the association of specific pathways with distinct biological processes. We identify 31 different combinations of TGF-β with other extracellular stimuli involved in non-canonical TGF-β pathways that regulate specific gene networks. Extensive analysis of gene expression data further demonstrates that genes sharing CADBIOM trajectories tend to be co-regulated. CONCLUSIONS: As applied here to TGF-β signaling, CADBIOM allows, for the first time, a full integration of highly complex signaling pathways into dynamic models that permit to explore cell responses to complex microenvironment stimuli.
ISSN: 1752-0509

inserm-00978313
http://www.hal.inserm.fr/inserm-00978313
http://www.hal.inserm.fr/inserm-00978313/document
http://www.hal.inserm.fr/inserm-00978313/file/1752-0509-8-30.pdf
DOI : 10.1186/1752-0509-8-30