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991.
Richard Kraemer Philipp Latzin Isabelle Pramana Pietro Ballinari Sabina Gallati Urs Frey 《Respiratory research》2009,10(1):106
Background and Aim
In patients with cystic fibrosis (CF) the architecture of the developing lungs and the ventilation of lung units are progressively affected, influencing intrapulmonary gas mixing and gas exchange. We examined the long-term course of blood gas measurements in relation to characteristics of lung function and the influence of different CFTR genotype upon this process.Methods
Serial annual measurements of PaO2 and PaCO2 assessed in relation to lung function, providing functional residual capacity (FRCpleth), lung clearance index (LCI), trapped gas (VTG), airway resistance (sReff), and forced expiratory indices (FEV1, FEF50), were collected in 178 children (88 males; 90 females) with CF, over an age range of 5 to 18 years. Linear mixed model analysis and binary logistic regression analysis were used to define predominant lung function parameters influencing oxygenation and carbon dioxide elimination.Results
PaO2 decreased linearly from age 5 to 18 years, and was mainly associated with FRCpleth, (p < 0.0001), FEV1 (p < 0.001), FEF50 (p < 0.002), and LCI (p < 0.002), indicating that oxygenation was associated with the degree of pulmonary hyperinflation, ventilation inhomogeneities and impeded airway function. PaCO2 showed a transitory phase of low PaCO2 values, mainly during the age range of 5 to 12 years. Both PaO2 and PaCO2 presented with different progression slopes within specific CFTR genotypes.Conclusion
In the long-term evaluation of gas exchange characteristics, an association with different lung function patterns was found and was closely related to specific genotypes. Early examination of blood gases may reveal hypocarbia, presumably reflecting compensatory mechanisms to improve oxygenation. 相似文献992.
Eric Jain Amos Bairoch Severine Duvaud Isabelle Phan Nicole Redaschi Baris E Suzek Maria J Martin Peter McGarvey Elisabeth Gasteiger 《BMC bioinformatics》2009,10(1):136-19
Background
The UniProt consortium was formed in 2002 by groups from the Swiss Institute of Bioinformatics (SIB), the European Bioinformatics Institute (EBI) and the Protein Information Resource (PIR) at Georgetown University, and soon afterwards the website was set up as a central entry point to UniProt resources. Requests to this address were redirected to one of the three organisations' websites. While these sites shared a set of static pages with general information about UniProt, their pages for searching and viewing data were different. To provide users with a consistent view and to cut the cost of maintaining three separate sites, the consortium decided to develop a common website for UniProt. Following several years of intense development and a year of public beta testing, the domain was switched to the newly developed site described in this paper in July 2008. 相似文献993.
994.
995.
Laurent Mamelli Sylvain Petit Jacqueline Chevalier Carmela Giglione Aurélie Lieutaud Thierry Meinnel Isabelle Artaud Jean-Marie Pagès 《PloS one》2009,4(7)
Background
Multi-drug resistant (MDR) bacteria have become a major concern in hospitals worldwide and urgently require the development of new antibacterial molecules. Peptide deformylase is an intracellular target now well-recognized for the design of new antibiotics. The bacterial susceptibility to such a cytoplasmic target primarily depends on the capacity of the compound to reach and accumulate in the cytosol.Methodology/Principal Findings
To determine the respective involvement of penetration (influx) and pumping out (efflux) mechanisms to peptide deformylase inhibitors (PDF-I) activity, the potency of various series was determined using various genetic contexts (efflux overproducers or efflux-deleted strains) and membrane permeabilizers. Depending on the structure of the tested molecules, two behaviors could be observed: (i) for actinonin the first PDF-I characterized, the AcrAB efflux system was the main parameter involved in the bacterial susceptibility, and (ii), for the lastest PDF-Is such as the derivatives of 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide, the penetration through the membrane was a important limiting step.Conclusions/Significance
Our results clearly show that the bacterial membrane plays a key role in modulating the antibacterial activity of PDF-Is. The bacterial susceptibility for these new antibacterial molecules can be improved by two unrelated ways in MDR strains: by collapsing the Acr efflux activity or by increasing the uptake rate through the bacterial membrane. The efficiency of the second method is associated with the nature of the compound. 相似文献996.
Background
The adult subventricular zone (SVZ) contains stem and progenitor cells that generate neuroblasts throughout life. Although it is well accepted that SVZ neuroblasts are migratory, recent evidence suggests their progenitor cells may also exhibit motility. Since stem and progenitor cells are proliferative and multipotential, if they were also able to move would have important implications for SVZ neurogenesis and its potential for repair.Methodology/Principal Findings
We studied whether SVZ stem and/or progenitor cells are motile in transgenic GFP+ slices with two photon time lapse microscopy and post hoc immunohistochemistry. We found that stem and progenitor cells; mGFAP-GFP+ cells, bright nestin-GFP+ cells and Mash1+ cells were stationary in the SVZ and rostral migratory stream (RMS). In our search for motile progenitor cells, we uncovered a population of motile βIII-tubulin+ neuroblasts that expressed low levels of epidermal growth factor receptor (EGFr). This was intriguing since EGFr drives proliferation in the SVZ and affects migration in other systems. Thus we examined the potential role of EGFr in modulating SVZ migration. Interestingly, EGFrlow neuroblasts moved slower and in more tortuous patterns than EGFr-negative neuroblasts. We next questioned whether EGFr stimulation affects SVZ cell migration by imaging Gad65-GFP+ neuroblasts in the presence of transforming growth factor alpha (TGF-α), an EGFr-selective agonist. Indeed, acute exposure to TGF-α decreased the percentage of motile cells by approximately 40%.Conclusions/Significance
In summary, the present study directly shows that SVZ stem and progenitor cells are static, that EGFr is retained on some neuroblasts, and that EGFr stimulation negatively regulates migration. This result suggests an additional role for EGFr signaling in the SVZ. 相似文献997.
Isabelle Defourny Andrea Minetti Géza Harczi Stéphane Doyon Susan Shepherd Milton Tectonidis Jean-Hervé Bradol Michael Golden 《PloS one》2009,4(5)
Background
There are 146 million underweight children in the developing world, which contribute to up to half of the world''s child deaths. In high burden regions for malnutrition, the treatment of individual children is limited by available resources. Here, we evaluate a large-scale distribution of a nutritional supplement on the prevention of wasting.Methods and Findings
A new ready-to-use food (RUF) was developed as a diet supplement for children under three. The intervention consisted of six monthly distributions of RUF during the 2007 hunger gap in a district of Maradi region, Niger, for approximately 60,000 children (length: 60–85 cm). At each distribution, all children over 65 cm had their Mid-Upper Arm Circumference (MUAC) recorded. Admission trends for severe wasting (WFH<70% NCHS) in Maradi, 2002–2005 show an increase every year during the hunger gap. In contrast, in 2007, throughout the period of the distribution, the incidence of severe acute malnutrition (MUAC<110 mm) remained at extremely low levels. Comparison of year-over-year admissions to the therapeutic feeding program shows that the 2007 blanket distribution had essentially the same flattening effect on the seasonal rise in admissions as the 2006 individualized treatment of almost 60,000 children moderately wasted.Conclusions
These results demonstrate the potential for distribution of fortified spreads to reduce the incidence of severe wasting in large population of children 6–36 months of age. Although further information is needed on the cost-effectiveness of such distributions, these results highlight the importance of re-evaluating current nutritional strategies and international recommendations for high burden areas of childhood malnutrition. 相似文献998.
Nicolas Penel Sylvie Negrier Isabelle Ray-Coquard Charles Ferte Patrick Devos Antoine Hollebecque Michael B. Sawyer Antoine Adenis Pascal Seve 《PloS one》2009,4(8)
Background
We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients.Methods
Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4).Results
The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5×the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0–1], 2 and [3]–[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values.Conclusions
We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy. 相似文献999.
Christel Depienne Delphine Bouteiller Boris Keren Emmanuel Cheuret Karine Poirier Oriane Trouillard Baya Benyahia Chlo Quelin Wassila Carpentier Sophie Julia Alexandra Afenjar Agns Gautier Franois Rivier Sophie Meyer Patrick Berquin Marie Hlias Isabelle Py Serge Rivera Nadia Bahi-Buisson Isabelle Gourfinkel-An Ccile Cazeneuve Merle Ruberg Alexis Brice Rima Nabbout Eric LeGuern 《PLoS genetics》2009,5(2)
Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism. 相似文献
1000.
Julien Franck Karim Arafah Mohamed Elayed David Bonnel Daniele Vergara Am��lie Jacquet Denis Vinatier Maxence Wisztorski Robert Day Isabelle Fournier Michel Salzet 《Molecular & cellular proteomics : MCP》2009,8(9):2023-2033
A decade after its inception, MALDI imaging mass spectrometry has become a unique technique in the proteomics arsenal for biomarker hunting in a variety of diseases. At this stage of development, it is important to ask whether we can consider this technique to be sufficiently developed for routine use in a clinical setting or an indispensable technology used in translational research. In this report, we consider the contributions of MALDI imaging mass spectrometry and profiling technologies to clinical studies. In addition, we outline new directions that are required to align these technologies with the objectives of clinical proteomics, including: 1) diagnosis based on profile signatures that complement histopathology, 2) early detection of disease, 3) selection of therapeutic combinations based on the individual patient''s entire disease-specific protein network, 4) real time assessment of therapeutic efficacy and toxicity, 5) rational redirection of therapy based on changes in the diseased protein network that are associated with drug resistance, and 6) combinatorial therapy in which the signaling pathway itself is viewed as the target rather than any single “node” in the pathway.MS has become a versatile tool that we are familiar with in large part due to important electronic and informatics advancements. The ability to obtain the molecular weight is one of the first steps in the identification of a molecule. With the addition of primary structural information mass spectrometry has become a useful technique to identify molecules within complex mixtures.Biological specimens, such as tissues, urine, or plasma, are complex and highly heterogeneous, which makes them inherently difficult to analyze. Further research and developments are necessary to achieve reliable biological models for understanding and studying pathologies. Therefore, it is of primary importance to identify the constituents of these systems and subsequently understand how they function within the framework of the tissue. With regard to clinical proteomics, there is the added dimension of disease, and therefore, the main goal is to characterize the cellular circuitry with a focus on the impact of the disease and/or therapy on these cellular networks.Mass spectrometry has become a centerpiece technology predominantly in the field of proteomics. Nonetheless a more comprehensive understanding of the constituents of biological systems will be aided by determining the constituent distribution. This anatomical dimension has been added through mass spectrometry imaging (MSI)1 especially using MALDI-MSI.MALDI is an ion source that is well compatible with the introduction of raw materials and surfaces. Shortly after its introduction, MALDI was used for direct tissue profiling. The first applications were neurobiological studies on dissected organs from the mollusk Lymnaea stagnalis (1–8), crustaceans (9), and other mollusks (10, 11). More recently, MALDI was used to generate profiles from tissue sections and ion images using a scanning method to analyze the surface (12) (Fig. 1). This led to the first MALDI MS tissue section imaging micrographs in 1997 (13–15). These studies were followed by 10 years of intense efforts to improve the sensitivity, reproducibility, data processing, tissue preservation, and preparation treatments to fully characterize the proteome leading to a clear improvement of molecular images (16–39) (Fig. 2).Open in a separate windowFig. 1.Schematic representation of the MALDI-MSI work flow. After tissue sectioning and transfer onto a conductive and transparent sample plate, the MALDI matrix is deposited, and data are acquired by recording mass spectra according to a raster of points covering the surface to be analyzed. Mass spectra recorded with their coordinates on the tissue are processed, and molecular images of the localization of molecules can be reconstructed. a.u., arbitrary units; ITO, idium tin oxide.Open in a separate windowFig. 2.Ten years'' evolution from one of the first MALDI images presented in 1999 at the 47th ASMS Conference on Mass Spectrometry and Allied Topics (left) (reprinted with permission of Caprioli and co-workers (84)) and molecular images obtained by our group for mouse stem cells injected in brain tissue sections (right) (M. Wisztorski, C. Meriaux, M. Salzet, and I. Fournier, unpublished results).These developments led to clinical studies using MALDI-MSI technology. Clinical proteomics has many objectives including 1) diagnosis based on signatures as a complement to histopathology, 2) early disease detection, 3) individualized selection of therapeutic combinations that best target the patient''s entire disease-specific protein network, 4) real time assessment of therapeutic efficacy and toxicity, 5) rational redirection of therapy based on changes in the diseased protein network that are associated with drug resistance, and 6) combinatorial therapy in which the signaling pathway itself is viewed as the target rather than any single “node” in the pathway.Based on these key objectives, can we consider MALDI-MSI a mature technology for use in clinical studies? What is the potential impact of this technology in anatomy/pathology and disease? By reviewing each objective, do we have sufficient evidence that MALDI-MSI satisfies the criteria imposed by clinical proteomics? We will now specifically address each of these key points. 相似文献