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The digital revolution has contributed to very large data sets (ie, big data) relevant for public health. The two major data sources are electronic health records from traditional health systems and patient-generated data. As the two data sources have complementary strengths-high veracity in the data from traditional sources and high velocity and variety in patient-generated data-they can be combined to build more-robust public health systems. However, they also have unique challenges. Patient-generated data in particular are often completely unstructured and highly context dependent, posing essentially a machine-learning challenge. Some recent examples from infectious disease surveillance and adverse drug event monitoring demonstrate that the technical challenges can be solved. Despite these advances, the problem of verification remains, and unless traditional and digital epidemiologic approaches are combined, these data sources will be constrained by their intrinsic limits. © The Author 2016.

Milinkovitch M.C.,Geneva Lab | Helaers R.,University of Namur | Depiereux E.,University of Namur | Tzika A.C.,Geneva Lab | Tzika A.C.,Roosevelt University
Genome Biology | Year: 2010

Background: Given the availability of full genome sequences, mapping gene gains, duplications, and losses during evolution should theoretically be straightforward. However, this endeavor suffers from overemphasis on detecting conserved genome features, which in turn has led to sequencing multiple eutherian genomes with low coverage rather than fewer genomes with high-coverage and more even distribution in the phylogeny. Although limitations associated with analysis of low coverage genomes are recognized, they have not been quantified.Results: Here, using recently developed comparative genomic application systems, we evaluate the impact of low-coverage genomes on inferences pertaining to gene gains and losses when analyzing eukaryote genome evolution through gene duplication. We demonstrate that, when performing inference of genome content evolution, low-coverage genomes generate not only a massive number of false gene losses, but also striking artifacts in gene duplication inference, especially at the most recent common ancestor of low-coverage genomes. We show that the artifactual gains are caused by the low coverage of genome sequence per se rather than by the increased taxon sampling in a biased portion of the species tree.Conclusions: We argue that it will remain difficult to differentiate artifacts from true changes in modes and tempo of genome evolution until there is better homogeneity in both taxon sampling and high-coverage sequencing. This is important for broadening the utility of full genome data to the community of evolutionary biologists, whose interests go well beyond widely conserved physiologies and developmental patterns as they seek to understand the generative mechanisms underlying biological diversity. © 2010 Milinkovitch et al.; licensee BioMed Central Ltd.

Lalive P.H.,University of Geneva | Neuhaus O.,Kliniken Landkreis Sigmaringen | Benkhoucha M.,University of Geneva | Burger D.,Geneva Lab | And 3 more authors.
CNS Drugs | Year: 2011

Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clinical effect to a shift in the cytokine secretion of CD4 T helper (Th) cells, growing evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is associated with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4 Th cells, CD8 T cells, Foxp3 regulatory T cells and antibody production by plasma cells have been reported; in addition, most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Experimental evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective andor neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimers or Parkinsons disease. In this review, we provide a comprehensive and critical overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate. © 2011 Adis Data Information BV. All rights reserved.

Scheckenbach K.E.L.,University of Geneva | Crespin S.,University of Geneva | Kwak B.R.,University of Geneva | Chanson M.,University of Geneva | Chanson M.,Geneva Lab
Journal of Vascular Research | Year: 2011

Inflammation is a highly regulated process with common but also specific characteristics in each tissue affected. Recruitment of leukocytes from the blood to the injured tissue is an important early step in the inflammatory cascade. This review highlights the role of connexins (Cxs) in the regulation of both acute and chronic inflammatory processes. Cxs form gap junction channels that provide a cytoplasmic continuity between adjacent cells allowing the intercellular exchange of ions and metabolites. Their structural halves form connexons or hemichannels. Each of them consists of 6 Cx proteins and hemichannels not taking part in gap junction formation but facilitating the release of small molecules such as ATP. Based on the differential distribution of various Cxs in different tissues such as the brain, lung capillaries and large blood vessels, our aim was to analyze the specific roles of Cxs in the inflammatory process in these tissues. Three typical sites of inflammation were chosen to shed light on similarities and differences in several types of responses: (1) atherosclerosis as a model for chronic inflammation, (2) the lung as an example of acute inflammation and (3) the 'immune-privileged' environment of the brain to highlight specific reactions of the vasculature to ischemic damage and inflammation at this site. © 2010 S. Karger AG, Basel.

Helaers R.,University of Namur | Milinkovitch M.C.,Geneva Lab
BMC Bioinformatics | Year: 2010

Background: The development, in the last decade, of stochastic heuristics implemented in robust application softwares has made large phylogeny inference a key step in most comparative studies involving molecular sequences. Still, the choice of a phylogeny inference software is often dictated by a combination of parameters not related to the raw performance of the implemented algorithm(s) but rather by practical issues such as ergonomics and/or the availability of specific functionalities.Results: Here, we present MetaPIGA v2.0, a robust implementation of several stochastic heuristics for large phylogeny inference (under maximum likelihood), including a Simulated Annealing algorithm, a classical Genetic Algorithm, and the Metapopulation Genetic Algorithm (metaGA) together with complex substitution models, discrete Gamma rate heterogeneity, and the possibility to partition data. MetaPIGA v2.0 also implements the Likelihood Ratio Test, the Akaike Information Criterion, and the Bayesian Information Criterion for automated selection of substitution models that best fit the data. Heuristics and substitution models are highly customizable through manual batch files and command line processing. However, MetaPIGA v2.0 also offers an extensive graphical user interface for parameters setting, generating and running batch files, following run progress, and manipulating result trees. MetaPIGA v2.0 uses standard formats for data sets and trees, is platform independent, runs in 32 and 64-bits systems, and takes advantage of multiprocessor and multicore computers.Conclusions: The metaGA resolves the major problem inherent to classical Genetic Algorithms by maintaining high inter-population variation even under strong intra-population selection. Implementation of the metaGA together with additional stochastic heuristics into a single software will allow rigorous optimization of each heuristic as well as a meaningful comparison of performances among these algorithms. MetaPIGA v2.0 gives access both to high customization for the phylogeneticist, as well as to an ergonomic interface and functionalities assisting the non-specialist for sound inference of large phylogenetic trees using nucleotide sequences. MetaPIGA v2.0 and its extensive user-manual are freely available to academics at © 2010 Helaers and Milinkovitch; licensee BioMed Central Ltd.

Oliva E.,Harvard University | Egger J.-F.,Geneva Lab | Young R.H.,Harvard University
American Journal of Surgical Pathology | Year: 2014

Twenty-seven endometrioid stromal sarcomas of the ovary from patients 38 to 76 (mean 56) years of age are reported. The tumors were unilateral in 20 cases and bilateral in 7. They were solid (9), solid and cystic (9), or predominantly cystic (6) when this information was known and ranged from 1 to 20 (mean 9.5) cm. The solid areas typically had a tan-yellow cut surface, with areas of hemorrhage and/or necrosis noted in 6; however, in addition, blood was often present in the cyst lumens. On microscopic examination, the predominant and frequently exclusive pattern was a diffuse growth of small cells with interspersed arterioles, the latter appearing round to elongated. A fibromatous pattern was present in 14 of the tumors but was extensive in only 3. A vague nodular growth was observed in 10 tumors but was never striking; a storiform growth was seen in 2 tumors, being conspicuous in 1. Hyaline plaques were present in 10 tumors but were striking in only 2. Sex cord-like or smooth muscle differentiation was seen in 7 and 6 tumors, respectively, being striking in 2 and 3 of them. Foam cells were present in 6 tumors. The tumors showed minimal cytologic atypia. The mitotic index ranged from <1 to 17/10 high-power fields (HPF), being <1/10 HPF in 12, 1 to 5/10 HPF in 9, 6 to 10/10 HPF in 2, and >10/10 HPF in 4 tumors. Infarct-type necrosis was noted in 12 tumors. Hemorrhage, typically recent, was seen in 20 cases, being conspicuous in 5. Ovarian endometriosis was intimately associated with the tumor in 16 cases. Seven patients had stage I tumors, 5 stage II, 13 stage III, and 2 stage IV. Follow-up information was available for 21 patients; 10 were alive and free of disease from 4 to 21 years postoperatively (follow-up being ≥11 y in 5); 6 were alive with disease from 1 to 22 years postoperatively; 5 patients are known to have died of disease, with the interval being unknown in 1, and 2, 4, 13, and 17 years in the others. Follow-up information was unavailable in the remaining 6 patients. These findings indicate that these tumors, as in the uterus, often have an indolent course with a better prognosis than other ovarian sarcomas, indicating the importance of correct diagnosis. The differential diagnosis of these neoplasms is in the first instance with a metastasis from the uterus; knowledge of the status of the uterus is paramount in this distinction. Associated ovarian endometriosis suggests a primary tumor. When a primary ovarian origin is determined, the differential diagnosis is most often with a sex cord-stromal tumor, particularly a granulosa cell tumor because of a diffuse growth of cells with scant cytoplasm. Copyright © 2014 by Lippincott Williams & Wilkins.

Milinkovitch M.C.,Geneva Lab | Helaers R.,University of Namur | Tzika A.C.,Geneva Lab | Tzika A.C.,Free University of Colombia
Genome Biology and Evolution | Year: 2010

Recent analyses indicated that genes with larger effect of knockout or mutation and with larger probability to revert to single copy after whole genome duplication are expressed earlier in development. Here, we further investigate whether tissue specificity of gene expression is constrained by the age of origin of the corresponding genes. We use 38 metazoan genomes and a comparative genomic application system to integrate inference of gene duplication with expression data from 17,503 human genes into a strictly phylogenetic framework. We show that the number of anatomical systems in which genes are expressed decreases steadily with decreased age of the genes' first appearance in the phylogeny: the oldest genes are expressed, on average, in twice as many anatomical systems than the genes gained recently in evolution. These results are robust to different sources of expression data, to different levels of the anatomical system hierarchy, and to the use of gene families rather than duplication events. Finally, we show that the rate of increase in gene tissue specificity correlates with the relative rate of increase in the maximum number of cell types in the corresponding taxa. Although subfunctionalization and increase in cell type number throughout evolution could constitute, respectively, the proximal and ultimate causes of this correlation, the two phenomena are intermingled. Our analyses identify a striking historical constraint in gene expression: the number of cell types in existence at the time of a gene appearance (through duplication or de novo origination) tends to determine its level of tissue specificity for tens or hundreds of millions of years. © The Author(s) 2009.

Seintou A.,Geneva Lab | Martinelli-Klay C.P.,Geneva Lab | Lombardi T.,Geneva Lab
International Journal of Oral and Maxillofacial Surgery | Year: 2014

The purpose of this study was to review the clinical, radiological, and histopathological profile of unicystic ameloblastoma (UA) in children using data from available case reports and reviews published between 1992 and 2012. A total of 513 publications were evaluated. A structured search of the literature was performed, with predefined criteria, using computer and manual searches. An evaluation and critical appraisal was done in three separate rounds. A total of 25 articles describing 51 cases satisfied the selection criteria and were thus included in the final review. UA was mostly found to be located in the mandible, often exhibiting a unilocular radiographic image. Enucleation alone resulted in the highest recurrence rate. According to the results of this study, luminal UAs are less aggressive and respond better to conservative treatment. In contrast, plexiform and mural types frequently result in recurrence. The use of Carnoy's solution in preventing recurrence remains to be established. © 2014 International Association of Oral and Maxillofacial Surgeons.

Irminger-Finger I.,Geneva Lab
Gynecologic Oncology | Year: 2010

Breast cancer is the leading cause of cancer death in women. Ovarian cancer, although less frequent, is detected very late, and survival is correlated to early detection. Therefore, better methods for early detection would help to increase the number of survivors. The incidence of young women diagnosed with breast cancer is increasing. These women and women who are at risk because of a family history of breast cancer would benefit from more accurate and less invasive screening methods than those in place today. A blood test based on BARD1, a protein that interacts with the breast cancer gene product BRCA1, is a promising candidate for fulfilling these conditions. The science behind BARD1 and its role in breast and ovarian cancer is explained in this article. © 2009 Elsevier Inc. All rights reserved.

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