2,876 research outputs found
Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts
No full textLynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families
Càncer colorectal hereditari: Aplicacions diagnòstiques de l'estudi de la dosi dels gens APC, MLH1 i MSH2
No full text[cat] Les síndromes de càncer colorectal (CCR) hereditari representen entre un 3% i un 5% de tots els casos de CCR i inclouen tots aquells individus amb un elevat grau d'agregació familiar. La més freqüent és la síndrome de Lynch, causada per la presència de mutacions en els gens reparadors del DNA, majoritàriament MLH1 i MSH2. La poliposi adenomatosa familiar (FAP) és la segona en incidència, es caracteritza per l'aparició de pòlips precursors a la neoplàsia colorectal i la seva causa principal és la presència de mutacions en el gen supressor tumoral APC. En els últims anys s'ha descobert que els grans reordenaments d'aquests gens són responsables de la malaltia en una part de les famílies que pateixen aquestes síndromes. A més, estudis d'expressió d'aquests gens en línia germinal han demostrat l'existència de desequilibris al·lèlics tant en famílies portadores de mutacions com en famílies on no es detecten mutacions en el DNA. L'objectiu d'aquesta tesi és l'estudi de la dosi en la dels gens MLH1, MSH2 i APC, implicats en la síndrome de Lynch i la FAP. D'aquesta forma, hem analitzat la dosi tant a nivell de DNA (grans reordenaments) com a nivell d'RNA (expressió específica d'al·lel), sempre treballant amb línia germinal de pacients. Els resultats aquí recollits permeten millorar l'estratègia de diagnòstic molecular de les famílies amb síndrome de Lynch i FAP que són ateses al nostre centre, al mateix temps que la comprensió del procés tumorogènic.[eng] Hereditary colorectal cancer (CRC) syndromes represent about 3% to 5% of all cases of CRC and include all those individuals with high familiar aggregation. The most frequent syndrome is Lynch syndrome, caused by the presence of mutations in the mismatch repair (MMR) genes, mostly MLH1 and MSH2. Familiar adenomatous polyposis (FAP) is the second in incidence, is characterized by precursor polyps and its mainly caused by mutations in the tumoral suppressor gene APC. Recently, it has been discovered that gross rearrangements of these genes are responsible of these two syndromes. Also, expression analyses of these genes in the germline have demonstrated the existence of allelic imbalances in both families carrying pathogenic mutations and families without detected mutations. Our aim was to study de dose of MLH1, MSH2 and APC genes in the germline of Lynch syndrome and polyposis families, respectively. To that end, we analyzed the dose at DNA level (gross rearrangements) and at RNA level (allele-specific expression) of these patients. The results summarized in this thesis permit improving the molecular diagnostic strategy in Lynch syndrome and FAP families, and also improve the knowledge of the tumorogenic process
The selective advantage of reaction norms for environmental tolerance
No full textA tolerance curve defines the dependence of a genotype's fitness on the state of an environmental gradient. It can be characterized by a mode (the genotype's optimal environment) and a width (the breadth of adaptation). It seems possible that one or both of these characters can be modified in an adaptive manner, at least partially, during development. Thus, we extend the theory of environmental tolerance to include reaction norms for the mode and the width of the tolerance curve. We demonstrate that the selective value of such reaction norms increases with increasing spatial heterogeneity and between-generation temporal variation in the environment and with decreasing within-generation temporal variation. Assuming that the maintenance of a high breadth of adaptation is costly, reaction, norms are shown to induce correlated selection for a reduction in this character. Nevertheless, regardless of the magnitude of the reaction norm, there is a nearly one to one relationship between the optimal breadth of adaptation and the within-generation temporal variation perceived by the organism. This suggests that empirical estimates of the breadth of adaptation may provide a useful index of this type of environmental variation from the organism's point of view
Free Zone Incentives in MERCOSUR Countries and WTO Law
No full textPublished source: Gabriel Gari, 'Free Zone Incentives in MERCOSUR Countries and WTO Law' (2011) 6 Global Trade and Customs Journal, Issue 5, pp. 223–244
ID: GTCJ2011031This article examines the consistency of the incentives offered by free zone regimes in Argentina, Brazil, Paraguay, and Uruguay with World Trade Organization (WTO) law. It suggests that some of the incentives offered to free zone users are inconsistent with the Agreement on Subsidies and Countervailing Measures (ASCM) because they constitute a ‘subsidy’ within the meaning of the ASCM, subject de iure or de facto to export performance, most notably, exemptions of direct taxes, exemptions of custom duties on the import of capital goods, exemptions of payment of social welfare charges, unqualified exemptions on payment of indirect taxes, and the possibility to supply goods or services to free zone users at promotional rates. By contrast, this article suggests that there are no significant inconsistencies between free zone incentives and the General Agreement on Trade in Services (GATS) but warns that the situation could change in the future if, as a result of multilateral negotiations, MERCOSUR countries opt for extending their GATS commitments to new sectors and modes of supply
Appendix_B – Supplemental material for Accuracy of Accelerometers for Measuring Physical Activity and Levels of Sedentary Behavior in Children: A Systematic Review
No full textSupplemental material, Appendix_B for Accuracy of Accelerometers for Measuring Physical Activity and Levels of Sedentary Behavior in Children: A Systematic Review by Brian A. Lynch, Tara K. Kaufman, Tamim I. Rajjo, K. Mohammed, Seema Kumar, M. Hassan Murad, Natalie E. Gentile, Gabriel A. Koepp, Shelly K. McCrady-Spitzer and James A. Levine in Journal of Primary Care & Community Health</p
Muller's ratchet and mutational meltdowns
No full textWe extend our earlier work on the role of deleterious mutations in the extinction of obligately asexual populations. First, we develop analytical models for mutation accumulation that obviate the need for time-consuming computer simulations in certain ranges of the parameter space. When the number of mutations entering the population each generation is fairly high, the number of mutations per individual and the mean time to extinction can be predicted using classical approaches in quantitative genetics. However, when the mutation rate is very low, a fixation-probability approach is quite effective. Second, we show that an intermediate selection coefficient (s) minimizes the time to extinction. The critical value of s can be quite low, and we discuss the evolutionary implications of this, showing that increased sensitivity to mutation and loss of capacity for DNA repair can be selectively advantageous in asexual organisms. Finally, we consider the consequences of the mutational meltdown for the extinction of mitochondrial lineages in sexual species
Appendix_A – Supplemental material for Accuracy of Accelerometers for Measuring Physical Activity and Levels of Sedentary Behavior in Children: A Systematic Review
No full textSupplemental material, Appendix_A for Accuracy of Accelerometers for Measuring Physical Activity and Levels of Sedentary Behavior in Children: A Systematic Review by Brian A. Lynch, Tara K. Kaufman, Tamim I. Rajjo, K. Mohammed, Seema Kumar, M. Hassan Murad, Natalie E. Gentile, Gabriel A. Koepp, Shelly K. McCrady-Spitzer and James A. Levine in Journal of Primary Care & Community Health</p
The mutational meltdown in asexual populations
No full textLoss of fitness due to the accumulation of deleterious mutations appears to be inevitable in small, obligately asexual populations, as these are incapable of reconstituting highly fit genotypes by recombination or back mutation. The cumulative buildup of such mutations is expected to lead to an eventual reduction in population size, and this facilitates the chance accumulation of future mutations. This synergistic interaction between population size reduction and mutation accumulation leads to an extinction process known as the mutational meltdown, and provides a powerful explanation for the rarity of obligate asexuality. We give an overview of the theory of the mutational meltdown, showing how the process depends on the demographic properties of a population, the properties of mutations, and the relationship between fitness and number of mutations incurred
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