Biomarqueurs en immunologie générale [Biomarkers in clinical immunology].

In a current perspective of individualized medicine, biomarkers appear as a simple and readily available aid to assist clinicians in the identification and monitoring of diseases whose diagnosis is difficult. Basically, we know the limited performance of medical history and of clinical examination; therefore, the use of laboratory tests is often seen as the panacea to solve the clinical enigma. The purpose of this article is to analyze a few biomarkers commonly processed in the immunology laboratory (AAN, ANCA, anti-tTG, rheumatoid factor and anti-CCP) and to review the principle, the usefulness and the performance of these tests in specific clinical situations. We will see that, far from supplanting history and physical examination, these immunological biomarkers take their full value as a supplement to clinical information!

Niveles de evidencia clínica y grados de recomendación.

An update of the levels of scientific evidence stating the varying degrees of recommendation for asymptomatic patients, indicating which procedures are most appropriate and what should be avoided all the systems described, we seek one that meets the principle of simplicity and utility. We chose for our setting the valuation of the Centre for Evidence-Based Medicine, Oxford (OCEBM). This classification has the advantage that assures us the knowledge on each scenario, its high degree of specialization. It also has the prerogative to clarify how it affects the lack of methodological rigor to the study design, reducing its assessment not only in the grading of the evidence, but also on the strength of recommendations.

Safety in vicinity of industrials plants: risk assessment and land use planning

The aim of this book is to survey on different Land Use Planning and safety approaches in vicinity of industrial plants. As this research is associated with three broad fields of Land Use Planning, safety and security, the set principle is to avoid unnecessary and over detailed information, but including the useful ones to provide a comprehensive resource which can be applicable for several purposes. Besides, the proposed method, which is explained in Chapter 7, can initiate a new field for future of Land Use Planning in vicinity of industrial plants.

Nutrient patterns and their food sources in an International Study Setting: report from the EPIC study.

BACKGROUND Compared to food patterns, nutrient patterns have been rarely used particularly at international level. We studied, in the context of a multi-center study with heterogeneous data, the methodological challenges regarding pattern analyses. METHODOLOGY/PRINCIPAL FINDINGS We identified nutrient patterns from food frequency questionnaires (FFQ) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study and used 24-hour dietary recall (24-HDR) data to validate and describe the nutrient patterns and their related food sources. Associations between lifestyle factors and the nutrient patterns were also examined. Principal component analysis (PCA) was applied on 23 nutrients derived from country-specific FFQ combining data from all EPIC centers (N = 477,312). Harmonized 24-HDRs available for a representative sample of the EPIC populations (N = 34,436) provided accurate mean group estimates of nutrients and foods by quintiles of pattern scores, presented graphically. An overall PCA combining all data captured a good proportion of the variance explained in each EPIC center. Four nutrient patterns were identified explaining 67% of the total variance: Principle component (PC) 1 was characterized by a high contribution of nutrients from plant food sources and a low contribution of nutrients from animal food sources; PC2 by a high contribution of micro-nutrients and proteins; PC3 was characterized by polyunsaturated fatty acids and vitamin D; PC4 was characterized by calcium, proteins, riboflavin, and phosphorus. The nutrients with high loadings on a particular pattern as derived from country-specific FFQ also showed high deviations in their mean EPIC intakes by quintiles of pattern scores when estimated from 24-HDR. Center and energy intake explained most of the variability in pattern scores. CONCLUSION/SIGNIFICANCE The use of 24-HDR enabled internal validation and facilitated the interpretation of the nutrient patterns derived from FFQs in term of food sources. These outcomes open research opportunities and perspectives of using nutrient patterns in future studies particularly at international level.

A molecular platform for the diagnosis of multidrug-resistant and pre-extensively drug-resistant tuberculosis based on single nucleotide polymorphism mutations present in Colombian isolates of Mycobacterium tuberculosis

Developing a fast, inexpensive, and specific test that reflects the mutations present in Mycobacterium tuberculosis isolates according to geographic region is the main challenge for drug-resistant tuberculosis (TB) control. The objective of this study was to develop a molecular platform to make a rapid diagnosis of multidrug-resistant (MDR) and extensively drug-resistant TB based on single nucleotide polymorphism (SNP) mutations present in therpoB, katG, inhA,ahpC, and gyrA genes from Colombian M. tuberculosis isolates. The amplification and sequencing of each target gene was performed. Capture oligonucleotides, which were tested before being used with isolates to assess the performance, were designed for wild type and mutated codons, and the platform was standardised based on the reverse hybridisation principle. This method was tested on DNA samples extracted from clinical isolates from 160 Colombian patients who were previously phenotypically and genotypically characterised as having susceptible or MDR M. tuberculosis. For our method, the kappa index of the sequencing results was 0,966, 0,825, 0,766, 0,740, and 0,625 forrpoB, katG, inhA,ahpC, and gyrA, respectively. Sensitivity and specificity were ranked between 90-100% compared with those of phenotypic drug susceptibility testing. Our assay helps to pave the way for implementation locally and for specifically adapted methods that can simultaneously detect drug resistance mutations to first and second-line drugs within a few hours.

¿Qué reformas necesita el sistema de financiación regional?

This paper argues that the current Spanish system of regional financing does not adequately respect the principles of equality, autonomy, responsibility and transparency that should guide its design. It also advances a series of recommendations for the reform of the system that can be classified into two broad headings: guaranteeing the effective application of the constitucional principle of equality and reinforcing the fiscal responsibility and the accountability of regional governments.

Prognostic role of genetic biomarkers in clinical progression of prostate cancer.

The aim of this study was to analyze the use of 12 single-nucleotide polymorphisms in genes ELAC2, RNASEL and MSR1 as biomarkers for prostate cancer (PCa) detection and progression, as well as perform a genetic classification of high-risk patients. A cohort of 451 men (235 patients and 216 controls) was studied. We calculated means of regression analysis using clinical values (stage, prostate-specific antigen, Gleason score and progression) in patients and controls at the basal stage and after a follow-up of 72 months. Significantly different allele frequencies between patients and controls were observed for rs1904577 and rs918 (MSR1 gene) and for rs17552022 and rs5030739 (ELAC2). We found evidence of increased risk for PCa in rs486907 and rs2127565 in variants AA and CC, respectively. In addition, rs627928 (TT-GT), rs486907 (AG) and rs3747531 (CG-CC) were associated with low tumor aggressiveness. Some had a weak linkage, such as rs1904577 and rs2127565, rs4792311 and rs17552022, and rs1904577 and rs918. Our study provides the proof-of-principle that some of the genetic variants (such as rs486907, rs627928 and rs2127565) in genes RNASEL, MSR1 and ELAC2 can be used as predictors of aggressiveness and progression of PCa. In the future, clinical use of these biomarkers, in combination with current ones, could potentially reduce the rate of unnecessary biopsies and specific treatments.

Enterprise Architecture Management Design: Towards Understanding Organizational Contingencies, Design Principles and Effectiveness

Despite the increasing popularity of enterprise architecture management (EAM) in practice, many EAM initiatives either do not fully meet the expected targets or fail. Several frameworks have been suggested as guidelines to EA implementation, but companies seldom follow prescriptive frameworks. Instead, they follow very diverse implementation approaches that depend on their organizational contingencies and the way of adopting and evolving EAM over time. This research strives for a broader understanding of EAM by exploring context-dependent EAM adoption approaches as well as identifying the main EA principles that affect EA effectiveness. Based on two studies, this dissertation aims to address two main questions: (1) EAM design: Which approaches do companies follow when adopting EAM? (2) EA principles and their impact: What impact does EA principles have on EA effectiveness/quality? By utilizing both qualitative and quantitative research methods, this research contributes to exploring different EAM designs in different organizational contingencies as well as using EA principles as an effective means to achieve principle-based EAM design. My research can help companies identify a suitable EAM design that fits their organizational settings and shape their EA through a set of principles.

Are the Policy Preferences of Relatively Poor Citizens Under-represented in the Swiss Parliament?

The principle of equal political representation can be undermined by differences in economic resources among citizens. Poor citizens are likely to hold policy preferences that differ from those of richer citizens. At the same time, their lack of resources can have as a consequence that these preferences are not taken into consideration by their representatives. Focusing on the case of the Swiss Parliament and using survey data on the opinions of citizens and MPs in the 2007-2011 legislature, this study investigates whether the income of citizens systematically affects the proximity of their policy preferences with stances of their representatives. It demonstrates that on economic issues MPs hold preferences that are generally less in favour of the state's intervention in the economy than the median citizen and that relatively poor citizens are less well represented as compared to citizens with high incomes. This remains true when taking into account only the opinions of the most knowledgeable citizens among these groups as well as when the focus is only on those who turned out to vote.

Unorthodox Humeanism

The thesis is situated in the domain of contemporary metaphysics of science. The question is which ontology fits best with our knowledge of the world. The method chosen is the one of evaluating the consequences of different ontological frameworks against the background of our scientific knowledge of the world. The thesis analyses the two main frameworks in today's metaphysics of science, Humeanism and dispositionalism. It advocates that only an unorthodox version of Humeanism and only an unorthodox version of dispositionalism can be defended, the unorthodox character of these versions consisting in taking the fundamental properties to be relations rather than intrinsic properties. The thesis then sets out in detail what such an unorthodox version of Humeanism amounts to. Chapters 1 and 2 introduce the standard versions of Humeanism and dispositionalism, focussing on the accounts of laws of nature and causation. Chapter 3 compares both these positions and concludes that as far as the orthodox versions are concerned, dispositionalism fares better than Humeanism, since it can avoid Humeanism's commitments to quidditism and humility. However, as is argued in chapter 4, instead of replying to the objections from quidditism and humility by switching to dispositionalism, there is an unorthodox version of Humeanism available that does not run into these problematic consequences and that is supported by science: if one takes the fundamental physical properties to be relations instead of intrinsic properties, the objection from quidditism is avoided, since there is no hidden intrinsic essence of relations. As regards the objection from humility, one can maintain that science is in principle able to provide knowledge of the fundamental relations that there are in the world so that there is no principled ignorance. Consequently, the thesis concludes that Humeanism and dispositionalism are on a par as regards the remaining charge of humility. Unorthodox Humeanism provides a competitive and adequate ontology in the light of contemporary science.

Quantifying ChIP-seq data: a spiking method providing an internal reference for sample-to-sample normalization.

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments are widely used to determine, within entire genomes, the occupancy sites of any protein of interest, including, for example, transcription factors, RNA polymerases, or histones with or without various modifications. In addition to allowing the determination of occupancy sites within one cell type and under one condition, this method allows, in principle, the establishment and comparison of occupancy maps in various cell types, tissues, and conditions. Such comparisons require, however, that samples be normalized. Widely used normalization methods that include a quantile normalization step perform well when factor occupancy varies at a subset of sites, but may miss uniform genome-wide increases or decreases in site occupancy. We describe a spike adjustment procedure (SAP) that, unlike commonly used normalization methods intervening at the analysis stage, entails an experimental step prior to immunoprecipitation. A constant, low amount from a single batch of chromatin of a foreign genome is added to the experimental chromatin. This "spike" chromatin then serves as an internal control to which the experimental signals can be adjusted. We show that the method improves similarity between replicates and reveals biological differences including global and largely uniform changes.

Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells.

Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.

Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value.

Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics.

Connectivity differences in brain networks.

The scenario considered here is one where brain connectivity is represented as a network and an experimenter wishes to assess the evidence for an experimental effect at each of the typically thousands of connections comprising the network. To do this, a univariate model is independently fitted to each connection. It would be unwise to declare significance based on an uncorrected threshold of α=0.05, since the expected number of false positives for a network comprising N=90 nodes and N(N-1)/2=4005 connections would be 200. Control of Type I errors over all connections is therefore necessary. The network-based statistic (NBS) and spatial pairwise clustering (SPC) are two distinct methods that have been used to control family-wise errors when assessing the evidence for an experimental effect with mass univariate testing. The basic principle of the NBS and SPC is the same as supra-threshold voxel clustering. Unlike voxel clustering, where the definition of a voxel cluster is unambiguous, 'clusters' formed among supra-threshold connections can be defined in different ways. The NBS defines clusters using the graph theoretical concept of connected components. SPC on the other hand uses a more stringent pairwise clustering concept. The purpose of this article is to compare the pros and cons of the NBS and SPC, provide some guidelines on their practical use and demonstrate their utility using a case study involving neuroimaging data.

The prosecution service function within the spanish criminal justice system

The Spanish judicial system is independent and headed by the Supreme Court. Spain has a civil law system. The criminal procedure is governed by the legality principle--by opposition to the opportunity or expediency principle--which implies that prosecution must take place in all cases in which sufficient evidence exists of guilt. Traditionally, the role of the PPS in Spain has been very limited during the investigative stage of the process. That stage is under the responsibility of the Examining Magistrate (EM). Since the end of the 1980s, a series of modifications has been introduced in order to extend the functions of the PPS. In 1988, the PPS received extended competences which allow them to receive reports of offenses. Upon knowing of an offense (reported or known to have been committed), the PPS can initiate the criminal proceeding. The PPS is also allowed to lead a sort of plea bargain under a series of restrictive conditions and only for some offenses. At the same time, the PPS received extended competences in the juvenile justice criminal proceeding in 2000. With all this said, the role of the PPS has not changed radically and, during the investigative stage of the process, their main role remains the presentation of the accusation, playing a more active role during the trial stage of the proceeding. In this article the national criminal justice system of Spain is described. Special attention is paid to the function of the PPS within this framework and its relationship to police and courts. The article refers to legal provisions and the factual handling of criminal cases.