IDH1/IDH2 mutations predict survival in glioma and AML

Mutations in the isocitrate dehydrogenase family genes 1 or 2 (IDH1/2) have been discovered by high through put sequencing approaches inglioma and acute myeloid leukemia (AML) and related myeloproliferativeneoplasms. In both diseases, the discovery of IDH mutations has identifieda prognostically new subtype with distinct pathogenetic evolution. Ingliomas mutations are mostly found in IDH1 (>90%). They are infrequent inprimary glioblastoma (GBM) (<10%), but common in secondary GBM thatevolve from lower grade glioma (60−90%). Mutations in IDH1 precede p53mutations or 1p/19q co-deletions in sporadic low grade glioma, hence arean early evant. Co-deletions of 1p/19q, characteristic for oligodenroglioma,are highly associated with IDH1/2 mutations, while they are mutuallyexclusive with EGFR amplifications, a hall mark of primary GBM. IDH1 or 2mutations are associated with younger patient age, but absent in childhoodgliomas, and have a better prognosis that seems to be consistent in gradeII through IV gliomas. In myeloid malignancies mutations are more likelyin IDH2 and are found in de novo and secondary AML (12−18%) andpre-leukemic clonal malignancies (5% chronic; 20% transformed). IDH1/2mutations are strongly associated with NPM1 mutations that are found in30% of novo cytogenetically normal AML. In CN-AML with mutated NPM1,without FLT3 internal tandem duplication (ITD) IDH mutations constitutean adverse prognostic factor. Mutations in the metabolic enzymes IDH1 or2 result in a neomorphic reaction, generating high levels of the metabolite2-hydroxyglutarate (2-HG). IDH mutations are mutually exclusive with TET2mutations in myeloid malignancies that led to the discovery that high levelsof 2-HG inhibit the a-KG dependent dioxygenase TET2. TET2 is involved inepigenetic regulation and mediates demethylation of DNA. This mechanismis in accordance with the association of a methylator phenotype with loss offunction of TET2 by mutation or indirectly by mutation of IDH1/2 in myeloidmalignancies and gliomas, respectively.Metabolism meets Epigenetics. These discoveries will have importantclinical implications: IDH1/2 mutants may serve as unique targets fortherapy. Further, the high concentrations of the onco-metabolite 2-HGgenerated by IDH1/2 mutants, may serve as biomarker in the serum ofpatients with myeloid malignancies and may be amenable by magneticresonance spectroscopy in glioma patients.

The Original Risk: Over-Theologizing Ethics and Under-Theologizing Sin

The project of articulating a theological ethics on the basis of liturgical anthropology is bound to fail if the necessary consequence is that one has to quit the forum of critical modern rationality. The risk of Engelhardt's approach is to limit rationality to a narrow vision of reason. Sin is not to be understood as the negation of human holiness, but as the negation of divine holiness. The only way to renew theological ethics is to understand sin as the anthropological and ethical expression of the biblical message of the justification by faith only. Sin is therefore a secondary category, which can only by interpreted in light of the positive manifestation of liberation, justification, and grace. The central issue of Christian ethics is not ritual purity or morality, but experience, confession and recognition of our own injustice in our dealing with God and men.

Fingermark Detection on Thermal Papers: Proposition of an Updated Processing Sequence

The detection of latent fingermarks on thermal papers proves to be particularly challenging because the application of conventional detection techniques may turn the sample dark grey or black, thus preventing the observation of fingermarks. Various approaches aiming at avoiding or solving this problem have been suggested. However, in view of the many propositions available in the literature, it gets difficult to choose the most advantageous method and to decide which processing sequence should be followed when dealing with a thermal paper. In this study, 19 detection techniques adapted to the processing of thermal papers were assessed individually and then were compared to each other. An updated processing sequence, assessed through a pseudo-operational test, is suggested.

European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring.

Given the increasing use of ambulatory blood pressure monitoring (ABPM) in both clinical practice and hypertension research, a group of scientists, participating in the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability, in year 2013 published a comprehensive position paper dealing with all aspects of the technique, based on the available scientific evidence for ABPM. The present work represents an updated schematic summary of the most important aspects related to the use of ABPM in daily practice, and is aimed at providing recommendations for proper use of this technique in a clinical setting by both specialists and practicing physicians. The present article details the requirements and the methodological issues to be addressed for using ABPM in clinical practice, The clinical indications for ABPM suggested by the available studies, among which white-coat phenomena, masked hypertension, and nocturnal hypertension, are outlined in detail, and the place of home measurement of blood pressure in relation to ABPM is discussed. The role of ABPM in pharmacological, epidemiological, and clinical research is also briefly mentioned. Finally, the implementation of ABPM in practice is considered in relation to the situation of different countries with regard to the reimbursement and the availability of ABPM in primary care practices, hospital clinics, and pharmacies.

Illicit drug profiling, reflection on statistical comparisons

This paper presents reflexions about statistical considerations on illicit drug profiling and more specifically about the calculation of threshold for determining of the seizure are linked or not. The specific case of heroin and cocaine profiling is presented with the necessary details on the target profiling variables (major alkaloids) selected and the analytical method used. Statistical approach to compare illicit drug seizures is also presented with the introduction of different scenarios dealing with different data pre-treatment or transformation of variables.The main aim consists to demonstrate the influence of data pre-treatment on the statistical outputs. A thorough study of the evolution of the true positive rate (TP) and the false positive rate (FP) in heroin and cocaine comparison is then proposed to investigate this specific topic and to demonstrate that there is no universal approach available and that the calculations have to be revaluate for each new specific application.

Cost of Illness and Contingent Valuation : Controlling for the Motivations of Expressed Preferences in an Attempt to Avoid Double-Counting

This paper addresses the issue of double counting of health impacts in the context of cost of illness valuation. Double counting occurs when estimates are jointly used, which rely on valuation techniques that overlap. As a solution, we propose to limit the scope of each of the valuation method to a specific range of impacts. In order to limit the contingentvaluation method to the exclusive valuation of intangible costs, we propose a three steps approach : (1) leave the respondents free to valuate the consequences which matter to them, (2) elicit respondent's motivations, (3) control for the influence motivations have on elicited values. This procedure was applied in a Swiss contingent-valuation. An econometric treatment was applied in order to limit the scope of the estimates of the contingent valuation method to intangibles,therefore the possibility to a combination of methods with the risk of double-counting and underestimating costs being kept to a minimum.

AIDS prevention: consensus and dissension regarding the meaning

Aim: In Western Europe, HIV/AIDS prevention has been based on the provision of information intended to lead the public to voluntarily adapt their behaviour so as to avoid the risk of virus transmission. Whether conveyed in a written or oral form, the messages of prevention are essentially verbal. Sociolinguistic research confirms that, even within a given culture, the meaning attributed to lexical items varies. It was hypothesised that understandings of the terms used in HIV/AIDS prevention in French-speaking Switzerland would vary, and research was undertaken to identify the level and nature of this variation both between and among those who transmit (prevention providers) and those who receive (the public) the messages. Method/issue: All HIV/AIDS prevention material available in French-speaking Switzerland in 2004 was assembled and a corpus of 50 key documents identified. Two series of lexical items were generated from this corpus: one composed of technical terms potentially difficult to understand, and the other, of terms used in everyday language with implicit, and therefore potentially variable, meaning. The two lists of terms were investigated in qualitative interviews in stratified purposive samples of the general public (n=60) and prevention providers (n=30), using standard socio-linguistic methodology. A further quantitative study (CATI) in the general population (17 - 49 yrs.; n=500) investigated understandings of 15 key prevention terms found in the qualitative research to have been associated with high levels of dissension. Results/comments: Selected aspects of the results will be presented. In illustration: meanings attributed to the different terms in both the public and the providers varied. For example, when a relationship is described as "stable", this may be understood as implying exclusive sexual relations or long duration, with an interaction between the two traits; the term "sexual intercourse" may or may not be used to refer to oral sex; "making love" may or may not necessarily include an act of penetration; the pre-ejaculate is qualified by some as sperm, and by others not... Understanding of frequently used "technical" terms in prevention was far from universal; for example, around only a half of respondents understood the meaning of "safer sex". Degree of understanding of these terms was linked to education, whereas variability in meaning in everyday language was not linked to socio-economic variables. Discussion: Findings indicate the need for more awareness regarding the heterogeneity of meaning around the terms regularly used in prevention. Greater attention should be paid to the formulation of prevention messages, and providers should take precautions to ensure that the meanings they wish to convey are those perceived by the receivers of their messages. Wherever possible, terms used should be defined and meanings rendered explicit.

Deregulation of the arginine deiminase (arc) operon in penicillin-tolerant mutants of Streptococcus gordonii.

Penicillin tolerance is an incompletely understood phenomenon that allows bacteria to resist drug-induced killing. Tolerance was studied with independent Streptococcus gordonii mutants generated by cyclic exposure to 500 times the MIC of penicillin. Parent cultures lost 4 to 5 log(10) CFU/ml of viable counts/24 h. In contrast, each of four independent mutant cultures lost &lt; or =2 log(10) CFU/ml/24 h. The mutants had unchanged penicillin-binding proteins but contained increased amounts of two proteins with respective masses of ca. 50 and 45 kDa. One mutant (Tol1) was further characterized. The two proteins showing increased levels were homologous to the arginine deiminase and ornithine carbamoyl transferase of other gram-positive bacteria and were encoded by an operon that was &gt;80% similar to the arginine-deiminase (arc) operon of these organisms. Partial nucleotide sequencing and insertion inactivation of the S. gordonii arc locus indicated that tolerance was not a direct consequence of arc alteration. On the other hand, genetic transformation of tolerance by Tol1 DNA always conferred arc deregulation. In nontolerant recipients, arc was repressed during exponential growth and up-regulated during postexponential growth. In tolerant transformants, arc was constitutively expressed. Tol1 DNA transformed tolerance at the same rate as transformation of a point mutation (10(-2) to 10(-3)). The tolerance mutation mapped on a specific chromosomal fragment but was physically distant from arc. Importantly, arc deregulation was observed in most (6 of 10) of additional independent penicillin-tolerant mutants. Thus, although not exclusive, the association between arc deregulation and tolerance was not fortuitous. Since penicillin selection mimicked the antibiotic pressure operating in the clinical environment, arc deregulation might be an important correlate of naturally occurring tolerance and help in understanding the mechanism(s) underlying this clinically problematic phenotype.

Nonclassical measurement error with applications to labor and development issues

Zero correlation between measurement error and model error has been assumed in existing panel data models dealing specifically with measurement error. We extend this literature and propose a simple model where one regressor is mismeasured, allowing the measurement error to correlate with model error. Zero correlation between measurement error and model error is a special case in our model where correlated measurement error equals zero. We ask two research questions. First, we wonder if the correlated measurement error can be identified in the context of panel data. Second, we wonder if classical instrumental variables in panel data need to be adjusted when correlation between measurement error and model error cannot be ignored. Under some regularity conditions the answer is yes to both questions. We then propose a two-step estimation corresponding to the two questions. The first step estimates correlated measurement error from a reverse regression; and the second step estimates usual coefficients of interest using adjusted instruments.

Comparative developmental and susceptibility to insecticide of Bolivian and Brazilian populations of Triatoma infestans

The triatomine bug Triatoma infestans probably originated in Bolivia and dispersed passively over wide areas of South America, where it is the principal vector of Trypanosoma cruzi. In the region of its probable origin this species shows colonization in two different ecotopes, so that it may be encountered in sylvatic as well as in artificial habitats. The sylvatic colonization pattern is not observed in the rest of its range, where T. infestans is exclusive to man-made habitats. The objective of this study was to compare several aspects of two T. infestans populations, one from Minas Gerais (Brazil) and the other from the Cochabamba Valley (Bolivia), with a view to elucidate the factors associated with the different colonization patterns observed for this species. The differences between the developmental cycle, weight, capacity to ingest blood and mortality rate of first instar nymphs should indicate more fragility of Brazilian population that may be related to its elimination possibility.

111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging.

This document provides general information about somatostatin receptor scintigraphy with (111)In-pentetreotide. This guideline should not be regarded as the only approach to visualise tumours expressing somatostatin receptors or as exclusive of other nuclear medicine procedures useful to obtain comparable results. The aim of this guideline is to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of (111)In-pentetreotide scintigraphy.

Human immunodeficiency virus/acquired immunodeficiency syndrome and tropical diseases: a Brazilian perspective

The paper summarizes recent findings on the epidemiology and pathogenesis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/Aids), highlighting the role of co-infections with major tropical diseases. Such co-infections have been studied in the Brazilian context since the beginning of the Aids epidemic and are expected to be more frequent and relevant as the Aids epidemic in Brazil proceeds towards smaller municipalities and the countryside, where tropical diseases are endemic. Unlike opportunistic diseases that affect basically the immunocompromised host, most tropical diseases, as well as tuberculosis, are pathogenic on their own, and can affect subjects with mild or no immunossuppression. In the era of highly active anti-retroviral therapies (HAART), opportunistic diseases seem to be on decrease in Brazil, where such medicines are fully available. Benefiting from HAART in terms of restoration of the immune function, putative milder clinical courses are expected in the future for most co-infections, including tropical diseases. On the other hand, from an ecological perspective, the progressive geographic diffusion of Aids makes tropical diseases and tuberculosis a renewed challenge for Brazilian researchers and practitioners dealing with HIV/Aids in the coming years.

Developing a Workplace Policy on Domestic Violence and Abuse (PDF 219KB)

This guide for employers has been produced by the Regional Steering Group on Domestic Violence in line with the strategy and action plan “Tackling Violence at Home” published in October 2005. The Regional Steering Group is a group of about 30 members representing the statutory and voluntary agencies involved in dealing with domestic violence. The guidance provides advice on how employers can develop increased awareness and more effective responses to domestic violence in the workplace for the benefit of all staff. The Regional Steering Group acknowledges that some employers already have good workplace policies in place and it encourages all employers across the public, private, voluntary and community sectors to use the guidance to develop a workplace policy on domestic violence. åÊ

Regional Advisory Committee on Cancer Third Report - November 2004 (PDF 166 KB)

The Regional Advisory Committee on Cancer (RACC) was established in 1997 to carry forward the recommendations of the 1996 Campbell Report and to provide advice to the Department of Health, Social Services and Public Safety on the future development of cancer services. (Appendix 1) The 27 members of RACC come from the Health and Social Services Councils (which represent the interests of the public), Trusts, Boards, primary care and the Department. Members are listed in Appendix 2 RACC held its first meeting in June 1997 and has continued to meet twice a year since then. The Northern Ireland Cancer Forum was established in 1999 and is a subgroup of RACC. It was recommended that a Forum should be developed to provide meeting point for all voluntary and statutory bodies dealing with cancer in Northern Ireland. The Forum has now met on seven occasions and continues to work well with a unity of purpose. åÊ åÊ

El perdó de l’ofés: la via adecuada per alleugerir les càrregues de la justícia? Estudi de la institució i de les alternatives per rendibilitzar els recursos de l’Administració de justícia

En aquesta recerca aportem les conclusions de la nostra investigació sobre la figura del perdó de l’ofès i la seva possible virtualitat com a mitjà per alleugerir l’Administració de Justícia. En primer lloc, analitzem la institució del perdó de l’ofès, en concret, la seva regulació en el nostre Codi penal, els seus antecedents històrics i aportem certes dades de Dret comparat que poden ajudar a l’estudi crític de la institució (1). En la segona part, estudiem els arguments a favor i en contra del perdó de l’ofès dins el sistema penal i ens pronunciem sobre la seva legitimitat com a mecanisme per rendibilitzar l’Administració de Justícia (2). En la tercera part, sobre la base de les conclusions anteriors, aportem una reflexió sobre les alternatives al perdó de l’ofès (3). Per últim, en la darrera part, formulem la nostra proposta final sobre els mecanismes per rendibilitzar els recursos de l’Administració de Justícia (4). Segons el nostre estudi, el perdó de l’ofès no és un bon mecanisme per alleugerir la feina de l’Administració de Justícia. En canvi, la reparació i la conciliació si poden operar com a substitutius de la pena en els supòsits de delictes de menor gravetat; en els processos penals per aquests delictes caldria introduir un intent obligatori de conciliació, com el del § 380 StPO alemany i, a més, convindria preveure en el Codi penal la facultat del jutge d’eliminar la responsabilitat penal en determinats supòsits de reparació de l’autor a la víctima del delicte.