Antimicrobial Photodynamic Therapy: Study of Bacterial Recovery Viability and Potential Development of Resistance after Treatment

Antimicrobial photodynamic therapy (aPDT) has emerged in the clinical field as a potential alternative to antibiotics to treat microbial infections. No cases of microbial viability recovery or any resistance mechanisms against it are yet known. 5,10,15-tris(1-Methylpyridinium-4-yl)-20-(pentafluorophenyl)-porphyrin triiodide (Tri-Py+-Me-PF) was used as photosensitizer. Vibrio fischeri and recombinant Escherichia coli were the studied bacteria. To determine the bacterial recovery after treatment, Tri-Py+-Me-PF (5.0 μM) was added to bacterial suspensions and the samples were irradiated with white light (40 W m−2) for 270 minutes. Then, the samples were protected from light, aliquots collected at different intervals and the bioluminescence measured. To assess the development of resistance after treatment, bacterial suspensions were exposed to white light (25 minutes), in presence of 5.0 μM of Tri-Py+-Me-PF (99.99% of inactivation) and plated. After the first irradiation period, surviving colonies were collected from the plate and resuspended in PBS. Then, an identical protocol was used and repeated ten times for each bacterium. The results suggest that aPDT using Tri-Py+-Me-PF represents a promising approach to efficiently destroy bacteria since after a single treatment these microorganisms do not recover their viability and after ten generations of partially photosensitized cells neither of the bacteria develop resistance to the photodynamic process

Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.status: publishe

Rapport du séminaire de l'OCDE sur l'analyse statistique des données de toxicité aquatique

Following a decision taken by the National Co-ordinators of the OECD Test Guideline Programme and the OECD Risk Assessment Advisory Body (RAAB) at their joint session in December 1995, an OECD Workshop on Statistical Analysis of Aquatic Ecotoxicity Data was held in Braunschweig, Germany on 15-17 October 1996. The workshop was hosted by the Biologische Bundesanstalt für Land-und Forstwirtschaft (BBA) in Braunschweig and was chaired by Dr Arno Lange of the German Umweltbundesamt (UBA). The objectives of the workshop were: • to review the options available for the analysis of data from ecotoxicity tests; • to compare their advantages and disadvantages; • to recommend (a) the most appropriate approach for deriving a summary parameter(s) which has (have) scientific validity, and (b) further work to be undertaken by the OECD and/or others, as appropriate. In plenary and working group sessions participants discussed statistical data analysis appropriate for single-species chronic/subchronic studies using a number of test concentrations, i.e. dose-response tests. Aquatic tests served as a basis for these discussions, however the issues addressed may be similar for toxicity tests in general. Background documents had been prepared on the following main existing data analysis approaches for such tests: analysis of variance/hypothesis testing (“ANOVA/NOEC approach”); regression analysis (based on empirical models); and mechanistic modelling (theory-based). It was concluded that the NOEC, as the main summary parameter of aquatic ecotoxicity tests, is inappropriate for a number of reasons (see detailed discussion in the report) and should therefore be phased out. It was recommended that the OECD should move towards a regression-based estimation procedure. The time course of effects should be incorporated in the analytical procedures, and the OECD should initiate a study of the available time-dependent regression models (both mechanistic and empirical) in order to select those which best meet its needs. The study should also address the issue of appropriate values of x for ECx and the optimal experimental designs. A steering group should be set up to direct the mathematical, statistical and biological work required to take the workshop recommendations forward. This group should include representatives from the appropriate scientific and regulatory communities.Suite à une décision des Coordinateurs nationaux du Programme de l’OCDE sur les Lignes directrices pour les essais et du Groupe consultatif de l’OCDE sur l’évaluation des risques (RAAB) lors de leur session conjointe en décembre 1995, un atelier de l’OCDE sur l’analyse statistique des données d’écotoxicité aquatique s’est tenu à Braunschweig, en Allemagne du 15 au 17 octobre 1996. L’atelier fut accueilli par le Biologische Bundesanstalt für Land-und Forstwirtschaft (BBA), sous la présidence du Docteur Arno Lange du Umweltbundesamt (UBA). L’atelier avait pour objectifs de: • examiner les différentes options existantes pour l’analyse des données des essais d’écotoxicité; • comparer leurs avantages et leurs inconvénients; • faire des recommandations concernant (a) l’approche la plus appropriée pour obtenir un/des paramètre(s) “résumé(s)” qui soi(en)t scientifiquement valides, et (b) les travaux ultérieurs qu’il conviendrait que l’OCDE et/ou d’autres mettent en oeuvre; Au cours des sessions plénières et des sessions de groupe de travail, les participants ont débattu de l’analyse statistique des données relatives aux études chroniques/subchroniques réalisées sur un seul organisme et utilisant un certain nombre de concentrations, c’est-à-dire les essais dits “dose-réponse”. Les essais dans le domaine aquatique ont servi de base aux discussions; cependant, les questions abordées peuvent être les mêmes pour les essais de toxicité et concernent les principales approches pour l’analyse des données d’essais que sont: l’analyse de la variance/hypothèse d’essai (“approche ANOVA/NOEC”) , l’analyse de régression (basée sur les modèles empiriques), et la modélisation méchanistique (basée sur la théorie). Il a été conclu que, pour un certain nombre de raisons (voir les arguments détaillés dans ce rapport), la NOEC ne convient pas comme principal paramètre “résumé” des essais d’écotoxicité aquatique et qu’elle devrait donc être progressivement abandonnée. Il a été recommandé que l’OCDE s’oriente vers une procédure d’estimation basée sur la régression. Les effets au cours de temps devraient être pris en compte dans les procédures analytiques, et l’OCDE devrait mettre en place une étude des modèles disponibles de régression dépendants du temps (à la fois méchanistique et empirique) afin de choisir ceux qui correspondent le mieux aux besoins de l’OCDE. L’étude devrait aussi aborder la question des valeurs appropriées de x pour l’ECx et celle de la conception optimale des essais. Un groupe directeur devrait diriger les travaux d’ordre mathématique, statistique et biologique nécessaires afin de mettre en place les recommandations de l’atelier. Ce groupe devrait être composé de représentants des communautés scientifiques et réglementaires compétentes.OECD Environmental Health and Safety Publication

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

Aims: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. Methods and results: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P &lt; 5.0 10−7), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. Conclusion: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM