A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: The European experience.

BACKGROUND: The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system. METHODS: The hematoxylin-eosin-stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics. RESULTS: The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR. CONCLUSIONS: Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the 1990 ISHLT classification to the "new" 2005 ISHLT classification. Morphologic suspicion of AMR in the 2004 system on hematoxylin-eosin-stained slides only was poor, highlighting the need for better standardization of morphologic criteria for AMR. Ongoing educational programs are needed to ensure standardization of diagnosis of both acute cellular and antibody-mediated rejection.

Inter-informant agreement and prevalence estimates for substance use disorders: direct interview versus family history method.

OBJECTIVES: Family studies typically use multiple sources of information on each individual including direct interviews and family history information. The aims of the present study were to: (1) assess agreement for diagnoses of specific substance use disorders between direct interviews and the family history method; (2) compare prevalence estimates according to the two methods; (3) test strategies to approximate prevalence estimates according to family history reports to those based on direct interviews; (4) determine covariates of inter-informant agreement; and (5) identify covariates that affect the likelihood of reporting disorders by informants. METHODS: Analyses were based on family study data which included 1621 distinct informant (first-degree relatives and spouses) - index subject pairs. RESULTS: Our main findings were: (1) inter-informant agreement was fair to good for all substance disorders, except for alcohol abuse; (2) the family history method underestimated the prevalence of drug but not alcohol use disorders; (3) lowering diagnostic thresholds for drug disorders and combining multiple family histories increased the accuracy of prevalence estimates for these disorders according to the family history method; (4) female sex of index subjects was associated with higher agreement for nearly all disorders; and (5) informants who themselves had a history of the same substance use disorder were more likely to report this disorder in their relatives, which entails the risk of overestimation of the size of familial aggregation. CONCLUSION: Our findings have important implications for the best-estimate procedure applied in family studies.

Transport pathways in the malaria-infected erythrocyte: characterization and their use as potential targets for chemotherapy

The intraerythrocytic malarial parasite is involved in an extremely intensive anabolic activity while it resides in its metabolically quiescent host cell. The necessary fast uptake of nutrients and the discharge of waste product, are guaranteed by parasite-induced alterations of the constitutive transporters of the host cell and the production of new parallel pathways. The membrane of the host cell thus becomes permeable to phospholipids, purine bases and nucleosides, small non-electrolytes, anions and cations. When the new pathways are quantitatively unimportant, classical inhibitors of native transporters can be used to inhibit parasite growth. Several compounds were found to effectively inhibit the new pathways and consequently, parasite growth. The pathways have also been used to introduce cytotoxic agents. The parasitophorous membrane consists of channels which are highly permeable to small solutes and display no ion selectivity. Transport of some cations and anions across the parasite membrane is rapid and insensitive to classical inhibitors, and in some cases it is mediated by specific antiporters which respond to their respective inhibitors. Macromolecules have been shown to reach the parasitophorous space through a duct contiguous with the host cell membrane, and subsequently to be endocytosed at the parasite membrane. The simultaneous presence of the parasitophorous membrane channels and the duct, however, is incompatible with experimental evidences. No specific inhibitors were found as yet that would efficiently inhibit transport through the channels or the duct.

Inter-relation of sylvatic and domestic transmission of Trypanosoma cruzi in areas with and without domestic vectorial transmission in Minas Gerais, Brazil

During the period 1980-1986, we captured triatomine bugs and mammalian reservoir hosts from sylvatic and domestic situations in different municipalities of the State of Minas Gerais. Trypanosoma cruzi was isolated from captured bugs, mammals and patients. After cultivation in LIT medium, the electrophoretic enzyme profiles were determined. We obtained atotal of 32 parasite isolates from regions with active domestic transmission, and 24 isolates form areas under control. For the first areas the results suggest introduction of T. cruzi from sylvatic habitats, through incursion of infected opossums and/or sylvatic T. sordida, which appears to have given rise to at least one acute human infection. Of particular interest is the finding of sylvatic opossums and a T. sordida nymph infected with ZB, that could indicate return of parasites from chronic human infections to sylvatic transmission cycles. For the areas under control we also interpret the results as interaction between sylvatic and domestic cycles of transmission, here through the invasion of houses by bugs carrying the Z1 zymodeme from the sylvatic environment. The Multivariate Correspondence Analysis gives a spatial description between the different parasite isolates and confirms the existence of a bridge in the opposite direction in the region with active vectorial transmission including the exporting of Z2 through the peridomestic environment into the sylvatic cycle. For the others areas this bridge corresponds especially to Panstrongylus megistus, importing Z1 into the domestic environment.

Inter-American Court, Crimes Against Humanity and Peacebuilding in South America

The present work contains a general overview of the sentences of the Inter-American Court of Human Rights (IACtHR), which have recognised that crimes against humanity are pre-existing in customary law, and do not prescribe, nor can they be subject to amnesty or pardon. Specific attention is paid to the consequent restrictions and opportunities offered by said verdicts to countries such as Argentina, Chile, Uruguay and Peru, which find themselves in postconflict transition processes and where peace has been negotiated with certain groups and state structures that are responsible for carrying out crimes against humanity. In doing so, special attention is paid to the impact of the recognition of the nature of crimes against humanity on the notion of the principle of legality, stricto sensu; on the development and evolution of the doctrine and the practice of international human rights law in the inter-American context; and finally on the aforementioned processes of transitional justice.

Diagnostic interview for genetic studies (DIGS): inter-rater and test-retest reliability of the French version.

The National Institute of Mental Health developed the semi-structured Diagnostic Interview for Genetic Studies (DIGS) for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS was translated into French in a collaborative effort of investigators from sites in France and Switzerland. Inter-rater and test-retest reliability of the French version have been established in a clinical sample in Lausanne. Excellent inter-rater reliability was found for schizophrenia, bipolar disorder, major depression, and unipolar schizoaffective disorder while fair inter-rater reliability was demonstrated for bipolar schizoaffective disorder. Using a six-week test-retest interval, reliability for all diagnoses was found to be fair to good with the exception of bipolar schizoaffective disorder. The lower test-retest reliability was the result of a relatively long test-retest interval that favored incomplete symptom recall. In order to increase reliability for lifetime diagnoses in persons not currently affected, best-estimate procedures using additional sources of diagnostic information such as medical records and reports from relatives should supplement DIGS information in family-genetic studies. Within such a procedure, the DIGS appears to be a useful part of data collection for genetic studies on major mood disorders and schizophrenia in French-speaking populations.

A study on the expressive power of some fragments of the modal µ-Calculus

Résumé Le μ-calcul est une extension de la logique modale par des opérateurs de point fixe. Dans ce travail nous étudions la complexité de certains fragments de cette logique selon deux points de vue, différents mais étroitement liés: l'un syntaxique (ou combinatoire) et l'autre topologique. Du point de vue syn¬taxique, les propriétés définissables dans ce formalisme sont classifiées selon la complexité combinatoire des formules de cette logique, c'est-à-dire selon le nombre d'alternances des opérateurs de point fixe. Comparer deux ensembles de modèles revient ainsi à comparer la complexité syntaxique des formules as¬sociées. Du point de vue topologique, les propriétés définissables dans cette logique sont comparées à l'aide de réductions continues ou selon leurs positions dans la hiérarchie de Borel ou dans celle projective. Dans la première partie de ce travail nous adoptons le point de vue syntax¬ique afin d'étudier le comportement du μ-calcul sur des classes restreintes de modèles. En particulier nous montrons que: (1) sur la classe des modèles symétriques et transitifs le μ-calcul est aussi expressif que la logique modale; (2) sur la classe des modèles transitifs, toute propriété définissable par une formule du μ-calcul est définissable par une formule sans alternance de points fixes, (3) sur la classe des modèles réflexifs, il y a pour tout η une propriété qui ne peut être définie que par une formule du μ-calcul ayant au moins η alternances de points fixes, (4) sur la classe des modèles bien fondés et transitifs le μ-calcul est aussi expressif que la logique modale. Le fait que le μ-calcul soit aussi expressif que la logique modale sur la classe des modèles bien fondés et transitifs est bien connu. Ce résultat est en ef¬fet la conséquence d'un théorème de point fixe prouvé indépendamment par De Jongh et Sambin au milieu des années 70. La preuve que nous donnons de l'effondrement de l'expressivité du μ-calcul sur cette classe de modèles est néanmoins indépendante de ce résultat. Par la suite, nous étendons le langage du μ-calcul en permettant aux opérateurs de point fixe de lier des occurrences négatives de variables libres. En montrant alors que ce formalisme est aussi ex¬pressif que le fragment modal, nous sommes en mesure de fournir une nouvelle preuve du théorème d'unicité des point fixes de Bernardi, De Jongh et Sambin et une preuve constructive du théorème d'existence de De Jongh et Sambin. RÉSUMÉ Pour ce qui concerne les modèles transitifs, du point de vue topologique cette fois, nous prouvons que la logique modale correspond au fragment borélien du μ-calcul sur cette classe des systèmes de transition. Autrement dit, nous vérifions que toute propriété définissable des modèles transitifs qui, du point de vue topologique, est une propriété borélienne, est nécessairement une propriété modale, et inversement. Cette caractérisation du fragment modal découle du fait que nous sommes en mesure de montrer que, modulo EF-bisimulation, un ensemble d'arbres est définissable dans la logique temporelle Ε F si et seulement il est borélien. Puisqu'il est possible de montrer que ces deux propriétés coïncident avec une caractérisation effective de la définissabilité dans la logique Ε F dans le cas des arbres à branchement fini donnée par Bojanczyk et Idziaszek [24], nous obtenons comme corollaire leur décidabilité. Dans une deuxième partie, nous étudions la complexité topologique d'un sous-fragment du fragment sans alternance de points fixes du μ-calcul. Nous montrons qu'un ensemble d'arbres est définissable par une formule de ce frag¬ment ayant au moins η alternances si et seulement si cette propriété se trouve au moins au n-ième niveau de la hiérarchie de Borel. Autrement dit, nous vérifions que pour ce fragment du μ-calcul, les points de vue topologique et combina- toire coïncident. De plus, nous décrivons une procédure effective capable de calculer pour toute propriété définissable dans ce langage sa position dans la hiérarchie de Borel, et donc le nombre d'alternances de points fixes nécessaires à la définir. Nous nous intéressons ensuite à la classification des ensembles d'arbres par réduction continue, et donnons une description effective de l'ordre de Wadge de la classe des ensembles d'arbres définissables dans le formalisme considéré. En particulier, la hiérarchie que nous obtenons a une hauteur (ωω)ω. Nous complétons ces résultats en décrivant un algorithme permettant de calculer la position dans cette hiérarchie de toute propriété définissable.

Estudio acústico de la variación inter e intralocutor en la frecuencia fundamental de hablantes bilingües de catalán y de castellano

Este trabajo pretende contribuir a establecer la individualidad de la voz de los hablantes bilingües equilibrados de catalán y de castellano a partir del análisis de la frecuencia fundamental y estudiar los efectos, en el nivel acústico, que el uso de una lengua u otra produce en este parámetro. Se pretende obtener, así, parte del conocimiento fonético necesario para la mejora de los sistemas de reconocimiento, identificación o verificación automáticos del locutor y proporcionar a los especialistas en fonética judicial nuevos datos acústicos para que puedan comparar con un mayor grado de certeza locutores dubitados e indubitados

The Inter-municipal Cooperation in Switzerland and the Trend towards Amalgamation

In Switzerland, the ongoing reforms of fiscal federalism put municipalities under increased fiscal stress. A majority of the municipalities had responded by increasing the cooperation with neighbouring municipalities over the last few years. Simultaneously, many discuss or are directly involved in a possible amalgamation project. Accordingly, the paper aimed at describing how cooperation has presently developed between Swiss municipalities, in order to illustrate the existing trend towards amalgamation. Current surveys helped us estimate the growing importance of inter-municipal arrangements together with the surge of amalgamations. A further goal was to investigate if cantonal financial incentives to municipal amalgamation essentially benefit the cantonal community, following the fiscal equivalence principle, or if they rather benefit amalgamating municipalities. In reality, equivalence does not exist. However, this may possibly be the condition to reduce inequality among amalgamating municipalities.

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes.

During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca(2+)-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.

Multilocus sequence analysis reveals the genetic diversity of European fruit tree phytoplasmas and supports the existence of inter-species recombination

The genetic diversity of three temperate fruit tree phytoplasmas ‘Candidatus Phytoplasma prunorum’, ‘Ca. P. mali’ and ‘Ca. P. pyri’ has been established by multilocus sequence analysis. Among the four genetic loci used, the genes imp and aceF distinguished 30 and 24 genotypes, respectively, and showed the highest variability. Percentage of substitution for imp ranged from 50 to 68% according to species. Percentage of substitution varied between 9 and 12% for aceF, whereas it was between 5 and 6% for pnp and secY. In the case of ‘Ca P. prunorum’ the three most prevalent aceF genotypes were detected in both plants and insect vectors, confirming that the prevalent isolates are propagated by insects. The four isolates known to be hypo-virulent had the same aceF sequence, indicating a possible monophyletic origin. Haplotype network reconstructed by eBURST revealed that among the 34 haplotypes of ‘Ca. P. prunorum’, the four hypo-virulent isolates also grouped together in the same clade. Genotyping of some Spanish and Azerbaijanese ‘Ca. P. pyri’ isolates showed that they shared some alleles with ‘Ca. P. prunorum’, supporting for the first time to our knowledge, the existence of inter-species recombination between these two species.

Health and Transport, Sources of Information

The Institute of Public Health in Ireland (IPH) has produced a series of reviews which look at the health impacts of identified subject areas. Four reviews have been produced in the areas of employment, transport, the built environment and education. All reviews may be found at http://www.publichealth.ie/ireland/hiaresources. This resource supplements the ‘Health Impacts of Transport’ report. It highlights a number of organisations whose work considers issues relevant to the relationship between health and transport.

IPH response to the National Transport Authority on the Greater Dublin Area Draft Transport Strategy 2011-2030

The remit of the Institute of Public Health in Ireland (IPH) is to promote cooperation for public health between Northern Ireland and the Republic of Ireland in the areas of research and information, capacity building and policy advice. Our approach is to support Departments of Health and their agencies in both jurisdictions, and maximise the benefits of all-island cooperation to achieve practical benefits for people in Northern Ireland and the Republic of Ireland.IPH has a keen interest in the interactions between transport and health. IPH has produced two papers in the recent past on this topic, the most recent being Active travel – healthy lives published in January 2011 which built on the 2005 publication Health impacts of transport. The IPH welcomes the draft transport strategy in terms of addressing each of the key messages outlined in the Active travel – healthy lives paper.IPH is interested in this area not only in terms of increasing ‘active travel’ for healthier lives, but also in terms of the environmental and social impacts of inequitable access to forms of private and public transport.