Opioid system genes in alcoholism: a case-control study in Croatian population.

Due to their involvement in dependence pathways, opioid system genes represent strong candidates for association studies investigating alcoholism. In this study, single nucleotide polymorphisms within the genes for mu (OPRM1) and kappa (OPRK1) opioid receptors and precursors of their ligands - proopiomelanocortin (POMC), coding for beta-endorphin and prodynorphin (PDYN) coding for dynorphins, were analyzed in a case-control study that included 354 male alcohol-dependent and 357 male control subjects from Croatian population. Analysis of allele and genotype frequencies of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN revealed no differences between the tested groups. The same was true when alcohol-dependent persons were subdivided according to the Cloninger's criteria into type-1 and type-2 groups, known to differ in the extent of genetic control. Thus, the data obtained suggest no association of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN with alcoholism in Croatian population.

Differential expression of proopiomelanocortin (POMC) transcriptional variants in human skin cells.

The aims of this study were to examine content and expression level of proopiomelanocortin (POMC) mRNA variants in human dermal fibroblasts (HDF) as compared to primary keratinocytes and HaCaT cells of keratinocyte origin. Primary fibroblasts and keratinocytes were obtained from normal human foreskin. Full-length and total (i.e. the full-length, truncated and/or alternatively spliced) POMC mRNA in skin cells were determined by qRT-PCR using specific probes. The full-length POMC mRNA in HDF is neither constitutively expressed, nor could be induced by corticotropin releasing hormone (CRH) or cytokines interferon γ (IFN-γ) and transforming growth factor-ß1 (TGF-ß1). However, the truncated/alternatively spliced POMC mRNA variants are constitutively expressed in HDF and could be moderately increased with CRH and the cytokines. Primary keratinocytes, in addition to truncated/alternatively spliced POMC mRNA variants, also constitutively express full-length POMC mRNA, both being downregulated during in vitro culturing. Unlike primary keratinocytes, HaCaT cells, express only truncated/alternatively spliced POMC mRNA variants. The level of POMC mRNA expression in HaCaT cells was associated with differentiation stage, being higher in more differentiated cells. Thus, in this study we have shown for the first time that HDF do not express the full-length POMC mRNA, either constitutively or upon activation, opposing to primary keratinocytes which constitutively express the full-length POMC mRNA as a minor variant. Although expressing only truncated/alternatively spliced POMC mRNA variant, HDF express POMC peptide, showing that those transcriptional variants are translatable. Truncated/alternatively spliced POMC mRNA variants, expressed both in HDF and keratinocytes are subjected to regulation, implicating their functionality. Furthermore, the IFN-γ-induced up-regulation at transcriptional level was associated with increased level of POMC peptide detected in HDF lysates. Thus, data of this study have shown that HDF express only truncated/alternatively spliced POMC mRNA variants, which are probably biologically relevant as they could be translated to POMC peptide, both constitutively and upon activation.

A consensus approach to maintain a knowledge based system in pathology.

The IDEM (Images and Diagnosis from Example in Medicine) software is a computerized environment able to store unambiguous descriptions of histopathologic images from pathologists. Medical imaging could benefit from such environments if they can easily and continuously be maintained. Within the IDEM environment, we developed a knowledge management module coupled with a consensus module to support knowledge acquisition and maintenance by the experts of the domain. Two pathologists, a senior and junior pathologist, reviewed fifty-three cases of breast pathology. Our findings indicate 1) that the IDEM knowledge management module allows experts to describe images by selecting terms and defining new ones if necessary, allowing the construction of a glossary for the domain and 2) that the consensus module, developed to store valid multi-experts cases, contributes also to validate new terms of the glossary and to refine semantic distance between terms. Such methodology could be applied to others highly evolving medical domains.

A property concept frame representation for flexible image-content retrieval in histopathology databases.

In histopathology databases, images descriptions are collections of properties provided by experts. Image content retrieval implies comparison of such properties. The objective of this work is to enrich the traditional attribute-value representation of properties in order to take into account the polymorphism and subjectivity of properties and to manage the comparison process. In this paper we define a property concept frame (PCF) representation based on fuzzy logic to handle both representation and comparison. Seven quantifiable morphological characteristics were selected from histopathological reports to illustrate the variety of fuzzy predicates and linguistic terms in properties. The PCF representation has been tested in the context of breast pathology. It is concluded that the PCF representation provides a unification scheme to retrieve in images morphological characteristics that are described in different ways. It may enhance the relevancy of applications in various contexts such as image content-based retrieval or case-based reasoning from images.

Towards content-based image retrieval in a HIS-integrated PACS.

Development of a Picture Archiving and Communications System (PACS) with a large and diverse set of medical images will lead to large digital libraries that can be accessed to provide improved support for patient care, research and education. New representational and retrieval models for clinical images are required to address these issues. The PACS at the Georges Pompidou Hospital (GPH) is integrated in the hospital information system (HIS), and several modalities from medical imaging departments have been attached to it. The two main axes of the GPH PACS project were 1) HIS-integration to allow hospital-wide access to the images based on demographic and procedure-type information and 2) the development of content-based image retrieval to enhance the medical impact of image retrieval in daily practice.

Integration of medical applications: the 'mediator service' of the SynEx platform.

Interoperability is a key issue and a long-term domain of research for distributed healthcare information systems. The SynEx European project provides open and standard integration platform for both new and legacy medical applications. It aims to provide access to hospital information services, patient records, and to medical knowledge, in a seamless way, hiding the distribution aspects and the heterogeneity of the underlying systems. In this study, we describe the SynEx 'mediator service', a software engineering component, that is used to facilitate the development of mediators between any pair of SynEx components and to manage the corresponding interchange messages. Both a C++ library and a Java package of a generic mediator model are provided with several ready-to-use specialisations for well-defined use. The use of the XML technology as a powerful data interchange format and as an efficient data structure converter is proposed and discussed.

A visual coding system in histopathology and its consensual acquisition.

Divergent descriptions of histopathologic images induce inter- and intra-observer variability in diagnosis. Even though a controlled terminology exists to describe medical imaging, pathologists do not always agree on the visual representation of the descriptive terms. The main purpose of our work is to define a methodology to build a standardized visual coding system unambiguously characterizing the terms of a microglossary. The methodology follows two steps: 1) the acquisition of experts' descriptions of images using the microglossary and 2) a consensus derivation. The procedure was applied on a set of 85 histopathological images of breast tumors described by two experts. Among the 339 objects selected in images, 176 were detected by both experts, 77% localized at the same place and 25% also identically labeled. The microglossary was enriched and illustrated via the resulting consensual descriptions. The contribution of this work supports relevant indexing of biomedical images and image-related information.

The "mediator service", a component to ease the integration of medical applications in the SynEx framework.

Interoperability is a key issue and a long-term domain of research for distributed healthcare information systems. The European project SynEx provides an open and standard integration platform for both new and legacy medical applications. It allows the collaboration of distributed and heterogeneous healthcare records and services. It aims to provide access to Hospital Information Services, to remote sources of medical data and to medical knowledge, in a seamless way, hiding the distribution aspects and the heterogeneity of systems. In this project, the Medical Informatics Department of the Broussais University Hospital is responsible for the development of the "Mediator Service". It is a software component of the SynEx platform which is used as a "glue" mechanism to provide a flexible way to facilitate the interchange between any pair of systems, with different nomenclatures and data structures. The Mediator Service uses a generic model of mediators to create, through specialization, specific mediators for practical cases. Based on this model, it offers a C++ library to be used as the tool case by the programmers, to reduce the development effort. The use of XML as a powerful data interchange format and as a data structure descriptor is proposed and evaluated.

IDEM: a Web application of case-based reasoning in histopathology.

Different software engineering and artificial intelligence methods can be used to design Internet retrieval of prototypical medical images. We used the case-based reasoning (CBR) approach to provide an 'intelligent' access to a collection of illustrated medical cases through the Internet. This paper presents a Web interface for the CBR system IDEM (image and diagnosis from examples in medicine) in the domain of breast pathology. Thanks to the definition of a similarity measure between the descriptions of cases we propose a flexible querying of the case-base and a quantitative browsing among cases through similarity links. The resemblance rates provided by the system argue for the quality and the relevancy of the retrieved data. The flexibility of the querying process is robust to missing information and could be adapted to a daily practice. The CBR approach is a promising method for a clinical relevant and an efficient retrieval of reference images and diagnosis clues through Internet.

Rationale and design considerations for a semantic mediator in health information systems.

Rapid development of community health information networks raises the issue of semantic interoperability between distributed and heterogeneous systems. Indeed, operational health information systems originate from heterogeneous teams of independent developers and have to cooperate in order to exchange data and services. A good cooperation is based on a good understanding of the messages exchanged between the systems. The main issue of semantic interoperability is to ensure that the exchange is not only possible but also meaningful. The main objective of this paper is to analyze semantic interoperability from a software engineering point of view. It describes the principles for the design of a semantic mediator (SM) in the framework of a distributed object manager (DOM). The mediator is itself a component that should allow the exchange of messages independently of languages and platforms. The functional architecture of such a SM is detailed. These principles have been partly applied in the context of the HELIOS object-oriented software engineering environment. The resulting service components are presented with their current state of achievement.

Unified modeling language and design of a case-based retrieval system in medical imaging.

One goal of artificial intelligence research into case-based reasoning (CBR) systems is to develop approaches for designing useful and practical interactive case-based environments. Explaining each step of the design of the case-base and of the retrieval process is critical for the application of case-based systems to the real world. We describe herein our approach to the design of IDEM--Images and Diagnosis from Examples in Medicine--a medical image case-based retrieval system for pathologists. Our approach is based on the expressiveness of an object-oriented modeling language standard: the Unified Modeling Language (UML). We created a set of diagrams in UML notation illustrating the steps of the CBR methodology we used. The key aspect of this approach was selecting the relevant objects of the system according to user requirements and making visualization of cases and of the components of the case retrieval process. Further evaluation of the expressiveness of the design document is required but UML seems to be a promising formalism, improving the communication between the developers and users.

Case based diagnosis in histopathology of breast tumours.

Relevant knowledge and decision making process in histopathology is mostly included in typical pathological cases encountered by the expert. In this article we address the issue of exploiting this knowledge in the diagnosis process. We present the first steps of a Case-Based-Reasoning (CBR) system that uses the previously resolved pathological cases in order to facilitate decision making and diagnosis formulation of a new case. The work has been performed in two phases. Firstly, an object-oriented model of the domain was developed and 35 pathological cases of breast tumours were represented within this model. Secondly, the functional architecture of the CBR system was designed and the main procedure, the selection of similar cases, was achieved. The selection procedure is based on an original similarity measure that takes into account both semantic and structural resemblances and differences between the cases. A first evaluation of the system was performed on several cases of the data base. The interest of the CBR approach in situations where heuristic rules cannot be clearly defined is discussed.

The number needed to treat: a clinically useful nomogram in its proper context.

The number needed to treat is a meaningful way of expressing the benefit of an active treatment over a control. It can be used either for summarising the results of a therapeutic trial or for medical decision making about an individual patient, but its use at the bedside has been impeded by the need for time consuming calculations. A nomogram has therefore been devised that will greatly simplify the calculations. Since calculations are now easy, the number needed to treat can be used to access the value of several interventions, although it does have its limitations. In particular it should not be used when it is not known whether the relative risk reduction associated with an intervention is constant for all levels of risk, or for periods of time longer than that studied in the original trials.

The HELIOS Unification Bus: a toolbox to develop client/server applications.

In the medical domain, new developments commonly rely on client/server architectures. But face to distributed environments, the software developers encounter a tremendously increasing complexity when building integrated applications. This paper presents the HELIOS Unification Bus (HUB), a communication integration framework for the HELIOS medical software engineering environment that allows the exchange of data between components that can be hosted on heterogeneous machines linked by a network. The HUB is developed as a C++ toolbox over UNIX and TCP/IP. It includes a message routing entity called router and a generic application programming interface (API), implemented as a C++ library, that allows to build easily software components compliant with the standardised HELIOS language. Messages conveyed by the bus are composite objects that are serialized to be transmitted over the bus using the ASN.1 ISO presentation protocol. The article describes the use of the bus to ease the development and execution of distributed medical applications and its role from the communication integration standpoint.

Analysing and developing object-oriented medical applications with HELIOS.

The HELIOS project promotes systematic reuse of existing software in a valuable methodological context. In order to reach this goal, the Analysis and Design Development Environment (ADDE) has been realized as a HELIOS component. This component includes the Analysis and Design sub-component (ADT), which supports the Rumbaugh's object-oriented methodology and the Insertion Retrieval Tool (IRT), which implements the reuse. The ADT sub-component enhances the quality of software development permitting a correct analysis, and design and a satisfactory documentation. The IRT Tool is dedicated to reuse by retrieving parts of existing applications (retrieve) and by qualifying elements just created or updated (insertion). A faceted system adapted to the medical domain allows an efficient search among the object database. Both tools contribute to reducing the cost of software development. This paper presents the design and the implementation of these tools in the HELIOS framework.

A reuse oriented Development Database: the HELIOS Object Information System.

This paper describes the Development Database of a Software Engineering Environment (SEE), that couples reuse and object-oriented technologies. We propose a classification model for the repository of reusable components that is a support for an efficient retrieval mechanism, and a reusable component model that considers components of large and low-granularity levels (e.g., application frameworks and methods of a given class). The reusable component model is based on the underlying idea that development components are not operational components since they do not have the same purpose. This model first represents each component as an aggregation of other sub-components, together with all information needed for its retrieval (e.g., classification and facets), its under-standing (e.g., informal functional description) and its dependencies with other development components, in particular the applications in which it occurs, since applications are considered also as abstract development components. This approach was tested thanks to an existing application which was loaded into the SEE. From that moment, it was possible to regenerate a new application in a reasonably short time. Moreover, the existence of a retrieval tool permits to validate the development components classification, but also put forward the importance of the qualification step. In particular, the versioning should be carefully processed. Furthermore the fact that all the development objects are built on an homogeneous model allows easier tools management and interapplication reusability.