Factor XI deficiency: two novel mutations in asymptomatic Italian patients.

SUMMARY: Factor XI (FXI) deficiency is a rare bleeding disorder, resulting in a wide range of bleeding manifestations, from asymptomatic bleeding to injury-related bleeding. To identify mutations in FXI-deficient patients and to establish a possible relationship between clinical phenotype and genotype, we studied two patients from Southern Italy with FXI deficiency. They were identified by presurgical or routine laboratory screening. None of them showed bleeding. Three different mutations were detected (Glu117Stop, Cys118Arg and Trp497Gly); two of them were novel (Cys118Arg and Trp497Gly). One patient (with severe FXI levels) showed a compound heterozygosity (Glu117Stop with Cys118Arg). Two novel missense mutations were highly conserved among different species. In our patients, bleeding tendency did not appear to be correlated with FXI levels or with a single mutation in heterozygosis. On the other hand, the compound heterozygosis might explain low FXI levels, but it is not associated with bleeding. Our data confirm that a severe FXI deficiency is not necessarily associated with bleeding.

Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A.

One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFalpha, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.

The impact of rotary blood pump in conjunction with mechanical ventilation on ventricular energetic parameters - numerical simulation.

OBJECTIVES: Aim of this work is to study the impact of left ventricular rotary blood pump assistance, on energetic variables, when mechanical ventilation (MV) of the lungs is applied. METHODS: Computer simulation was used to perform this study. Lumped parameter models reproduce the circulatory system. Variable elastance models reproduce the Starling's law of the heart for each ventricle. After the reproduction of ischemic heart disease left ventricular assistance was applied using a model of rotary blood pump. The pump speed was changed in steps and was assumed to be constant during each step. The influence of mechanical ventilation was introduced by different values of positive mean thoracic pressure. RESULTS: The increase of the rotational speed has a significant influence on some ventricular energetic variables. In fact it decreased left ventricular external work, left and right ventricular pressure-volume area and the left ventricular efficiency. Finally, it increased the right ventricular efficiency but had no influence on the right ventricular external work. The increase of thoracic pressure from -2 to +5 mmHg caused a significant decrease of external work, pressure-volume area (right ventricular pressure-volume area dropped up to 50%) and an increase of right ventricular efficiency (by 40%) while left ventricular efficiency remained almost stable. CONCLUSIONS: Numerical simulation is a very suitable tool to predict changes of not easily measurable parameters such as energetic ventricular variables when mechanical assistance of heart and/or lungs is applied independently or simultaneously.

Clinical guidelines as plans--an ontological theory.

OBJECTIVE: Clinical guidelines are special types of plans realized by collective agents. We provide an ontological theory of such plans that is designed to support the construction of a framework in which guideline-based information systems can be employed in the management of workflow in health care organizations. METHOD: The framework we propose allows us to represent, in formal terms, how clinical guidelines are realized through the actions of individuals or ganized into teams. We provide various levels of implementation representing different levels of conformity on the part of health care organizations. RESULT: Implementations built in conformity with our framework are marked by two dimensions of flexibility that are designed to make them more likely to be accepted by health care professionals than standard guideline-based management systems. They do justice to the fact 1) that responsibilities within a health care organization are widely shared, and 2) that health care professionals may on different occasions be non-compliant with guidelines for a variety of well justified reasons. CONCLUSION: The advantage of the framework lies in its built-in flexibility, its sensitivity to clinical context, and its ability to use inference tools based on a robust ontology. One disadvantage lies in its complicated implementation.

Modelling in the study of interaction of Hemopump device and artificial ventilation.

The aim of this work is to evaluate in different ventricular conditions the influence of joint mechanical ventilation (MV) and Hemopump assistance. To perform this study, we used a computer simulator of human cardiovascular system where the influence of MV was introduced changing thoracic pressure to positive values. The simulation confirmed that haemodynamic variables are highly sensitive to thoracic pressure changes. On the other hand, Hemopump assistance raises, among the others, mean aortic pressure, total cardiac output (left ventricular output flow plus Hemopump flow) and coronary flow. The simulation showed that the joint action of Hemopump and positive thoracic pressure diminishes these effects.

In vivo and simulation study of artificial ventilation effects on energetic variables in cardiosurgical patients.

OBJECTIVES: The analysis of energetic ventricular variable changes during artificial ventilation, obtained by numerical simulation was done. Twenty-one sets of hemodynamic parameters for eight cardiosurgical patients were used to estimate left and right stroke work. The data were collected for three methods of ventilation: conventional, lung-protective (with minute ventilation diminished by half) and high frequency ventilation (with frequency 5, 10, or 15 Hz). METHODS: The computer simulator (CARDIOSIM) of the cardiovascular system, was used as a tool to calculate values of energetic ventricular variables for conditions that corresponded to these during in vivo measurements. Different methods of ventilation caused differences of intrathoracic pressure, haemodynamic and finally energetic ventricular variables. The trends of these variable changes were the same in in vivo and simulation studies, in the whole range of intrathoracic pressure changes (Pt = 1.5-3.5 mmHg). RESULTS: As values of main hemodynamic variables like cardiac output or arterial, systemic and pulmonary pressures were very close in both studies. Cardiac index and left ventricular stroke work also differed less than 10% for all examined patients and computer simulation. In a case of right ventricular stroke work the difference between in vivo data and simulation was a bit greater than 10% for two of eight patients under study. CONCLUSIONS: Our comparative analysis proved that numerical simulation is a very useful tool to predict changes of main hemodynamic and energy-related ventricular variables caused by different levels of positive Pt. It means that it can help an anesthesiologist to choose an appropriate method of artificial ventilation for cardiosurgical patients.

Understanding systematic conceptual structures in polysemous medical terms.

Polysemy is a bottleneck for the demanding needs of semantic data management. We suggest the importance of a well-founded conceptual analysis for understanding some systematic structures underlying polysemy in the medical lexicon. We present some cases studies, which exploit the methods (ontological integration and general theories) and tools (description logics and ontology libraries) of the ONIONS methodology defined elsewhere by the authors. This paper addresses an aspect (systematic metomymies) of the project we are involved in, which investigates the feasibility of building a large-scale ontology library of medicine that integrates the most important medical terminology banks.

[Effect of Ruboxyl (nitroxyl derivative of daunorubicin) on hepatic metastases of colorectal carcinoma]. / Aktivnost' Ruboxyla (nitroxil'nogo proizvodnogo daunomitsina) pri metastazakh v pechen' kolorektal'nogo raka.

Inhibition by ruboxyl, a nitroxyl derivative of daunorubicin, source preparation and 5-fluorouracil was compared in metastases of experimental colorectal carcinoma to murine liver. The indices of metastasis inhibition were 84.43 and 70%, respectively. In rats receiving the drugs by continuous intravenous infusion for 7 days, the number of metastases was reduced (ruboxyl--1.0 +/- 1.4; 5-fluorouracil 3.2 +/- 1.3.

Toward a standard for guideline representation: an ontological approach.

Guidelines for clinical practice are being introduced in an extensive way in more and more different fields of medicine They have the potentialities of improving the quality and cost-efficiency of care in an increasingly complex health care delivery environment. Computerization may increase the effectiveness of both the information retrieval of guidelines and the management of guideline-based care. The scenario is evolving from stand-alone workstations to telematics applications that enable guidelines development and dissemination. However, such a knowledge sharing requires the definition of formal models for guidelines representation. The models should have a clear semantics in order to avoid ambiguities. The role of ontologies is that of making explicit the conceptualizations behind a model. In this paper we present our library of ontologies and point out its role for integrating existing guideline models and defining standard representations.

Toward a general model for the description of multimedia clinical data.

The patient folder integrates information originating from heterogeneous sources. For this reason computerized tools for patient data management should exploit the advantages of multimediality and offer an integrated environment for data presentation, and image and biosignal visualization. Object-oriented modeling is the best approach for designing systems for multimedia patient folder management. We propose an object-oriented model, able to define the entities constituting the patient folder and their logical organization. This model has sufficient flexibility to adapt to the most varied clinical environments. It allows the physician to structure the information needed for his/her patient folder without employing a programming language.

An ontological analysis of the UMLS Metathesaurus.

Paper-based terminology systems cannot satisfy anymore the new desiderata of healthcare information systems: the demand for re-use and sharing of patient data, their transmission and the need of semantic-based criteria for purposive statistical aggregation. The unambiguous communication of complex and detailed medical concepts is now a crucial feature of medical information systems. Ontologies can support a more effective data and knowledge sharing in medicine. In this paper we briefly survey our ontological analysis and integration of various top-levels of terminologies and we report the main results of the ontological analysis of the UMLS Metathesaurus.

WWW-available conceptual integration of medical terminologies: the ONIONS experience.

We present the most applicable aspects of our research in the conceptual integration of terminologies. From past experience, we claim that the conceptualizations provided for terminological ontologies need to be philosophically and linguistically grounded. We developed ONIONS, a methodology for integrating domain terminologies by exploiting a library of generic ontologies. Our current focus is on flexible and cooperative modelling of terminological ontologies. We adopt modular and negotiable architectures of ontologies and some WWW-oriented tools, such as Ontolingua and Ontosaurus.

SMART: a system supporting medical activities in real-time.

This paper describes the system SMART whose goal is real-time assistance to physicians who execute diagnostic or therapeutic protocols in a clinical context. SMART is able to retrieve a protocol from its knowledge base and to monitor its execution step by step for a single patient. Different protocols for different patients can be followed at the same time in a health care structure. The prototype realized supports the execution of protocols for evaluating surgical risks. It has been implemented according to the specifications given by the 4th Surgical Clinic of "Policlinico Umberto I" and reflects the activities actually performed in that hospital. However, the protocol model defined is general purpose and we envisage an easy application to other contexts and therefore to the informatization of other protocols.

CADMIO: computer aided design for medical information objects.

The growth of the computational capability and the tools of graphic software is nowadays available in an integrated manner into the development environments, thus permitting the realization of tool kits capable of handling information that is complex and of different kinds such as the typical medical information. This has given a great impulse to the creation of electronic medical folders joining together with new and stimulating functionality with respect to the usual paper document [1]. In the present work, we propose a tool capable of defining a multimedia electronic medical folder and representing its architecture through a layout that is formed on the basis of the particular data types to be handled. This tool is capable of providing an integrated view of data that, even though they are close in cognitive sense, are often stored and represented apart in the practice. Different approaches to the browsing feature are giving within the system, thus the user can personalize the way of viewing the information stored into the folder or can let the system guide the browsing.

Modeling the management of protocols as the kernel of a healthcare information system.

A conceptual model of a health care structure is described. The management of protocols viewed as structured, flexible, and coherent descriptions of activities aimed to solve specific problems in the system is the kernel of the model. A global approach to the protocols is proposed. Each protocol is modeled from two points of view: the nature of the actions (clinical, administrative, programming, and control) and the life cycle of protocols (theoretical, customized, and performed). In our approach the patient folder not only records information about the patient, but also contains and controls the execution of the protocols planned to be performed on the patient. As a consequence, all aspects related to protocol execution are chronologically reported in the folder in a federated manner. In this way the patient folder becomes a complex, multifaceted object, able to capture all information needed to evaluate the patient evolution in a given period.

A survey of telemedicine in Italy.

Italy has a tradition of experimental telemedicine which dates back to the early 1970s. However, despite promising experience, widespread diffusion of telemedicine services has not occurred. The Ministry of Research recognized the potential of telemedicine for improving the quality of health care and reducing costs, and has launched a national plan for financing research and training. The plan is expected to have a major impact on the organization of telemedicine research in Italy. In this paper we describe the current situation, outline the structure of the national plan, and survey various applications in different fields, such as teleconsulting, teleradiology and telemonitoring.

Patient records: from single events to elements for health planning.

Data collected in patient records are not only the kernel of a ward information system, but also the groundwork for planning and evaluating services in health care. The aim of this study was to analyze the problem of aggregate data generation starting from separate items in patient records. After describing the different uses of patient record data, we outline the process which generates aggregates data starting from individual records. This process leads to the definition of the "view on aggregation" as an intermediate step between patient records and aggregate data. A simplified schema is presented based on the Entity-Relationship model representing a conceptual model of the integration of aggregate data and patient record items. Finally, the role is discussed of automation in this process and the perspectives for its implementation.

An object-oriented tool for the generation and management of multimedia patient folders.

Computer-based patient folders are evolving from the simple reproduction of traditional paper documents toward active tools, able to support the whole diagnostic and therapeutic process. The advent of multimediality has given emphasys to the idea of computerized folder, i.e. a collection of heterogeneous kinds of documents pertaining different media. In this paper we present a tool implementing generation and management of multimedia patient folders showing its architecture and functionalities and the innovative interaction paradigms adopted. The tool realized allows medical users to choose the concepts desired in their target application and generates a customized patient folder management system by means of a friendly interface and without the need of a programming language. The system automatically created can be effectively employed for reporting and storing clinical cases.