Clinical and molecular analysis of human reproductive disorders in Brazilian patients

Several genes that influence the development and function of the hypothalamic-pituitary-gonadal-axis (HPG) have been identified. These genes encode an array of transcription factors, matrix proteins, hormones, receptors, and enzymes that are expressed at multiple levels of the HPG. We report the experience of a single Endocrinology Unit in the identification and characterization of naturally occurring mutations in families affected by HPG disorders, including forms of precocious puberty, hypogonadism and abnormal sexual development due to impaired gonadotropin function. Eight distinct genes implicated in HPG function were studied: KAL, SF1, DAX1, GnRH, GnRHR, FSHß, FSHR, and LHR. Most mutations identified in our cohort are described for the first time in literature. New mutations in SF1, DAX1 and GnRHR genes were identified in three Brazilian patients with hypogonadism. Eight boys with luteinizing hormone- (LH) independent precocious puberty due to testotoxicosis were studied, and all have their LH receptor (LHR) defects elucidated. Among the identified LHR molecular defects, three were new activating mutations. In addition, these mutations were frequently associated with new clinical and hormonal aspects, contributing significantly to the knowledge of the molecular basis of reproductive disorders. In conclusion, the naturally occurring genetic mutations described in the Brazilian families studied provide important insights into the regulation of the HPG.

Molecular biology and clinical implication of hepatitis C virus

Hepatitis C virus (HCV) was first described in 1989 as the putative viral agent of non-A non-B hepatitis. It is a member of the Flaviviridae family and has been recognized as the major causative agent of chronic liver disease, including chronic active hepatitis, cirrhosis and hepatocellular carcinoma. HCV is a positive RNA virus with a genome containing approximately 9500 nucleotides. It has an open reading frame that encodes a large polyprotein of about 3000 amino acids and is characterized by extensive genetic diversity. HCV has been classified into at least 6 major genotypes with many subtypes and circulates within an infected individual as a number of closely related but distinct variants known as quasispecies. This article reviews aspects of the molecular biology of HCV and their clinical implication.

Clinical signs of pneumonia in children: association with and prediction of diagnosis by fuzzy sets theory

The present study compares the performance of stochastic and fuzzy models for the analysis of the relationship between clinical signs and diagnosis. Data obtained for 153 children concerning diagnosis (pneumonia, other non-pneumonia diseases, absence of disease) and seven clinical signs were divided into two samples, one for analysis and other for validation. The former was used to derive relations by multi-discriminant analysis (MDA) and by fuzzy max-min compositions (fuzzy), and the latter was used to assess the predictions drawn from each type of relation. MDA and fuzzy were closely similar in terms of prediction, with correct allocation of 75.7 to 78.3% of patients in the validation sample, and displaying only a single instance of disagreement: a patient with low level of toxemia was mistaken as not diseased by MDA and correctly taken as somehow ill by fuzzy. Concerning relations, each method provided different information, each revealing different aspects of the relations between clinical signs and diagnoses. Both methods agreed on pointing X-ray, dyspnea, and auscultation as better related with pneumonia, but only fuzzy was able to detect relations of heart rate, body temperature, toxemia and respiratory rate with pneumonia. Moreover, only fuzzy was able to detect a relationship between heart rate and absence of disease, which allowed the detection of six malnourished children whose diagnoses as healthy are, indeed, disputable. The conclusion is that even though fuzzy sets theory might not improve prediction, it certainly does enhance clinical knowledge since it detects relationships not visible to stochastic models.

Promoting Healthy Lifestyles with Personalized, APOE Genotype Based Health Information: The Effects on Psychological-, Health Behavioral and Clinical Factors

There is an increasing demand for individualized, genotype-based health advice. The general population-based dietary recommendations do not always motivate people to change their life-style, and partly following this, cardiovascular diseases (CVD) are a major cause of death in worldwide. Using genotype-based nutrition and health information (e.g. nutrigenetics) in health education is a relatively new approach, although genetic variation is known to cause individual differences in response to dietary factors. Response to changes in dietary fat quality varies, for example, among different APOE genotypes. Research in this field is challenging, because several non-modifiable (genetic, age, sex) and modifiable (e.g. lifestyle, dietary, physical activity) factors together and with interaction affect the risk of life-style related diseases (e.g. CVD). The other challenge is the psychological factors (e.g. anxiety, threat, stress, motivation, attitude), which also have an effect on health behavior. The genotype-based information is always a very sensitive topic, because it can also cause some negative consequences and feelings (e.g. depression, increased anxiety). The aim of this series of studies was firstly to study how individual, genotype-based health information affects an individual’s health form three aspects, and secondly whether this could be one method in the future to prevent lifestyle-related diseases, such as CVD. The first study concentrated on the psychological effects; the focus of the second study was on health behavior effects, and the third study concentrated on clinical effects. In the fourth study of this series, the focus was on all these three aspects and their associations with each other. The genetic risk and health information was the APOE gene and its effects on CVD. To study the effect of APOE genotype-based health information in prevention of CVD, a total of 151 volunteers attended the baseline assessments (T0), of which 122 healthy adults (aged 20 – 67 y) passed the inclusion criteria and started the one-year intervention. The participants (n = 122) were randomized into a control group (n = 61) and an intervention group (n = 61). There were 21 participants in the intervention Ɛ4+ group (including APOE genotypes 3/4 and 4/4) and 40 participants in the intervention Ɛ4- group (including APOE genotypes 2/3 and 3/3). The control group included 61 participants (including APOE genotypes 3/4, 4/4, 2/3, 3/3 and 2/2). The baseline (T0) and follow-up assessments (T1, T2, T3) included detailed measurements of psychological (threat and anxiety experience, stage of change), and behavioral (dietary fat quality, consumption of vegetables, - high fat/sugar foods and –alcohol, physical activity and health and taste attitudes) and clinical factors (total-, LDL- HDL cholesterol, triglycerides, blood pressure, blood glucose (0h and 2h), body mass index, waist circumference and body fat percentage). During the intervention six different communication sessions (lectures on healthy lifestyle and nutrigenomics, health messages by mail, and personal discussion with the doctor) were arranged. The intervention groups (Ɛ4+ and Ɛ4-) received their APOE genotype information and health message at the beginning of the intervention. The control group received their APOE genotype information after the intervention. For the analyses in this dissertation, the results for 106/107 participants were analyzed. In the intervention, there were 16 participants in the high-risk (Ɛ4+) group and 35 in the low-risk (Ɛ4-) group. The control group had 55 participants in studies III-IV and 56 participants in studies I-II. The intervention had both short-term (≤ 6 months) and long-term (12 months) effects on health behavior and clinical factors. The short-term effects were found in dietary fat quality and waist circumference. Dietary fat quality improved more in the Ɛ4+ group than the Ɛ4- and the control groups as the personal, genotype-based health information and waist circumference lowered more in the Ɛ4+ group compared with the control group. Both these changes differed significantly between the Ɛ4+ and control groups (p<0.05). A long-term effect was found in triglyceride values (p<0.05), which lowered more in Ɛ4+ compared with the control group during the intervention. Short-term effects were also found in the threat experience, which increased mostly in the Ɛ4+ group after the genetic feedback (p<0.05), but it decreased after 12 months, although remaining at a higher level compared to the baseline (T0). In addition, Study IV found that changes in the psychological factors (anxiety and threat experience, motivation), health and taste attitudes, and health behaviors (dietary, alcohol consumption, and physical activity) did not directly explain the changes in triglyceride values and waist circumference. However, change caused by a threat experience may have affected the change in triglycerides through total- and HDL cholesterol. In conclusion, this dissertation study has given some indications that individual, genotypebased health information could be one potential option in the future to prevent lifestyle-related diseases in public health care. The results of this study imply that personal genetic information, based on APOE, may have positive effects on dietary fat quality and some cardiovascular risk markers (e.g., improvement in triglyceride values and waist circumference). This study also suggests that psychological factors (e.g. anxiety and threat experience) may not be an obstacle for healthy people to use genotype-based health information to promote healthy lifestyles. However, even in the case of very personal health information, in order to achieve a permanent health behavior change, it is important to include attitudes and other psychological factors (e.g. motivation), as well as intensive repetition and a longer intervention duration. This research will serve as a basis for future studies and its information can be used to develop targeted interventions, including health information based on genotyping that would aim at preventing lifestyle diseases. People’s interest in personalized health advices has increased, while also the costs of genetic screening have decreased. Therefore, generally speaking, it can be assumed that genetic screening as a part of the prevention of lifestyle-related diseases may become more common in the future. In consequence, more research is required about how to make genetic screening a practical tool in public health care, and how to efficiently achieve long-term changes.

Research in the clinical setting : a qualitative study of the value of play research in the continuing education of occupational therapists.

Occupational therapists have always recognized playas an important part of a child's life. However, until recently play has been viewed as a medium for reaching treatment goals, rather than as an activity that is valuable in and of itself. If occupational therapists think of playas the primary activity or occupation of childhood, then play should be a very important area of focus for paediatric clinicians. In order to assist children to become as independent as possible with play and to have fulfilling play experiences the occupational therapist needs to have a clear understanding of how to assess, set goals which lead towards competence in play, and promote play. Recent play literature has placed importance on play behaviours and looking at the relationship between the child and both the human and nonhuman environment. Believing that play and playfulness can and should be promoted, for children with physical disabilities, requires that therapists learn new assessment and intervention strategies. A new assessment tool, The Test of Playfulness, was developed by Bundy in 1994. It addressed play behaviours and environmental influences. The author, a co-investigator and eight occupational therapists were involved in a playfulness study using this test to compare the playfulness of children with physical disabilities with their able-bodied peers. After the study was completed the author questioned whether or not involvement in the playfulness study was enough of a change agent to bring about transformative learning in order to further the eight occupational therapists' education about play.This study investigated changes in either the therapists' thinking about play or their behaviour in their clinical practice. The study also examined the participants' retention of knowledge about the Test of Playfulness. The eight therapists who had been involved in the playfulness study (participants) were matched with eight therapists who had not been involved (nonparticipants). The therapists were interviewed 9 to 12 months after completion of the playfulness study. They were asked to describe various scenarios of play and open ended prompts were used to elicit the therapists' perceptions of play, good play, the role or value of play, environmental and gender influences on play, play assessment and intervention, and play research, for children with and without disabilities. The participants were also prompted to discuss their experience with the playfulness study. A self-report questionnaire was also completed at the end of the interview. The results of the study demonstrated that: (a) the play research project was a good format for continuing the participants' education about play; (b) their thinking had changed about play; (c) according to self report, they had used this new knowledge in their clinical practice; and (d) the participants remembered the items on the Test of Playfulness and could use them in describing various aspects of play. This study found that participating in a play research project had been an effective method of professional development. It also highlighted the need for increased awareness of the recent literature on play and the developing role of the occupational therapist in the assessment and intervention of play.

Aspects méthodologiques, mesure et facteurs associés à l’autonomie des patients utilisant les technologies de dialyse péritonéale à domicile

La dialyse péritonéale (DP) est une thérapie d’épuration extra-rénale qui peut se réaliser à domicile par l’entremise d’une technologie. Elle exige, du patient certaines aptitudes, (motivation et compétence) et de l’équipe de soins, une organisation particulière pour arriver à une autonomie d’exécution de l’épuration. Dans un contexte de thérapie à domicile, comme celui de la dialyse péritonéale, le niveau d’autonomie des patients ainsi que les facteurs qui y sont associés n’ont pas été examinés auparavant. C’est l’objet de cette thèse. En se fondant sur la théorie de l’autodétermination et sur une revue de la littérature, un cadre conceptuel a été développé et fait l’hypothèse que trois types de facteurs essentiels pourraient influencer l’autonomie. Il s’agit de facteurs individuels, technologiques et organisationnels. Pour tester ces hypothèses, un devis mixte séquentiel, composé de deux volets, a été réalisé. Un premier volet qualitatif - opérationnalisé par des entrevues auprès de 12 patients et de 11 infirmières - a permis, d’une part, d’explorer et de mieux définir les dimensions de l’autonomie pertinente dans le cadre de la DP; d’autre part de bonifier le développement d’un questionnaire. Après validation, ce dernier a servi à la collecte de données lors du deuxième volet quantitatif et alors a permis d’obtenir des résultats auprès d’un échantillon probabiliste (n =98), tiré de la population des dialysés péritonéaux du Québec (N=700). L’objectif de ce deuxième volet était de mesurer le degré d’autonomie des patients, d’examiner les associations entre les facteurs technologiques, organisationnels ainsi qu’individuels et les différentes dimensions de l’autonomie. Des analyses univariées et multivariées ont été réalisées à cet effet. Les résultats obtenus montrent que quatre dimensions d’autonomie sont essentielles à atteindre en dialyse à domicile. Il s’agit de l’autonomie, sur le plan clinique, technique, fonctionnel (liberté journalière) et organisationnel (indépendance par rapport à l’institution de soins). Pour ces quatre types d’autonomie, les patients ont rapporté être hautement autonomes, un résultat qui se reflète dans les scores obtenus sur une échelle de 1 à 5 : l’autonomie clinique (4,1), l’autonomie technique (4,8), l’autonomie fonctionnelle (4,1) et l’autonomie organisationnelle (4,5). Chacun de ces types d’autonomie est associé à des degrés variables aux trois facteurs du modèle conceptuel : facteurs individuels (motivation et compétence), technologique (convivialité) et organisationnels (soutien clinique, technique et familial). Plus spécifiquement, la motivation serait associée à l’autonomie fonctionnelle. La convivialité serait associée à l’autonomie clinique, alors que la myopathie pourrait la compromettre. La convivialité de la technologie et la compétence du patient contribueraient à une meilleure autonomie organisationnelle. Quant à l’autonomie sur le plan technique, tous les patients ont rapporté être hautement autonomes en ce qui concerne la manipulation de la technologie. Ce résultat s’expliquerait par une formation adéquate mise à la disposition des patients en prédialyse, par le suivi continu et par la manipulation quotidienne pendant des années d’utilisation. Bien que dans cette thèse la technologie d’application soit la dialyse péritonéale, nous retenons que lorsqu’on transfère la maîtrise d’une technologie thérapeutique à domicile pour traiter une maladie chronique, il est primordial d’organiser ce transfert de telle façon que les trois facteurs techniques (convivialité), individuels (motivation, formation et compétence), et organisationnels (soutien de l’aidant) soient mis en place pour garantir une autonomie aux quatre niveaux, technique, clinique, fonctionnel et organisationnel.

Rhythmic Masticatory Muscle Activity during Sleep: Etiology and Clinical Perspectives

L’activité rythmique des muscles masticateurs (ARMM) pendant le sommeil se retrouve chez environ 60% de la population générale adulte. L'étiologie de ce mouvement n'est pas encore complètement élucidée. Il est cependant démontré que l’augmentation de la fréquence des ARMM peut avoir des conséquences négatives sur le système masticatoire. Dans ce cas, l'ARMM est considérée en tant que manifestation d'un trouble moteur du sommeil connue sous le nom de bruxisme. Selon la Classification Internationale des Troubles du Sommeil, le bruxisme est décrit comme le serrement et grincement des dents pendant le sommeil. La survenue des épisodes d’ARMM est associée à une augmentation du tonus du système nerveux sympathique, du rythme cardiaque, de la pression artérielle et elle est souvent en association avec une amplitude respiratoire accrue. Tous ces événements peuvent être décrits dans le contexte d’un micro-éveil du sommeil. Cette thèse comprend quatre articles de recherche visant à étudier i) l'étiologie de l’ARMM pendant le sommeil en relation aux micro-éveils, et à évaluer ii) les aspects cliniques du bruxisme du sommeil, du point de vue diagnostique et thérapeutique. Pour approfondir l'étiologie de l’ARMM et son association avec la fluctuation des micro-éveils, nous avons analysé le patron cyclique alternant (ou cyclic alternating pattern (CAP) en anglais), qui est une méthode d’analyse qui permet d’évaluer l'instabilité du sommeil et de décrire la puissance des micro-éveils. Le CAP a été étudié chez des sujets bruxeurs et des sujets contrôles qui ont participé à deux protocoles expérimentaux, dans lesquels la structure et la stabilité du sommeil ont été modifiées par l'administration d'un médicament (la clonidine), ou avec l'application de stimulations sensorielles (de type vibratoire/auditif) pendant le sommeil. Dans ces deux conditions expérimentales caractérisées par une instabilité accrue du sommeil, nous étions en mesure de démontrer que les micro-éveils ne sont pas la cause ou le déclencheur de l’ARMM, mais ils représentent plutôt la «fenêtre permissive» qui facilite l'apparition de ces mouvements rythmiques au cours du sommeil. Pour évaluer la pertinence clinique du bruxisme, la prévalence et les facteurs de risque, nous avons effectué une étude épidémiologique dans une population pédiatrique (7-17 ans) qui était vue en consultation en orthodontie. Nous avons constaté que le bruxisme est un trouble du sommeil très fréquent chez les enfants (avec une prévalence de 15%), et il est un facteur de risque pour l'usure des dents (risque relatif rapproché, RRR 8,8), la fatigue des muscles masticateurs (RRR 10,5), les maux de tête fréquents (RRR 4,3), la respiration bruyante pendant le sommeil (RRR 3,1), et divers symptômes liés au sommeil, tels que la somnolence diurne (RRR 7,4). Ces résultats nous ont amenés à développer une étude expérimentale pour évaluer l'efficacité d'un appareil d'avancement mandibulaire (AAM) chez un groupe d'adolescents qui présentaient à la fois du bruxisme, du ronflement et des maux de tête fréquents. L'hypothèse est que dans la pathogenèse de ces comorbidités, il y a un mécanisme commun, probablement lié à la respiration pendant le sommeil, et que l'utilisation d'un AAM peut donc agir sur plusieurs aspects liés. À court terme, le traitement avec un AAM semble diminuer l'ARMM (jusqu'à 60% de diminution), et améliorer le ronflement et les maux de tête chez les adolescents. Cependant, le mécanisme d'action exact des AAM demeure incertain; leur efficacité peut être liée à l'amélioration de la respiration pendant le sommeil, mais aussi à l'influence que ces appareils pourraient avoir sur le système masticatoire. Les interactions entre le bruxisme du sommeil, la respiration et les maux de tête, ainsi que l'efficacité et la sécurité à long terme des AAM chez les adolescents, nécessitent des études plus approfondies.

Nanostructure des particules polymériques : aspects physiques, chimiques et biologiques

Les nanotechnologies appliquées aux sciences pharmaceutiques ont pour but d’améliorer l’administration de molécules actives par l’intermédiaire de transporteurs nanométriques. Parmi les différents types de véhicules proposés pour atteindre ce but, on retrouve les nanoparticules polymériques (NP) constituées de copolymères “en bloc”. Ces copolymères permettent à la fois l’encapsulation de molécules actives et confèrent à la particule certaines propriétés de surface (dont l’hydrophilicité) nécessaires à ses interactions avec les milieux biologiques. L’architecture retenue pour ces copolymères est une structure constituée le plus fréquemment de blocs hydrophiles de poly(éthylène glycol) (PEG) associés de façon linéaire à des blocs hydrophobes de type polyesters. Le PEG est le polymère de choix pour conférer une couronne hydrophile aux NPs et son l’efficacité est directement liée à son organisation et sa densité de surface. Néanmoins, malgré les succès limités en clinique de ces copolymères linéaires, peu de travaux se sont attardés à explorer les effets sur la structure des NPs d’architectures alternatives, tels que les copolymères en peigne ou en brosse. Durant ce travail, plusieurs stratégies ont été mises au point pour la synthèse de copolymères en peigne, possédant un squelette polymérique polyesters-co-éther et des chaines de PEG liées sur les groupes pendants disponibles (groupement hydroxyle ou alcyne). Dans la première partie de ce travail, des réactions d’estérification par acylation et de couplage sur des groupes pendants alcool ont permis le greffage de chaîne de PEG. Cette méthode génère des copolymères en peigne (PEG-g-PLA) possédant de 5 à 50% en poids de PEG, en faisant varier le nombre de chaînes branchées sur un squelette de poly(lactique) (PLA). Les propriétés structurales des NPs produites ont été étudiées par DLS, mesure de charge et MET. Une transition critique se situant autour de 15% de PEG (poids/poids) est observée avec un changement de morphologie, d’une particule solide à une particule molle (“nanoagrégat polymére”). La méthode de greffage ainsi que l’addition probable de chaine de PEG en bout de chaîne principale semblent également avoir un rôle dans les changements observés. L’organisation des chaînes de PEG-g-PLA à la surface a été étudiée par RMN et XPS, méthodes permettant de quantifier la densité de surface en chaînes de PEG. Ainsi deux propriétés clés que sont la résistance à l’agrégation en conditions saline ainsi que la résistance à la liaison aux protéines (étudiée par isothermes d’adsorption et microcalorimétrie) ont été reliées à la densité de surface de PEG et à l’architecture des polymères. Dans une seconde partie de ce travail, le greffage des chaînes de PEG a été réalisé de façon directe par cyclo-adition catalysée par le cuivre de mPEG-N3 sur les groupes pendants alcyne. Cette nouvelle stratégie a été pensée dans le but de comprendre la contribution possible des chaines de PEG greffées à l’extrémité de la chaine de PLA. Cette librairie de PEG-g-PLA, en plus d’être composée de PEG-g-PLA avec différentes densités de greffage, comporte des PEG-g-PLA avec des PEG de différent poids moléculaire (750, 2000 et 5000). Les chaines de PEG sont seulement greffées sur les groupes pendants. Les NPs ont été produites par différentes méthodes de nanoprécipitation, incluant la nanoprécipitation « flash » et une méthode en microfluidique. Plusieurs variables de formulation telles que la concentration du polymère et la vitesse de mélange ont été étudiées afin d’observer leur effet sur les caractéristiques structurales et de surface des NPs. Les tailles et les potentiels de charges sont peu affectés par le contenu en PEG (% poids/poids) et la longueur des chaînes de PEG. Les images de MET montrent des objets sphériques solides et l'on n’observe pas d’objets de type agrégat polymériques, malgré des contenus en PEG comparable à la première bibliothèque de polymère. Une explication possible est l’absence sur ces copolymères en peigne de chaine de PEG greffée en bout de la chaîne principale. Comme attendu, les tailles diminuent avec la concentration du polymère dans la phase organique et avec la diminution du temps de mélange des deux phases, pour les différentes méthodes de préparation. Finalement, la densité de surface des chaînes de PEG a été quantifiée par RMN du proton et XPS et ne dépendent pas de la méthode de préparation. Dans la troisième partie de ce travail, nous avons étudié le rôle de l’architecture du polymère sur les propriétés d’encapsulation et de libération de la curcumine. La curcumine a été choisie comme modèle dans le but de développer une plateforme de livraison de molécules actives pour traiter les maladies du système nerveux central impliquant le stress oxydatif. Les NPs chargées en curcumine, montrent la même transition de taille et de morphologie lorsque le contenu en PEG dépasse 15% (poids/poids). Le taux de chargement en molécule active, l’efficacité de changement et les cinétiques de libérations ainsi que les coefficients de diffusion de la curcumine montrent une dépendance à l’architecture des polymères. Les NPs ne présentent pas de toxicité et n’induisent pas de stress oxydatif lorsque testés in vitro sur une lignée cellulaire neuronale. En revanche, les NPs chargées en curcumine préviennent le stress oxydatif induit dans ces cellules neuronales. La magnitude de cet effet est reliée à l’architecture du polymère et à l’organisation de la NP. En résumé, ce travail a permis de mettre en évidence quelques propriétés intéressantes des copolymères en peigne et la relation intime entre l’architecture des polymères et les propriétés physico-chimiques des NPs. De plus les résultats obtenus permettent de proposer de nouvelles approches pour le design des nanotransporteurs polymériques de molécules actives.

Psychosexual aspects of vulvovaginal pain.

Vulvovaginal pain problems are major health concerns in women of childbearing age. Controlled studies have shown that vulvovaginal pain can adversely affect women and their partners’ general psychological well-being, relationship adjustment and overall quality of life. These women have significantly lower levels of sexual desire, arousal, and satisfaction, as well as a lower intercourse frequency than normal controls. They also report more anxiety and depression, in addition to more distress about their body image and genital self-image. Empirical studies indicate that specific psychological and relationship factors may increase vulvovaginal pain intensity and its psychosexual sequelae. Randomized clinical trials have shown that psychosexual interventions, namely cognitive-behavioral therapy (CBT), are efficacious in reducing vulvovaginal pain and improving associated psychosexual outcomes. Women reporting significant psychological, sexual and/or relationship distress should be referred for psychosexual treatment. A multimodal approach to care integrating psychosexual and medical management is thought to be optimal.

Infectious aspects and the etiopathogenesis of rheumatoid arthritis

Infections are believed to contribute to the maturation of the immune system from the innate to the adaptive phases and therefore may take part in the induction of autoimmune conditions. In the current study, we present an extensive analysis conducted on sera samples of patients with rheumatoid arthritis in order to seek evidence of previous or coexisting infectious processes using the Bio-Rad BioPlex immunoassay analyzer. We detected higher rates of serological evidence of infections with Epstein–Barr virus and cytomegalovirus viruses. Our findings may indicate a role of these viruses in the pathogenesis of RA.

Lipids and the immune response: from molecular mechanisms to clinical applications

Purpose of review This review critically evaluates recent studies investigating the effects of fatty acids on immune and inflammatory responses in both healthy individuals and in patients with inflammatory diseases, with some reference to animal studies where relevant. It examines recent findings describing the cellular and molecular basis for the modulation of immune function by fatty acids. The newly emerging area of diet-genotype interactions will also be discussed, with specific reference to the anti-inflammatory effects of fish oil. Recent findings Fatty acids are participants in many intracellular signalling pathways. They act as ligands for nuclear receptors regulating a host of cell responses, they influence the stability of lipid rafts, and modulate eicosanoid metabolism in cells of the immune system. Recent findings suggest that some or all of these mechanisms may be involved in the modulation of immune function by fatty acids. Summary Human studies investigating the relationship between dietary fatty acids and some aspects of the immune response have been disappointingly inconsistent. This review presents the argument that most studies have not been adequately powered to take into account the influence of variation (genotypic or otherwise) on parameters of immune function. There is well-documented evidence that fatty acids modulate T lymphocyte activation, and recent findings describe a range of potential cellular and molecular mechanisms. However, there are still many questions remaining, particularly with respect to the roles of nuclear receptors, for which fatty acids act as ligands, and the modulation of eicosanoid synthesis, for which fatty acids act as precursors.

Refinement of the Clinical Scenario Evaluation Framework for Assessment of Competing Development Strategies with an Application to Multiple Sclerosis

When competing strategies for development programs, clinical trial designs, or data analysis methods exist, the alternatives need to be evaluated in a systematic way to facilitate informed decision making. Here we describe a refinement of the recently proposed clinical scenario evaluation framework for the assessment of competing strategies. The refinement is achieved by subdividing key elements previously proposed into new categories, distinguishing between quantities that can be estimated from preexisting data and those that cannot and between aspects under the control of the decision maker from those that are determined by external constraints. The refined framework is illustrated by an application to a design project for an adaptive seamless design for a clinical trial in progressive multiple sclerosis.

Ontology modeling for generation of clinical pathways

Purpose: Increasing costs of health care, fuelled by demand for high quality, cost-effective healthcare has drove hospitals to streamline their patient care delivery systems. One such systematic approach is the adaptation of Clinical Pathways (CP) as a tool to increase the quality of healthcare delivery. However, most organizations still rely on are paper-based pathway guidelines or specifications, which have limitations in process management and as a result can influence patient safety outcomes. In this paper, we present a method for generating clinical pathways based on organizational semiotics by capturing knowledge from syntactic, semantic and pragmatic to social level. Design/methodology/approach: The proposed modeling approach to generation of CPs adopts organizational semiotics and enables the generation of semantically rich representation of CP knowledge. Semantic Analysis Method (SAM) is applied to explicitly represent the semantics of the concepts, their relationships and patterns of behavior in terms of an ontology chart. Norm Analysis Method (NAM) is adopted to identify and formally specify patterns of behavior and rules that govern the actions identified on the ontology chart. Information collected during semantic and norm analysis is integrated to guide the generation of CPs using best practice represented in BPMN thus enabling the automation of CP. Findings: This research confirms the necessity of taking into consideration social aspects in designing information systems and automating CP. The complexity of healthcare processes can be best tackled by analyzing stakeholders, which we treat as social agents, their goals and patterns of action within the agent network. Originality/value: The current modeling methods describe CPs from a structural aspect comprising activities, properties and interrelationships. However, these methods lack a mechanism to describe possible patterns of human behavior and the conditions under which the behavior will occur. To overcome this weakness, a semiotic approach to generation of clinical pathway is introduced. The CP generated from SAM together with norms will enrich the knowledge representation of the domain through ontology modeling, which allows the recognition of human responsibilities and obligations and more importantly, the ultimate power of decision making in exceptional circumstances.

Integrated clinical pathway management for medical quality improvement-based on a semiotically inspired systems architecture

Clinical pathway is an approach to standardise care processes to support the implementations of clinical guidelines and protocols. It is designed to support the management of treatment processes including clinical and non-clinical activities, resources and also financial aspects. It provides detailed guidance for each stage in the management of a patient with the aim of improving the continuity and coordination of care across different disciplines and sectors. However, in the practical treatment process, the lack of knowledge sharing and information accuracy of paper-based clinical pathways burden health-care staff with a large amount of paper work. This will often result in medical errors, inefficient treatment process and thus poor quality medical services. This paper first presents a theoretical underpinning and a co-design research methodology for integrated pathway management by drawing input from organisational semiotics. An approach to integrated clinical pathway management is then proposed, which aims to embed pathway knowledge into treatment processes and existing hospital information systems. The capability of this approach has been demonstrated through the case study in one of the largest hospitals in China. The outcome reveals that medical quality can be improved significantly by the classified clinical pathway knowledge and seamless integration with hospital information systems.