Dissertations / Theses on the topic 'Therapeutically'

In the last 10 years there has been a growth in working collaboratively with sex offenders by focusing on goals, tailoring treatment to the needs of the client, and an emphasis on therapist features (Andrews & Bonta, 2003 ; Ward, 2002). This thesis explored how sex offender treatment workers are responding to working with sex offenders in light of the changes. The introduction covers the key concepts and theory relevant to the thesis, and highlights the aims. The second chapter is a systematic literature review investigating the impact of working therapeutically with sex offenders. The review highlighted the extent sex offender treatment workers are impacted by their work was inconclusive. The third chapter focused on critiquing the Trauma Symptom Inventory (TSI; Briere, 1995) as a potential tool that could be used to assess distress in sex offender treatment workers. The critique revealed that the TSI had good reliability and validity. The fourth chapter explored the experiences of sex offender treatment workers using semi-structured interviews. All participants reported enjoying their work despite experiencing some negatives (i. e., intrusive images, suspiciousness, and concerns about clients re-offending). This chapter also highlighted that sex offender treatment workers reported using a range of coping strategies to manage the work. In addition, it was found that sex offender treatment workers believed a genuine interest in the work, hope, optimism, self-efficacy, and circumstances outside of work were related to enhanced resilience. The last chapter of the thesis involved discussing the implications of the findings from each of the chapters.

In numerous countries, including the United Kingdom (UK), America, Australia, and Sweden, Social and Emotional Learning (SEL) initiatives represent a dominant manifestation of ‘therapeutic education’ (TE) which has emerged in response to growing concerns about the emotional well-being and mental health of children and young people. Implemented by a diverse range of lay experts, including teachers, teaching assistants, coaches and consultants, SEL-work emphasises the teaching of socio-emotional skills. Drawing on a critical realist framework, this thesis explores the ways in which SEL, is constructed both through language and practice and the wider implications of these discursive constructions for professional subjectivities. This research employs a realist ethnographic design across three school sites in the East Midlands area of the UK. Qualitative data, gathered through interviews, in-depth observations and documentary materials reveal a number of tensions within these constructions of SEL. In addition, an analysis of the qualitative data draws attention to an emerging and idealised professional subjectivity, namely, the teacher as charismatic emotional hero. The thesis argues that, despite some positive constructions of SEL, therapeutic practices in schools are often a site at which the psychopathologisation of children occurs.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references.
Modern molecular biology, biochemical, and chemical techniques have made it possible to identify individual natural products that possess pharmacological activity from medicinal plants. While approximately 50% of all new FDA-approved small molecule therapeutics in the past 40 years were natural products or natural product analogs, challenges including limited natural resources and the difficulty of solving the total synthesis or semi-synthesis of natural products has limited our ability to harness the full diversity of chemical structures provided by nature to treat human diseases. One solution to these challenges is the elucidation of plant specialized metabolite biosynthetic pathways. Identifying and characterizing the enzymes involved in specialized metabolite biosynthesis will provide insight into the evolution of enzymes performing interesting chemistries and provide new tools for the enzymatic production of therapeutically promising natural products. The goal of this dissertation is to explore the aspects of both medicinal chemistry and the elucidation of biosynthetic pathways that can contribute to the development of novel therapeutics. First, we analyzed the structure-activity relationship of analogs of the the flavonoid icariin and identified analogs with improved potency in inhibiting human phosphodiesterase-5. We subsequently identified and characterized a novel flavonoid prenyltransferase and O-methyltransferase from the medicinal herb Epimedium sagittatum that is known to produce many bioactive prenylated and methylated flavonoids.
by Yasmin-Pei Chau.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering

To guide therapeutic decision making, the pharmacokinetics (PK) of certain toxic drugs are typically studied in blood. A drug’s blood concentration is thus acting as a surrogate for its target site concentration. However, a drug’s target is often extravascular and measuring tissue concentrations would be more meaningful. Furthermore, blood sampling is painful and can be challenging for some patients such as children, seriously ill, and old patients; it is, however, currently the standard method for drug testing. Current research suggests that a tissue fluid called interstitial fluid (ISF) can be sampled in minimal amounts without pain and can be used to quantify certain drugs. However, to successfully use this fluid for therapeutic drug monitoring, researchers still face three main challenges: sampling ISF, determining the concentrations and PK of drugs in ISF and their relation to blood concentrations, and quantifying drugs in very small volumes. To improve these challenges, we studied all three areas. First, we reviewed and evaluated methods of extracting ISF. Second, we studied ISF and blood concentrations of 13 drugs in a rabbit model to evaluate their PK. And third, we developed a method for quantifying a drug in just 2 µL of serum from rabbits. Currently available methods need larger sample volumes, whereas ISF is only available in small amounts. We found that many of the drugs we tested in a single-dose study were readily detectable in ISF (vancomycin, gentamicin, methotrexate, cisplatin, carboplatin, valproic acid, phenobarbital, mycophenolic acid and theophylline) and their PK parameters were determined using non-compartmental analysis. Furthermore, steady-state concentrations were predicted from the single-dose study for blood and ISF. At equilibrium, ISF drug concentrations were higher (vancomycin and gentamicin) and more stable compared to blood concentrations. For vancomycin these predictions were confirmed in an additional in vivo study. We further found that the concentration vs. time course of some drugs (vancomycin, gentamicin, methotrexate, valproic acid, phenobarbital, mycophenolic acid, digoxin and theophylline) could be well described by compartmental models. This study shows that ISF can be a valuable matrix for therapeutic drug monitoring and merits further studies to ascertain its clinical utility.
Pharmaceutical Sciences, Faculty of
Graduate

Email usage for mental health services is on the rise. However, research in this area is scarce and focused on its effectiveness. Although preliminary etherapy effectiveness research shows positive results, little research exists that explores e-therapy practice. Thus literature relies on face-to-face therapy theories to make sense of e-therapist processes. However, the perceptions and processes of e-therapists may be affected by the differences in mediums. This study aimed to further the understanding of e-therapy practice by exploring e-therapists' perceptions of how they interact therapeutically. The qualitative methods of Interpretative phenomenological analysis were used. The author conducted semi-structured interviews with 12 e-therapists who used CBT techniques, six interviews were conducted via email and six via computer-mediated telephone. Email and telephone transcripts were analysed separately for recurrent themes. Major themes that arose from both telephone and email interview analyses addressed how etherapists perceived the differences between face-to-face and email therapy interaction affected their practice, specifically the absence of face-to-face contact resulted in a sense of loss of traditional therapy concepts, immediacy and presence. Other themes referred to e-therapist intentions of forging and strengthening therapeutic relationships via email by using email's time delay to thoroughly consider and edit responses, its boundary flexibility to adhere to client needs and preferences and its textual nature to better understand client issues. One major theme which arose from the email interview data referred to participant preferences for email over face-to-face interaction, highlighting that they viewed the distance from clients and the process of writing as enabling them to construct higher quality therapy responses. Implications of these findings were that e-therapists perceived that while some email-specific aspects caused challenges, others were facilitative in their therapy practices. New e-therapy processes were discussed in the context of current literature. However further e-therapy-specific and clientfocused research is needed.

The research literature reveals a widespread reluctance on the part of therapists to work with older people therapeutically as it is believed to be an unrewarding experience and of little benefit for this cohort. This is in contrast to empirical research which shows that therapeutic interventions can be effective and beneficial for older people. There is little literature that looks at the lived experience of therapists who work with older people and none from a counselling psychology perspective. It is therefore hoped that gaining a phenomenological understanding of the experience will provide insight and understanding into the lived experience of therapists who work with older adults. The research question was: 'What is the experience of working therapeutically with the older client?' A qualitative methodology, Interpretative Phenomenological Analysis (IPA) (Smith and Osborn, 2003) was employed for both the conduct and the analysis of the research. Purposive sampling enabled the selection of seven participants for whom the research question was relevant. Semi-structured interview were carried out with three counselling psychologists and four therapists. The age range of the participants was 31-68 years; there were two males and five females. Three master themes emerged: (1) in respect of age - doing therapy differently; (2) the impact of the older client on the therapist; and (3) the reluctant therapist. A description of the master themes, and related constituent themes, is presented and discussed. Although these findings are consonant with the relevant research literature, the research is unique in capturing not only the therapist's lived experience but that of the counselling psychologist as well. It is therefore an important and significant contribution to the field of therapeutic work with older people and a vital addition to the counselling psychology literature. The results of the analysis and implications for counselling psychology are discussed.

This present thesis focuses on compounds related to the epidithiodiketopiperazine (ETP) family of natural products, their synthesis and biological effects. The domain of natural products has long been recognized as an invaluable source of lead structures for the discovery and development of novel therapeutic agents, with the motif being one example that has long been recognized for its potent biological effects which are directly related to the disulfide bridge at the central core. The first chapter provides a detailed analysis of the ETP family of natural products with both the monomeric and dimeric family members being described to provide an overview of this diverse family of compounds and their corresponding biological effects. The second section in this chapter highlights the various synthetic strategies adopted by a number of different research groups and attempts to classify these into the varying approaches towards the central core. Finally the section closes with a description of dimeric natural products and their biological effects in relation to the potent activity observed from the dimeric ETP congeners. The results of our own approach towards the ETP core are described in the third chapter which commences with the synthesis of disubstituted ETPs and expands towards our efforts in synthesizing their tri and tetrasubstituted counterparts. Efforts to extend this chemistry towards dimeric ETPs are also described and our successful routes towards these complex compounds are discussed. The following section of this chapter outlines the successful biological evaluation of the ETP compounds that were synthesised with relevance to their effects in a surrogate model of tuberculosis, cancer cells via inhibition of the hypoxia pathway and activity against the feline immunodeficiency virus. The final chapter provides a formal description of the experimental results and procedures with full characterisation of the data for each compound.

It is recognised that emotional and relational difficulties can have a negative influence on children's wellbeing, academic performance and behaviour. These same issues can affect adults who care for and work with children. In this thesis, interventions that are designed to help a child or adult address such problems are considered to be therapeutic. Within educational psychology, there is much debate about whether educational psychologists (EPs) should work therapeutically. Those who choose to work in this way appear to face additional challenges. I wanted to explore this issue by using a reflective process to engage with the narratives that EPs told regarding their experiences of using therapeutic interventions within their role. The study is positioned within an approach to ontological and epistemological concerns that can be described as social constructionist. Two EPs were invited to tell their story within an unstructured interview. The narratives that emerged were a joint construction within a particular context. I analysed the narratives using a self-reflective process informed by my therapeutic training, and thematic analysis as suggested by Braun and Clarke (2006). The findings suggested that at the heart of therapeutic work were good relationships with children and adults. The EPs involved in this study reported that they found such work rewarding. However, they often faced challenges when building and sustaining these relationships. They identified that there was limited time to deliver such work and that training and supervision were often inadequate. The process of the study offered an alternative approach to research and practice within educational psychology, one that placed greater value upon personal narratives and experience. Key words: Therapeutic intervention, social constructionism, narrative, the dynamic nature of knowledge, self-reflection, and thematic analysis.

This narrative inquiry explored the meaning that graduate students in a counselling psychology program ascribed to the experience of life review. Life review is defined as an evaluative process of intentionally revisiting past events and memories in order to integrate these experiences into the present. The particular method of life review employed in this study was guided autobiography, a group-based approach to life review in which participants write autobiographical stories, read the stories aloud in a group setting, and receive comments and feedback from fellow group members. Previous research in the life review literature has predominately focused on investigating the use of life review with older adults nearing the end of life, has relied heavily on quantitative research methods, and has identified the outcomes of life review, rather than explored the process. The current research contributes to the literature by exploring life review from a qualitative perspective with a younger demographic, by focusing on the underlying meaning- making processes of life review, and by exploring therapeutically meaningful experiences fostered in a guided autobiography group. Participants’ narrative accounts of their experiences in a guided autobiography workshop are presented in this document, and contribute to understanding the viability of life review to promote personal change in the lives of adults in young to mid-adulthood. Twelve thematic findings were generated in this research, which confirm and extend prior research. Novel contributions to the literature include identifying key therapeutic processes that occurred in each phase of the guided autobiography process and the frequency with which they occurred. The most frequently occurring therapeutic processes were a sense of connection, new awareness and insight, and making sense or new meaning out of past experiences. Based on these findings, the study concludes that life review is beneficial for a younger population and suggests it can promote experiences that support personal change in the lives of individuals in young to mid-adulthood. Specific recommendations are made for the therapeutic application of life review, most notably the proposal that an individual follow-up interview be added as a final phase to the guided autobiography process to enhance therapeutic gains.

This thesis considers Educational Psychologists' (EPs) views of references to therapy in A review of the functions and contribution of educational psychologists in England and Wales in light of "Every Child Matters: Change for Children" (Farrell et al, 2006). A grounded theory methodological approach was undertaken, contributing three core categories to existing theoretical knowledge about EPs and therapeutic interventions: seeking demystification and clarity in relation to the language of therapy and therapeutic interventions and the appropriateness for EPs; a changing future for EPs; a frustrated conditional desire for therapeutic work. These core categories will be discussed in the context of existing literature. Associated recommendations have been made for the EP profession, Local Authorities, Educational Psychology Services (EPSs) and individual EPs.

Pharmacogenetics involves research into the hereditary basis for the different responses of individuals to drugs or other environmental pollutants. Several functional genetic polymorphisms of drug metabolising enzymes, transporters, receptors and other drug targets have been identified and characterised and these polymorphisms may be responsible for interethnic differences in drug disposition and disease risk. Few studies have focussed on ethnic African populations. Several genes that have known genetic polymorphism and have clinical implications for disease risk and/or treatment of patients were evaluated in a sample of the Ghanaian (West African) population. Catechol-O-methyltransferase (COMT) catalyses the 0-methylation of neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. Ethnic differences in COMT activity have been observed in several populations. Previous studies suggest that the homozygous low activity allele (COMT*L) is less common in individuals of African origin than Caucasians. COMT genotyping was performed using a mini-sequencing method in 195 healthy Ghanaians. The frequency of the homozygous low activity allele was 6%. In Caucasians it is 31%. This study provides confirmation that the low activity COMT allele is less common in individuals of African origin. This finding may be important clinically with regards to the treatment of many neuropsychiatric disorders and in the pathophysiology of various human disorders including oestrogen-induced cancers, Parkinson's disease, depression and hypertension. This thesis aimed to determine the allele frequency of therapeutically important genetic polymorphisms in an African (Ghanaian) population. The data was then compared to other ethnic populations. The marked racial and ethnic differences in the frequency of functional polymorphisms in these drug- and xenobiotic-metabolising enzymes, transporters, receptors and other drug targets shows that ethnic origin needs to be considered in studies aimed at discovering whether specific genotypes or phenotypes are associated with disease risk or drug toxicity. Genotyping prior to treatment may be essential, as 95% of the Ghanaian subjects genotyped had between one and four mutations in the therapeutically important genes analysed. Genotyping assays specific for predominant mutant alleles should be used in different ethnic groups.

In this study, it was aimed to develop a bioprocess using the Pichia pastoris expression system as an alternative to the mammalian system used in industry, for production of the therapeutically important glycoprotein, erythropoietin, and to form stoichiometric and kinetic models. Firstly, the human EPO gene, fused with a polyhistidine-tag and factor-Xa protease target site, in which cleavage produces the native termini of EPO, was integrated to AOX1 locus of P. pastoris. The Mut+ strain having the highest rHuEPO production capacity was selected. The glycosylation profile of rHuEPO was characterized by MALDI-ToF MS and Western blotting. The native polypeptide form of human EPO was obtained for the first time in P. pastoris expression system, after affinity-purification, deglycosylation and factor-Xa protease digestion. Thereafter, effects of medium components and pH on rHuEPO production and cell growth were investigated in laboratory-scale bioreactors. Sorbitol was shown to increase production efficiency when added as a co-substrate. Moreover, a cheap alternative nutrient, the byproduct of biodiesel industry, crude-glycerol, was suggested for the first time for P. pastoris fermentations. Furthermore, methanol feeding strategy was investigated in fed-batch pilot-scale bioreactors, producing 70 g L-1 biomass and 130 mg L-1 rHuEPO at t=24h. Moreover, metabolic flux analysis by using the stoichiometric model formed, which consisted of m=102 metabolites and n=141 reactions, proved useful in further understanding the P. pastoris metabolism. Finally, the first structured kinetic model formed for r-protein production with P. pastoris successfully predicted cell growth, substrate consumption and r-product production rates, where rHuEPO production kinetics was associated with AOX production and proteolytic degradation.

En réponse à une stimulation sonore, la cellule ciliée interne libère du glutamate qui va activer des récepteurs distribués sur le bouton post-synaptique. Les courants post-synaptiques vont ensuite dépolariser la terminaison périphérique des neurones auditifs primaires, et initier le déclenchement d'un potentiel d'action. Tandis que la connaissance des mécanismes pré-synaptiques a considérablement progressé ces 10 dernières années, les mécanismes responsables de l'initiation des potentiels d'action sont encore méconnus. Dans cette étude, nous avons déterminé les conductances ioniques nécessaires au déclenchement des potentiels d'action. Les paramètres biophysiques des conductances (Na et K) ont été identifiés (algorithme d'identification trace entière) à partir d'enregistrements de patch clamp acquis sur les corps cellulaires. Un modèle mathématique de nœud de Ranvier a ensuite été développé en faisant l'hypothèse que les canaux présents sur le corps cellulaire et sur un nœud de Ranvier étaient de même nature mais en densités différentes. Les paramètres de ce modèle ont été identifiés pour reproduire les potentiels d'action extracellulaire au moyen d'un algorithme de descente du gradient. Nous avons identifié i) un courant Na entrant rapide (GNa activation: V1/2=-33 mV, act< 0.5 ms; inactivation: V1/2=-61 mV, inact < 2 ms) et deux courants K sortants, un rectifiant retardé activé à haut seuil (GKH, activation: V1/2=-41 mV; act < 2.5 ms) et un activé à bas seuil (GKL, activation: V1/2=-56 mV; act < 5 ms). Le modèle de nœud de Ranvier génère des potentiels d'action extracellulaire similaires à ceux enregistrés in vivo. La différence de durée du potentiel d'action observée le long de l'axe tonotopique (i.e. 450 µs de durée pic à pic à 1 kHz contre 250 µs à 20 kHz) s'explique parfaitement par un gradient de densité en canaux ioniques le long de la cochlée (GNa~78 nS, GKL~9 nS, GKH~3 nS à 1 kHz contre GNa~90 nS, GKL~12 nS, GKH ~6 nS à 20 kHz). Cette étude a permis d'identifier les conductances ioniques et les densités de canaux responsables de l'initiation des potentiels d'action dans les neurones auditifs primaires. Elle suggère que la coopération entre le courant Na et des 2 courants K est probablement à l'origine de la haute fréquence de décharge de ces neurones. Le modèle de nœud de Ranvier permet en outre de tester de nouvelles stratégies de stimulation électrique dans le contexte de l'implant cochléaire.

The first project presented here was generated around 1 calcitriol (1,25D₃), and novel low-calcemic analogues (VDAs). The hypothesis of this study was that VDAs may be effective in Diffuse Large B cell Lymphoma. It has been demonstrated that 1,25D₃ and certain VDAs displayed moderate cytotoxic and pro-apoptotic actions upon DLBCL cells. Additionally, 1,25D₃ and VDAs used in a combination with antidepressant clomipramine displayed concentration anti-stimulatory actions upon activated normal B-cells. The second part of the study is focused around a novel immunomodulator CX1001, data from which is currently confidential. The third project has been built around GPR61. I have demonstrated that myc-tagged GPR61 is expressed in the cell membrane and is subject to N-glycosylation. The N12S mutant of GPR61, which is not subject to N-glycosylation, is also expressed on the cell surface. Treating the cells with tunicamycin reduces cell membrane expression of non-mutated and mutated proteins. Furthermore, GPR61 mRNA and protein are expressed in white blood cells with significantly increased level of expression of the protein in Th17 cells.

Les traitements anti-cancéreux conventionnels (chirurgie, radiothérapie, chimiothérapie) ne se révèlent pas très efficaces contre certains types de cancers, en particulier contre les tumeurs cérébrales très vascularisées et agressives. C’est pourquoi il faudrait développer rapidement de nouvelles thérapies. Dans notre laboratoire, nous proposons l’intégrine α5β1 comme nouvelle cible potentielle dans le traitement des gliomes malins. L’intégrine α5β1 est impliquée dans de nombreux processus vitaux pour la cellule et est surexprimée pendant la néoangiogenèse et dans certaines tumeurs en particulier les astrocytomes et les glioblastomes. Ainsi les objectifs de notre travail ont consisté en (1) la caractérisation de l’intégrine α5β1 dans deux lignées d’astrocytomes humains, les cellules A172 et U87, et (2) l’exploration des effets du SJ749, un antagoniste non-peptidique spécifique de l’intégrine α5β1, sur la prolifération des cellules A172 et U87. Les résultats obtenus montrent que :(1) les deux lignées cellulaires expriment l’intégrine α5β1. Les cellules A172 expriment de manière prédominante l’intégrine α5β1 alors que les cellules U87 possèdent un panel plus large d’intégrines incluant des récepteurs pour la fibronectine, le collagène et VCAM1. Les cellules U87 expriment environ deux fois plus d’intégrine α5β1 que les cellules A172. L’intégrine α5β1 retrouvée dans les cellules A172 se révèle atypique par son taux de sialylation élevé et elle confère aux cellules des avantages pour leur développement en conditions non-adhérentes. (2) l’antagoniste SJ749 empêche bien l’adhérence des cellules A172 et U87 à la fibronectine mais se révèle moins efficace sur l’inhibition de la prolifération. Les effets du SJ749 sur les deux lignées tumorales sont dépendants du taux d’expression de la sous-unité α5, de la lignée cellulaire et des conditions de croissance. Les informations développées ici apportent des éclairages sur l’optimisation de la recherche de vrais antagonistes de l’intégrine α5β1 qui ne sera plus basée uniquement sur leur capacité à bloquer l’adhérence mais principalement sur celle à inhiber la signalisation intracellulaire mediée par cette intégrine
It is clear that conventional anti-cancer treatments (surgery, radiotherapy, chemotherapy) are not very efficient against certain types of cancer, particularly against abundantly vascularized, aggressive cerebral tumors. That is why novel targeted therapies are urgently needed. In our laboratory, we proposed α5β1 integrin as a novel promising target in the treatment of malignant gliomas. Alpha5beta1 integrin is implicated in many vital cellular processes and is overexpressed during neoangiogenesis and on certain tumors especially astrocytomas and glioblastomas. Therefore our aims were (1) to characterize α5β1 integrin in two model astrocytoma cell lines, A172 and U87, and (2) to explore the effect of SJ749, specific non-peptidic antagonist of α5β1, on proliferation of A172 and U87 cells. Our results showed that: (1) both cell lines expressed α5β1 integrin. A172 expressed predominantly α5β1 integrin whereas U87 cells had a larger set of integrins including receptors for fibronectin, collagen and VCAM1. U87 cells expressed about two times more α5β1 integrin than A172 cells. Alpha5beta1 integrins presented in A172 cells were atypical with abundant sialylation and conferred a growth advantage under non-adherent conditions. (2) SJ749 blocked effectively the adhesion of A172 and U87 cells on fibronectin but was less efficient in the inhibition of proliferation. The effect of SJ749 on both tumor cells depended on a threshold level of α5 expression, cell types and on growing conditions. The information obtained here will help in a search for new generation antagonists of α5β1 integrins which will block not only adhesion but principally the integrin-mediated signaling

Endothelial progenitor cells (EPC) are bone-marrow derived circulating cells participating in angiogenesis and vascular homeostasis. Reduced numbers of circulating EPC are observed in patients with various cardiovascular diseases and are related to an increased risk for future cardiovascular events and death. Little is known about functional changes. The aim of this thesis was to study the function of EPC from patients with coronary artery disease (CAD) or with cardiovascular risk factors such as diabetes or advanced age. In particular, underlying molecular mechanisms were examined and potential therapeutic approaches were explored. CAD patients had reduced EPC numbers, which were correlated with increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor. In vitro, ADMA impaired EPC function which could be restored by statin treatment. In addition, EPC number and function decreased with age. Treatment of volunteers with growth hormone increased EPC levels and improved EPC function. Animal and in vitro studies showed the EPC increase to be directly mediated by the insulin-like growth factor 1 (IGF-1), which enhanced endothelial NOS expression of the EPC in a phosphoinositide-3-kinase/Akt dependent manner. Growth hormone-mediated increase in IGF-1 reversed age-related EPC dysfunction. Finally, function of EPC from patients with type II diabetes mellitus was analysed. Uncoupling of eNOS occurred within diabetic EPC and resulted in enhanced superoxide anion formation with subsequent EPC dysfunction. EPC dysfunction was protein kinase C-dependent, associated with reduced intracellular tetrahydrobiopterin (BH4) concentrations and reversible after exogenous BH4 treatment. Impairment of EPC function is likely to contribute to the pathogenesis of vascular disease in diabetes mellitus. In conclusion, mechanisms underlying EPC dysfunction in various cardiovascular diseases were investigated and novel treatment approaches for dysfunctional EPC were explored. The knowledge may provide clues for the therapy and prevention of certain cardiovascular diseases.

The central scientific objective of this thesis was to take a broad multidisciplinary approach to make use of the full potential information to battle EDs, utilizing an interactive and translational approach running from basic science through to the clinic. In our studies we assessed a.) clinical factors and comorbidity [namely substance use in EDs (Studies 1 to 3)], b.) psychosocial, behavioural and environmental correlates of EDs (Studies 4 to 7) and c.) treatment effectiveness of specific forms of ED interventions (Studies 8 to 9).

Our first line of investigation comprised Studies 1 to 3 and assessed the comorbidity of substance use in EDs. The results of these studies suggest that compared to healthy controls, substance use was higher in individuals with EDs (Studies 1 and 3), that the presence of a family history of alcohol dependence was associated with the comorbidity of EDs and substance use (Study 2) that substance use was particularly prevalent in patients with bulimic characteristics (Studies 1 to 3) and that EDs and substance abuse may represent expressions of a fundamental predisposition to addictive behaviour possibly related to the genetically influenced traits such as novelty seeking (Study 2). Furthermore, we revealed some significant differences for the specific forms of drugs in people with EDs (Studies 1 and 3), which emphasize the significance of assessing various drug types in EDs. Finally we also observed cross-cultural differences across various European countries in the prevalence of substance use in EDs and healthy controls (Study 3).

The second research area was labelled psychological, behavioural and environmental correlates of EDs. In our animal study (Study 4) we found that contextual conditioning of eating response was more effective when high than low density caloric food was used. This result indicates that animal models are useful for analyzing and identifying human-animal links in feeding related behaviours.

Studies 5 and 6 assessed which early individual and family eating patterns play a role in the development of EDs. Our findings agree with the growing body of research indicating that a variety of environmental and social factors are associated with dysfunctional individual and family eating patterns (e.g. food used as individualization, control and rules about food) during the first years of life and which if not detected on time could lead to a subsequent ED. Conversely, healthy eating (including eating breakfast) was negatively linked to the development of a subsequent ED. Only a few differences across ED subtypes were observed. Finally some cross-cultural differences also emerged (Study 6).

In Study 7 we compared anger expressions in individuals with EDs and healthy controls and explored the relation among ED symptoms, comorbid psychopathology, personality traits and impulsive behaviours. The results indicated that individuals with EDs obtained significantly higher scores than controls on maladaptive anger expressions. When different purging methods were assessed independently, the frequency of laxative use was associated with anger suppression. ED symptoms and specific personality traits were also positively associated to different anger expressions. At last, we observed that inappropriate anger expressions were related to self-harming behaviours.

Finally our last research line assessed the effectiveness of various treatments for EDs. In Study 8 we compared full and subthreshold BN in terms of personality, clinical characteristics and short-term response to a psychoeducational therapy. The results showed that full-BN and sub-BN share common psychopathological symptoms and personality traits. Furthermore, no differences in therapy outcome were observed in terms of general ED symptomatology and psychopathology. In Study 9 we described and assessed a non-symptom oriented CBT treatment in a congenitally blind women. A dramatic reduction in ED symptoms was observed after the maintaining and triggering factors had been reduced.

To conclude, relatively little research has been performed towards understanding the aetiology of EDs. The findings from our investigations represent a major enhancement in the state of the art of EDs, and lead to the development of a new overall etiological model of EDs. The model we propose is a general understanding of how various ED predisposing and precipitating factors might eventually lead to EDs, and maintain the course of a disorder. Future work should address the effects of genes, environment and gene-environment interaction on the development and maintenance of EDs. Of specific interest is the query of which of these factors are non-specifically related to mental disorders and which factors may be more explicit factors that predispose an individual to EDs and related states, but not to mental disorders in general. The answers to these questions should hopefully become perceptible in the next couple of years.
El objetivo principal de esta tesis ha sido el abordar los Trastornos de la alimentación (TCA) desde una aproximación multidisciplinar, que nos ayude a combatir los TCA desde una perspectiva traslacional, en la que confluyan investigaciones básicas y aplicadas. En nuestros estudios hemos analizado en profundidad los siguientes aspectos: a.) Factores clínicos y comorbilidad [especialmente abuso de sustancias en TCA] (Estudios 1 a 3); b.) Correlatos psicosociales, conductuales y ambientales en TCA (Estudios 4 a 7); y c.) Eficacia de tratamientos específicos en TCA (Estudios 8 a 9).
Nuestra primera línea de investigación (Estudios 1-3), ha estudiado la comorbilidad de abuso de sustancias en TCA. Los resultados de estos estudios sugieren que: a) abuso de sustancias es más prevalente en TCA que en sujetos de control (Estudios 1 y 3); b) la presencia abuso de sustancias en pacientes con TCA, está asociada a historia familiar previa de dependencia de alcohol (Estudio 2); c) abuso de sustancias es especialmente prevalente en pacientes con características bulímicas (Estudios 1 a 3); y d) que presencia de abuso de sustancias en TCA puede ser expresión de una predisposición a conductas adictivas, cuya susceptibilidad viene determinada por rasgos de personalidad específicos (búsqueda de sensaciones) (Estudio 2). Asimismo, encontramos aspectos diferenciales en TCA, en base al tipo de droga que consumen (Estudio 1 y 3), hecho que enfatiza la importancia de evaluar los distintos tipos de drogas utilizados por estos pacientes. Finalmente, encontramos diferencias culturales entre distintos países europeos, respecto a la prevalencia de abuso de sustancias en TCA, al ser comparados con grupos de control (estudio 3).

Como segunda área de investigación, nos centramos en aspectos psicológicos, conductuales y ambientales en TCA. En un estudio, realizado siguiendo un modelo animal (estudio 4), encontramos que el condicionamiento contextual de respuesta alimentaria es más efectivo cuando es utilizado un alimento con alta densidad calórica, que cuando se utiliza un alimento con baja densidad calórica. Estos resultados sugieren qué modelos animales son útiles a la hora de analizar e identificar asociaciones entre comportamiento en humanos y animales, respecto a su conducta alimentaria.

En los estudios 5 y 6 se analizaron en qué medida conductas alimentarias tempranas y patrones alimentarios en la familia, influyen en la aparición posterior de un TCA. Los resultados de estos estudios sugieren, en concordancia con un creciente volumen estudios recientes, la influencia que poseen aspectos ambientales y sociales en el desarrollo posterior de una conducta alimentaria anormal (p.e., control y reglas entorno a la alimentación). Por contrario, patrones alimentarios regulares (p.e., desayunar antes de ir al colegio) se encontró negativamente asociado (factor protector) a subsecuente desarrollo de un TCA. Asimismo, fueron encontradas limitadas diferencias entre subtipos diagnósticos, aunque algunas hacían referencia al contexto cultural (estudio 6).

En el estudio 7 comparamos la expresión de ira en sujetos con un TCA y un grupo control, y analizamos su asociación con sintomatología alimentaria, psicopatología general comórbida, rasgos de personalidad y conductas impulsivas. Nuestros resultados indicaron que pacientes con TCA manifestaban sentimientos de ira de forma más inadecuada que grupos control. Al analizar los distintos procedimientos de purga, la frecuencia de abuso de laxantes iba asociada a supresión de sentimientos de ira.
La sintomatología alimentaria y algunos rasgos de personalidad se asociaban a determinadas formas inadecuadas de expresión de sentimientos. Asimismo, observamos que una inadecuada expresión de sentimientos en TCA se asociaba con una mayor frecuencia de conductas autoagresivas.

Finalmente, en nuestra última línea de investigación analizamos la eficacia de distintos tipos de tratamiento en TCA. En el estudio 8 comparamos casos totales y parciales de Bulimia nerviosa, en base rasgos de personalidad, sintomáticas alimentaria, psicopatología general y respuesta a un tratamiento de carácter psicoeducativo. Los resultados indicaron que los casos totales y parciales de BN comparten similitudes sintomáticas, psicopatológicas y de personalidad. Asimismo, no se obtuvieron diferencias respecto a la respuesta al tratamiento entre ambos grupos de pacientes. En el estudio 9, describimos y evaluamos un tratamiento cognitivo-conductual no centrado en los síntomas alimentarios, en una paciente ciega. En este caso, fue constatada una drástica reducción de los síntomas alimentarios tras este tipo de tratamiento.

En conclusión, hasta el momento, existen escasas referencias en la literatura que sirvan para esclarecer los aspectos etiopatológicos implicados en TCA. Los resultados obtenidos en nuestras investigaciones ayudan sobre el conocimiento actual de TCA, y contribuyen al desarrollo de un nuevo modelo multimodal de entendimiento de éstos. El modelo que proponemos combina la interacción de diversos factores (predisponentes, precipitantes y mantenedores). Trabajos futuros deberían prestar atención a la relevancia que tienen factores genéticos, ambientales e interacción genes-ambiente, en el desarrollo y mantenimiento de los TCA. Un especial interés presenta la pregunta de cuáles de estos factores son específicos para trastornos mentales y cuáles los son para TCA de forma específica.
RESUM:

L'objectiu principal d'aquesta tesi ha estat l'abordar els Trastorns de la conducta alimentària (TCA) des d'una aproximació multidisciplinar, que ens ajudi a combatre'ls des d'una perspectiva traslacional, en la que conflueixin investigacions bàsiques i aplicades. En els nostres estudis hem analitzat en profunditat els següents aspectes: a.) Factors clínics i comorbilitat [especialment abús de substàncies en TCA] (Estudis 1 a 3); b.) Correlats psicosocials, conductuals i ambientals en TCA (Estudis 4 a 7); i c.) Eficàcia de tractaments específics en TCA (Estudis 8 a 9).

La nostra primera línia d'investigació (Estudis 1 a 3), ha estudiat la comorbilitat d'abús de substàncies en TCA. Els resultats d'aquests estudis suggereixen que: a) l'abús de substàncies és més prevalent en TCA que en subjectes control (Estudis 1 i 3); b) la presència d'abús de substàncies en pacients amb TCA, està associada a història familiar prèvia de dependència d'alcohol (Estudi 2); c) l'abús de substàncies és especialment prevalent en pacients amb característiques bulímiques (Estudis 1 a 3); i d) que la presència d'abús de substàncies en TCA pot ser expressió d'una predisposició a conductes addictives, la susceptibilitat de les quals ve determinada per trets de personalitat específics (recerca percaça de sensacions) (Estudi 2). Així mateix, trobem aspectes diferencials en TCA, en base al tipus de droga que consumeixen (Estudis 1 i 3), fet que emfatitza la importància d'avaluar els diferents tipus de drogues utilitzats per aquests pacients. Finalment trobem diferències culturals entre distints països europeus, respecte a la prevalença d'abús de substàncies en TCA, al ser comparats amb grups control (Estudi 3).

Com a segona àrea d'investigació, ens centrem en aspectes psicològics, conductuals i ambientals en TCA. En un estudi realitzat seguint un model animal (Estudi 4), trobem que el condicionament contextual de resposta alimentària és més efectiu quan s'utilitza un aliment amb alta densitat calòrica, que quan se'n utilitza un amb baixa densitat calòrica. Aquests resultats suggereixen que els models animals són útils a l'hora d'analitzar i identificar associacions entre comportament en humans i animals, respecte la seva conducta alimentària.

En els estudis 5 i 6 es varen analitzar fins a quin punt conductes alimentàries primerenques i patrons alimentaris en la família influeixen en l'aparició posterior d'un TCA. Els resultats d'aquests estudis suggereixen, en concordància amb un volum creixent d'estudis recents, la influència que tenen aspectes ambientals i socials en el desenvolupament posterior d'una conducta alimentària anormal (per exemple, control i normes entorn a l'alimentació). Tanmateix, patrons alimentaris regulars (per exemple, esmorzar abans d'anar a l'escola) estaven negativament associats (factor protector) al subseqüent desenvolupament d'un TCA. Així mateix, es varen trobar diferències limitades entre subtipus diagnòstics. Finalment, es varen trobar algunes diferències en relació al context sociocultural. (Estudi 6).

En l'estudi 7 vàrem comparar expressió d'ira en subjectes amb un TCA i un grup control, i vàrem analitzar la seva associació amb simptomatologia alimentària, psicopatologia general comòrbida, trets de personalitat i conductes impulsives. Els nostres resultats varen indicar que pacients amb TCA manifestaven sentiments d'ira de forma més inadequada que grups control. A l'analitzar els diferents procediments de purga, la freqüència d'abús de laxants anava associada a la supressió de sentiments d'ira.
La simptomatologia alimentària i determinats trets de personalitat, s'associaven a determinades formes inadequades d'expressió de sentiments. Així mateix, vàrem observar que una expressió inadequada de sentiments en TCA anava associada a una freqüència major de conductes autoagressives.

Finalment, en la nostra darrera línia d'investigació vàrem analitzar l'eficàcia de diferents tipus de tractament en TCA. En l'estudi 8 vàrem comparar casos totals i parcials de Bulímia nerviosa (BN), en base a trets de personalitat, simptomatologia alimentària, psicopatologia general i resposta a un tractament de caràcter psicoeducatiu. Els resultats varen indicar que els casos totals i parcials de BN, comparteixen similituds simptomatològiques, psicopatològiques i de personalitat. Així mateix, no es varen obtenir diferències respecte a la resposta del tractament entre ambdós grups de pacients. En l'estudi 9, vàrem descriure i avaluar un tractament cognitiu-conductual no centrat en els símptomes alimentaris, en una pacient cega. En aquest cas es va constatar una reducció dràstica dels símptomes alimentaris després d'aquest tipus de tractament.
Fins el moment, existeixen escasses referències en la literatura que serveixin per aclarir els aspectes etiopatogènics implicats en els TCAs.

Els resultats obtinguts en les nostres investigacions ajuden en el coneixement actual dels TCA i contribueixen al desenvolupament d'un nou model multimodal per la comprensió de la seva etiologia. El model que proposem combina la interacció de diversos factors (predisponents, precipitants i mantenidors). Els treballs futurs haurien de incidir en la rellevància que tenen els factors genètics, ambientals i la interacció d'ambdós, en el desenvolupament i manteniment dels TCA. És d'especial interès la qüestió de quins d'aquests factors són específics per trastorns mentals i quins ho són per TCA.

There is increasing evidence that psychological stress and associated mood disorders are linked with, and can adversely affect the course of inflammatory bowel disease (IBD). Stress is perceived to be relieved by smokers, and this, like a lack of knowledge about its adverse effects, and nicotine dependence, could contribute to continued smoking by patients with Crohn’s disease (CD). Stress has previously been shown to influence disease course in patients with inactive ulcerative colitis (UC) but its influence in acute severe UC is not known. Emerging trial evidence supports the suggestion that psychologically-orientated therapy may ameliorate IBD-associated mood disorders, but there is no strong data yet to indicate that stress management has a beneficial effect on the activity or course of IBD. In addition gut-focussed hypnotherapy has been successfully used in the setting of functional bowel disorders. The 4 main hypotheses tested in thesis are: 1. In patients with IBD: (1) poor knowledge of the effects of smoking on their disease and/or (2) high nicotine dependence explain the higher prevalence of smoking in CD than UC 2. Anxiety, depression and stress are more common and worsen outcome in patients with acute severe UC. 3. Stress management in the form of psychotherapy given by a counsellor has a beneficial effect on the activity and course of IBD. 4. Gut-focussed hypnotherapy reduces the relapse rate in patients with UC. The major findings are as follows: 1. Despite more patients with CD being smokers, they were better informed about the effects of smoking on their own disease than UC patients. Nicotine dependence was no higher in patients with CD than UC. In IBD patients as a whole, nicotine dependence was lower than in smokers’ clinic clients and comparable to that of the general population, suggesting that most IBD patients could be weaned off smoking successfully in the IBD clinic.

This investigation was accomplished in the Experimental Station Tunshi Productive Unit Sheep Goat, located to an altitude of 2747 m.s.n.m. and with an average temperature of 13.1°C, it located to 8 kilometers of Riobamba route to Licto and in the Laboratory of Microbiology of the Cattle Sciences Faculty of the Espoch, during 120 days (November of 1998 to February of 1999). The principal objective was that of to evaluate the effect terapeutics of the plant Spigelia anthelmia against parasitesinternal in lambs, for something which is 20 lambs native males with ages that fluctuated of 6 to 9 months, these animals stayed in estabulación fed with forage of good quality (alfalfa + ray grass) and concentrated. Then of the period of adjustment were effected exams coprologycs quantitative to determine the load parasites initial, then was them applied 4 treatments with 5 repetitions each one, the experimental unit was 1 lamb. For the evaluations of PGI, they were studied the days 1,2,3,4,5,6,15,30,45,60 subsequent to the application; to determine the percentages of efficiency against PGI were studied the days 15, 30, 45 and 60; to determine the efficiency to combat Pulmonary Parasites were evaluated the days 15,30 and 60 subsequent to the application. The laboratory techniques that were employed were that of Mc Master, Flotation, Sedimentation, Migration. The obtained results were submitted to the techniques of the ADEVA and Contrast Ortogonals at the levels of probabilities of 0.05 and 0.01, establishing that the alcaloide Spiegilina contained in the Spigelia anthelmia produced a decrease of HPG of PGI without arriving to zero, this effect would be caused by the decrease of the female adult, its action in eggs, juvenile states, adult males is done not know; this plant did not show positive effects against PP; they were not observed sound effects. For it previously exposed is recommended to prove this plant in different forms of preparations and in not ruminant addressee and to evaluate findings post – mortem and Productive Parameters. To prefer the Panvermín L front to the Virbamec by the cost for the gastrointestinal and pulmonary parasites treatment in lambs native.

PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO
COORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR
PROGRAMA DE SUPORTE À PÓS-GRADUAÇÃO DE INSTS. DE ENSINO
Trauma e regressão são dois conceitos que sempre suscitaram debates e mesmo controvérsias em Psicanálise. No decorrer da presente tese, procuramos analisar o desenvolvimento de ambos nas teorizações de Freud e de alguns dos principais teóricos das relações objetais precoces, dentre os quais destacam-se Donald Winnicott e Michael Balint, que, na esteira das mudanças operadas na teoria e na técnica analíticas por Sàndor Ferenczi, ampliaram de forma original o escopo teórico em torno de determinados fenômenos clínicos que implicam em formas singulares de sofrimento subjetivo. Neste sentido, buscamos articular nossa reflexão com alguns outros conceitos fundamentais propostos por esses autores; mais especificamente, os conceitos de amor primário e falha básica em Balint, e os de holding e fenômenos transicionais em Winnicott. A partir daí, sustentamos que o pensamento teórico-clínico baseado no modelo relacional tem possibilitado uma melhor apreensão dos processos determinantes da constituição psíquica e das diferentes formas de subjetivação e elaboração do trauma, nas quais a compreensão da situação analítica como campo comum inconsciente passa a ser relevante para o processo terapêutico.
Trauma and regression are concepts that have always raised some debate and controversy in Psychoanalysis. Throughout the present thesis, the development of both will be analyzed in Freud s theories and also in some of the main authors on the early object relations, among which Donald Winnicott and Michael Balint stand out for improving the changes made in the analysis theory and techniques developed by Sàndor Ferenczi. The two enlarged in an inventive way the theoretical scope around certain clinical phenomena that bring about unique subject suffering. In this line of thought, this paper aims to associate some reflection to other fundamental concepts proposed by these authors; more specifically, the concepts of primary love and of basic fault in Balint, and those of holding and transitional phenomena in Winnicott. On this ground, it can be concluded that the clinical-theoretical thinking based on the relational model has enabled a better apprehension of the processes which are essential in the psychic constitution and in the various ways to take power over and elaborate on trauma, in which understanding of the analytical situation, as an unconscious common ground turns out to be relevant for the therapeutical process.

This review concentrates on findings described in the recent literature on the response of cells and tissues to electromagnetic fields (EMF). Models of the causal interaction between different forms of EMF and ions or biomolecules of the cell will be presented together with our own results in cell surface recognition. Naturally occurring electric fields are not only important for cell-surface interactions but are also pivotal for the normal development of the organism and its physiological functions. A further goal of this review is to bridge the gap between recent cell biological studies (which, indeed, show new data of EMF actions) and aspects of EMF-based therapy, e.g., in wounds and bone fractures
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

This review concentrates on findings described in the recent literature on the response of cells and tissues to electromagnetic fields (EMF). Models of the causal interaction between different forms of EMF and ions or biomolecules of the cell will be presented together with our own results in cell surface recognition. Naturally occurring electric fields are not only important for cell-surface interactions but are also pivotal for the normal development of the organism and its physiological functions. A further goal of this review is to bridge the gap between recent cell biological studies (which, indeed, show new data of EMF actions) and aspects of EMF-based therapy, e.g., in wounds and bone fractures.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

High grade serous (HGS) epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC) are among the poorest prognosis neoplasms; both are characterised by defects in DNA damage repair mechanisms, high levels of genomic instability, intra-tumoural heterogeneity and resistance, intrinsic or acquired, to conventional chemotherapy. The DNA damaging agents, gemcitabine and platinum are standard treatments for patients with PDAC and EOC, respectively. Here it is demonstrated that time of onset and levels of DNA double strand breaks (DSB), does not correlate with response to these drugs in PDAC and EOC cell lines. Instead, the duration of these lesions/time of repair differs between drug-sensitive and -resistant cell lines. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, it is demonstrated that cisplatin and gemcitabine exposure induces an AKT-dependent, pro-survival, DNA damage response in clinically cisplatin-resistant but not -sensitive cells. AKT is phosphorylated specifically on Serine 473 by DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which is involved in the early stages of DSB repair by the non-homologous end-joining (NHEJ) pathway. Inhibition of DNA-PKcs and/or AKT restores platinum sensitivity in a panel of clinically resistant HGS EOC and PDAC cell lines. This study also identifies that restoration of cisplatin sensitivity by DNA-PKcs inhibition is independent of its role in the NHEJ. Unexpectedly, inhibiting DNA-PKcs was shown to decrease both NHEJ and homologous recombination (HR) activities, and whilst studying the DNA-PKcs effect on EOC and PDAC cell lines, a novel regulatory interaction between DNA-PKcs and RAD51, which assists in the repair of DNA DSB via the HR pathway, was also identified. It is suggested here that the method by which DNA-PKcs is controlling RAD51 is via ubiquitin-mediated proteasomal degradation and this appears to be a cancer-specific feature. It was also identified that RAD51 can be ubiquitinated on three different lysine sites and all of these sites are required for the proteasomal-degradation of RAD51 following DNA-PKcs inhibition. Implications of this finding in the clinical setting could be substantial, as here it is shown that targeting DNA-PKcs downregulates both HR and NHEJ pathways, restoring chemotherapy response in EOC and PDAC cell lines.

Understanding the molecular underpinnings of neuronal dysfunction and degeneration involved in Huntington’s disease is a goal of increasing urgency for society and scientific community. In this Thesis we have studied different proteins and signaling pathways, specifically altered by the presence of mutant huntingtin, as new potential candidates to develop pharmacological strategies to treat or delay motor and cognitive deficits in Huntington’s disease. AIM 1. To study the contribution of CBP/CREB pathway in the cognitive deficits present in Huntington’s disease. AIM 2. To study the molecular mechanisms involved in neurotrophic support dysfunction in Huntington’s disease. 2.1. To analyze the role of p75NTR/TrkB receptors in the major striatal vulnerability in Huntington’s disease. 2.2. To study the role of p75NTR in cognitive deficits in Huntington’s disease. AIM 3. To study the molecular mechanisms involved in corticostriatal dysfunction in Huntington’s disease. 3.1. To characterize corticostriatal deficits in HD mouse models and analyze the role of Kalirin-7 in the alteration of corticostriatal excitatory synapses in HD. AIM 4. To study the role of Cdk5 in cognitive deficits in Huntington’s disease. AIM 5. To study the role of D1R-H3R heteromers in neuronal cell death and cognitive deficits in Huntington’s disease.
La malaltia de Huntington (MH) és un desordre neurodegeneratiu caracteritzat per la disfunció i mort neuronal de regions específiques del cervell. La regió més afectada és l’estriat (nuclis caudat i putamen en humans), tot i que en estadis més avançats de la malaltia s’ha descrit una atròfia i pèrdua neuronal del còrtex cerebral i hipocamp (Vonsattel et al., 1985;Vonsattel and DiFiglia, 1998). La temprana disfuncionalitat de les neurones hipocampals i corticals es creu crítica per restablir les deficiències cognitives i de memòria en aquesta patologia. La malaltia s’hereta de forma autosòmica dominant i és causada per la mutació del gen IT15, localitzat en el braç curt del cromosoma 4 (4p.16.3), que codifica per la proteïna anomenada huntingtina (htt). Aquesta mutació va ser identificada l’any 1993 com una expansió de repeticions del triplet CAG que codifiquen per una regió poliglutamínica (poliQ) a l’extrem N-terminal de la proteïna htt (350KDa) (HDCRG, 1993). En individus sans, el nombre de repeticions oscil·la de 6 a 35; quan el nombre de repeticions d’aquest triplet és superior a 40, l’individu desenvoluparà la malaltia. Les primeres manifestacions de la malaltia solen produir-se als 35 anys d’edat conduint a la mort 15-­20 anys després de l’aparició dels símptomes (Bates, 2003;Martin and Gusella, 1986). La simptomatologia inclou disfunció motora, associada majoritàriament a l’atròfia estriatal, acompanyada de trastorns cognitius i emocionals associats a l’afectació corticoestriatal i hipocampal que son de manifestació primerenca, fins i tot prèvia a la simptomatologia motora. Aquestes alteracions cognitives i emocionals constitueixen un dels pilars discapacitants en aquesta patologia, per això al llarg d’aquesta Tesi doctoral proposem un estudi dual que ens permeti definir diverses estratègies terapèutiques dirigides al tractament d’ambdues simptomatologies: motora i cognitiva. Si bé es coneix que aquesta mutació és la causant de la malaltia, avui en dia no es coneixen els mecanismes cel·lulars i moleculars responsables de la disfunció i mort neuronal en la MH. Diversos estudis han postulat que la pèrdua de funció de la proteïna wild-type i/o el guany de funció de la proteïna mutada (mhtt) juguen un paper clau en el desenvolupament de la malaltia. Així s’ha descrit que l’expressió de la proteïna huntingtina mutada resulta en l’alteració de diversos processos cel·lulars i moleculars, tals com l’agregació proteica, alteracions en el sistema ubiqüitina­proteosoma, desregulació en la maquinària transcripcional així com en la remodelació de la cromatina, alteracions en la síntesi proteica, reducció del suport tròfic, alteracions en les vies de senyalització intracel·lulars, alteració en la homeòstasis del calci, dany mitocondrial, excitotoxicitat, activació de caspases, alteracions en les interaccions proteïna-proteïna i alteració en la circuiteria neuronal (Cattaneo et al., 2005;Zuccato and Cattaneo, 2009). En aquesta Tesis ens hem centrat en estudiar alguns dels mecanismes moleculars implicats en la mort neuronal, així com en els dèficits cognitius i alteracions en la plasticitat sinàptica produïda per la presència de la huntingtina mutada, mitjançant l’estudi de les alteracions produïdes en: 1) maquinària transcripcional, 2) suport neurotròfic, 3) canvis estructurals en les sinapsis excitadores, 4) senyalització de proteïnes cinasa i fosfatasa i 5) formació d’heteròmers entre receptors acoblats a proteïnes G.

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
The CD5 and CD6 lymphocyte surface receptors are highly homologous members of the Scavenger Receptor Cystein Rich (SRCR) superfamily mainly expressed by all T lymphocytes and the B1a subpopulation of B cells. Although the ultimate function/s are far from being completely understood, CD5 and CD6 are known to play a relevant role in both lymphocyte development and differentiation by negatively modulating the survival/death-inducing intracellular signals generated during the antigen recognition. Recently, this group has developed a transgenic mouse line which expresses a soluble form of human CD5, likely blocking the ligand-receptor interactions mediated by CD5 and interfering with normal lymphocyte response. This study was aimed at furthering the study of the recombinant soluble human CD5 Transgenic(rshCD5Tg) mouse phenotypical analysis, its response to antigen stimuli and tumor implantation; the function of rshCD6 was also tested. It was observed that rshCD5Tg mice display an exacerbated immune response, likely due to a reduction in the number of T and B cells with regulatory/suppressive function (Treg, B1a, B10 cells) and the increase in effector cells (NKT, MZ B cells). In agreement with these phenotypical characteristics, the functional analysis of rshCD5Tg mice showed enhanced immune responses to Tdependent and –independent antigens, as well as enhanced anti-tumoral responses, with or without concomitant chemotherapy treatment. Importantly, both the phenotypical and functional findings could be reproduced in wild-type mice following prolonged infusion of purified exogenous rshCD5 protein. Overall, these results argue in favor of a relevant role of CD5-mediated molecular interactions in the homeostasis of functionally relevant lymphocyte subpopulations and open the possibility for CD5-based therapeutical interventions in different disease settings such as cancer, infection and immunodeficiency.

Autism is a spectrum of developmental disorders, with onset in early childhood affecting social, communicative and imaginative development. Numerous theories have been proposed regarding the aetiology of autistic spectrum disorders (ASD), yet the condition remains poorly understood. Children with ASD tend to suffer from severe dietary and/or gastrointestinal (GI) problems (including abdominal pain, constipation, diarrhoea and bloating). These symptoms may be associated with disruption of the indigenous gut flora promoting overgrowth of potentially pathogenic (toxin producing) microorganisms. The primary aim of this research was to provide a detail overview of the gut microbiota of ASD children and study the effect of selected probiotics on the gut microbiota, gut function and associated symptoms (i. e. behaviour) of ASD children. The gut microbiota of ASD children was compared to that of non-ASD control groups (siblings and unrelated children). Changes in bacterial gut populations were assessed using fluorescence in situ hybridisation (FISH) targeting relevant gut bacterial groups in a culture independent manner. The gut microbiota of ASD children contained higher levels of Clostridium histolyticum subgroup (Clostridium clusters I and II) bacteria than that of non-ASD children. Screening probiotic bacteria for their ability to inhibit the growth of Clostridium perfringens was assessed in vitro. Six probiotics (namely, L. plantarum NCIMB 41114, L. acidophilus JVT5, L. pentosus JCM 1558, L. rhamnosus GG 1003, L. plantarum 903 and L. plantarum WCFS1) showed statistically significant inhibition of C. perfringens (although many others were also tested). These probiotics were further tested in batch culture fermentation systems to investigate whether they could beneficially modulate the faecal bacterial populations of children with ASD. Probiotic supplementations increased the levels of lactobacilli/enterococci populations and demonstrated a degree of anti-microbial action against C. histolyticum subgroup. L. plantarum WCFS 1 was then used in a double-blind, placebo-controlled, randomized cross-over feeding study in ASD. Administration of L. plantarum WCFSI significantly increased numbers of lactobacilli/enterococci in the faecal flora of ASD children compared to a placebo. No modulation of the C. histolyticum subgroup was seen during the study. A significant improvement in bowel function was observed with probiotic administration. Moreover, the total behaviour problem score was significantly lower after L. plantarum WCFS 1 administration compared to the placebo. This study supports the hypothesis that probiotic therapy may modulate the, GI microbiota composition in ASD individuals and alleviate GI symptoms of ASD individuals.

Microesferas lipídicas (ML) são excelentes sistemas de delivery de drogas e são relativamente estáveis. O Objetivo deste trabalho foi desenvolver um sistema capaz de encapsular proteínas antigênicas da membrana de L. amazonensis. Proteínas de membrana são importantes na formulação de vacinas, uma vez que estas proteínas são os primeiros componentes celulares a entrarem em contato com a célula hospedeira, provocando e mediando a resposta imune. Esta é uma ferramenta útil para evitar ou inativar a invasão do parasita. As ML são constituídas por óleo de soja (OS), dipalmitoilfosfatidilcolina (DPPC), colesterol e extrato de proteínas solubilizadas (EPS) (previamente tratadas para remoção do detergente). Primeiramente foram ensaiadas formulações de ML contendo álcool polivinílico (PVA). Estudos de microscopia eletrônica de varredura (MEV) mostraram que as ML são formadas quando PVA 3% (p/v) é usado na formulação. Além disso, foi feito marcação das proteínas com isotiocianato de fluoresceína (FITC) e a microscopia de fluorescência revelou a presença de estruturas esféricas fluorescentes, o qual indicou a encapsulação das proteínas na região lipofílica das ML. A presença do PVA na formulação das ML acarretou em algumas limitações cruciais para a continuidade da nossa pesquisa, levando a substituição deste pelo glicerol. Com o objetivo de otimizar nossa formulação foram avaliadas cinco diferentes formulações contendo glicerol 2,5% (p/v). Nestas formulações foram avaliadas as relações molares de DPPC:Colesterol:OS. As partículas formadas apresentaram um diâmetro médio de 200nm, baixa polidispersão, e estabilidade por um período de 30 dias, de acordo com ensaios de espalhamento de luz dinâmico. Ensaios de gradiente de densidade de sacarose das ML mostraram que proteínas e lipídios se encontram juntos no gradiente de sacarose (5-50% p/v) sugerindo que a preparação de ML foi homogênea e que as proteínas estão interagindo com este sistema lipídico. Termogramas obtidos por calorimetria diferencial de varredura (DSC) corroboram com a formação de um sistema de ML-proteína estáveis, além de fornecer indícios que as proteínas se encontram localizadas no núcleo oleoso das ML. Os resultados mostraram que foram encapsulados 85% das proteínas do EPS nas microesferas, e que estas não perderam sua atividade antigênica mesmo após todo o complexo processo de preparação do sistema. Estudos de viabilidade dos macrófagos peritoneais murinos e o ensaio de geração de nitrito mostraram que o sistema ML associado às proteínas não apresenta efeito citotóxico para os macrófagos e ainda estimula a produção de NO nos mesmos. Com isso, podemos sugerir que ML contendo proteínas antigênicas de membrana de L. amazonensis parece ser um promissor sistema para terapia da leishmaniose.
Lipid microspheres (LM) are excellent drug delivery systems and they are also relatively stable. The aim of this work was to develop a lipid-based system to encapsulate antigenic membrane proteins from Leishmania amazonensis. Membrane proteins are important for vaccine formulation because these proteins are the first ones to get in contact with the host cell, triggering the cell mediated immune response. This is a useful tool to avoid or to inactivate parasite invasion. LM are constituted by soybean oil (SO), dipalmitoylphosphatidylcholine (DPPC), cholesterol and solubilized protein extract (SPE) (previously treated to remove detergent). First, the LM formulations containing polyvinylic alcohol (PVA) were assayed. Scanning electronic microscopy (SEM) studies have shown that LM are formed when 3% PVA (w/v) is used in the formulation. Besides, proteins were marked with fluorescein Isothiocyanate (FITC) and the fluorescence microscopy showed the presence of fluorescent spherical structures, which indicated protein encapsulation in the lipophilic region of the LM. The presence of PVA in the LM formulation has caused some crucial limitations for the continuity of the research, leading to its substitution for glycerol. In order to optimize the system, five different formulations containing 2.5% glycerol (w/v) were evaluated for DPPC:Cholesterol:OS molar ratios. The particles formed (LM-protein) presented an average diameter of 200 nm, low polydispersion and good stability for a period of 30 days, according to dynamic light scattering assays. Isopycnic density gradient centrifugation of LM-protein showed that proteins and lipids floated in the sucrose gradient (5-50% w/v) suggesting that the LM preparation is homogeneous and that the proteins are interacting with these systems. Thermograms obtained by differential scanning calorimetry (DSC) corroborate with the formation of a stable LM system, besides giving indication that proteins are located in the oily LM core. The results show that 85% of the SPE proteins were encapsulated in the LM without loosely their antigenic activity even after the system preparation process. Viability studies of the peritoneal macrophage murines and the nitrate assay generation have shown that system does not have a cytotoxic effect for the macrophages and it yet stimulate their NO production. Therefore, we conclude that LM, encapsulated with L. amazonensis membrane antigenic proteins seems to be a promising system for for therapy of Leishmaniasis

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Fibromyalgia is a chronic pain syndrome that is associated with a variety of symptoms and subjective complaints, related to worsening and maintenance of pain. This complexity is not taken into account in an integrated way in the treatment models for chronic pain. Generally the interventions target an isolated aspect of pain, like the interpersonal function, a related cognitive distortion or the role of fear. The present study aims to construct a set of treatment goals for an integrative psychological intervention with Fibromyalgia. This endeavor was based on the real-life context of five patients with Fibromyalgia, though the reports and the experiences in a psychotherapy group. The participants were women between 45 and 52 years of age. The data were collected through semi-structured open interviews and recordings of the 12 sessions of psychotherapy. The interventions were based on the experiences that appeared in the group, guided by current trends in behavioral therapy. The data were submitted to inductive analysis, following the directives of grounded theory. The treatment goals that emerged from this work were then organized in five themes, namely: Interpersonal Experiences, Interpersonal Coping Strategies, Subjective Meanings, Negative Emotions, and Positive Emotions.
A Fibromialgia é uma síndrome dolorosa crônica que vem associada a uma variedade de sintomas e queixas subjetivas relacionadas à exacerbação e manutenção da dor. Esta complexidade não é levada em conta, de forma integrada, nos modelos de tratamento para dor crônica. Geralmente as intervenções tomam como alvo um aspecto isolado da dor, como a função interpessoal, a distorção cognitiva envolvida ou o papel do medo. Este estudo teve como objetivo construir um conjunto de alvos para um tratamento psicológico integrativo da Fibromialgia. Baseou-se para isso no contexto de vida de cinco portadoras de Fibromialgia, a partir dos relatos e das vivências das participantes durante uma psicoterapia de grupo. As participantes eram do sexo feminino com idade entre 45 e 52 anos. Os dados foram coletados por meio de entrevistas abertas semi-estruturadas e gravações das 12 sessões de psicoterapia. As intervenções foram baseadas nas vivências que surgiram no grupo e norteadas pelas tendências atuais da terapia comportamental. Os dados foram submetidos à análise indutiva seguindo os preceitos da Grounded Theory. Os alvos terapêuticos que emergiram deste trabalho foram agrupados em cinco temas, são eles: Vivências Interpessoais, Estratégias de Enfrentamento Interpessoal, Vivências Subjetivas, Emoções Negativas e Emoções Positivas.

Estudos têm demonstrado que o microambiente tumoral é rico em ATP e adenosina, sugerindo o envolvimento da sinalização purinérgica no desenvolvimento e/ou manutenção do câncer. Ainda, o receptor purinérgico P2X7, conhecido pelo seu papel na indução de apoptose, encontra-se reduzido em alguns tecidos tumorais em comparação aos tecidos saudáveis, indicando que a sua redução possa ser um mecanismo de resistência celular à apoptose. Dessa forma, compreender o papel da sinalização purinérgica no contexto do câncer se torna indispensável e permite que novas abordagens terapêuticas sejam implementadas. Nesse trabalho, avaliamos a função dos nucleotídeos e nucleosídeos da adenina, bem como do receptor P2X7 na indução da morte celular em células de câncer cervical. Também verificamos o efeito do heat shock na potencialização da atividade do receptor P2X7 frente à curta exposição ao ATP em células de câncer de cólon. De acordo com os nossos resultados, o efeito citotóxico do ATP extracelular nas linhagens de câncer cervical é mediado principalmente pela ação do seu metabólito adenosina, que ao entrar no interior das células, promove o aumento dos níveis intracelulares de AMP, ativação de AMPK, aumento da p53 e indução de autofagia. O papel do receptor P2X7 nesse contexto parece ser apenas coadjuvante, visto que o seu bloqueio ou silenciamento impediu em apenas 20% a morte celular. Além disso, utilizando células de câncer de cólon, nós demonstramos que o heat shock aumenta a funcionalidade do receptor P2X7, independente da interação com heat shock proteins ou canais do tipo conexina/panexina, potencializando o efeito citotóxico do ATP. Esse efeito parece estar relacionado à mudanças na composição e arquitetura da membrana celular, visto que o uso do agente fluidizador de membrana benzil álcool foi capaz de mimetizar o efeito do heat shock na potencialização do receptor P2X7 a 37ºC. Este estudo fornece evidências adicionais sobre o papel da sinalização purinérgica no contexto da biologia celular tumoral e abre novas perspectivas para o uso dos nucleotídeos de adenina associados a hipertermia como agentes adjuvantes na terapia do câncer.
The tumor microenvironment is rich in ATP and adenosine, suggesting an involvement for purinergic signaling in cancer development and surveillance. The P2X7 receptor, among the P2 purinergic receptors, is broadly recognized as the “death receptor”, because it promotes cell apoptosis when exposed to high levels of extracellular ATP. Researches have been shown that P2X7 protein levels are decreased at the tumor site in comparison to adjacent healthy tissue, suggesting a mechanism of tumor escape to cell death. Thus, understanding purinergic signaling in a cancer context becomes urgent and opens a new field for therapeutic strategies. Here, we evaluated adenine nucleotides and nucleosides cytotoxicity, as well as P2X7 role in cell death induction using cervical cancer cell lines. Indeed, we investigated heat shock effect on P2X7 functionality through exposing colon cancer cell shortly to ATP at 40ºC. According to our data, adenosine uptake formed from ATP metabolism is the main responsible for the extracellular ATP cytotoxicity in cervical cancer cells. While inside of the cell, adenosine is converted to AMP, leading to AMPK activation, p53 increase and autophagy induction. ATP induced cell death per se through P2X7 in this context seems to be less important, since P2X7 blockage or knocking down reduced only 20% of cell death. In colon cancer cells, we found that heat shock stress was able to increase P2X7 pore formation independently of heat shock protein interaction or native pore-forming transporters association (e.g pannexin-or connexin-type channels), thus leading to an increase ATP cytotoxicity. The mechanism enrolled in this process seems to be related to changes in the lipid composition and architecture of membrane, as the membrane fluidizer benzyl alcohol could reproduce heat stress effect in potentiating P2X7 activation at 37ºC. In conclusion, our work provides further evidence for a purinergic signaling role in the cancer biology context and opens new perspectives for the utility of purine-based drugs associated to hypertermia as adjunctive agents in cancer therapy.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
This thesis analyzed the selection of plants in local medical systems based on two main investigative axes. In the first axis we investigated the role of the local perception of illness in the selection of medicinal plants. In the second axis we seek to understand the relationships among the factors availability and resource efficacy in the differential use of medicinal plants. For this, we conducted interviews with local experts in two communities located in the municipality of Crato, Ceará, Northeastern Brazil. Semi-structured interviews were applied with the experts to obtain information on medicinal plants, illnesses in which plants are used, symptoms perceived by people for each illness and the perception of informants on the effectiveness of each plant mentioned. In addition, a participatory workshop was held to access the perceptions of informants on the relationship between illnesses. In a second step, the experts conducted a ranking of most used plants for each illness and then they indicated the criteria used to justify the position of each plant in the ordering. The local perception of illnesses is important in the selection of medicinal resources as the repertoire of medicinal plants varies as informants perceive different subtypes of the same illness. Furthermore, it was observed that people tend to select plants based on the perception of symptoms of illnesses, since illnesses sharing symptoms also share a common set of plants. It was also observed that the factors (1) perceived availability and (2) the perceived therapeutical efficacy were important in the differential use of medicinal plants; however, the two factors are not necessarily correlated in the differential use. Furthermore, the perceived efficacy cannot always be associated with the recognition of organoleptic properties. The present findings allow us to advance in the understanding of the factors involved both in structure and functionality of local medical systems, such as the local perception of illnesses, the availability and the efficacy of the medicinal resource efficacy.
A presente tese analisou a seleção de plantas em sistemas médicos locais, tomando como base dois eixos investigativos. No primeiro eixo, investigamos o papel da percepção local de doenças na seleção de plantas medicinais. No segundo eixo, buscamos entender as relações entre os fatores disponibilidade e eficácia do recurso no uso diferencial de plantas medicinais. Para isso, realizamos entrevistas com especialistas locais em duas comunidades localizadas no município do Crato, Ceará, no nordeste brasileiro. Com os especialistas, foram aplicadas entrevistas semiestruturadas para obter informações sobre as plantas medicinais, as doenças em que as plantas são empregadas, os sintomas percebidos pelas pessoas para cada doença e a percepção dos informantes sobre a eficácia medicinal de cada planta mencionada. Além disso, uma oficina participativa foi realizada para acessar as percepções dos informantes sobre as relações entre as doenças. Em um segundo momento, os especialistas realizaram um ordenamento das plantas mais usadas para cada doença e, em seguida, indicaram o critério utilizado para justificar a posição de cada planta no ordenamento. A percepção local de doenças é importante na seleção de recursos medicinais, já que o repertório de plantas medicinais varia quando os informantes percebem subtipos diferentes de uma mesma doença. Além disso, foi observado que as pessoas tendem a selecionar plantas com base na percepção dos sintomas das doenças, uma vez que doenças que compartilham sintomas apresentam também um conjunto de plantas comuns. Observou-se também que os fatores disponibilidade percebida e a percepção de eficácia terapêutica foram critérios que se destacaram no uso diferencial de plantas medicinais, no entanto, os dois fatores não necessariamente estão correlacionados no uso diferencial. Ademais, nem sempre a percepção de eficácia pode estar associada com o reconhecimento de propriedades organolépticas. Os presentes achados nos permitem avançar na compreensão dos fatores que estão envolvidos tanto na estrutura como na funcionalidade de sistemas médicos locais, tais como a percepção local de doença, a disponibilidade e eficácia do recurso medicinal.

[EN] Interaction is defined as the realization of a reciprocal action between two or more people or things. Particularly in computer science, the term interaction refers to the discipline that studies the exchange of information between people and computers, and is generally known by the term Human-Computer Interaction (HCI). Good design decisions and an adequate development of the software is required for efficient HCI to facilitate the acceptability of computer-based applications by the users. In clinical settings it is essential to eliminate any barrier and facilitate the interaction between patients and the system. A smooth communication between the user and the computer-based application is fundamental to maximise the advantages and functionalities offered by the system. The design of these applications must consider the personal and current needs of the user by applying a User-Centered Design methodology. The main purpose of this research work is to contribute in the improvement of HCI-based applications addressed to the clinical context, particularly to enhance computer-based interactive sessions to support people suffering from a mental disorder such as Major Depression (MD). Thanks to the advances in Artificial Intelligence techniques, it is now possible to partially automate complex tasks such as the continuous provision of Cognitive-Behavioural Therapies (CBTs) to patients. These CBTs require good levels of adaptability and variability during the interaction with the patient that facilitates the acceptability in the user, an optimal usability and good level of engagement for a successful mid/long term use of the application and treatment adherence. The modelling of complex deliberative and affective processes in artificial systems can be applied to support the prevention and treatment of mental health related issues, enhancing the continuous and remote assistance of patients, saving some economical and clinical resources and reducing the waiting lists in the health services. In this regard, the efforts of this Thesis have been concentrated on the research of two main lines: (1) the generation and planning of adequate contents in an interactive system to support the prevention and treatment of MD based on characteristics of the user; and (2) the modelling of relevant affective processes able to communicate the contents in an emotional effective way taking into account the importance of the affective conditions associated with the MD in the users. Rule Based Systems and the appraisal theory of emotions have been the roots used to develop the main two modules of the computational Framework presented: the Contents Management and the Emotional Modules. Finally, the obtained Framework was integrated into two interactive systems to evaluate the achievement of the research objectives. The first system has been developed in the context of the Help4Mood European research project and its main aim was to support the remote treatment of patients with MD. The second scenario was a system developed to prevent MD and suicidal thoughts in the University community, which was developed in the context of the local PrevenDep research project. These evaluations have indicated that the proposed Framework has reached good levels of usability and acceptability in the target users thanks to the personalizations and adaptation capabilities of the contents and in the way how these contents are communicated to the user. The research work and the obtained results in this Thesis has contributed to the state of the art in HCI-based systems used as support in therapeutic interventions for the prevention and treatment of MD. This was obtained by the combination of a personalized content management to the patient, and the management of the affective processes associated to these pathologies. The developed work also identifies some research lines that need to be addressed in future works to get better HCI systems used for therapeutic purposes.
[ES] Interactuar se define como la realización de una acción recíproca entre dos o más personas o cosas. Particularmente en informática, el término interacción se refiere a la disciplina que estudia el intercambio de información entre las personas y computadoras, y suele conocerse por el término anglosajón Human-Computer Interaction (HCI). Un buen diseño y un adecuado desarrollo del software es necesario para lograr una HCI eficiente que facilite la aceptabilidad del sistema por el usuario. En entornos clínicos es fundamental eliminar cualquier tipo de barrera y facilitar la interacción entre los pacientes y el computador. Es de vital importancia que haya una buena comunicación entre usuario y computador, por este motivo el sistema debe de estar diseñado pensando en las necesidades actuales, cambiantes y personales del usuario, basándose en la metodología de diseño centrado en el usuario. El propósito principal de esta investigación es la identificación de mejoras en HCI aplicada en entornos clínicos, en concreto para dar soporte a personas con trastornos mentales como la Depresión Mayor (DM) y que precisan de terapias psicológicas adecuadas y continuas. Gracias a técnicas de Inteligencia Artificial, es posible automatizar eficientemente ciertas acciones asociadas a los procesos de las terapias cognitivo-conductuales (CBTs, del inglés Cognitive-Behavioural Therapies). Los sistemas de ayuda a la CBT, requieren de una adaptabilidad y variabilidad en la interacción para favorecer la usabilidad del sistema y asegurar la continuidad de la motivación del paciente. Una buena gestión de esta automatización influiría en la aceptabilidad de los pacientes y podría mejorar su adherencia a los tratamientos y por consiguiente mejorar su estado de salud. Adicionalmente, la unión de procesos deliberativos dinámicos pueden liberar recursos clínicos, mejorando el control de los pacientes, y reduciendo los tiempos de espera y los costes económicos. En este sentido, los esfuerzos de esta Tesis se han centrado en la investigación de dos líneas diferentes: (1) la selección y planificación adecuada de los contenidos presentados durante la interacción a través de una planificación dinámica y personalizada, y (2) la adecuación de la comunicación de los contenidos hacia el paciente tomando en cuenta la importancia de los procesos afectivos asociados a estas patologías. Los Sistemas Basados en Reglas (SBR) han sido la herramienta utilizada para dar soporte a los dos módulos principales que componen el Framework presentado en esta Tesis: el módulo de gestión de los contenidos y el módulo emocional. Concluida la fase de diseño, desarrollo y testeo, el Framework fue adaptado e integrado en sistemas reales, para validar la viabilidad y la adecuación del marco de trabajo de esta Tesis. En primer lugar, el sistema se aplicó durante tres años en el tratamiento de la DM en varios centros clínicos europeos en el contexto del Proyecto Europeo de investigación Help4Mood. Finalmente, el sistema fue evaluado en la tarea de prevención de la DM y del suicidio en el Proyecto Local de investigación PrevenDep, de un año de duración. El feedback de estas evaluaciones demostraron que el HCI del Framework tiene unos niveles altos de usabilidad y aceptación, gracias a la personalización, variabilidad y adaptación de los contenidos y de la comunicación de los mismos. Los experimentos computacionales llevados a cabo en esta Tesis han permitido avanzar el estado del arte de sistemas computacionales emocionales aplicados en entornos terapéuticos para la prevención y tratamiento de la DM. Principalmente, gracias a la combinación de una gestión personalizada de los contenidos hacia el paciente tomando en cuenta la importancia de los procesos afectivos asociados a estas patologías. Este trabajo abre nuevas líneas de investigación, como la aplicación de este sistema en otras patologías de salud mental en las qu
[CAT] Interactuar es defineix com la realització d'una acció recíproca entre dos o més persones o coses. Particularment en informàtica, el terme interacció es refereix a la disciplina que estudia l'intercanvi d'informació entre les persones i computadores, i es sol conèixer pel terme anglosaxó Human-Computer Interaction (HCI). Un bon disseny i un adequat desenvolupament del software és necessari per aconseguir una HCI eficient que faciliti l'acceptabilitat del sistema per l'usuari. En entorns clínics és fonamental eliminar qualsevol tipus de barrera i facilitar la interacció entre els pacients i el computador. És de vital importància que hi hagi una bona comunicació entre l'usuari (o pacient) i el computador, per aquest motiu el sistema ha d'estar dissenyat pensant en les necessitats actuals, cambiants i personals de l'usuari, basant-se en la metodologia de disseny centrat en l'usuari. El propòsit principal d'aquesta investigació és la identificació de millores en HCI aplicada en entorns clínics, en concret per donar suport a persones amb trastorns mentals com la Depressió Major (DM) i que precisen de teràpies psicològiques adequades i contínues. Gràcies a tècniques d'Intel·ligència Artificial, és possible automatitzar eficientment certes accions asociades al processos de les teràpies cognitiu-conductuals. Els sistemes computacionals de ajuda a la CBT, requereixen d'una adaptabilitat i variabilitat en la interacció per afavorir la usabilitat del sistema i assegurar la continuïtat de la motiviació del pacient. Una bona gestió d'aquesta automatització influiria en l'acceptabilitat dels pacients i podria millorar la seva adherència als tractaments i per tant millorar el seu estat de salut. Addicionalment, la unió de processos deliberatius dinàmics poden alliberar recursos clínics, millorant el control dels pacients, i reduint els temps d'espera i els costos econòmics. En aquest sentit, els esforços d'aquesta Tesi s'han centrat en la investigació de dues línies diferents: (1) la selecció i planificació adequada dels continguts presentats durant la interacció a través d'una planificació dinàmica i personalitzada, i (2) l'adequació de la comunicació dels continguts cap al pacient tenint en compte la importància dels processos afectius associats a aquestes patologies. Els Sistemes Basats en Regles (SBR) han estat la eina utilitzada per donar suport als dos mòduls principals que componen el Framework presentat en aquesta Tesi: el mòdul de gestió dels continguts oferits a l'usuari; i el mòdul emocional. Conclosa la fase de disseny, desenvolupament i testeig, el Framework va ser adaptat als dominis corresponents i integrat en sistemes madurs per ser avaluat en dos escenaris reals, per validar la viabilitat i l'adequació del Framework d'aquesta tesi. Primerament, el sistema es va aplicar durant tres anys en el tractament de la DM major en diversos centres clínics europeus en el context del Projecte Europeu d'investigació Help4Mood. Finalment, el sistema va ser avaluat en la tasca de prevenció de la DM i del suïcidi al Projecte Local d'investigació PrevenDep, d'un any de durada. El feedback de les avaluacions han demostrat que el HCI del Framework obté uns nivells alts d'usabilitat i acceptació, gràcies a la personalització, variabilitat i adaptació dels continguts i de la comunicació. Els experiments computacionals duts a terme en aquesta Tesi han permès avançar l'estat de l'art de sistemes computacionals emocionals aplicats en entorns terapèutics per a la prevenció i tractament de la DM. Principalment, gracies a la combinació d'una gestió personalitzada dels continguts cap al pacient tenint en compte la importància dels processos afectius associats a aquestes patologies. Aquest treball obre noves línies d'investigació, com l'aplicació d'aquest sistema en altres patologies de salut mental en què sigui recomanable l'aplicació de sessions terapèutiques.
Bresó Guardado, A. (2016). A Computational Framework for Planning Therapeutical Sessions aimed to Support the Prevention and Treatment of Mental Health Disorders using Emotional Virtual Agents [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/64082
TESIS