Le réarrangement FIP1L1-PDGFRA (F/P), identifié de manière récurrente dans les leucémies chroniques à éosinophiles, est à l’origine d’une activation constitutive de l’activité tyrosine kinase de la chaîne α du récepteur au PDGFR. Les mécanismes concourant à la prolifération éosinophile exclusive et au profil de cytotoxicité spécifique à cette leucémie sont encore mal élucidés. Ce récepteur PDGFRα;, principalement exprimé dans les cellules mésenchymateuses, y exerce des effets prolifératifs et chimiotactiques, en partie induits par la production intracellulaire de dérivés réactifs de l’oxygène (ROS). Ces constatations nous ont amené à étudier les perturbations du métabolisme oxydatif dans la leucémie F/P+, en utilisant une approche d’étude globale du protéome d’éosinophiles de sujets F/P+, comparé à des éosinophiles de sujets contrôles. Dans ce travail, nous avons démontré qu’il existe, dans les éosinophiles F/P+, une dérégulation de nombreuses protéines impliquées dans la signalisation redox intracellulaire. De plus, les modifications d’expression de certaines d’entre elles (peroxiredoxine-2, src-homology-2 domain containing tyrosine phosphatase-1 ou SHP-1), non retrouvées dans les éosinophiles de patients ayant un syndrome hyperéosinophilique idiopathique, et identifiées dans une lignée cellulaire exprimant F/P, semblent spécifiquement induites par F/P. L’activation du PDGFRα; dans les éosinophiles F/P+ est donc à l’origine d’un déséquilibre du métabolisme oxydatif dont les conséquences sur la différenciation vers le lignage éosinophile ou sur la cytotoxicité seront discutées. / The FIP1L1-PDGFRA (F/P) fusion gene, identified as a recurrent molecular finding in chronic eosinophilic leukemia, induces a constitutive activation of the kinase domain of PDGFRα. However, the molecular events contributing to the predominant eosinophil lineage expansion and to the singular cytotoxicity profile of eosinophils in this leukemia remain unclear. PDGFRα;, mainly expressed in mesenchymal cells, possesses proliferative and chemotactic properties, which are, in part, mediated by the intracellular production of reactive oxygen species (ROS). These observations prompted us to investigate the disturbances of the redox signaling in the F/P-associated leukemia, using a comparative study of the proteome of F/P+-eosinophils and eosinophils of healthy controls. Here, we report, in F/P+-eosinophils, the abnormal expression of numerous proteins implicated in oxidative metabolism. Furthermore, changes in expression of particular proteins (peroxiredoxine-2 and src-homology-2 domain containing tyrosine phosphatase-1) appears specific to F/P-Eos compared to patients with idiopathic hypereosinophilic syndrome, and could be demonstrated in F/P-expressing cell line EOL-1. Thus, the activation of PDGFRα; in F/P+-eosinophils leads to a global disturbance of the redox signaling, whose consequences on the differentiation toward eosinophil lineage and cytotoxicity will be discussed.

This thesis explored significant other responses to CFS/ME in association with patient illness outcomes and symptom maintenance utilising a multi-method approach; a systematic review, cross-sectional, longitudinal and momentary methods were included. The review identified empirical evidence for two potential interpersonal mechanisms. The evidence suggested that significant other beliefs and responses, dyadic relationship quality, and patient outcomes associated with each mechanism were different. Dyadic belief incongruence was also highlighted as important with respect to relationship quality. Thus, potential research questions and current methodological limitations were identified; the subsequent empirical papers presented attempted to address these. The first empirical study (Chapter 3) utilised the Expressed Emotion (EE) framework to investigate the impact of critical comments and EOI; no cross-sectional associations between EE and patient outcomes were observed. A longitudinal design was also employed to examine the predictive validity of EE. Longitudinally, high critical comments predicted higher fatigue severity; further analyses indicated that depression mediated this relationship. High EOI was also predictive of higher fatigue severity at follow-up. This was the first study to examine EE within a CFS/ME sample; the longitudinal impact of high-EE upon patient outcomes suggests that it is a potentially beneficial target for future interventions. Paper 2 (Chapter 4) sought to examine the factors that might contribute to significant other EE by examining significant other illness beliefs and dyadic belief incongruence. The results indicated that significant others rated as high-EE had stronger illness models, more negative beliefs about the consequences associated with the condition, and negative emotional representations. These findings identify those beliefs that may be particularly important for high-EE within the current patient group. Overall dyadic belief incongruence was not important for EE-rating; high-EE dyads reported similar illness beliefs, whilst low-EE significant others reported more optimistic beliefs about the condition. These findings suggest that optimistic beliefs about the condition may be better for both significant other and patient outcomes. The final empirical study (Chapter 5) examined the associations between significant other negative and solicitous responses and fluctuations in patient illness outcomes on a momentary basis. The impact of significant other responses was largely transitory; changes in patient outcomes did not extend past the current momentary assessment. Negative significant other responses were associated with momentary increases in symptom severity; patient distress partially mediated this relationship. Patient-perceived solicitous responses were associated with increased activity limitation, but reduced disability reported at the same momentary assessment. These results suggest that momentary reports capture more dynamic processes than observed in traditional cross-sectional analyses. Taken together, the findings presented within this thesis provide further evidence for the impact of significant other factors on patient outcomes. The evidence for the hypothesised mechanism associated with critical EE was consistent throughout studies. However, the evidence for the role of EOI currently requires further exploration. Finally, the results suggest that the development of significant other-focussed interventions may be beneficial for both patient and significant other outcomes.

Background: Chronic Kidney Disease (CKD) is a worldwide public health problem. There are few studies in Latin America, especially in primary care settings. Our objective was to determine the prevalence, stages, and associated factors of CKD in primary care setting. Methods: We did a retrospective secondary analysis of a database from the Diabetes and Hypertension Primary Care Center of the Peruvian Social Security System (EsSalud) in Lima, Peru. We defined CKD as the presence of eGFR <60 mL/min and/or albuminuria >30 mg/day in 24 h, according to Kidney Disease: Improving Global Outcomes (KDIGO). Factors associated with CKD were evaluated with Poisson Regression models; these factors included age, gender, type 2 diabetes mellitus (DM2), hypertension (HTN), body mass index (BMI), and uric acid. Associations were described as crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI). Results: We evaluated 1211 patients (women [59%], mean age 65.8 years [SD: 12.7]). Prevalence of CKD was 18%. Using the estimated glomerular filtration rate (eGFR), the prevalence was 9.3% (95% CI 5.3 – 13.3) in patients without HTN or DM2; 20.2% (95% CI 17.6 – 22.8) in patients with HTN, and 23.9% (95% CI 19.4 – 28.4) in patients with DM2. The most common stages were 1 and 2 with 41.5% and 48%, respectively. Factors associated with CKD in the adjusted analysis were: age in years (PR = 1.03, 95% CI 1.01 – 1.04), DM2 (PR = 3.37, 95% CI 1.09 – 10.39), HTN plus DM2 (PR = 3.90, 95% CI 1.54 – 9.88), and uric acid from 5 to <7 mg/dL (PR = 2.04, 95% CI 1.31 – 3.19) and ≥7 mg/dL (PR = 5.19, 95% CI 3.32 – 8.11). Conclusions: Prevalence of CKD in the primary care setting population was high. CKD is more frequent in the early stages of the disease, and individuals with hypertension, DM2, older age and hyperuricemia have higher prevalence of CKD.

Background: The clinical and pathological presentation of COPD is heterogeneous. ‘Chronic bronchitis’ is a phenotype of COPD, which is a clinical diagnosis of a productive cough of ≥ 3 months for ≥ 2 consecutive years. Chronic bronchitis is associated with worse lung function, frequent exacerbations, recurrent hospitalisations and premature death in patients with COPD. Chronic bronchitis sufferers can be further subphenotyped into those who produce sputum during exacerbation or during winter months only and those who are ‘persistent sputum producers,’ who experience mucous hypersecretion throughout the year. An improved understanding of persistent sputum producers is the object of this thesis. Aims: 1) To compare the clinical characteristics and airway inflammatory biomarker profile of COPD persistent sputum producers to that of COPD sputum non-producers 2) To investigate the short term repeatability of sputum parameters in COPD persistent sputum producers 3) To study the expression and relationship of mucins, hypoxia inducible factor (HIF-1α) and carbonic anhydrase IX (CAIX) in COPD persistent sputum producers. Methods: 1) Lung physiology, health status, sputum inflammatory biomarkers and sputum culture results were compared between COPD persistent sputum producers and sputum non-producers 2) Repeatability of spontaneous and induced sputum parameters at 8 weeks was assessed in COPD persistent sputum producers 3) Immunohistochemistry was performed on bronchial biopsies of COPD persistent sputum producers and control groups (COPD sputum non-producers, smokers with normal lung function and lifelong healthy non-smokers with normal lung function) to study the expression of MUC5AC, MUC5B, HIF-1α and CAIX 4) The association between HIF-1α and MUC5B expression was investigated in vitro. Results and Conclusions: The findings suggest that 1) COPD persistent sputum producers have clinically more severe disease, increased airway inflammation, increased impact on health status, increased rate of bacterial colonization and higher number of exacerbations compared to COPD sputum non-producers 2) Induced sputum is repeatable over short term in COPD persistent sputum producers 3) Expression of MUC5B, HIF-1α and CAIX is increased in COPD persistent sputum producers compared to COPD sputum non-producers, smokers with normal lung function and healthy non-smokers 4) HIF-1α can potentially cause increased MUC5B expression. This work reveals potential targets for the development of novel therapies to limit mucous hypersecretion in COPD.

La douleur chronique est souvent associée à la dépression et l’anxiété. Ces pathologies entretiennent des liens complexes qui ont été largement étudiés. Cependant en France, nous manquons d’informations permettant d’améliorer la prise en charge psychothérapeutique de ces patients. Le but de ce travail est d’améliorer la compréhension de l’influence des facteurs psychopathologiques et cognitifs dans la douleur chronique.Étude 1 : Une étude quantitative a été réalisée auprès d’un échantillon de 228 étudiants. L’analyse des croyances associées à la douleur a permis de mettre en lumière une perception positive du vécu de la sensation douloureuse. Ainsi, ils ne perçoivent pas la douleur comme étant un phénomène stable dans le temps ou mystérieux ; de plus, ils ne manifestent pas de sentiment de culpabilité lié à la douleur. Les résultats indiquent également que les participants ont des perceptions rationnelles des médicaments. Ils considèrent cependant qu’il y a une surconsommation des médicaments. Étude 2 : Une étude quantitative a été réalisée auprès d’un échantillon de 247 personnes atteintes de fibromyalgie. Dans cette étude, 93 % des participants présentaient des symptômes dépressifs, et 94 % présentaient des symptômes anxieux. En outre, des symptômes dépressifs sévères sont retrouvés dans 25 % des cas et 43 % des participants présentent une anxiété sévère. Les différentes analyses de régression réalisées ont montré que la relation entre la symptomatologie anxio-dépressive et la douleur est partiellement médiatisée par les croyances associées à la douleur.Étude 3 : Une étude quantitative a été menée auprès de 247 personnes atteintes de fibromyalgie. Les analyses de corrélation ont montré un lien entre la symptomatologie anxio-dépressive, les mesures relatives à la douleur, les croyances associées à la douleur, la dramatisation, la flexibilité psychologique et l’optimisme. L’analyse de régression multiple indique que les croyances associées à la douleur, l’optimisme et la flexibilité psychologique prédisent 58 % de la variance des scores de dramatisation. Une analyse en cluster a permis de mettre en évidence trois profils cognitifs : les catastrophistes, les modérés et les flexibles optimistes. Des analyses de variance ont montré que ces clusters se différenciaient au niveau des scores de dépression, d’anxiété, d’intensité et d’impact de la douleur. Le profil catastrophiste obtenait les scores les plus élevés à ces différentes mesures. / Chronic pain is often associated with depression and anxiety. These pathologies have complex links that have been widely studied. In France, however, there are few studies that provide information on psychotherapeutic treatment of these patients. The overall objective of this work is to improve understanding of psychopathological and cognitive factors linked to chronic pain. Study 1: A quantitative study was carried out on a sample of 228 students. An analysis of beliefs associated to pain provided insight into the concept of pain sensation. The participants perceived pain as an instable phenomenon over time, were not likely to associate pain with mysterious origins, and did not link pain to feelings of guilt. The results also showed that the participants had rational beliefs about medication, although they tended to believe that medication was overused. Study 2: A quantitative study was conducted on a sample of 247 fibromyalgia sufferers. In this study, 93 % of participants presented depressive symptoms, and 94 % presented anxiety symptoms. Severe depressive symptoms were found in 25 % of cases, and 43 % of participants reported severe anxiety. Regressions analyses showed that the relationship between depressive symptoms, anxiety and pain is partially mediated by beliefs associated with pain.Study 3: A quantitative study was conducted on a sample of 247 people suffering from fibromyalgia. Correlation analyses showed a link between anxio-depressive symptoms, measures related to pain, pain-related beliefs, dramatization, psychological flexibility, and optimism. A multiple regression analysis indicated that beliefs associated with pain, optimism and psychological flexibility predicted 58 % of the variance in scores of dramatization. A cluster analysis highlighted three cognitive profiles in these patients: ‘catastrophics’, ‘moderates’ and ‘flexible optimistics’. Analyses of variance showed that cluster groups differed in levels of depression, anxiety, intensity, and impact of pain. ‘Catastrophics’ had higher scores on these measures.

INTRODUCTION Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients’ knowledge about their disease. In 2011 the Kidney Disease Knowledge Survey (KiKS) was developed: a questionnaire that assesses the specific knowledge about chronic kidney disease in pre-dialysis patients. OBJECTIVE To translate to Spanish, culturally adapt and validate the Kidney Disease Knowledge Survey questionnaire in a population of patients with pre-dialysis chronic kidney disease. METHODS We carried out a Spanish translation and cross-cultural adaptation of the Kidney Disease Knowledge Survey questionnaire. Subsequently, we determined its validity and reliability. We determined the validity through construct validity; and reliability by evaluating its internal consistency and its intra- observer reliability (test-retest). RESULTS We found a good internal consistency (Kuder-Richardson = 0.85). The intra-observer reliability was measured by the intra-class correlation coefficient that yielded a value of 0.78 (95% CI: 0.5-1.0). This value indicated a good reproducibility; also, the mean difference of -1.1 test-retest SD 6.0 (p = 0.369) confirms this finding. CONCLUSION The translated Spanish version of the Kidney Disease Knowledge Survey is acceptable and equivalent to the original version; it also has a good reliability, validity and reproducibility. Therefore, it can be used in a population of patients with pre-dialysis chronic kidney disease.

Introduction—Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients' knowledge about their disease. In 2011, the Kidney Disease Knowledge Survey (KiKS) was developed, a questionnaire that assesses the specific knowledge about CKD in pre-dialysis patients. Objective—To translate to Spanish, culturally adapt and validate the questionnaire KiKS in a population of patients with pre-dialysis CKD. Methods—The translation and cultural adaptation of KiKS was performed. Subsequently, its validity and reliability were determined. The validity was evaluated by construct validity; and the reliability by its internal consistency and its intra-observer reliability (test-retest). Results—A good internal consistency was found (Kuder-Richardson = 0.85). Regarding intraobserver reliability, the intraclass correlation coefficient with a value of 0.78 (95% CI: 0.5–1.0) indicated a good reproducibility; the mean difference of −1.1 test-retest S.D. 6.0 (p = 0.369) confirm this.

Ph.D. / Chronic Fatigue Syndrome (CFS) is a disabling and poorly understood multisystem illness. The illness is characterised by the principal symptom of persistent or intermittent unexplained fatigue, and has physical, psychological, social and community implications. Since CFS remains unexplained by a conventional biomedical diagnosis, confusion and controversy surround the illness. The confusing and controversial issues are the diagnosis, etiology, psychiatric states and the role of psychosocial factors. The overall aim of this study was to investigate the role of certain psychosocial factors, namely personality preferences or type, coping resources, locus of control and Type A behaviour pattern (TABP), in CFS. The total sample consisted of 70 subjects from four samples, namely the CFS patient sample (n = 21), coronary heart disease (CHD) patient sample (n = 14), depression patient sample (n = 15) and healthy sample (n = 20). The CHD patient, depression patient and healthy samples were included for comparative value. The broad hypothesis was that specific personality preferences or types as well as specific coping resources, locus of control and TABP would be characteristic of the CFS patient sample. The second hypothesis was that the CFS patient sample would significantly differ from the comparative samples on these psychosocial factors. Finally, it was hypothesised that the psychosocial factors would be correlated and hence have predictive value for the development and maintenance of CFS. On the Myers-Briggs Type Indicator' s (MBTI®), the CFS patient sample was found to have an over-representation of the introversion (61.9 %), intuition (52.4 %), feeling (66.7 %) and judging (76.2 %) preferences. An analysis of the type distribution and frequencies resulted in two whole types, namely ISFJ and INFJ. A normative interpretation of the Coping Resources Inventory° (CRI©) profile revealed that the CFS patient sample's coping resources in the various domains of cognitive, social, emotional, spiritual/philosophical, physical and total resources were below the mean. The results of the Locus of Control (LOC) Questionnaire revealed that the CFS patient sample primarily utilises an internal locus of control. However, the sample was also found to have a low state of self-regulation. In comparison to the healthy sample, the CFS patient sample had a significantly higher external locus of control. These findings lead to the hypothesis that during stressful situations (such as illness), the CFS patient sample's low state of self-regulation may result in them utilising an external locus of control. The CFS patient sample was found to have a higher mean TABP score than the mean TABP score of the total sample. This sample was also found to have a significantly higher mean TABP score than the healthy sample. Hence, it was concluded that the CFS patient sample exhibited a TABP. The Mann-Whitney U tests were utilised to determine the differences between the CFS patient sample and the various comparative samples. Various of the assessed psychosocial factors were found to differ significantly. However, most of the differences were found between the coping resources of the various samples. Correlations were drawn between the various assessed dimensions to determine whether the psychosocial factors have predictive value. On the MBTI®, a preference for sensing was associated with an external locus of control whereas a preference for judging was associated with a high TABP. A high TABP was associated with a high external locus of control. An external locus of control and TABP have been identified in previous studies on chronic illnesses as predisposing and maintenance factors. Hence, it was hypothesised that a preference for sensing and for judging respectively may be personality preferences that play a role in the development and maintenance of CFS. Subsequently, a high external locus of control and a high TABP respectively were also hypothesised to be predisposing and maintenance factors. The findings of the correlations also lead to the hypothesis that CFS patients with an extraversion and a thinking preference respectively have the ability to cope more effectively with their illness and may even recover quicker. Chronic Fatigue Syndrome patients with a high internal locus of control and a high state of self-regulation were also hypothesised to have a better overall ability to cope with their illness and may hence recover quicker. The final conclusion of the study's findings was that personality preferences and type, coping resources, locus of control and TABP interact within a complex matrix of socio-behavioural and biological factors in the development and maintenance of CFS. The value of the study is the identification of individuals at risk for the development of CFS and the psychosocial factors involved in the development and maintenance of CFS. In addition to this value, the MBTI ® results can be used to alert psychologists to the issues frequently associated with each MBTI® preference and can hence assist psychologists in the psychotherapeutic treatment of CFS patients. The results of the coping resources' deficits can also assist psychologists in the design and development of stress management programmes for CFS patients.

M.Tech. / The aim of this study was to compare the effectiveness of cervical adjustment therapy, dry needling of the levator scapulae muscle and a combination of the two in the treatment of chronic mechanical neck pain. Forty-five patients were recruited via posters and advertisements from in and around the University of Johannesburg. The participants had to present with bilateral neck pain, decreased range of motion and an active levator scapulae muscles trigger point, which was diagnosed using range of motion and trigger point examination. The participants were randomly allocated into three groups of fifteen participants each. Prior to treatment a full case history, physical examination and cervical regional examination were performed to ensure that the patients were eligible to partake in the clinical trial. Group 1 was the adjusting group; group 2 was the combination group while group 3 was the needling group. Participants were treated five times over a period of three weeks. The objective measurements used in this clinical trial involved a cervical range of motion instrument (C.R.O.M., Performance Attainment Associates) and an algometer (Wagner Instruments). Subjective measurements were achieved using the Neck Pain and Disability Index (Appendix G) and the Numerical Pain Rating Scale (Appendix H). Each measurement was taken prior to treatment on the first and third visits and after treatment on the fifth visit with three measurements per participant overall. The statistical analysis was conducted using the Kruskal-Wallis, Friedman and Wilcoxon tests to compare data. The results indicated that the three groups responded favourably to their respective treatments. Overall, this study has indicated that dry needling of the Levator scapulae muscle provides no statistically significant contribution to the conservative treatment of mechanical neck pain caused by levator scapulae trigger points.

This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes.