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A thesis Submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg for the Degree of Doctor of Philosophy. / The purpose of this thesis was to construct a comprehensive battery of standardised tests that was robust in terms of its psychometric characteristics to evaluate visual-perceptual-motor (V-P-M) function in the adult who had suffered a Cerebro-Vascular- Accident (C.V.A.). This was to meet the need for the occupational therapist to target specific deficits and thereby to provide an effective treatment to patients. Work done by the candidate with patients, the literature as well as a review of existing tests demonstrated the need for such a test battery. Up to this time, tests available do not meet all the requirements for a reliable and valid assessment tool for adult V-P-M function. This demanded that the tests compiled for this thesis be based on a sound theoretical model, supplied information on age related changes in function and had undergone rigorous psychometric testing. It was also nescessary that normative data based on information collected from a random sarnote of the population for whom the test was intended and which would include a wide range of age groups, be collected. in order to fulfil these requirements the construction of this test battery followed the eleven steps necessary to produce tests ready for the final stage (step twelve) l.e. the collection of the normative data. ( Abbreviation abstract ) / AC2017

Introduction: Cardiovascular disorders contribute significantly to mortality and morbidity amongst patient's psychotic disorders such as schizophrenia and bipolar mood disorders. In addition to conventional risk factors for cardiovascular disorders (smoking, alcohol use, inadequate physical activity, hypertension, diabetes, dyslipidaemia, obesity and metabolic syndrome, and non-modifiable factors such as sex, age and social-economic status) exposure to potentially traumatic events, psychological distress, comorbidity of other medical conditions, and use of antipsychotics may also increase cardiovascular risk in patients with psychosis. There is also evidence to suggest that intervention to mitigate such cardiovascular risk factors are suboptimal, hence contributing to poor outcomes. Despite growing interest in cardiovascular health, there remains a paucity of data on the prevalence of the various cardiovascular risk factors among patients with psychosis in low resource settings such as Sub-Saharan Africa. This is likely to differ from high resource contexts given social-cultural and economic differences as well as differences in the health systems. In order to design contextually relevant cardiovascular risk screening, treatment and prevention guidelines that can be integrated into routine care of the mentally ill patients in low- and middle-income countries (LMICs), further work in this setting is warranted. Objectives: The aim of this thesis was to establish the cardiovascular risk profile among patients treated for psychotic disorders at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Western Kenya. Specific objectives were as follows: 1. To conduct a literature review on the burden and etiological mechanisms of cardiovascular risk in patients with psychosis, with a focus on LMIC. 2. To compare the prevalence, as well as sociodemographic and clinical correlates, of conventional cardiovascular risk factors (smoking, alcohol intake, poor diet, and lack of exercise, diabetes mellitus, hypertension, obesity, dyslipidaemia and metabolic syndrome) in patients with psychosis versus matched controls. 3. To establish the prevalence and correlates of non-conventional risk factors; psychological distress, traumatic events (lifetime and childhood trauma) and comorbid medical disorders in patients with psychosis and controls, and to delineate how these risk factors contribute to the overall cardiovascular risk. 4. To describe current psychopharmacological treatments and explore potential associations with cardiovascular risk among patients with psychosis. 5. To explore the overall 10-year cardiovascular disease risk, as well as the social demographic and clinical correlates among patients and controls. 6 .To determine the proportion of untreated metabolic disorders (hypertension, diabetes mellitus, and dyslipidaemia) in patients with psychotic disorders and matched controls. Methods: This was a cross-sectional descriptive survey comparing 300 patients with psychosis and 300 controls at Moi Teaching and Referral Hospital, Western Kenya. A paper based researcher-administered questionnaire was used to collect data on demographic variables (age, sex, education level, and marital status), and risk factors (smoking, alcohol intake, diet, physical activity). We used the Composite International Diagnostic Interview (CIDI) to assess for presence of other chronic medical disorders. Data on childhood trauma were obtained using the Childhood Trauma Questionnaire (CTQ) while the Life Events Checklist (LEC) was used to obtain data on lifetime exposure to potentially traumatic events. Data on psychological distress among controls were obtained using the Kessler-10 questionnaire. Measurements of weight, height, abdominal circumference and blood pressure were taken from each of the participants. Blood was drawn for measurement of glucose level and lipid profile. Data analysis was undertaken using Stata version 15. T-tests were used to compare continuous variables while Pearson chi-squared tests was used for categorical variables. Regression modelling was undertaken to assess associations between sociodemographic and clinical predictor variables and the cardiovascular risk factors. Results: Data collection took place between July 2018 and March 2019. The mean age of patients was 33 years and of controls was 35 years. Compared to controls, patients were more likely to be unmarried (46% vs 33% p< 0.001), and were reduced among females (OR 0.41 p20). The estimated 10 year cardiovascular risk was significantly associated with female Sex (p=0.007), age (p <0.001), current tobacco smoking (p <0.001) and metabolic syndrome (P<0.001). Among the patients, 280 (94.3%) patients were on antipsychotics with the majority (86.5%) being treated with olanzapine. Of all the participants with diabetes 60% among patients and 22% among controls were not on treatment. Of the total number of participants with hypertension, 65% of patients and 47% controls were not on treatment. Conclusion: In the study setting of Eldoret, Western Kenya, patients with psychosis were found to have high levels of lifestyle cardiovascular risk factors such as smoking, inadequate intake of fruits and vegetables and inadequate physical activity. They were also found to have high rates of metabolic disorders such as hypertension, obesity, metabolic syndrome and dyslipidaemia. There was no evidence of increased cardiovascular risk among participants exposed to traumatic life events, with those experiencing psychological distress or those with other chronic medical disorders. The use of olanzapine was not significantly associated with increased cardiovascular risk in this setting. There was an identifiable gap in the treatment of cardiovascular risk factors in this setting. Given these findings, we recommend efforts to address these risk factors by development of protocols to ensure screening for these risk factors, adequate documentation and appropriate treatment.

O estudo da associação entre doença arterial coronariana e coronariopatias (DAC), stress e personalidade tem produzido grande volume de pesquisas, cujos resultados indicam correlação significante entre stress e personalidade com DAC. O campo da psicocardiologia emergiu recentemente como uma especialização da medicina comportamental, tendo por objetivo a busca de evidências das associações existentes entre traços de personalidade e outras variáveis psicossociais, com a etiologia, a ocorrência e o prognóstico da DAC. O Padrão Comportamental Tipo A (TABP) e a Personalidade Tipo D (TDP) são construtos que relacionam personalidade a desfechos cardíacos e estados crônicos de stress, constituindo estilos diferenciados de coping. TABP é um construto multidimensional considerado como fator de risco independente para a ocorrência de DAC, caracterizado principalmente por hostilidade, raiva, impaciência, ambição, estilo de fala rápido e urgência do tempo. Mais recentemente, o conceito da TDP foi proposto com base no do Modelo dos Cinco Fatores de Personalidade (FFM). TDP é caracterizada pela interação simultânea de afetividade negativa e inibição social. O indivíduo TDP vive permanentemente um estado emocional permeado por sentimentos negativos, ao mesmo tempo em que inibe a expressão desta afetividade negativa em situações de interações sociais. Esta overview teve por objetivo investigar as evidências obtidas em revisões sistemáticas (RSs), com ou sem metanálise, sobre a associação do TABP e da TDP com eventos coronarianos. Foram pesquisadas as bases de dados: Clinical Trials, Cochrane Library, Dissertation Abstracts, EMBASE, LILACS, MEDLINE/PubMed e PsychINFO. Dois revisores avaliaram independentemente os títulos e os resumos de todas as RSs identificadas na busca eletrônica. Foram identificadas onze RSs que atenderam aos critérios de inclusão, sete sobre TABP e quatro sobre TDP; além de uma overview sobre TABP. As evidências sumarizadas das RSs convergiram para uma associação quase nula entre TABP e DAC, mesmo quando hostilidade e raiva foram usados como sinônimos de TABP. Por outro lado, as RSs que investigaram a associação entre TDP e DAC acharam evidências robustas, especialmente em prognosticar evolução negativa de pacientes TDP com DAC preexistente. A avaliação dos efeitos de fatores psicossociais na etiologia, desenvolvimento e prognóstico de doenças cardíacas tem importantes implicações clínicas e é essencial para diagnosticar indivíduos com propensão à DAC para ações preventivas e para o sucesso de programas de reabilitação cardíaca. A possibilidade de o cardiologista avaliar seus pacientes quanto à probabilidade de desenvolver DAC tem grande implicação para a prática médica por seu valor profilático e prevencionista. Estudos prospectivos recentes evidenciaram que a afetividade positiva é associada à saúde cardíaca com efeitos benéficos na reabilitação cardíaca / Studies on the association of cardiac heart disease (CHD), stress and personality have being producing an enormous volume of research, with results indicating a significant correlation among stress, personality and coronary disease. The field of psychocardiology arose as a specific area of behavioral medicine. It aims searching for evidence on existing associations between personality traits and the ethiology, incidence and prognosis of (CHD). The Type A Behavior Pattern (TABP) and the Type D Personality (TDP) are constructs associated with cardiac endpoints and are components of a chronic stress condition, wich produces differentiated coping styles. TABP is a multidimensional construct considered as an independent risk factor for the incidence of CHD, characterized mainly by hostility, anger and time urgency. More recently, the TDP concept was proposed on the basis of the Five-Factor Model of Personality (FFM). TDP is characterized by the simultaneous interaction of negative affectivity and social inhibition. The TDP individual experiences a permanent emotional state permeated by negative feelings, at the same time he or she inhibits the expression of this negative affectivity in social interactions. The objective of this overview is to investigate evidence obtained by systematic reviews (SRs), with or without meta-analyses, on the association of TABP and TDP with coronary events. Clinical Trials, Cochrane Library, Dissertation Abstracts, EMBASE, LILACS, MEDLINE/PubMed and PsychINFO data bases have been consulted. The titles and abstracts of all SRs identified through electronic search were analysed by two indepent reviewers. Eleven identified SRs met the inclusion criteria, seven on TABP and four on TDP, besides an overview on TABP. In this overview, summarized evidence of the SRs on TABP converged to an almost null association between TABP and CHD. Otherwise, the SRs which investigated the association between TDP and CHD found robust evidence, specially in the prognosis of negative evolution of TDP patients with previous CHD. The assesment of the psychosocial factors effects in the ethiology, development and prognosis of cardiac disease has important clinical implication and is essential to assess individuals with propensity to CHD in order to adopt preventive actions and to the success of cardiac rehabilitation programs. The possibility that cardiologists have to diagnose their patients on the likelihood to develop CHD has relevant implications to the medical practice for its prophylatic and preventive value. Recent prospective studies found evidence that positive affectivity is associated to cardiac health with beneficial effects in cardiac rehabilitation

O estudo da associação entre doença arterial coronariana e coronariopatias (DAC), stress e personalidade tem produzido grande volume de pesquisas, cujos resultados indicam correlação significante entre stress e personalidade com DAC. O campo da psicocardiologia emergiu recentemente como uma especialização da medicina comportamental, tendo por objetivo a busca de evidências das associações existentes entre traços de personalidade e outras variáveis psicossociais, com a etiologia, a ocorrência e o prognóstico da DAC. O Padrão Comportamental Tipo A (TABP) e a Personalidade Tipo D (TDP) são construtos que relacionam personalidade a desfechos cardíacos e estados crônicos de stress, constituindo estilos diferenciados de coping. TABP é um construto multidimensional considerado como fator de risco independente para a ocorrência de DAC, caracterizado principalmente por hostilidade, raiva, impaciência, ambição, estilo de fala rápido e urgência do tempo. Mais recentemente, o conceito da TDP foi proposto com base no do Modelo dos Cinco Fatores de Personalidade (FFM). TDP é caracterizada pela interação simultânea de afetividade negativa e inibição social. O indivíduo TDP vive permanentemente um estado emocional permeado por sentimentos negativos, ao mesmo tempo em que inibe a expressão desta afetividade negativa em situações de interações sociais. Esta overview teve por objetivo investigar as evidências obtidas em revisões sistemáticas (RSs), com ou sem metanálise, sobre a associação do TABP e da TDP com eventos coronarianos. Foram pesquisadas as bases de dados: Clinical Trials, Cochrane Library, Dissertation Abstracts, EMBASE, LILACS, MEDLINE/PubMed e PsychINFO. Dois revisores avaliaram independentemente os títulos e os resumos de todas as RSs identificadas na busca eletrônica. Foram identificadas onze RSs que atenderam aos critérios de inclusão, sete sobre TABP e quatro sobre TDP; além de uma overview sobre TABP. As evidências sumarizadas das RSs convergiram para uma associação quase nula entre TABP e DAC, mesmo quando hostilidade e raiva foram usados como sinônimos de TABP. Por outro lado, as RSs que investigaram a associação entre TDP e DAC acharam evidências robustas, especialmente em prognosticar evolução negativa de pacientes TDP com DAC preexistente. A avaliação dos efeitos de fatores psicossociais na etiologia, desenvolvimento e prognóstico de doenças cardíacas tem importantes implicações clínicas e é essencial para diagnosticar indivíduos com propensão à DAC para ações preventivas e para o sucesso de programas de reabilitação cardíaca. A possibilidade de o cardiologista avaliar seus pacientes quanto à probabilidade de desenvolver DAC tem grande implicação para a prática médica por seu valor profilático e prevencionista. Estudos prospectivos recentes evidenciaram que a afetividade positiva é associada à saúde cardíaca com efeitos benéficos na reabilitação cardíaca / Studies on the association of cardiac heart disease (CHD), stress and personality have being producing an enormous volume of research, with results indicating a significant correlation among stress, personality and coronary disease. The field of psychocardiology arose as a specific area of behavioral medicine. It aims searching for evidence on existing associations between personality traits and the ethiology, incidence and prognosis of (CHD). The Type A Behavior Pattern (TABP) and the Type D Personality (TDP) are constructs associated with cardiac endpoints and are components of a chronic stress condition, wich produces differentiated coping styles. TABP is a multidimensional construct considered as an independent risk factor for the incidence of CHD, characterized mainly by hostility, anger and time urgency. More recently, the TDP concept was proposed on the basis of the Five-Factor Model of Personality (FFM). TDP is characterized by the simultaneous interaction of negative affectivity and social inhibition. The TDP individual experiences a permanent emotional state permeated by negative feelings, at the same time he or she inhibits the expression of this negative affectivity in social interactions. The objective of this overview is to investigate evidence obtained by systematic reviews (SRs), with or without meta-analyses, on the association of TABP and TDP with coronary events. Clinical Trials, Cochrane Library, Dissertation Abstracts, EMBASE, LILACS, MEDLINE/PubMed and PsychINFO data bases have been consulted. The titles and abstracts of all SRs identified through electronic search were analysed by two indepent reviewers. Eleven identified SRs met the inclusion criteria, seven on TABP and four on TDP, besides an overview on TABP. In this overview, summarized evidence of the SRs on TABP converged to an almost null association between TABP and CHD. Otherwise, the SRs which investigated the association between TDP and CHD found robust evidence, specially in the prognosis of negative evolution of TDP patients with previous CHD. The assesment of the psychosocial factors effects in the ethiology, development and prognosis of cardiac disease has important clinical implication and is essential to assess individuals with propensity to CHD in order to adopt preventive actions and to the success of cardiac rehabilitation programs. The possibility that cardiologists have to diagnose their patients on the likelihood to develop CHD has relevant implications to the medical practice for its prophylatic and preventive value. Recent prospective studies found evidence that positive affectivity is associated to cardiac health with beneficial effects in cardiac rehabilitation

La dysoxie (hypoxie/hyperoxie) résulte de l’inadéquation entre la consommation en oxygène et ses apports, provoquant altérations du métabolisme cellulaire et impact physiopathologique majeur. L’hypoxie et l’inflammation font intervenir les facteurs HIF-1a et NF-kB qui activent le système adénosinergique. L’hypoxie augmente la concentration d’adénosine, entraîne une surexpression d’A2AR et induit une immunosuppression lymphocytaire T. Nous avons fait l‘hypothèse que l’inflammation via NF-kB influençait la suppression lymphocytaire adénosinergique; qu’une hyperhomocystéinémie favoriserait l’inflammation en modifiant la viabilité lymphocytaire; qu’in vivo, la réponse adénosinergique était modulée par l’hyperoxie. Des lymphocytes T ont été soumis à une inflammation (agents mitogènes) et à une hypoxie chimique (CoCl2). Nous avons analysé l’expression de NF-kB, HIF-1α, A2AR et évalué les concentrations en adénosine, adénosine déaminase, AMPc, et homocystéine. Enfin, nous avons étudié les effets de l’hyperoxie/hyperbarie sur la réponse adénosinergique. L’hypoxie stimule la réponse adénosinergique : NF-kB induit HIF-1α qui augmente l’expression d’A2AR, favorisant l’immunosuppression. L’inhibition de NF-kB par H2S bloque l’immunosuppression via HIF-1α/A2AR. In vivo, l’hyperoxie inhibe la réponse adénosinergique via la diminution de l’expression d’A2AR. Hypoxie et hyperoxie ont un effet en miroir sur le système adénosinergique. Manipuler la concentration en O2 permet de piloter système immunitaire et inflammation via A2AR. L’utilisation d’H2S pourrait traiter des pathologies à fort impact en santé publique, tels des troubles cardiovasculaires favorisés par l’hyperhomocystéinémie. / Dysoxia (hypoxia/hyperoxia) results from an impaired balance between oxygen-supply concentration and cellular metabolism causing various disorders. Hypoxia and inflammation involve HIF-1a and NF-kB factors and are linked via the adenosinergic response. Hypoxia increase adenosine concentration and A2A receptors (A2AR) expression which induces T-lymphocyte suppression. We hypothesized that during hypoxia, inflammation influences adenosinergic immunosuppression via NF-kB. As homocysteine promotes inflammation, which is considered as a risk factor, we hypothesized that hyperomocysteinemia affects T-cell viability and adenosinergic response. Effects of hyperoxic and hyperbaric conditions on adenosinergic system remain unclear. NF-kB, HIF-1α, and A2AR expression were studied using T-cells stimulated by mitogens under hypoxic conditions (CoCl2). Adenosine, adenosine deaminase, cAMP concentration and homocysteine metabolism were analyzed. Effect of hyperoxia on the adenosinergic pathway was addressed in a rat model using pressure chambers. HIF-1α production was induced by hypoxia, A2AR expression increased following NF-kB activation that enhanced lymphocyte-suppression. Inhibition of NF-kB by H2S resulted in improved cell-viability by down-regulating A2AR-mediated-immunosuppression. Hyperhomocysteinemia increased H2S production (transsulfuration-pathway). We also found in rat that hyperoxia repressed the adenosinergic response. Manipulating blood oxygen level constitutes an effective mean to control the immune response and inflammation via the adenosinergic system. Acting on A2AR expression via H2S production may control cardiovascular-disorders with high impact on public health.