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Thesis (MScMedSc)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease in Western countries and is considered the hepatic manifestation of the Metabolic Syndrome (MetS). Its heterogeneous nature ranges from hepatic steatosis through steatohepatitis to advanced fibrosis and cirrhosis where the ingestion of significant amounts of alcohol has been excluded. The disease profile of NAFLD and its necro-inflammatory subset Nonalcoholic Steatohepatitis (NASH) were described in the parent study, which provided a clinically well-characterised patient cohort for the present investigation. South African patients with NASH had significantly higher mean serum cholesterol and triglyceride levels than those with fatty liver only. The objective of this study was to implement a high-throughput real-time polymerase chain reaction (PCR) method in our laboratory to enable the assessment of cardiovascular genetic risk factors in NAFLD patients. The specific aims were to determine the clinical utility and perform analytical validation of each mutation included in the multi-gene cardiovascular disease (CVD) screening assay. The Pathology Supported Genetic Testing (PSGT) concept developed at our department provides a practical approach to personalized medicine. The CVD multi-gene screen analyses key metabolic pathways relating to atherogenic dyslipidaemia, chronic inflammation, hypercoagulation and iron dysregulation implicated in insulin resistance, which is known to be a universal factor in the pathogenesis of NAFLD. Deleterious low-penetrance mutations in the APOE (APOE2 and E4 alleles), MTHFR (677C>T and 1298A>C), F2 (20210G>A), FV (1691G>A, Leiden) and HFE (C282Y and H63D) genes were included for analysis due to their important role as genetic contributors to these biological processes. A total of 178 patients diagnosed with NAFLD and 75 controls were studied using direct DNA sequencing and a RT-PCR system for mutation detection. In addition, two patients with high ferritin levels were included as case studies. A significant association was found between HFE mutations and elevated Alanine Transaminase (ALT) levels in the NAFLD population (p = 0.04). This discovery is interpreted as the identification of a subset of patients at greater risk of developing progressive liver damage who would benefit most from genetic testing to direct more aggressive therapy at an earlier stage. The necessity of an integrative, systems-based network approach was demonstrated to more accurately distinguish between Hereditary Haemochromatosis (HH) and Insulin Resistance-associated Hepatic Iron Overload (IR-HIO) syndrome in obese patients. The PSGT approach to personalized medicine facilitates diagnosis of CVD subtypes, prevention of cumulative risk and the formulation of gene-based intervention programs tailored to the needs of the patient. These findings support the clinical utility of the CVD multi-gene test to guide chronic disease risk management in patients with NAFLD. The HFE mutation detection component of this test is of particular relevance in directing an effective treatment strategy in patients with a medical history of CVD and/or high iron stores. / AFRIKAANSE OPSOMMING: Nie-Alkoholiese Vettige Lewer Siekte (NAFLD) is die mees algemene kroniese lewer siekte in Westerse lande en word bestempel as die hepatiese manifestasie van die Metaboliese Sindroom (MetS). Die heterogene natuur van NAFLD strek van hepatiese steatose deur steatohepatietis tot gevorderde fibrose en sirrose waar grootskaalse alkohol inname uitgesluit is. Die siekte-profiel van NAFLD en sy nekro-inflammatoriese subtipe Nie-Alkoholiese Steatohepatietis (NASH) is reeds beskryf in die ouer studie, wat ‗n klinies goed-gekarakteriseerde pasiënt groep vir die huidige ondersoek daar gestel het. Suid-Afrikaanse pasiënte met NASH het beduidend hoër gemiddelde serum cholesterol en trigliseried vlakke in vergelyking met slegs vettige lewer. Die doel van hierdie studie was om ‗n hoë deurvoer rieëltyd polimerase kettingreaksie (RT-PCR) metode in ons laboratorium te implimenteer om kardiovaskulêre genetiese risiko faktore in NAFLD pasiënte te ondersoek. Die spesifieke mikpunte was om die kliniese nut en analitiese geldigheid van elke mutasie wat ingesluit is in die multi-geen kardiovaskulêre siekte (KVS) siftings toets vas te stel. Die Patologie Ondersteunde Genetiese Toetsing (PSGT) konsep wat by ons departement ontwikkel is, verskaf ‗n praktiese benadering tot persoonlike medisyne. Die KVS multi-geen toets analiseer belangrike metaboliese weë verwant aan atherogene dyslipidemie, kroniese inflammasie, oormatige bloedstolling en yster disregulering wat betrokke is by insulien weerstand wat bekend is as ‗n universele factor in the patogenese van NAFLD. Nadelige lae-penetrasie mutasies in die APOE (APOE2 en E4 allele), MTHFR (677C>T en 1298A>C) F2 (20210G>A), FV (1691G>A, Leiden) en HFE (C282Y en H63D) gene was ingesluit vir analise as gevolg van hul belangrike rol as genetiese bydraers tot die bogenoemde biologiese prosesse. ‗n Totaal van 178 pasiënte gediagnoseer met NAFLD en 75 kontroles is bestudeer deur gebruik te maak van direkte DNA volgordebepaling en ‗n RT-PCR metode vir mutasie opsporing. Twee pasiënte met verhoogde ferritien vlakke is ook as gevalle studies ingesluit. ‗n Beduidende assosiasie is gevind tussen HFE mutasies en verhoogde Alanien Transaminase (ALT) vlakke in die NAFLD studiepopulasie (p = 0.04) wat aanduidend is van ‗n subgroup van pasiënte wat die meeste baat sal vind uit genetiese toetsing om meer aggressiewe behandeling te rig op' n vroeër stadium. Die noodsaaklikheid van 'n geïntegreerde, stelsels-gebaseerde netwerk benadering is gewys om meer akkuraat te onderskei tussen Oorerflike Hemochromatose (HH) en Insulien Weerstand-geassosieerde Hepatiese Yster Oorlading (IR-HIO) sindroom in vetsugtige pasiënte. Die PSGT benadering tot persoonlike medisyne formuleer geen-gebaseerde intervensie programme aangepas tot die behoeftes van die pasiënt ek maak diagnose van KVS-subtipes en voorkoming van kumulatiewe risiko moontlik. Hierdie bevindinge ondersteun die kliniese nut van die KVS multi-geen toets om riglyne vir die risikobestuur van kroniese siektes soos NAFLD daar te stel. Die HFE mutasie opsporings komponent van hierdie toets is van besondere belang om 'n effektiewe strategie vir die behandeling van pasiënte met 'n mediese geskiedenis van KVS en/of hoë yster vlakke daar te stel.

<p>This thesis identifies and systematizes two categories ofpractical problems that stem from work and working environmentcontexts: workplace privacy and occupational health risks. Thefocus of the discussion is on ethical justification. Do we havereason to accept a certain level of (potential) harm toemployees by virtue of the fact that they are employees, and ifso, under what circumstances? The thesis consists of a briefintroduction and three essays.</p><p>In<i>Essay</i>I, it is argued that employees have a prima facieright to privacy, but that this right can be overridden bycompeting moral principles that follow, explicitly orimplicitly, from the contract of employment. Three types ofjustification are specified: those that refer to the employer'sinterests, those that refer to the interests of the employee,and those that refer to the interests of third parties. A setof ethical criteria is developed and used in the subsequentessay to determine the moral status of infringement ofworkplace privacy.</p><p>In<i>Essay</i>II, these criteria are applied to three broadcategories of intrusive workplace practices: (1) monitoring andsurveillance, (2) genetic testing, and (3) drug testing.Scenarios are used to show that such practical ethical problemscan be handled systematically using proposed guidelines. It isalso shown that some practices are dubious and at least some ofthem can be replaced by less intrusive means of ensuring thedesired outcome, for instance efficiency or safety in aworkplace.</p><p><i>Essay</i>III deals with the fact that health and safetystandards for employees are less protective than those thatapply to the public. Emphasis is put on the distinction betweenexposure and risk, and this distinction is claimed to be a keyfactor in the relevance of arguments in favour of such doublestandards. The analysis of 'double standards' for public andoccupational exposure to risk aims to show that a justificationof such standards is closely linked to two separate types ofissues, namely empirical and normative issues. It is claimedthat this kind of differentiation seems to be supported neitherby a reasonable conception of the contract of employment nor byany obvious ethical principle that is applicable to workplacesor work situations in general.</p><p><b>Key words:</b>Contract of employment, double standards,drug testing, ethics, ethical justification, exposure, genetictesting, health and safety standards, privacy, surveillance,risks, work, work environment</p>

Sy, Hing Yee. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves lxxiv-xciv). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese; appendixes I-III in Chinese.

Orientadores: Vera Lúcia Gil da Silva Lopes, Iscia Teresinha Lopes Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T11:59:54Z (GMT). No. of bitstreams: 1 Monteiro_FabiolaPaoliMendes_M.pdf: 4745618 bytes, checksum: 220053db4f2a750f68c332b998074576 (MD5) Previous issue date: 2012 / Resumo: A deleção 22q11. 2 é a mais frequente deleção intersticial na espécie humana, ocorrendo em aproximadamente 1/4000 nascidos vivos. Esta pode manifestar-se através de amplo espectro fenotípico, já sendo descritas mais de 180 manifestações clínicas asociadas. Frequências da deleção variando de 0% a 75% têm sido encontradas em diferentes estudos dependendo da manifestação primária escolhida, bem como do desenho do estudo e critérios de inclusão utilizados. Muitos estudos foram realizados com o propósito de definir quais pacientes deveriam ser triados para a deleção 22q11.2 em populações com distintas manifestações da mesma, visando uma abordagem com maior custo-efetividade, porém ainda hoje um consenso não foi atingido e a questão ainda é debatida. Até o presente momento, não existem estudos direcionados a definir, de maneira objetiva, qual ou quais destes dismorfismos sugestivos têm maior relevância durante a avaliação dismorfológica de indivíduos com diferentes manifestações do espectro da deleção. Com o objetivo de contribuir na definição de critérios clínicos e dismorfológicos que possam otimizar a indicação da realização de exame confirmatório, foram investigados 194 pacientes divididos em quatro grupos clínicos - Suspeita de deleção com alterações palatais {Grupo 1), suspeita de deleção sem alterações palatais (Grupo 11), malformações cardíacas associadas ao espectro da deleção 22ql1.2 {Grupo III) e indivíduos com dignóstico de esquizofrenia {Grupo IV). Todos foram testados para a deleção 22q11.2 por meio da técnica de Multiplex Ligant-Probe Amplification (MLPA). Para cada grupo, um checklist específico, incluindo dismorfismos e outras características clínicas, foi desenvolvido e aplicado. Pacientes do Grupo IV foram examinados independentemente por dois geneticistas clínicos, a fim de definir a presença de dismorfismos relacionados às síndromes de deleção 22ql1.2 (22q11.2DS) e a concordância na indicação de testes confirmatórios. A deleção 22q11.2 foi detectada em 45 pacientes {23,2%), assim distribuídos: 35/101 {34;7%) do Grupo I, 4/18 (22,2%) do Grupo 11, 6/52 {11,5%) do Grupo III e em nenhum indivíduo do Grupo IV. A taxa de concordância entre os dois observadores para indicação de exame confirmatório para o Grupo IV foi de 91,3%. Os dados clínicos foram analisados por distribuição de frequência e estatisticamente em cada um dos grupos e subgrupos. Cada grupo clínico foi discutido de forma independente e seus resultados comparados àqueles previamente descritos por outros pesquisadores. Sinais clínicos entre indivíduos com deleção e sem deleção foram comparados, sendo signifcantes para a suspeição das 22q11.2DS: face alongada (p<0,001), pálpebras "hooded" (p=0,015), nariz típico (p=0,041), conformação tubular do nariz (p=0,046) e hipoplasia alar (p=0,012). Os resultados demonstram objetivamente que algumas características dismórficas têm maior probabilidade de estarem associadas à presença da deleção 22q11.2. Baseados nos resultados obtidos e na revisão da literatura, é proposta uma abordagem sistemática para triagem de pacientes com manifestações distintas do espectro da deleção 22q11.2, visando uma melhor relação de custo-efetividade / Abstract: The 22q11.2 deletion is the most frequent intersticial deletion in the human species, occurring in approximately 1/4000 live births. It is associated with a wide phenotypic spectrum, with over 180 clinical manifestations already described. Distinct approaches have detected frequencies of the deletion ranging from 0% to 75%, depending on the primary manifestation of the studied population and selection criteria. Many studies have been conducted to define which patients would be eligible for screening for the 22q11.2 deletion, though so far the issue is still up for debate. To the best of our knowledge, no study has been directed towards objectively defining which suggestive dysmorphisms are relevant while evaluating individuals with distinct manife.stations of the 22q11.2 deletion syndromes (22q11.2DS) . In order to contribute to the delineation of possible clinical and dysmorphologic guidelines and to optimize decision to proceed with confirmatory testing, 194 individuals were evaluated. Group I- clinical suspicion of 22q11.2DS with palatal anomalies, Group II -clinical suspicion without palatal anomalies, Group Ill -cardiac malformations associated with the 22q11.2DS and Group IV- schizophrenic patients. All of them were evaluated and tested for the 22q11.2 deletion using Multiplex ligation-dependent probe amplification (M LPA). Group-specific checklists were developed to collect dysmorphologic and clinical data. Also, patients from Group IV were examinated independently by two clinical geneticists, in order to define the presence of suggestive 22ql1.2DS dysmorphisms and concordance rate in indication to proceed with laboratorial investigation. The 22q11.2 deletion was detected in 45 patients (23.2%), distributed as such: Group I 35/101 (34.7%), Group 114/18 (22.2%), Group Ill 6/52 (11.5%) and none from Group IV. Concordance of clinical features and indication of confirmatory test in Group IV by two examiners was 91.3%. Clinical data was analyzed by frequency and statistical tests. Each group was independently discussed and the results compared to those previously described by other researchers. Several independent dysmorphisms were compared between individuals with and without the 22q11.2 deletion, and a long face (p<0.001), hooded eyelids (p=0.015), a tubular conformation (p=0.046) or other forms of typical nose (p=0.041), and alar hypoplasia (p=0.012) were statiscally more likely to be found in patients that tested positive for the deletion. Conclusions: The results objectively demonstrate that some dysmorphic features have a higher probability of being correlated to the presence of the 22q11.2DS. Based on these results and the review of the literature, a systematic approach for screening patients with distinct manifestations of the 22ql1.2DS in a more cost-effective way is proposed / Mestrado / Genetica Medica / Mestra em Ciências Médicas

This thesis identifies and systematizes two categories ofpractical problems that stem from work and working environmentcontexts: workplace privacy and occupational health risks. Thefocus of the discussion is on ethical justification. Do we havereason to accept a certain level of (potential) harm toemployees by virtue of the fact that they are employees, and ifso, under what circumstances? The thesis consists of a briefintroduction and three essays. InEssayI, it is argued that employees have a prima facieright to privacy, but that this right can be overridden bycompeting moral principles that follow, explicitly orimplicitly, from the contract of employment. Three types ofjustification are specified: those that refer to the employer'sinterests, those that refer to the interests of the employee,and those that refer to the interests of third parties. A setof ethical criteria is developed and used in the subsequentessay to determine the moral status of infringement ofworkplace privacy. InEssayII, these criteria are applied to three broadcategories of intrusive workplace practices: (1) monitoring andsurveillance, (2) genetic testing, and (3) drug testing.Scenarios are used to show that such practical ethical problemscan be handled systematically using proposed guidelines. It isalso shown that some practices are dubious and at least some ofthem can be replaced by less intrusive means of ensuring thedesired outcome, for instance efficiency or safety in aworkplace. EssayIII deals with the fact that health and safetystandards for employees are less protective than those thatapply to the public. Emphasis is put on the distinction betweenexposure and risk, and this distinction is claimed to be a keyfactor in the relevance of arguments in favour of such doublestandards. The analysis of 'double standards' for public andoccupational exposure to risk aims to show that a justificationof such standards is closely linked to two separate types ofissues, namely empirical and normative issues. It is claimedthat this kind of differentiation seems to be supported neitherby a reasonable conception of the contract of employment nor byany obvious ethical principle that is applicable to workplacesor work situations in general. Key words:Contract of employment, double standards,drug testing, ethics, ethical justification, exposure, genetictesting, health and safety standards, privacy, surveillance,risks, work, work environment

Gegenstand: Seit der vollständigen Entschlüsselung des menschlichen Genoms ist es mit geringem Aufwand möglich, Menschen über das Vorliegen erblich (mit-)bedingter Erkrankungen - sogar vor deren Ausbruch - zu informieren. „Gentests“ sind jedoch umstritten. Neben Vorteilen wie der Ermöglichung präventiver medizinischer Maßnahmen oder möglichst frühzeitiger Interventionen werden auch immense Nachteile für das Individuum, wie z.B. eine hohe psychosoziale Belastung, deutlich. Die tatsächliche Inanspruchnahme genetischer Untersuchungen hängt in erheblichem Maße von den persönlichen Einstellungen ab. Besonders große Bedeutung wird hierbei den behandelnden Ärzten zuteil, die Patienten hinsichtlich der Möglichkeiten und Einschränkungen von genetischen Untersuchungen beraten. Ziel dieser Studie war es, die Einstellungen zu genetischen Untersuchungen bei angehenden Medizinern zu erfragen und die Ergebnisse über mehrere Jahre hinweg miteinander zu vergleichen. Zusätzlich wurde der Einfluss verschiedener Determinanten auf die Einstellungen zu genetischen Untersuchungen erfasst. Untersuchungsmethoden: In drei unabhängigen Fragebogenerhebungen wurden in den Jahren 2001 (N = 129), 2010 (N = 196) und 2016/17 (N = 134) Medizinstudierende zu ihren Einstellungen zu genetischen Untersuchungen befragt. Hierfür wurde ein 13 Items umfassender Fragebogen genutzt, der aus einer finnischen Studie übernommen wurde und positive und negative Aspekte sowie Befürchtungen und Vertrauen bzgl. genetischer Untersuchungen erfasst. Zusätzlich wurden die Variablen Religion, Politik, Geschlecht, Alter und Persönlichkeit erfasst. Ergebnisse: Medizinstudierende sind genetischen Untersuchungen gegenüber sowohl kritisch als auch befürwortend eingestellt. Sie sehen tendenziell jedoch mehr positive Effekte. Die Berechnungen von ANOVAs ergaben, dass im Jahresverlauf positive Aspekte konstant bleiben, negative Aspekte und Befürchtungen abnehmen und das Vertrauen zunimmt. Regressionsanalysen ergaben, dass die Einstellungen zu genetischen Untersuchungen durch die Religion (religiöse Menschen sind Gentests gegenüber kritischer eingestellt) und die Persönlichkeit (verträgliche Menschen sind positiver eingestellt, emotional stabile haben mehr Befürchtungen), nicht jedoch durch die politische Orientierung, Geschlecht und Alter beeinflusst werden. Geschlecht und Alter bedingten ausschließlich den Einfluss der Persönlichkeit auf die Einstellungen zu genetischen Untersuchungen. Schlussfolgerung: Die Zunahme Gentests befürwortender Einstellungen von Medizinstudierenden während der vergangenen 16 Jahre bei gleichzeitiger kritischer Auseinandersetzung mit der Thematik ist positiv zu bewerten. Nur so kann eine patientenorientierte, non-direktive Beratung bzgl. genetischer Untersuchungen gelingen. Um diese zu unterstützen, sollten psychosoziale Aspekte humangenetischer Beratung ausnahmslos Gegenstand der universitären Ausbildung Medizinstudierender sein. / Purpose: Since the advent of whole-genome sequencing, little effort is necessary to individually inform people about the presence of hereditary diseases, even before symptoms appear. However varying opinions exist regarding the application of genetic testing. There are various recognizable advantages, such as enabling early medical interventions or preventive measures, as well as immense disadvantages e.g. high psychosocial strain. The actual use of genetic testing depends, to a considerable extent, on the personal attitudes of respective individuals. Of particular importance are the attending physicians, advising the patients on possibilities and limitations of genetic testing. The objective of this study was to investigate future physician’s attitudes towards genetic testing, and to observe potential changes in their attitudes over a certain period of time. Additionally, the influence of different determinants on the attitude towards genetic testing was examined. Methods: Medicine students were questioned on three independent measurements in 2001 (N = 129), 2010 (N = 196) and 2016/17 (N = 134) on their attitudes towards genetic testing. For this purpose a German version of a Finnish questionnaire consisting of 13 items covering approval, disapproval, concern and trust regarding genetic testing was used. Additionally religiosity, political opinion, sex, age and personality were determined. Results: In general medicine students show positive as well as negative attitudes regarding genetic testing. There is a tendency towards a slightly more positive opinion. ANOVA results indicate no changes in approval regarding genetic testing during the different measurements. In contrast to these results disapproval and concerns decreased whereas trust increased. Regression analysis demonstrated that people with a religious affiliation held a less favorable view of genetic testing. People with a higher level in Agreeableness demonstrate a higher level of approval whereas people with a higher level in Emotional Stability show more concerns regarding genetic testing. There was no influence in the categories of political opinion, sex and age. The effect of the personality on the attitudes towards genetic testing was influenced by sex and age. Conclusions: The increase of approving opinions of medicine students towards genetic testing during the last 16 years, despite simultaneous and critical debate regarding the same topic, can be evaluated as a positive development. It can help to ensure a patient-centered and non-directive genetic counseling. In support of this development, psychosocial aspects of genetic counseling should, without exception, be included in university education.

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