Regulation of members of the angiopoietin family by Kaposi sarcoma herpesvirus

Kaposi sarcoma herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), a vascular tumour of endothelial cells. The angiopoictin family arc a group of secreted glycoproteins whose members play important roles in tumour vascularisation. The primary aim of this work was to investigate how KSHV regulated members of the angiopoictin family through the construction of a selected KSHV lentiviral expression library. Angiopoietin-2 (Ang2) is an important angiogenic factor which binds to the receptor Tie2 and is up-regulated in KS. Using a constructed KSHV lcntiviral library, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR) were found to up-regulate Ang2 in lymphatic endothelial cells (LEC). Both vIL6 and vGPCR up-regulated Ang2 in a paracrine manner and caused an up-regulation of Ang2 through the mitogen-activated protein kinase pathway. Gene expression microarray analysis identified how other factors important for Ang2 function, and other members of the angiopoietin family, were regulated by KSHV infection of LEC. Angiopoietin-like 2 (Angptl2) has been shown to be important for proper vascularisation. My aim was to investigate the regulation of Angptl2 by KSHV and to start to investigate the function of Angptl2 in KS and cancer in general. Angptl2 is up-regulated in KS and in KSHV-infected LEC and is expressed in a variety of other neoplasms however, its expression profile did not correlate with expected angiogenic factors. The KSHV encoded viral interferon regulatory factor-1 (vIRFl) up-regulated Angptll expression in LEC and vIRFl increased Angpttt promoter activity using the first 1 kb of the Angptl2 promoter. Over-expression of Angptl2 in a mouse tumorigenesis model affected tumour growth resulting in smaller and more necrotic tumours. Ang2 and Angptl2 are likely to play important roles in KS pathogenesis. These angiopoietins along with the molecular mechanisms regulating their expression might present future targets for anti-KS therapeutics

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Prevention of chronic kidney disease and its consequences:The role of socioeconomic status

Preventie van chronische nierziekte en de gevolgen daarvan: de rol van sociaal-economische status Chronische nierziekte (CNZ) is een belangrijk oorzaak van de wereldwijde ziektelast, wat heeft geleid tot een pleidooi voor betere preventie van CNZ. Dit vereist een beter inzicht in andere risicofactoren voor CNZ, naast traditionele risicofactoren als diabetes en hypertensie. Een lage sociaaleconomische status (SES) is daarvan een voorbeeld. Dit proefschrift heeft als doel de huidige kennis over de rol van SES in het ontstaan van CNZ te vergroten en in te gaan op de consequenties daarvan voor preventie. Om dit doel te bereiken is alle kennis uit epidemiologische studies over dit onderwerp samengevat en zijn grote Amerikaanse en Nederlandse gegevensbestanden geanalyseerd. De resultaten suggereren dat het risico van CNZ bij een lage SES vrij groot is in vergelijking met een hoge SES (ongeveer 40% hoger). Om een beter inzicht te krijgen in de additionele risico’s van mensen met een lage SES kan de methode om SES te meten worden verbeterd. In Nederland lijkt het risico het hoogst voor mensen met een laag opleidingsniveau, terwijl het risico in de Verenigde Staten (VS) het hoogst is voor mensen met een laag inkomen. Het extra risico op CNZ voor mensen met een laag inkomen in de VS kan een gevolg zijn van de kosten vanwege gebruik van gezondheidszorg. Het verbeteren van het meten van CNZ markers kan tevens bijdragen aan het identificeren van mensen met CNZ die veel risico lopen op schadelijke gevolgen voor hun gezondheid. Tot slot lijkt het gewenst de huidige screening op CNZ uit te breiden met mensen met een lage SES, hoewel aanvullend onderzoek nodig is om de kosteneffectiviteit van een dergelijke benadering te evalueren

Areca nut chewing and dependency syndrome: Is the dependence comparable to smoking? a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Areca nut is the seed of fruit oriental palm known as <it>Areca catechu</it>. Many adverse effects of nut chewing have been well documented in the medical literature. As these nuts are mixed with some other substances like tobacco and flavouring agents, it has been hypothesized that it might also cause some dependency symptoms among its users. Therefore, the objective of this study was to investigate dependency syndrome among areca nut users with and without tobacco additives and compare it with dependency associated with cigarette smoking among the male Pakistani population.</p> <p>Methods</p> <p>This was an observational cross sectional study carried out on healthy individuals, who were users of any one of the three products (areca nut only, areca nut with tobacco additives, cigarette smokers). Participants were selected by convenience sampling of people coming to hospital to seek a free oral check up. Information was collected about the socio-demographic profile, pattern of use and symptoms of dependency using the DSM-IV criteria for substance dependence. We carried out multiple logistic regressions to investigate association between socio-demographic profile, pattern of substance use and dependency syndrome.</p> <p>Results</p> <p>We carried out final analysis on 851 individuals, of which 36.8% (n = 314) were areca nut users, 28.4% (n = 242) were the chewers of areca with tobacco additives and 34.7% (n = 295) were regular cigarette smokers. Multivariate analyses showed that individuals using areca nut with tobacco additives were significantly more likely to have dependency syndrome (OR = 2.17, 95% CI 1.39-3.40) while cigarette smokers were eight times more likely to have dependency syndrome as compared to areca nut only users.</p> <p>Conclusions</p> <p>Areca nut use with and without tobacco additives was significantly associated with dependency syndrome. In comparison to exclusive areca nut users, the smokers were eight times more likely to develop dependence while areca nut users with tobacco additives were also significantly more likely to suffer from the dependence.</p

Shared decision making and medication adherence in patients with COPD and/or asthma:the ANANAS study

Background: Medication adherence to inhalation medication is suboptimal in patients with COPD and asthma. Shared decision making (SDM) is proposed as an intervention to improve medication adherence. Despite its wide promotion, evidence of SDM's association with greater medication adherence is scarce. Also, it is unknown to what degree patients presently experience SDM and how it is associated with medication adherence.Objective: To (i) assess the level of SDM and (ii) medication adherence, (iii) explore the relation between SDM and medication adherence and iv) investigate possible underlying mechanisms.Methods: Cross-sectional observational study. A survey was distributed among Dutch patients with COPD and/or asthma using inhaled medication. Medication adherence was measured using the Test of Adherence to Inhalers (TAI-10), and SDM by the 9-item Shared Decision-Making questionnaire (SMD-Q-9). Feeling of competence, relatedness and feeling of autonomy from the Self-Determination Theory (SDT) were considered as possible mechanisms. The primary outcome was adherence.Results: A total of 396 patients with complete information on relevant covariates were included. Mean SDM-Q-9 score was 26.7 (SD 12.1, range 0-45) and complete adherence was 41.2%. The odds ratio for the association of SDM with adherence was 1.01 (95% CI: 0.99, 1.02). This only changed minimally when adjusted for mediators (mediating effect &lt;3%).Conclusion: The patient experienced level of SDM in daily practice and medication adherence have room for improvement. No association between SDM and medication adherence was observed. Factors related to feeling of competence, relatedness and feeling of autonomy did not meaningfully explain this finding. </p