Thyroid hormone transport into liver cells: its (patho)physiological significance

In the experiments described in this thesis transmembrane transport of thyroid hormones into liver cells is investigated, in particular the regulatory role of this transport process in the bioavailability of thyroid hormones in (patho )fysiological conditions. This first chapter is an introduction to the studies described in Chapters 3-9. It opens with a short description of different aspects regarding thyroid hormones, i.e. synthesis, transport in blood to the different organs, transport into cells, nuclear binding and the different routes of intracellular metabolism. Only the main issues will be discussed here. The isolated rat liver perfusion system was used to study the transport process in most of our studies. Therefore, this perfusion system is also described in this chapter and compared to isolated rat hepatocytes in primary culture, in which many studies on thyroid hormone transport have been performed. Furthermore, a twocompartment model, which describes thyroid hormone kinetics in the liver perfusion system, is dealt with here. At the end of the chapter the scope of the thesis and a short overview of the questions that were addressed are presente

De schoonheid van het verval

In de tijd dat hoogleraren zich nog een eigen chauffeur konden veroorloven, lang geleden dus, was er een hoogleraar die regelmatig lezingen hield. Op een avond was hij weer op weg naar een lezing en plotseling stelde zijn chauffeur in de auto een vraag. ‘Professor’, zei hij, ‘Iedere keer als u een lezing houdt, zit ik in de zaal te luisteren. Ik heb uw verhaal nu zo vaak gehoord dat ik denk dat ik die lezing ook wel eens kan geven. Wat zou u ervan vinden als we vanavond de rollen eens zouden omdraaien?’.Rede, in verkorte vorm uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar met als leeropdracht nucleaire biologie aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 23 maart 200

Programme Aid Evaluation:

Summaries With the introduction of Structural Adjustment Programmes, the objectives of programme aid shifted from relief of foreign exchange constraints to supporting policy reforms. The appraisal criteria for providing programme aid were modified accordingly, but the evaluation criteria did not change. A review of evaluation studies of Dutch programme aid and of Aide Memoires of Joint Evaluation Missions in the framework of the Special Programme of Assistance to African countries undertaking structural adjustment suggests the need for an appropriate multi?donor forum that addresses both the economic and institutional aspects of the macro?effectiveness of programme aid

Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy

Purpose: Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA-folate conjugate. Methods: Radiolabelling of the DOTA-folate was carried out via standard procedures using 111InCl3 and 177LuCl3, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of 111In-DOTA-folate (radiofolate 1) or 177Lu-DOTA-folate (radiofolate 2) (1MBq, 1nmol per mouse). Pemetrexed (PMX, 400μg) was injected 1h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24h after injection of the radiofolate (40-50MBq, 3nmol per mouse). Results: The hydrophilic character of the DOTA-folate was represented by a low log D value (radiofolate 1 −4.21±0.11). In vivo, maximal tumour uptake was found 4h after injection (radiofolate 1 5.80±0.55%ID/g; radiofolate 2 7.51±1.25%ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates (radiofolate 1 55.88±3.91%ID/g; radiofolate 2 57.22±11.05%ID/g; 4h after injection). However, renal uptake was reduced by preinjection of PMX (radiofolate 1 9.52±1.07%ID/g; radiofolate 2 13.43±0.54%ID/g; 4h after injection) whereas the tumour uptake was retained (radiofolate 1 6.32±0.41%ID/g; radiofolate 2 8.99±0.43%ID/g; 4h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. Conclusion: The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PM

Evaluation of the Perceived Persuasiveness Questionnaire:User-Centered Card-Sort Study

Background: eHealth technologies aim to change users’ health-related behavior. Persuasive design and system features can make an eHealth technology more motivating, engaging, or supportive to its users. The Persuasive Systems Design (PSD) model incorporates software features that have the possibility to increase the persuasiveness of technologies. However, the effects of specific PSD software features on the effectiveness of an intervention are still largely unknown. The Perceived Persuasiveness Questionnaire (PPQ) was developed to gain insight into the working mechanisms of persuasive technologies. Although the PPQ seems to be a suitable method for measuring subjective persuasiveness, it needs to be further evaluated to determine how suitable it is for measuring perceived persuasiveness among the public. Objective: This study aims to evaluate the face and construct validity of the PPQ, identify points of improvement, and provide suggestions for further development of the PPQ. Methods: A web-based closed-ended card-sort study was performed wherein participants grouped existing PPQ items under existing PPQ constructs. Participants were invited via a Massive Open Online Course on eHealth. A total of 398 people (average age 44.15 years, SD 15.17; 251/398, 63.1% women) completed the card sort. Face validity was evaluated by determining the item-level agreement of the original PPQ constructs. Construct validity was evaluated by determining the construct in which each item was placed most often, regardless of the original placement and how often 2 items were (regardless of the constructs) paired together and what interitem correlations were according to a cluster analysis. Results: Four PPQ constructs obtained relatively high face validity scores: perceived social support, use continuance, perceived credibility, and perceived effort. Item-level agreement on the other constructs was relatively low. Item-level agreement for almost all constructs, except perceived effort and perceived effectiveness, would increase if items would be grouped differently. Finally, a cluster analysis of the PPQ indicated that the strengths of the newly identified 9 clusters varied strongly. Unchanged strong clusters were only found for perceived credibility support, perceived social support, and use continuance. The placement of the other items was much more spread out over the other constructs, suggesting an overlap between them. Conclusions: The findings of this study provide a solid starting point toward a redesigned PPQ that is a true asset to the field of persuasiveness research. To achieve this, we advocate that the redesigned PPQ should adhere more closely to what persuasiveness is according to the PSD model and to the mental models of potential end users of technology. The revised PPQ should, for example, enquire if the user thinks anything is done to provide task support but not how this is done exactly

Effectiveness of customary use of phytosterol/-stanol enriched margarines on blood cholesterol lowering.

Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials