De eetbuistoornis is de meest voorkomende eetstoornis en komt in vergelijking met anorexia en boulima veel meer onder alle lagen van de bevolking voor. Wereldwijd is er een gebrek aan kennis over... Show moreDe eetbuistoornis is de meest voorkomende eetstoornis en komt in vergelijking met anorexia en boulima veel meer onder alle lagen van de bevolking voor. Wereldwijd is er een gebrek aan kennis over de eetbuistoornis. Door gebrekkige (h)erkenning krijgen individuen met een eetbuistoornis vaak verkeerde zorg, waardoor de eetbuien juist toenemen. Daarnaast zijn er lange wachttijden voor specialistische behandeling en heeft niet iedereen toegang tot behandeling. Deze these is tweeledig: er wordt onderzoek gedaan naar risicofactoren van de eetbuistoornis in Arabische landen en twee diagnostische vragenlijsten worden gevalideerd. In Nederland wordt de werkzaamheid van een traditionele en een digitale begeleide zelfhulp behandeling onderzocht. In Arabische landen bleken een hoog BMI en lichaamsontevredenheid geassocieerd te zijn met eetstoornispathologie. De eating disorder examination questionnaire meet accuraat eetstoornisklachten en de body shape questionnaire lichaamsontevredenheid. In Nederland blijkt cognitive behavioral therapy een werkzame behandeling voor de eetbuistoornis, zowel op de traditionale manier, als digitaal aangeboden. De digitale variant vergroot de toegang tot specialistische zorg en kan mogelijk de lange wachttijden voor behandeling verkorten. Show less
eHealth is most effective when integrated into conventional health care in a “hybrid” health care model. In order to achieve high-quality hybrid health care, eHealth must benefit patients and must... Show moreeHealth is most effective when integrated into conventional health care in a “hybrid” health care model. In order to achieve high-quality hybrid health care, eHealth must benefit patients and must be effectively integrated and organized within regular health care. This thesis describes the evaluation of eHealth from both a patient perspective and an organizational perspective. Chapters 2 and 3 present patients’ views of an online patient portal. Chapters 4 and 5 describe the factors that affect the organization of high-quality hybrid health care and use these as inputs to develop a tailored quality management model and accompanying self-assessment questionnaire: the Hybrid Health Care Quality Assessment (HHQA) (Chapter 5). Health care organizations can use the model and questionnaire to gain insight into ways of improving the quality of their hybrid care. Show less
This thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for... Show moreThis thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for chemotherapy outcome.Preclinical research is evaluated, which shows that short-term fasting during chemotherapy is effective. The effects of short-term fasting in humans is not evident yet. Although the first small clinical studies of short-term fasting as adjunct to chemotherapy are promising in terms of decreased toxicity and enhanced efficacy, the exact mechanism and effects are not established yet. More studies and a longer follow-up are needed to prove this.Insulin-like growth factor 1 (IGF-1) and insulin are members of the IGF-1 pathway, which is involved in cell growth and proliferation. The effects of the IGF-1 pathway on chemotherapy outcome and the pathway itself as target for cancer therapy are described. The disappointing results of clinical studies of IGF-1R inhibitors may be caused by the complexity of the IGF-1R pathway. Lowering both insulin and IGF-1, perhaps with a short-term fasting intervention, serves as a possible target in cancer therapy. Show less
During the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of... Show moreDuring the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of inefficacious compounds but also in overlooking of promising drug candidates. This is not different for the mGlu2 receptor for which no drugs are available on the market so far despite enormous drug discovery efforts. Therefore, there is a need to improve the molecular understanding of key in vitro parameters that drive in vivo efficacy. Hence, this thesis focuses on the concepts of target binding kinetics and functional efficacy of both allosteric and orthosteric ligands of the mGlu2 receptor. Show less
Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly... Show moreElectroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly treatment resistant depression, acute mania, and schizophrenic syndromes. Safety of ECT increases the efficacy of therapy and provides fulfillment of a series of required treatments resulting in longer treatment effect of ECT. During the last few decades, researchers have been attempting to improve the effectiveness of ECT, to learn how and why it works, and to understand its risks and adverse side effects. As a result, the safety and efficacy of ECT has been improved and its indications have been relatively defined to increase the efficiency of outcome of therapy. While there has been considerable improvement in safety features, further investigation have been done to promote both the safety and efficacy of the treatment. Such efforts could increase our knowledge on the biological mechanisms involved in effectiveness of ECT that might result in discovery of new treatments. In this dissertation, we investigate how preprocedural medications could improve the safety and efficacy of ECT and further investigated the potential role of pharmacogenetics in the efficacy of ECT and procedural side effects such as cognitive disorders. Show less
Treatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects.... Show moreTreatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects. Furthermore, treatment is not effective in all patients. Currently, pre-treatment predictors for efficacy and toxicity in systemic treatment of ACC are scarce. Germline genetic variation in genes encoding for enzymes involved in pharmacokinetics or pharmacodynamics of cytotoxic drugs could explain intra-patient differences in treatment effects. Pharmacogenetic studies aim at finding such germline genetic predictors. This thesis focusses on pharmacogenetics of capecitabine and oxaliplatin in treatment of ACC. First, it is established that results derived from DNA in archived tumor samples can be reliably compared to those using DNA from peripheral blood leukocytes. Then, germline genetic markers in MTHFR and MTRR, as well as markers derived from an in vitro genome-wide association study (GWAS) are tested for their association with capecitabine toxicity. Next, effects of ERCC1 genotype on oxaliplatin cytotoxicity in vitro and in clinical association analysis are addressed. The influence of genetic variation in organic cation transporters on oxaliplatin-induced neurotoxicity is examined. Lastly, the results of a GWAS searching for germline predictors of treatment efficacy of capecitabine, oxaliplatin and bevacizumab, with or without cetuximab, are presented. Show less
Neonatal health care is provided with medication and protocols for almost all morbidities. Before the use of these medicines is allowed, they are extensively studied and tested for efficacy and... Show moreNeonatal health care is provided with medication and protocols for almost all morbidities. Before the use of these medicines is allowed, they are extensively studied and tested for efficacy and safety. As patient population and knowledge on specific diseases changes with time, repeated evaluation of efficacy and safety of current used policies is of paramount importance. In this thesis six __Neonatal Pearls__ are presented: six relatively rare clinical conditions, of which a retrospective study evaluates the efficacy, safety and/or long term consequences of the current protocol. Despite their retrospective design and relatively small sample size, they are all of significant value and may serve as potential foundations for future protocol adjustments and randomized controlled trials. The evaluated clinical conditions and policies include: -Fetal, neonatal and developmental outcomes of lithium exposed pregnancies -Neonatal outcome in allo-immune thrombocytopenia after maternal treatment with antenatal intravenous immunoglobulin - Repeated courses of ibuprofen for closure of a patent ductus arteriosus - Use of rifampin in persistent coagulase negative staphylococcal bacteremia in neonates - Outcome and management in neonatal thrombocytopenia due to maternal idiopathic thrombocytopenic purpura - Short and long term outcome of neonatal hyperglycemia in very preterm infants Show less
In this project we investigated the difference between efficacy (treatment outcome investigated in randomized clinical trials, RCTs) and effectiveness (treatment outcome when these treatments are... Show moreIn this project we investigated the difference between efficacy (treatment outcome investigated in randomized clinical trials, RCTs) and effectiveness (treatment outcome when these treatments are applied in daily psychiatric practice) for major depressive disorder. Treatment outcome and patient features in daily practice were assessed with routine outcome monitoring. We found that effectiveness is significantly lower than efficacy. In RCTs, a stringent patient selection is applied bij inclusion/exclusion criteria. We found that patients in daily practice do differ significantly from participants in RCTs with respect to baseline severity, comorbid disorders, suicidality and employment status. However, we found that these differences have very little influence on treatment outcome. In other words, if, hypothetically, only patients who are eligible for participation in RCTs for major depressive disorder would be tre ated, treatment success would not improve dramatically. Show less
In this thesis, we focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. We investigated the potential associations of germline genetic... Show moreIn this thesis, we focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. We investigated the potential associations of germline genetic variations with the efficacy or toxicity of treatment. We genotyped a selection of SNPs in paired tumor tissue and blood samples of colorectal cancer patients (Chapter 3). Next, we present an overview of clinical and pharmacogenetic factors that have been described to influence irinotecan toxicity (Chapter 4). We investigated the association of febrile neutropenia and drug efficacy with the UGT1A1 genotype in Chapter 5. In Chapter 6, we investigated the GSTP1 Ile105Val SNP with regard to irinotecan efficacy in terms of progression-free survival. We also provide an overview of pharmacogenetic, pharmacokinetic and pharmacodynamic data on this platinum derivative (Chapter 7). In Chapter 8, we transfected ERCC1 negative cells with an ERCC1 gene, containing either the codon 118C or 118T genotype, in order to establish differences in cell survival or DNA repair. In chapter 9 we describe our investigations on the cumulative neurotoxicity and efficacy of oxaliplatin. In chapter 10, an explorative study is described that investigates associations of survival and toxicity in patients receiving oxaliplatin, using a SNP array. Show less
The objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics... Show moreThe objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics of onset and offset of the pharmacological effects at the mu-opioid receptor, 2) selectivity of action (antinociception versus respiratory depression), 3) the interspecies extrapolation of the PK-PD correlation of the antinociceptive and respiratory depressant effect, 4) the role of active metabolites, 5) kinetics of antagonism of the respiratory depressant effect. Preclinical investigations were performed to develop and validate mechanism-based PK-PD models for the effects of opioids on antinociception and respiration. These PK-PD models were subsequently applied to characterize the effects of buprenorphine and fentanyl in humans. It was shown that the developed PK-PD model can be used to predict the efficacy and safety outcome of opioids in animals. Furthermore, the PK-PD model had excellent properties to enable animal-to-human extrapolation of the efficacy and safety outcome. Show less
The present thesis deal with the diagnostic boundaries between hypochondriasis and obsessive compulsive disorder and between hypochondriasis and another somatoform disorder called non-cardiac chest... Show moreThe present thesis deal with the diagnostic boundaries between hypochondriasis and obsessive compulsive disorder and between hypochondriasis and another somatoform disorder called non-cardiac chest pain. These studies showed that hypochondriasis and both other disorders are valid disorders based on diagnosis-specific symptoms. Furthermore, in the thesis the first randomized controlled trial comparing the efficacy of cognitive behavioural therapy, and a double-blind SSRI (paroxetine) and pill-placebo is described. The short term effects (4 months) and the long term (5 years) of both treatments were compared to each other and to the placebo. It can be concluded that both are effective treatments for hypochondriasis compared to the placebo in the short term, but the significant differences between both active treatments in ameliorating hypochondriacal symptoms disappears during the follow-up, although CBT is more effective in ameliorating comorbid depressive and psychoneurotic symptoms during the follow-up period than the placebo. Furthermore, CBT results in less use of additional psychological or medical help during the follow-up. Finally, the psychometric properties of the first clinician-administered semi-structured interview, the hypochondriasis Y-BOCS, were described. This interview seemed reliable and valid addition to the assessment arsenal measuring hypochondriacal symptoms. Show less
