Judicial policy lines in the criminal sanctioning of environmental offenses: an empirical study.

We analyze judicial policy lines concerning criminal environmental sanctioning using a unique European dataset of individual criminal cases, including case-specific information on offenses and offenders. We investigate policy choices made by criminal judges in lower courts as well as the relevant court of appeal. The sanctioning policy of judges proofs to be varied as well as consistent. Judges decide to postpone convictions for cases they deem less important. They carefully balance effective and suspended sanctions, in general using them as substitutes, but in specific cases opting to use them cumulatively. Overall, judges in lower courts balance environmental and classic criminal law and aim at protecting individuals and their possessions as well as the environment.

High Throughput Micro-Well Generation of Hepatocyte Micro-Aggregates for Tissue Engineering

The main challenge in hepatic tissue engineering is the fast dedifferentiation of primary hepatocytes in vitro. One successful approach to maintain hepatocyte phenotype on the longer term is the cultivation of cells as aggregates. This paper demonstrates the use of an agarose micro-well chip for the high throughput generation of hepatocyte aggregates, uniform in size. In our study we observed that aggregation of hepatocytes had a beneficial effect on the expression of certain hepatocyte specific markers. Moreover we observed that the beneficial effect was dependent on the aggregate dimensions, indicating that aggregate parameters should be carefully considered. In a second part of the study, the selected aggregates were immobilized by encapsulation in methacrylamide-modified gelatin. Phenotype evaluations revealed that a stable hepatocyte phenotype could be maintained during 21 days when encapsulated in the hydrogel. In conclusion we have demonstrated the beneficial use of micro-well chips for hepatocyte aggregation and the size-dependent effects on hepatocyte phenotype. We also pointed out that methacrylamide-modified gelatin is suitable for the encapsulation of these aggregates

Relationships Between Religion and Intolerance Towards Muslims and Immigrants in Europe:A Multilevel Analysis

This paper examines relationships between religiosity and intolerance towards Muslims and immigrants among Europeans living in non-Muslim majority countries by applying multilevel modeling to European Values Study data (wave four, 2010). Thus relationships across 44 national contexts are analyzed. The analysis found large between-country differences in the overall levels of intolerance towards immigrants and Muslims. Eastern Europeans tend to be more intolerant than Western Europeans. In most countries Muslims are less accepted than immigrants,—a finding which reflects that in post-9/11 Europe Islamophobia is prevalent and many still see Muslims with suspicion. A key result is that believing matters for the citizen’s attitudes towards Muslims and immigrants. Across Europe, traditional and modern fuzzy beliefs in a Higher Being are strongly negatively related to intolerance towards immigrants and Muslims, while fundamentalism is positively related to both targets of intolerance. Religious practice and denominational belonging on the other hand matter far less for the citizen’s propensity to dislike the two out-groups. With the only exception of non-devout Protestants who do not practice their religion, members of religious denominations are not more intolerant than non-members. The findings are valid for the vast majority of countries although countries differ in the magnitude of the effects

Legitimacy intermediation in the multilevel European polity and its collapse in the euro crisis

This essay re-examines the dual – republican and liberal – foundations of democratic legitimacy in the Western traditions of normative political theory. Considered in isolation, the European Union conforms to liberal standards but cannot satisfy republican criteria. Given these conflicting standards, debates on the alleged European democratic deficit have remained inconclusive. Moreover, they have failed to pay sufficient attention to the multilevel character of the European polity and to the normative potential of legitimacy intermediation in its two-step compliance and legitimating relationships. I argue, however, that the capacity of democratic member states to legitimate the exercise of European governing functions is being destroyed in the present euro crisis, and I briefly discuss the implications of this new constellation.In der westlichen Tradition der normativen politischen Theorie beruht demokratische Legitimität auf der doppelten Grundlage republikanischer und liberaler Prinzipien. Für sich betrachtet entspricht die Europäische Union zwar liberalen Kriterien, aber eben nicht den republikanischen Anforderungen. Angesichts so unterschiedlicher Kriterien konnte es auch im Streit über das angebliche europäische Demokratiedefizit keine Einigung geben. Überdies ignorierte diese Diskussion den Mehrebenen-Charakter der europäischen Politik und das normative Potenzial der Legitimationsvermittlung zwischen Union und Bürgern durch die demokratisch verfassten Mitgliedstaaten. Die gegenwärtige Eurokrise allerdings zerstört die Fähigkeit demokratischer Mitgliedstaaten, die Ausübung europäischer Herrschaftsfunktionen zu legitimieren. Der Aufsatz erörtert die Implikationen dieser neuen Konstellation.1 Introduction 2 Legitimacy discourses The republican discourse The liberal discourse Differences 3 Constitutional democracies – and the European Union? 4 Legitimacy intermediation in the multilevel European polity 5 The end of legitimacy intermediation in the euro crisis Monetary Union and the failure of output legitimacy Rescuing the euro through supranational intervention 6 Legitimate supranational government? Input-oriented European legitimacy? 7 Reducing the burden on European legitimacy Reference

Prediction of response and outcome to anti-TNF agents in the treatment of inflammatory bowel diseases

Crohn’s disease (CD) and ulcerative colitis (UC), the main subtypes of inflammatory bowel disease (IBD), are characterized by chronic inflammation in the gastrointestinal tract, and bare a substantial morbidity and decreased quality of life. Worldwide incidence and prevalence rates of IBD are rising, especially in developing countries, and first presentation is shifting to younger ages. IBD is believed to result from a dysregulated mucosal immune response towards the gut microbiota in a genetic susceptible host, likely triggered by environmental factors. The treatment of IBD is targeted at decreasing the exaggerated adaptive immune response, in which tumor necrosis factor α (TNF) plays a key role. The introduction of monoclonal antibodies directed against TNF (e.g. infliximab and adalimumab) have resulted in a radical change of IBD management. Anti-TNF agents have led to superior outcomes, healing of mucosal lesions, and a reduction in hospitalisation and surgery rates in both CD and UC. However, therapy failure remains an important issue. Around 10-30% of IBD patients will not experience any benefit from these drugs, referred to as primary-non response (PNR), and more importantly, approximately 40% of patient will lose response over time. Being able to predict the short- and long-term response of a drug, would allow individualised treatment decisions, maximising efficacy and minimising toxicity and unnecessary costs. Therefore, the main objective of this PhD project was to identify host-, treatment-, or disease- related factors that are predictive or associated with PNR and loss of response (LOR) to anti-TNF agents in patients with IBD. First aim: Predicting primary non-response to infliximab in Crohn’s disease The mechanisms behind primary non-response (PNR) are still incompletely understood and are most likely multifactorial. In a first part, we investigated the influence of disease characteristics, genetic risk loci and antimicrobial antibodies on primary response to infliximab in CD, to ultimately develop a matrix-based prediction tool for PNR to infliximab (Chapter 3). We could demonstrate that older age at infliximab start, lower BMI and a history of IBD-related surgery were the main factors influencing PNR to infliximab in CD. Using these parameters, we constructed a clinically useful, matrix-based prediction tool, which demonstrated that for a given CD patient the predicted probabilities of PNR to infliximab could range from 0.2% to 53%, depending on their age, BMI and surgery status. In a second part, we investigated the evolution of inflammatory cytokines and biomarkers during infliximab induction treatment and studied the impact of inflammatory burden relative to that of drug and anti-drug antibody concentrations in relation to primary response (Chapter 4). We found that during induction therapy with infliximab in CD patients, the degree of inflammatory burden seems more determining for PNR than drug related aspects. Second aim: Predicting secondary loss of response to anti-TNF agents In a first part, a variable number of tandem repeats (VNTR) polymorphism in the neonatal Fc receptor gene, was studied. FcRn is a receptor responsible for extending half-life of IgG antibodies, and therefore individual differences in the length of this tandem repeat may affect anti-TNF concentrations during induction therapy (Chapter 5). This is of relevance as adequate drug concentrations during anti-TNF induction therapy have proven to be beneficial for long-term drug response. We could demonstrate that carriage of VNTR2/VNTR3 genotype was associated with 14% lower infliximab concentrations and 24% lower adalimumab concentrations during induction therapy. In a second part, we investigated the role of genetic susceptibility in formation of anti-drug antibodies. The formation of anti-drug antibodies is one of the main reasons for secondary loss of response (LOR), as this results in an increased clearance of the drug and an impaired efficacy. We hypothesized that HLA-DRB1 alleles, responsible for presenting antigens to the adaptive immune system, might influence the formation of antibodies towards infliximab (ATI) (Chapter 6). We found that IBD patients carrying the HLA-DRB1*03 allele are almost seven times more likely to develop ATI than patients who do not carry this allele. In a final part, we investigated which host-, disease-, and treatment-related factors influence the long-term infliximab failure in CD patients (Chapter 7). We found that CD patients with only ileal disease location, disease duration > 1 year, hemoglobin <13.5 g/dL, prior use of anti-TNF, absence of therapeutic drug monitoring use, and first dose optimization within the first year of treatment will experience infliximab failure more sooner than those who do not have these risk factors. In conclusion, this PhD project has further expanded on the knowledge of primary and secondary non-response to anti-TNF agents and highlighted (i) the importance of clinical factors and inflammatory burden in primary non-response to infliximab in CD patients, (ii) the role of host genetics in lower early anti-TNF concentrations and in formation of antibodies towards infliximab, and (iii) the relevance of taking into account risk factors for long-term infliximab failure in CD patients. Our findings represent another step towards an improved and more individualised treatment strategy in patients with IBD.T A B L E O F C O N T E N TS A bbreviations .......................................................................................................................................... c CHAPTER 1: INTRODUCTION ...................................................................................................................3 1.1 Inflammatory bowel disease .........................................................................................................3 1.1.1 Epidemiology..........................................................................................................................3 1.1.2 Pathogenesis ..........................................................................................................................4 1.1.3 Diagnosis and disease assessment .......................................................................................11 1.1.4 Treatment options................................................................................................................14 1.2 TNF antagonists ...........................................................................................................................17 1.2.1 TNF, TNF antagonist structure and mechanisms of action...................................................17 1.2.2 Efficacy and optimal use.......................................................................................................19 1.2.3 Treatment failure and loss of response................................................................................21 1.2.4 Therapeutic drug monitoring ...............................................................................................24 1.2.5 Pharmacokinetic properties of anti-TNF agents...................................................................26 1.3 References...................................................................................................................................29 CHAPTER 2: GENERAL AIM AND OBJECTIVES ........................................................................................43 CHAPTER 3: A MATRIX-BASED MODEL PREDICTS PRIMARY RESPONSE TO INFLIXIMAB IN CROHN’S DISEASE .................................................................................................................................................47 3.1 Introduction.................................................................................................................................48 3.2 Methods ......................................................................................................................................49 3.3 Results .........................................................................................................................................52 3.4 Discussion ....................................................................................................................................55 3.5 Supplementary files.....................................................................................................................59 3.6 References...................................................................................................................................61 CHAPTER 4: EVOLUTION OF CYTOKINES AND INFLAMMATORY BIOMARKERS DURING INFLIXIMAB INDUCTION THERAPY AND THE IMPACT OF INFLAMMATORY BURDEN ON PRIMARY RESPONSE IN PATIENTS WITH CROHN’S DISEASE .......................................................................................................65 4.1 Introduction.................................................................................................................................65 4.2 Methods ......................................................................................................................................67 4.3 Results .........................................................................................................................................69 4.4 Discussion ....................................................................................................................................72 4.5 References...................................................................................................................................77 CHAPTER 5: A GENETIC VARIATION IN THE NEONATAL FC RECEPTOR AFFECTS ANTI-TNF DRUG CONCENTRATIONS IN INFLAMMATORY BOWEL DISEASE .....................................................................81 5.1 Introduction.................................................................................................................................82 5.2 Methods ......................................................................................................................................83 b 5 . 3 R e s u l t s .........................................................................................................................................86 5.4 Discussion....................................................................................................................................91 5.5 Supplementary files.....................................................................................................................96 5.6 References...................................................................................................................................97 CHAPTER 6: IMMUNOGENICITY TO INFLIXIMAB IS ASSOCIATED WITH HLA-DRB1 .............................101 6.1 Letter to the editor....................................................................................................................101 6.2 Supplementary files...................................................................................................................104 6.3 References.................................................................................................................................105 CHAPTER 7: PROGNOSTIC FACTORS FOR LONG-TERM INFLIXIMAB TREATMENT IN CROHN’S DISEASE PATIENTS: A 20-YEAR SINGLE CENTER EXPERIENCE............................................................................109 7.1 Introduction...............................................................................................................................110 7.2 Methods ....................................................................................................................................111 7.3 Results .......................................................................................................................................115 7.4 Discussion..................................................................................................................................118 7.5 Supplementary files...................................................................................................................122 7.6 References.................................................................................................................................123 CHAPTER 8: CONCLUDING DISCUSSION ..............................................................................................127 SUMMARY...........................................................................................................................................139 ENGLISH SUMMARY ........................................................................................................................139 NEDERLANDSTALIGE SAMENVATTING ............................................................................................142 POPULAR SUMMARY.......................................................................................................................145 DANKWOORD......................................................................................................................................147 CURRICULUM VITAE AND LIST OF PUBLICATIONS...............................................................................151nrpages: 156status: publishe

Milieucriminaliteit in het beleid van de strafrechter: bestraffen tussen Haus en Brundtland

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Comparison of criminal and administrative penalties for environmental offenses

We conduct a counterfactual analysis to measure the treatment difference between administrative and criminal enforcement of environmental violations. Our aim is to control for the selection bias effect and make a comparison of how similar offenses are treated in both enforcement tracks. This analysis is relevant to answer the question of how deterrence and welfare in a combined criminal-administrative enforcement system compare with an enforcement system relying on criminal penalization only. This is an important question given the observed shift towards two-track penalization systems, combining administrative and criminal penalization, for environmental enforcement in the European Union. We apply matching techniques on a unique dataset of environmental enforcement cases to control for sample selection bias. We match different enforcement cases, based on case characteristics and estimate the average treatment effect for these cases. Overall, we find that the marginal penalty is slightly lower in administrative enforcement compared to criminal enforcement.status: publishe