This thesis explores the use of plea bargaining in the context of international crimes, and begins with a descriptive account of the plea bargaining that has taken place at the International... Show moreThis thesis explores the use of plea bargaining in the context of international crimes, and begins with a descriptive account of the plea bargaining that has taken place at the International Criminal Tribunal for the former Yugoslavia, the International Criminal Tribunal for Rwanda, and the Special Panels for Serious Crimes in East Timor. The thesis then turns to a normative justification of plea bargaining. In particular, because very limited resources are available for the prosecution of international crimes, most international offenders will not suffer criminal sanctions even in situations where the political will exists to bring them to justice. Because prosecuting only small numbers of (usually high-level) offenders does not advance the penological goals associated with international criminal prosecutions, the thesis argues that conventional plea bargaining - that is, the kind of plea bargaining practiced in national jurisdictions - is justified in the international context as a means of enhancing criminal accountability. The thesis goes on to construct an innovative guilty-plea system that incorporates restorative-justice principles, such as truth-telling, victim participation, and reparations. Such a restorative-justice guilty plea process serves not only to increase the number of offenders who can be prosecuted but also to advance reconciliatory goals more traditionally associated with non-prosecutorial mechanisms, such as truth commissions and reparations schemes. Show less
Following the general introduction regarding the epidemiology, aetiology, assessment and treatment of the frozen shoulder in Chapter 1 this thesis is divided into two parts: Part I describes the... Show moreFollowing the general introduction regarding the epidemiology, aetiology, assessment and treatment of the frozen shoulder in Chapter 1 this thesis is divided into two parts: Part I describes the results of the physiotherapeutic treatment of the frozen shoulder by means of mobilization techniques; Part II describes the clinical evaluation of the frozen shoulder and other shoulder disorders by various measurement instruments. Part I Physiotherapeutic treatment of the frozen shoulder. Chapter 2 shows a multiple-subject case study in 7 patients with a unilateral frozen shoulder treated with end-range mobilization techniques. Chapter 3 presents the results of a randomized controlled trial, comparing two treatment strategies with mobilization techniques in 100 patients with a unilateral frozen shoulder. In this trial we performed a cost-utility analysis comparing both mobilization techniques with respect to societal costs and quality-adjusted life years. Next a burden-of-illness study is presented estimating the impact of the frozen shoulder on costs and health. The results of this economic evaluation are presented in Chapter 4. Part II Clinical evaluation of the frozen shoulder and other shoulder disorders. Chapter 5 describes a new method of measuring shoulder positions by means of a three-dimensional electromagnetic tracking system. In a group of 15 healthy volunteers, two observers performed repeated measurements to examine the inter-trial, inter-day, inter-observer and intersubject reliability. In Chapter 6 the clinical application of the three-dimensional electromagnetic tracking device was tested on 10 patients with a unilateral frozen shoulder. The three-dimensional movement patterns of affected and non-affected shoulders were compared before and after 3 months treatment by means of end-range mobilization techniques. The translation, adaptation and validation of the Shoulder Rating Questionnaire into the Dutch language is discussed in Chapter 7 while the responsiveness of the Shoulder Function Assessment scale in 35 patients with rheumatoid arthritis suffering from shoulder complaints is presented in Chapter 8. Chapter 9 describes a comparison between two portable dynamometers in the assessment of shoulder and elbow strength in order to determine the practical applicability and the measurement properties of both devices. Finally, in Chapter 10, the findings and conclusions of the preceding chapters are summarized and indications for further research are discussed. Show less
Bot is een dynamisch weefsel en wordt voortdurend afgebroken door osteoclasten, de botafbrekende cellen, terwijl de osteoblasten (botvormende cellen) vervolgens weer voor botaanmaak zorgen.... Show moreBot is een dynamisch weefsel en wordt voortdurend afgebroken door osteoclasten, de botafbrekende cellen, terwijl de osteoblasten (botvormende cellen) vervolgens weer voor botaanmaak zorgen. Osteoporose, ook wel botontkalking genoemd, is een skeletziekte die wordt gekarakteriseerd door een lage botmassa en het verlies van botstructuur. Dit leidt tot een verhoogde kans op botbreuken. Osteoporose wordt veroorzaakt doordat de botafbraak door de osteoclasten groter is dan de botaanmaak door osteoblasten Tot nu toe zijn medicijnen tegen osteoporose vooral gericht op het remmen van de botafbraak (zoals bijvoorbeeld bisphosphonaten). Al eerder verloren gegaan bot kan nog niet worden hersteld. Daarom wordt nu gezocht naar medicijnen die de botvorming kunnen stimuleren. Een van de potenti_le kandidaten is het parathyroid hormoon (PTH) en het gerelateerde eiwit (PTHrP). PTH is een bekende stimulator van botafbraak, maar als PTHrP of PTH in lage doseringen met tussenpozen wordt gegeven dan stimuleert het juist de botvorming. Hoe deze tegenstrijdige effecten van PTHrP en PTH tot stand komen is nog niet bekend. Om het werkingsmechanisme van PTHrP en PTH te onderzoeken en om andere nieuwe anabole medicijnen te ontwikkelen is een betere kennis van de botvormende cel, de osteoblast noodzakelijk. Doel van het onderzoek Het doel van het onderzoek beschreven in dit proefschrift was om verschillende aspecten van osteoblast differentiatie te bestuderen. Osteoblast differentiatie is het ontwikkelingsproces van voorlopercellen, de mesenchymale stamcellen, tot osteoblasten. In dit proefschrift is als model de KS483 cellijn gebruikt. KS483 cellen kunnen differentiëren van een voorlopercel tot een osteoblast, een vetcel (adipocyte) of een kraakbeencel (chondrocyte) afhankelijk van het gebruikte medium en de kweekomstandigheden. De differentiatie van KS483 cellen naar osteoblasten duurt 18 dagen en is verdeeld in verschillende fases. Eerst vermenigvuldigen de cellen zich (proliferatie fase), daarna wordt er een botmatrix gemaakt (matrix productie en maturatie fase) waarna deze matrix verkalkt (mineralisatie fase) Tijdens het differentiatieproces van voorlopercel naar gespecialiseerde cel heeft de voorlopercel signalen nodig om te weten hoe hij zich moet ontwikkelen (figuur 2). Voor de differentiatie naar osteoblast zijn er verschillende signaalroutes belangrijk waaronder de BMP, Hedgehog (Hh) en Wnt/b-catenine routes. Daarnaast zijn RunX2 en osterix essenti_le transcriptiefactoren voor osteoblast differentiatie. Zonder deze transcriptiefactoren is er geen differentiatie naar osteoblasten mogelijk. In dit proefschrift hebben we de effecten en de regulatie van deze belangrijke signaalroutes tijdens osteoblast differentiatie geanalyseerd. Daarnaast hebben we ook gekeken naar de interactie van deze routes met PTHrP en PTH. BMP signaalroute In hoofdstuk 2 zijn de effecten van de BMP signaalroute op osteoblast differentiatie beschreven. Tijdens alle differentiatie fases komen verschillende BMPs, BMP receptoren, intracellulaire signaalmoleculen (Smads) en BMP antagonisten tot expressie. Om na te gaan wat de mogelijke rol van BMP signalering tijdens osteoblast differentiatie is, werden BMPs weggevangen door BMP antagonisten toe te dienen. De BMP antagonisten blokkeerden osteoblast differentiatie, wat werd bepaald door de activiteit van alkalische fosfatase (ALP), een osteoblast marker, en de hoeveelheid mineraal in de extracellulaire matrix te meten. Uit deze experimenten bleek dat de productie van BMPs door de osteoblast noodzakelijk is tijdens het gehele differentiatieproces. De behandeling van KS483 cellen met BMPs resulteerde in stimulatie van ALP activiteit en de hoeveelheid mineraal tijdens alle fases van osteoblast differentiatie, wat suggereert dat BMPs niet alleen belangrijk zijn voor de initiatie van de differentiatie, maar ook voor de matrix productie en mineralisatie. Hedgehog signaalroute Een rol voor de Hedgehog (Hh) signaalroute tijdens osteoblast differentiatie was eerder aangetoond in een studie waarin Hh de initiatie van osteoblast differentiatie in de botkoker stimuleerde. In hoofdstuk 3 wordt de rol van Hedgehog tijdens matrix productie en mineralisatie en het werkingsmechanisme beschreven. Eerst is de expressie (hoeveelheid mRNA) van Indian Hh (IHh), de botspecifieke Hh, de Hh receptoren (Ptc1 en Smo) en de intracellulaire signaalmoleculen (Gli__s) bestudeerd. De expressie van IHh, Gli1 en Ptc1 was verhoogd tijdens de matrix maturatie fase, terwijl de expressie van de andere moleculen gelijk bleef. IHh expressie werd ook gevonden in de osteoblasten in de humerus van een groeiend humaan skelet. Behandeling van de KS483 cellen met Hh eiwit resulteerde in een matig verhoogde ALP activiteit, terwijl de mineralisatie sterk werd gestimuleerd. Deze effecten werden geremd door de Hh antagonist cyclopamine, dat op zichzelf geen effect had op de differentiatie. Vervolgens werd bepaald tijdens welke fase van osteoblast differentiatie de Hh signaleringsroute belangrijk is. Uit deze experimenten bleek dat voorlopercellen reageerden op Hh, terwijl osteoblasten niet konden worden gestimuleerd. De Hh ge_nduceerde differentiatie werd compleet geremd door toedienen van BMP antagonisten, wat suggereert dat Hh signalering afhankelijk is van functionele BMP signalering. Toedienen van Hh en BMPs aan KS483 cellen resulteerde in synergistisch verhoogde ALP activiteit en mineralisatie. Experimenten toonden aan dat deze synergie op het niveau van de vroege Hh signaal transductie lag, en niet op het niveau van vroege BMP signalering. Hh stimuleerde niet alleen de osteoblast differentiatie, maar remde ook de differentiatie naar adipocyte. Deze data suggereren dat Hh signalering de ontwikkeling van voorlopercellen naar osteoblast stimuleert ten koste van de vetcelvorming. Een andere rol van Hh is de stimulatie van maturatie van vroege osteoblasten. Wnt/b-catenine signaalroute Een belangrijke rol voor de Wnt/b-catenine signaalroute in botvorming is recent aangetoond. Een aantal studies hebben laten zien dat Wnt/b-catenine signalering de proliferatie en differentiatie van osteoblasten stimuleert. In hoofdstuk 5, hebben we de rol van Wnt/b-catenine signalering tijdens matrix vorming en mineralisatie nader bestudeerd. Het toedienen van Wnt3A of LiCl, een stimulator van de Wnt/b-catenine route, aan KS483 cellen had geen enkel effect op de initiatie van de differentiatie, wat suggereert dat de Wnt/b-catenine signalering al maximaal aanstaat in deze cellen. Dit bleek ook uit experimenten met de Wnt antagonist Dkk-1, waarin toediening van Dkk-1 de initiatie van osteoblast differentiatie remde. Behandeling van KS483 cellen met Wnt3A of LiCl resulteerde in een remming van matrix mineralisatie. LiCl remde ook de mineralisatie van muizen beenmerg cellen. Opvallend was dat Wnt3A alleen in vroege osteoblasten de Wnt/b-catenine signaalroute kon aanzetten, terwijl LiCl dit kon in alle stadia van differentiatie. Dit zou kunnen komen door verlaagde expressie van Wnt receptoren, of door verhoogde expressie van Wnt antagonisten in volwassen osteoblasten. Experimenten toonden aan dat de expressie van Wnt receptoren niet veranderde tijdens osteoblast differentiatie, terwijl de expressie van de Wnt antagonisten juist werd ge_nduceerd. Dit zou kunnen betekenen dat de Wnt antagonisten Dkk-1 en Dkk-2 Wnt/b-catenine signalering remmen, wat noodzakelijk is voor mineralisatie van de matrix. Om dit te onderzoeken, werden stabiele KS483 cellijnen gemaakt waarin Dkk-1 of Dkk-2 expressie sterk werd verminderd (Dkk-1si en Dkk-2si). Differentiatie en cel proliferatie waren geremd in de Dkk-2si, terwijl mineralisatie was geremd in Dkk-1si en Dkk-2si. Samenvattend: remming van de Wnt/b-catenine signalering door inductie van de expressie van de antagonisten Dkk-1 en Dkk-2 is essentieel voor matrix mineralisatie. Werkingsmechanisme van PTH en PTHrP In hoofdstuk 6 laten we zien dat PTHrP en PTH de differentiatie van voorlopercel naar osteoblast remt, onafhankelijk van de dosering, tijd van toevoegen of de differentiatie status van de cel. Deze remming zou kunnen plaatsvinden doordat PTHrP belangrijke signaalroutes voor osteoblast differentiatie remt of doordat PTHrP osteoblast specifieke transcriptiefactoren remt. Deze remming kan plaatsvinden op allerlei niveaus, zoals (1) remming van de expressie van factoren in de BMP of Hh signaalroutes, (2) remming van de signalering van deze signaalroutes of (3) remming van de expressie of activiteit van de transcriptiefactoren RunX2 en Osterix. Om na te gaan of PTHrP osteoblast differentiatie kon remmen door de BMP route te blokkeren hebben we BMPs en PTHrP toegediend aan KS483 cellen. PTHrP kon inderdaad de BMP ge_nduceerde osteoblast differentiatie remmen en omgekeerd. Uit andere experimenten bleek echter dat deze remming waarschijnlijk indirect is. PTHrP zou ook een remmend effect kunnen hebben op osteoblast differentiatie door de Hh route te onderdrukken. Interacties tussen PTHrP en de Hh route waren al eerder beschreven in de groeischijf. PTHrP kon de Hh ge_nduceerde osteoblast differentiatie remmen en omgekeerd kon hedgehog het effect van PTHrP opheffen. Een van de oorzaken hiervan kan zijn dat in ongedifferentieerde cellen PTHrP de expressie van componenten van de Hh signaal route kon remmen. KSFrt model systeem In hoofdstuk 4 hebben we een model gemaakt waarbij KS483 cellen kunnen worden gebruikt om gemakkelijk en reproduceerbaar stabiele cellijnen te maken door middel van plaats specifieke homologe recombinatie. Daarvoor werd een unieke FRT site ge_ntroduceerd in het genoom (DNA) van de KS483 cellen, waardoor de KSFrt cellijnen ontstonden. Deze FRT site werd vervolgens gebruikt om genen te introduceren in het genoom in combinatie met positieve selectie door middel van een verandering in resistentie tegen antibiotica. Het voordeel van dit systeem is, dat er altijd __n kopie van het gen terechtkomt op dezelfde plek in het genoom. In de KSFrt cellen kunnen bepaalde genen worden ge_ntroduceerd en kan de expressie van genen worden verhoogd. De expressie van genen kan ook sterk worden verminderd door middel van RNA interference (RNAi). Daarvoor is een nieuwe RNAi vector gemaakt waarbij met de introductie van een kopie van de RNAi vector de expressie van een gen voldoende kan worden geremd. Dit model kan worden gebruikt om allerlei (onbekende) genen te introduceren, of juist de expressie van bepaalde genen te verminderen, en vervolgens de effecten te bekijken op de differentiatie naar osteoblast, adipocyte of chondrocyte. Deze studies kunnen als uitgangspunt worden gebruikt voor de ontwikkeling van medicijnen die specifiek op de osteoblast zijn gericht Show less
This thesis describes clinical and immunological aspects of immunoablative therapy and autologous stem cell transplantation (HDC + SCT) in patients with refractory rheumatoid arthritis (RA).... Show moreThis thesis describes clinical and immunological aspects of immunoablative therapy and autologous stem cell transplantation (HDC + SCT) in patients with refractory rheumatoid arthritis (RA). Rheumatoid arthritis is a chronic systemic disease of unknown etiology, characterized by multiple immune abnormalities. Chapter 1 addresses the backgrounds and rationale of this treatment modality in experimental and human rheumatic autoimmune diseases. Its rationale is based on the premise that the immune abnormalities underlying human autoimmune disease can be corrected by HDC and that SCT ensures recapitulation of a naive , self-tolerant, immune system. HDC + SCT was shown to be effective in animal models with autoimmune diseases and patients with an hematological malignancy and concomitant rheumatic disease. Based on these observations a study protocol for patients with refractory rheumatoid arthritis was developed. Chapter 2 describes the result of a decision analysis that was undertaken to investigate whether any beneficial effects of HDC + SCT outweigh its attending risks and treatment-related mortality (TRM) in a chronic but nonlethal disease like RA. A Markov model was employed because it allows summation of consecutive health states. In this model we compared HDC+SCT versus continued pharmacological treatment in patients with active disease who have previously failed standard treatments (methotrexate, combination therapy, TNF-blockade) taking into account the possibility that events and outcomes vary or recur in time. With a TRM < 3.3%, HDC+SCT appeared to be the preferred treatment. The efficacy required to compensate for a TRM of 10% (e.g. after HLA-identical allogeneic SCT) was found to represent a potentially realistic scenario: a 50-70% improvement would need to be attained after transplantation in 60% of patients and maintained for 6 months, with a durable good clinical response being required in 20% of patients. Chapter 3 describes the results of a survey on treatment preference in RA patients and rheumatologists. Specifically, it was examined whether the risks of HDC + ASCT are acceptable to RA patients and rheumatologists and whether risk taking by patients was associated with disease characteristics, socio-economic parameters and/or personality traits. This was based on a realistic scenario by means of a patient preference method in which the trade-off between short-term risks and possible long-term gain of HSCT was investigated. It was shown that patients willing to accept risk of death had significantly higher VAS disease activity, VAS pain and HAQ. The patients who were willing to accept a risk of TRM related to HSCT the median required duration of benefit given a TRM of 2 % was 5 years (range 1-15). Physicians also required a median duration of benefit of 5 years. Chapter 4 describes the clinical and immunological effects of HDC + SCT in fourteen patients with intractable RA. From a technical viewpoint the treatment steps appeared feasible in all patients. The consecutive procedures of the treatment were well tolerated by most patients. Hematological recovery was uneventful in all patients, showing an inverse relationship with the age of the patient. Longlasting lymphopenia was observed, which could mainly be attributed to slow recovery of naive CD4+ T lymphocytes. With respect to efficacy, mobilization resulted in transient amelioration of disease activity in 5/14 patients (defined as ACR20 before conditioning), which was reinforced by the intensification of conditioning and transplantation procedures. In 8/12 of the patients clinical meaningful improvements (defined as good response according to EULAR response criteria) were recorded in more than 50% of follow-up visits. 4/12 patients failed to improve. The individual clinical response at 3 months was found to be predictive for the subsequent disease course. These disease courses displayed a dichotomous pattern, enabling categorization in 'responders' and 'nonresponders'. Nonresponders did not differ from responders with respect to disease or patient related variables, such as age, disease activity and duration, previous therapy, presence of rheumatoid factor. Chapter 5 reports the effects of high dose chemotherapy and autologous stem cell transplantation (HDC + ASCT) on joint damage in patients with severe rheumatoid arthritis (RA). Eight patients with intractable RA treated with HDC + ASCT at a a single center institution were longitudinally monitored for disease activity and joint damage. Profound effects on DAS and joint damage were documented during the 2 years following the intervention. As for the DAS, the beneficial effects persisted although DMARDs ultimately needed to be reinstituted in all patients at different intervals after HDC + ASCT to maintain low levels of disease activity. The robust effects of HDC + ASCT on disease activity translated into a significant reduction in the rate of joint damage by 85% that was most marked in the first year after the intervention when most patients were off-DMARDs. This study thus demonstrates that a short and intensive immunosuppressive treatment with a single agent retards the rate of joint reduction, even at extended follow-up. Chapter 6 was undertaken to advance our understanding of the immunological effects of high dose chemotherapy and autologous stem cell transplantation (HDC+ASCT) in rheumatoid arthritis (RA). The induction of (partial) remission was associated with strong baseline expression and subsequent reduction of CD3, CD4, and the differentiation markers CD27 and the CD45-isoforms (RA,RB,RO) in synovium, while expression of these markers had returned to baseline levels at the 1-year biopsy, at a time disease had relapsed to varying extents in most patients. Of interest was the high proportion of CD45RB+ CD3+ T cells at 3 months post-transplant. This subset has recently been reported to be increased in peripheral blood of RA patients versus healthy controls, reflecting accelerated differentiation of naive CD45RA T cells under the influence of inflammation. These data provide strong evidence for an active role of T cells in the perpetuation of disease activity. Chapter 7 showes that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor T-cell reconstitution in RA following high dose chemotherapy. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the TREC content of CD4 T-cell demonstrating a direct effect of IL-7 on thymic activity. The aim of chapter 8 was to analyse whether HDC + HSCT can increase the quality of life and the perception of general health of previously therapy-resistant, progressive RA patients. The quality of life during 5 years following HDC + HSCT in eight patients with refractory RA was investigated. This study demonstrates significant improvement of the quality of life, notably in the first 2 years post-tranplantation. It was also shown that the utility scores of transplanted patients improved and that the gained QALYs for RA patients treated with HDC + HSCT outweighs a TRM lower than 2.8 %. In parallel with our study, other phase I/II studies were initiated to assess feasibility, toxicity and efficacy in small groups of patients. The results from these heterogeneous studies are difficult to compare, but the treatment steps appeared feasible and safe in all patients. No unexpected major toxicity or treatment related mortality occurred, although in several patients infectious complications necessitating extra hospital admissions for parenteral antibiotic treatment were observed. One patient died as a consequence of sepsis. Recurrence of disease activity occurred in most patients usually within 2 years. Therefore this procedure is unlikely to be curative, however the use of disease modifying antirheumatic drugs (DMARDs) after recurrence of disease resulted in substantial improvement of disease activity in a majority of patients. Interestingly, patients had been refractory to these drugs (even in higher doses) before transplantation, suggesting that some degree of sensitivity to conventional drugs had been regained. Long term remissions as well as relapses and progressive disease have been reported both in RA and other autoimmune diseases with the various regimens used but no definite conclusions with regard to T-cell depletion of the graft and/or conditioning regimen can be drawn. Brodsky et al. [7] reported that a conditioning regimen of cyclophosphamide 200 mg/kg without stem cell rescue resulted in duration of aplasia that lasted longer than seen after autologous transplantation. Apparently enough stem cells survive this conditioning regimen to regenerate the immune system. Moore et al. conducted a randomized trial to compare T cell depleted versus unmanipulated SCT after high dose chemotherapy (cyclophosphamide 200 mg/kg). 17 patients with T cell depleted autologous SCT and 14 patients with unmanipulated autologous SCT were treated. There were no significant differences with respect to length or quality of remissions between the two groups [11]. An analysis of the EBMT/EULAR database on 73 RA patients treated with high dose chemotherapy and autologous SCT found a significant response (at least ACR 50% response) in 67% of patients. Some disease activity was seen during follow-up, but the severity of flares was reported to be less in many and about half showed a response to antirheumatic medication that they had failed previously [12]. McColl et al described a patient with refractory, active RA who was treated with cyclophosphamide 50 mg/kg antithymocyte globulin 90 mg/kg and SCT from his identical twin brother [13]. Four years posttransplantation the patient was still free of disease symptoms (Wicks, personal communication) without antirheumatic medication. Syngeneic lymphocytes from the healthy donor or new populations of T cells derived from donor stem cells could have dispelled host T cells. These data do not allow definitive conclusions on whether the immunological effects of the treatment are only quantitative ('debulking' of inflammatory load) or qualitative as well (e.g. tolerization of pathogenic T lymphocytes). Based on the results of Brodsky [1] (conditioning regimen with high dose cyclophosphamide without SCT) one can speculate on the role of the autologous graft. Stem cells are capable of surviving high dose treatment with cyclophosphamide and disease remissions can apparantly be caused by the cyclophosphamide-induced immunoablation itself without the possible immunomodulation of the SCT. The question remains whether autologous SCT is capable of immunomodulation by regeneration of naive tolerant lymphocytes or merely serves as a rescue to shorten the aplastic period. From a T-cell centered perspective it might be inferred from the present studies that not all pathogenic T lymphocytes were eradicated or that some had been reinfused with the graft. This would imply that remissions can only be achieved by further intensification, e.g. by in vivo T cell depletion. Clearly, this could add to the toxicity. From the patient's and treating physician's perspective, responses were clinically meaningful in a majority of patients with resultant enhanced quality of life. It remains to be shown that any superior efficacy of a more rigorous approach will compensate for increased toxicity in terms of quality-adjusted-life-expectancy [14]. The aformentioned studies indicate that autologous SCT is not curative for refractory RA. The observed reappearence of the autoimmune disease after autologous SCT can be attributed to many factors, including: 1. Survival of autoaggressive lymphocyte (either T- or B cells), synoviocytes or macophages despite high dose chemotherapy. 2. Reinfusion of autoaggressive lymphocytes together with the stem cells. 3. Renewed activation of autoaggressive lymphocytes as a result of exposure to novel autoantigens 4. Reapparence of the autoimmune disease because defective stem cells were reinfused or 5. A combination of the above. Most protocols used did not increase immunosuppression to the point of immunoablation. More intensive immunoablative conditioning regimen followed by autologous SCT might induce more prolonged remissions. The concept that remissions may be maximized by removing pathogenic cells from the stem cell product has not been shown in humans, so the role of T cells in the graft remains, thus far, unclear. Allogeneic transplantation has not yet been tested as a primary treatment for patients with RA due to risks of transplant related mortality and graft versus host disease. Allogeneic SCT may be more effective than autologous SCT if intrinsic stem cell abnormalities exist in RA and if host hematopoiesis and abnormal immune cell populations can be eradicated via a graft vs autoimmunity effect. Furthermore allogeneic SCT in RA would offer an opportunity to investigate whether self-tolerance can be restored. Recent advances in allografting have improved safety, thereby allowing application in non-malignant conditions such as RA. The described cases are limited in number and differ in ways of stem cell collection, T and B cell depletion of the graft and conditioning regimen. The disease severity and the response in patients with RA also differs greatly. Therefore it should be emphasized that progress in the development of this novel treatment modality can only be achieved by multicenter studies, employing uniform eligibility criteria, treatment regimens and study parameters. Adequate assessment of risk/benefit requires properly designed and conducted prospective randomized controlled trials with a long follow-up. The issue is whether intense immune suppression aimed at immunoablation is superior to continuous moderate immune suppression with respect to toxicity and efficacy. Furthermore it should be investigated whether these effects can be maintained during a longer follow-up. Show less
The book examines what is understood as the 'publicness' of 'public administration'. The original meanings which are given to the concept of publicness in political and social thought are traced... Show moreThe book examines what is understood as the 'publicness' of 'public administration'. The original meanings which are given to the concept of publicness in political and social thought are traced and reformulated in terms of the study of public administration. Show less
Surfaces play an important role in chemical reactions: the metal surface in the car exhaust catalyst reduces the amount of harmful species. In the interstellar medium and the earth's stratosphere,... Show moreSurfaces play an important role in chemical reactions: the metal surface in the car exhaust catalyst reduces the amount of harmful species. In the interstellar medium and the earth's stratosphere, ice surfaces play an important role both by the formation of molecules and by the destruction of ozone in the atmosphere. To understand reactions on a surface it is essential to know the structure of the surface and the interaction of the surface with adsorbed species. The first part of this thesis describes a study of the surface of an ice film. The surface of the film can change before the bulk of the ice film changes. This surface structure - chaotic or ordered - determines the reactivity of the surface and has therefore important consequences for reactions in the interstellar medium and the earth's stratosphere. To better understand the interaction between the surface and the adsorbed particles the energy transfer between these two has been studied. As described in the second part of this thesis, this energy transfer depends strongly on how and where the molecules are adsorbed on the surface - on atomic length scale. This fundamental study is possibly relevant for the development of new chemical processes, in which the use of sunlight plays an important role and for the further development of the car exhaust catalyst. Show less
This thesis describes several topics on angiogenesis and screening in uveal melanoma, the most frequent eye tumour in adults. The expression of vascular endothelial growth factor and other... Show moreThis thesis describes several topics on angiogenesis and screening in uveal melanoma, the most frequent eye tumour in adults. The expression of vascular endothelial growth factor and other angiostimulating factors in this tumour are described. In a second part, the use of different screening tests in screening for metastases of uveal melanoma is investigated. Show less
There is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid... Show moreThere is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid metabolism, which can eventually lead to tissue damage due to elevated plasma fatty acid levels, e.g. in case of a heart attack. However, hypoxia is not a normally occurring situation in healthy mammals as opposed to many fish species, because water is a relative poor source of oxygen. In hypoxic fish therefore, noradrenaline mediates a decrease in lipid metabolism, and we believe that this is a general protection mechanism in fish against lipid poisoning. There is a clear difference in the mode of breathing between mammals and fish, namely air- vs. water-breathing. Hence, we hypothesise that this difference is the cause for the opposing effects of noradrenaline. Therefore, we studied the effects of hypoxia on an air-breathing fish, the African catfish. However, physiologically this species reacted the same as other water-breathing fish, namely by means of a reduced lipid metabolism. Additionally, we demonstrated that, despite the opposing effects on the lipid metabolism, the transduction pathways in fish and mammals are very alike, and thus only a minor change has occurred in the course of evolution. This research has aided in a better understanding of the evolutionary changes in lipid metabolism.|Er is een fundamenteel verschil tussen zoogdieren en vissen in hoe het vetmetabolisme onder hypoxie (=zuurstoftekort) wordt veranderd door het stresshormoon noradrenaline. In zoogdieren leidt hypoxie tot een verhoogd vetmetabolisme, wat uiteindelijk zelfs weefselschade kan veroorzaken door te hoge vetzuurgehaltes, b.v. bij een hartaanval. Gezonde zoogdieren komen normaliter niet in zuurstofnood, in tegenstelling tot veel vissoorten, omdat water een relatief arme zuurstofbron is. In hypoxische vissen daalt dan ook het vetmetabolisme door noradrenaline, en wij denken dat dit een beschermingsmechanisme is tegen een vetzuurvergiftiging. Er is een duidelijk verschil in de manier van ademhalen van zoogdieren en vissen, respectievelijk lucht- en waterademhaling, en dit verschil ligt mogelijkerwijs ten grondslag aan deze verschillende effecten van noradrenaline; dit is de centrale hypothese van het onderzoek. Daarom is gekeken naar het effect van zuurstoftekort bij een luchtademhalende vissoort, de Afrikaanse meerval. Deze vis bleek echter fysiologisch hetzelfde te reageren als waterademhalende vissen, namelijk een verlaagd vetmetabolisme. Daarnaast is aangetoond dat, ondanks tegenovergestelde effecten op het vetmetabolisme, de aansturingmechanismen in vissen en zoogdieren vergelijkbaar zijn, en dat er dus maar een minimale verandering in de evolutie heeft plaatsgevonden. Dit onderzoek heeft bijgedragen tot een beter begrip van de evolutionaire veranderingen in het vetmetabolisme. Show less
