Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis : linking genetic predisposition to clinical outcome

Rheumatoid arthritis (RA) is a disease characterized by arthritis of mainly the small joints of the hands and feet, which is thought to be the result of an autoimmune response. It is the most common inflammatory arthritis with a prevalence of 0.5-1.0% in European and North-American populations 1. There is substantial geographic variation in the occurrence of RA with very high prevalences reported in native American-Indian populations 2, and very low prevalences in populations from South-East Asia 3. The disease is approximately three times more frequent in women than in men, and the prevalence increases with age. Besides the potentially destructive arthritis, patients can be affected by various extraarticular features such as secondary Sj_gren__s syndrome, interstitial lung disease, pericarditis and pleuritis. Fortunately, the advent of tumor necrosis factor (TNF) inhibitors and other biological agents have led to a therapeutic revolution for patients with rheumatoid arthritis 4. Instead of having to resign to an inevitably progressive and debilitating disease course, modern-day treatment aims at achieving the lowest possible disease activity and ultimately remission. Nonetheless, rheumatoid arthritis continues to be a major cause of (partial) disability and of loss of productivity, and is associated with substantial economic costs 5. Classification criteria for the disease were first phrased in 1956 6 after Sir Alfred Garrod had introduced the term rheumatoid arthritis in 1876 in an attempt to counteract the unsatisfactory use of designations such as __chronic rheumatism__ and __rheumatic gout__ 7. The purpose of the classification criteria was to facilitate both clinical diagnosis and scientific research. For many years since, the 1987 American College of Rheumatology (ACR) classification criteria have been used to this end, despite the fact that the incorporation of items such as erosive radiographic changes led to limited diagnostic value of these criteria for patients with early arthritis 8. In order to facilitate the study of persons with earlier stages of disease, the ACR and the European League Against Rheumatism (EULAR) have recently developed the 2010 classification criteria for RA as shown in Table 1 9. It is worthwhile to note that these criteria are based on patient characteristics which were associated with the decision by the physician to start treatment with methotrexate. These criteria are a reflection of the shift towards increasingly earlier diagnosis and treatment of rheumatoid arthritis.The research described in this thesis was supported by ZonMW (AGIKO grant). The printing of this thesis was financially supported by Abbott BV, Euro-Diagnostica, Janssen Biologics BV, the J.E. Jurriaanse foundation, Merck Sharp & Dohme BV, Pfizer BV, Phadia BV, the Dutch Arthritis Association (het Reumafonds), Roche Nederland BV, Teva Pharma BV en UCB Pharma BV.UBL - phd migration 201

Exact solution of a model DNA-inversion genetic switch with orientational control

DNA inversion is an important mechanism by which bacteria and bacteriophage switch reversibly between phenotypic states. In such switches, the orientation of a short DNA element is flipped by a site-specific recombinase enzyme. We propose a simple model for a DNA inversion switch in which recombinase production is dependent on the switch state (orientational control). Our model is inspired by the fim switch in Escherichia coli. We present an exact analytical solution of the chemical master equation for the model switch, as well as stochastic simulations. Orientational control causes the switch to deviate from Poissonian behaviour: the distribution of times in the on state shows a peak and successive flip times are correlated.Comment: Revised version, accepted for publicatio

Stirring by blinking rotlets in a bounded Stokes flow

A blinking rotlet model is used for the analysis of stirring in a Stokes flow in a rectangular domain. After the two-dimensional biharmonic equation is solved analytically, the associated velocity field of a pair of blinking rotlets positioned symmetrically on the y -axis, is used studying the stirring qualities of this blinking rotlet model. Contour kinematic simulations are performed in order to obtain information about the chaotic behaviour of a blob of passive tracer material put in this flow field

Out of hand: prevalence and joint patterning of hand and wrist osteoarthritis in medieval Dutch populations

IntroductionOsteoarthritis (OA) is a common disease that degrades the cartilage in synovial joints, eventually leading to the direct destruction of bone. Today, OA is often observed in the hands and wrists, yet there have been few dedicated studies in past populations. This research aims to investigate how the living environment impacts the occurrence and patterning of hand and wrist OA in the medieval Netherlands.Materials & MethodsThe skeletal remains of 226 adult individuals from three sites (urban Alkmaar, rural Klaaskinderkerke, and urban hospital Kampen) were analysed to shed light on past prevalence and variation in affected joints between contextually different populations. The operational definition from Waldron (2009) was used to diagnose OA. ResultsExpectedly, a significant relationship between age and OA prevalence was found, χ2(2, N=226)=26.72, p2(2, N=226)=.75, p=0.68). Interestingly, even though the age distribution between the sites was similar, a clear interpopulation difference in overall hand and wrist OA prevalence was observed: hospital (32%), urban (12%) and rural (5%). Joint-specific patterning also showed variation between the sites, with OA predominance in the lateral wrist (thumb-base/wrist joint complex) in the urban hospital population, and in the medial wrist (piso-triquetral) in the urban population.  ConclusionsThese results suggest that population context plays a significant role in OA occurrence. Differences in OA prevalence and patterning may suggest different activities or risk factors depending on the environment, which need to be explored further and on a larger scale. Bioarchaeolog

Making Sense of the Law and Society Movement

This article aims to deepen scholarly understanding of the Law and Society Movement (L&S) and thereby strengthen debates about the relation between Empirical Legal Studies (ELS) and L&S. The article departs from the observation that ELS, understood as an initiative that emerged in American law schools in the early 2000s, has been quite successful in generating more attention to the empirical study of law and legal institutions in law schools, both in- and outside the US. In the early years of its existence, L&S – another important site for the empirical study of law and legal institutions – also had its center of gravity inside the law schools. But over time, it shifted towards the social sciences. This article discusses how that happened, and more in general explains how L&S became ever more diverse in terms of substance, theory and methods

Transfection of small numbers of human endothelial cells by electroporation and synthetic amphiphiles

OBJECTIVES: This study compared the efficiency of electroporation and synthetic amphiphiles. (SAINT-2pp/DOPE) in transfecting small numbers of human endothelial cells.METHODS AND RESULTS: Optimal transfection conditions were tested and appeared to be 400 V and 960 microF for electroporation and a 10:1 ratio for concentrations of SAINT-2pp/DOPE: plasmid. Using these conditions, cell concentrations were lowered step-wise and we were able to transfect as few as one thousand cells with both methods. For detection of transfection of a small number of cells a sensitive assay was needed (Luciferase). A plasmid containing the neomycin resistance gene was used to determine the transfection rate expressed in colony forming units by counting colonies after selection. At low plasmid concentrations this transfection rate was within the same range for both electroporation and SAINT-2pp/DOPE transfection. Fluorescent in situ hybridisation of metaphase chromosomes of transfected endothelial cells using the plasmid as a probe showed that stable integration was possible with both methods.CONCLUSIONS: Electroporation and a synthetic amphiphile, SAINT-2pp, provide the possibility of transfecting small numbers of cells resulting in stable integration of low plasmid concentrations. The availability of this technology is important in order to obtain functional endothelial cell lines from various human blood vessels for research purposes.</p

The role of autoantibodies in the pathophysiology of rheumatoid arthritis

Pathophysiology and treatment of rheumatic disease