Insights into the pathophysiology of ankylosing spondylitis: contributions from animal models

The introduction of anti-tumor necrosis factor strategies has significantly changed the perspective and outcome of patients with ankylosing spondylitis and related spondyloarthritides. This breakthrough has also boosted further research efforts into the mechanisms of disease. As human tissue specimens of the spine and sacroiliac joints are very difficult to obtain and rarely allow mechanistic studies, most of the new concepts have emerged from different animal models of disease. In this review, we summarize insights into the role of HLA-B27 based on transgenic rat and mouse models, efforts into the identification of cell populations stimulating inflammation and molecular studies of pathological bone formation leading to ankylosis. Important progress has been made and novel hypotheses were put forward. These include the impact of HLA-B27 on endoplasmic reticulum stress and the unfolded protein response, the role of stromal cells in inflammation, the entheseal stress hypothesis and the identification of the bone morphogenetic protein and WNT signaling pathways as therapeutic targets for ankylosis.     

Health programs struggling with complexity: a case study of the Dutch 'PreCare' project

This article aims to understand the effects of rationalized health programs (the basic components of which are efficiency, calculability, predictability and control) on local practices. We discuss how a successful U.S. intervention in preventive youth health care (the Nurse Family Partnership) has been translated and adapted within a Dutch setting. The Dutch version of the program is called 'PreCare'. The empirical analysis highlights the effects of rationalized health programs on local practices, in terms of the amount of work required, how local practices are disciplined, how these programs (re)draw boundaries, the 'travel expenditures' involved (and developed 'coping strategies'), and how local practices (try to) reshape the program. Our empirical analysis builds on a combination of qualitative methods. We conducted 16 semi-structured interviews with 19 people involved in the PreCare program. The majority of the interviews were conducted between July and November 2008. We also conducted an analysis of relevant documents related to the PreCare intervention and protocol. Furthermore, we observed at several meetings, including case conferences and management intervision meetings. The article makes a theoretical and practical contribution to the field. Theoretically, we show how the rationalization process is linked to a broader development of quantification and how both developments are based on a particularly modern ontology and epistemology in which what is considered 'real' and 'knowledgeable' becomes closely tied to what is measurable. The article offers a different conceptualization of rationalized health programs, one that acknowledges the need to standardize some elements, but also recognizes the need to be open and flexible toward local practices. We specifically focus on the tools that are able to deal with both the need to standardize and the need to be open toward local practices. We suggest that '(re)writing devices' are a fruitful category of tools for this purpose.     

Validation of the Activities of Community Transportation model for individuals with cognitive impairments

Purpose. To develop a theoretical, functional model of community navigation for individuals with cognitive impairments: the Activities of Community Transportation (ACTs).

Methods. Iterative design using qualitative methods (i.e. document review, focus groups and observations). Four agencies providing travel training to adults with cognitive impairments in the USA participated in the validation study.

Results. A thorough document review and series of focus groups led to the development of a comprehensive model (ACTs Wheels) delineating the requisite steps and skills for community navigation. The model was validated and updated based on observations of 395 actual trips by travellers with navigational challenges from the four participating agencies. Results revealed that the ‘ACTs Wheel’ models were complete and comprehensive.

Conclusions. The ‘ACTs Wheels’ represent a comprehensive model of the steps needed to navigate to destinations using paratransit and fixed-route public transportation systems for travellers with cognitive impairments. Suggestions are made for future investigations of community transportation for this population.     

Health and disease as practical concepts: exploring function in context-specific definitions

Medicine, Health Care and Philosophy - Despite the longstanding debate on definitions of health and disease concepts, and the multitude of accounts that have been developed, no consensus has been...     

Laxity characteristics of normal and pathological murine knee joints in vitro

The aim of this study was to validate a device developed previously to measure laxity of murine knee joints and to investigate whether experimentally induced pathological conditions result in measurable laxity. The laxity characteristics of normal murine knee joints were derived from measurements of 25 left knees of normal mice. Reporducible, nonlinear s-shaped load-displacement curves were determined, and parameters of anterior-posterior translation, varus-valgus rotation, and compliance were calculated from the curves. No differences were found between the left and right knee joints of eight mice. The average displacement between 0.8 N of anterior force and 0.8 N of posterior force was 0.47 ± 0.10 mm. The endpoint compliances for anterior and posterior displacements were 0.16 ± 0.03 and 0.16 ± 0.04 mm/N, respectively. The average rotation between a 4 Nmm valgus moment and a 4 Nmm varus moment was 17.4 ± 3.3°. The endpoint compliances for varsus and valgus rotations were 1.1 ± 0.7 and 1.0 ± 0.3°/Nmm, respectively. Storage of the joints at ?70°C had no effect on laxity. We also studied the parameters of laxity after pathology of the knee joint was induced. Zymosan-induced or antigen-induced arthritis did not increase laxity of the joint. In an osteoarthritis model induced by injection of collagenase, laxity was markedly increased. In conclusion, laxity in the knees of mice can be measured reproducibly, and changes in the characteristics of laxity due to pathological conditions can be quantified.     

Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

Natural killer T (NKT) cells are CD1d-restricted lymphoid cells and are characterized by an invariant T-cell receptor, which in humans consists of a Valpha24 chain paired with a Vbeta11 chain. These cells are known for their rapid production of large amounts of cytokines (e.g., IFN-gamma and IL-4), thereby modulating other cells of the immune system such as T cells, NK cells and dendritic cells. NKT cells have been reported to play important regulatory roles in many immune responses, including antitumor immune responses. Here, we demonstrate an age-dependent decrease in circulating Valpha24(+)Vbeta11(+) NKT cell numbers in both healthy controls and cancer patients and demonstrate that in both groups females have higher NKT cell levels compared to males. In a large group of 120 cancer patients, we show that circulating Valpha24(+)Vbeta11(+) NKT cell numbers are about 50% lower than in age- and gender-matched healthy controls and that this decrease is independent of tumor type or tumor load. This decrease was not restored upon tumor removal by means of surgery or radiotherapy. Even though the percentage of NKT cells that secrete IFN-gamma, as detected by ELISPOT, is normal in cancer patients, the absolute number of circulating IFN-gamma-secreting NKT cells is reduced. Together, our results suggest that the reduced circulating Valpha24(+)Vbeta11(+) NKT cell numbers in cancer patients are not affected by tumor load, but might actually reflect a risk factor for tumor development, e.g., by hampering efficient tumor immunosurveillance.