Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis.

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity

Data Work in a Knowledge-Broker Organization: How Cross-Organizational Data Maintenance shapes Human Data Interactions.

The term Human-Data Interaction (HDI) conceptualizes the growing importance of understanding how people need and desire to use and interact with data. Previous HDI cases have mainly focused on the interface between personal health data and the healthcare sector. This paper argues that it is relevant to consider HDI at an organisational level and examines how HDI can look in such a context, where data and data maintenance are core assets and activities. We report on initial findings of a study of a knowledge-broker organisation, where we follow how data are produced, shared, and maintained in a cross-organisational context. We discuss similarities and differences of HDI aroundpersonal health data and cross-organisational data maintenance. We propose to extend the notion of HDI to include the complexity of cross-organisational data work

Effectiveness and cost-effectiveness of a blended exercise intervention for patients with hip and/or knee osteoarthritis:Study protocol of a randomized controlled trial

Background Exercise therapy in patients with hip and/or knee osteoarthritis is effective in reducing pain, increasing physical activity and physical functioning, but costly and a burden for the health care budget. A web-based intervention is cheap in comparison to face-to-face exercise therapy and has the advantage of supporting in home exercises because of the 24/7 accessibility. However, the lack of face-to-face contact with a professional is a disadvantage of web-based interventions and is probably one of the reasons for low adherence rates. In order to combine the best of two worlds, we have developed the intervention e-Exercise. In this blended intervention face-to-face contacts with a physical therapist are partially replaced by a web-based exercise intervention. The aim of this study is to investigate the short- (3 months) and long-term (12 months) (cost)-effectiveness of e-Exercise compared to usual care physical therapy. Our hypothesis is that e-Exercise is more effective and cost-effective in increasing physical functioning and physical activity compared to usual care. Methods/Design This paper presents the protocol of a prospective, single-blinded, multicenter cluster randomized controlled trial. In total, 200 patients with OA of the hip and/or knee will be randomly allocated into either e-Exercise or usual care (physical therapy). E-Exercise is a 12-week intervention, consisting of maximum five face-to-face physical therapy contacts supplemented with a web-based program. The web-based program contains assignments to gradually increase patients’ physical activity, strength and stability exercises and information about OA related topics. Primary outcomes are physical activity and physical functioning. Secondary outcomes are health related quality of life, self-perceived effect, pain, tiredness and self-efficacy. All measurements will be performed at baseline, 3 and 12 months after inclusion. Retrospective cost questionnaires will be sent at 3, 6, 9 and 12 months and used for the cost-effectiveness and cost-utility analysis. Discussion This study is the first randomized controlled trial in the (cost)-effectiveness of a blended exercise intervention for patients with osteoarthritis of the hip and/or knee. The findings will help to improve the treatment of patients with osteoarthritis. Keywords: Osteoarthritis, Physical activity, Blended care e-Healt

Post-imperialism, postcolonialism and beyond: towards a periodisation of cultural discourse about colonial legacies

Taking German history and culture as a starting point, this essay suggests a historical approach to reconceptualising different forms of literary engagement with colonial discourse, colonial legacies and (post-) colonial memory in the context of Comparative Postcolonial Studies. The deliberate blending of a historical, a conceptual and a political understanding of the ‘postcolonial’ in postcolonial scholarship raises problems of periodisation and historical terminology when, for example, anti-colonial discourse from the colonial period or colonialist discourse in Weimar Germany are labelled ‘postcolonial’. The colonial revisionism of Germany’s interwar period is more usefully classed as post-imperial, as are particular strands of retrospective engagement with colonial history and legacy in British, French and other European literatures and cultures after 1945. At the same time, some recent developments in Francophone, Anglophone and German literature, e.g. Afropolitan writing, move beyond defining features of postcolonial discourse and raise the question of the post-postcolonial

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

TNFR1 inhibition with a nanobody protects against EAE development in mice

TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG(35-55)-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of Tc-99m-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS

Association of Common Variants in TNFRSF13B, TNFSF13, and ANXA3 with Serum Levels of Non-Albumin Protein and Immunoglobulin Isotypes in Japanese

We performed a genome-wide association study (GWAS) on levels of serum total protein (TP), albumin (ALB), and non-albumin protein (NAP). We analyzed SNPs on autosomal chromosomes using data from 9,103 Japanese individuals, followed by a replication study of 1,600 additional individuals. We confirmed the previously- reported association of GCKR on chromosome 2p23.3 with serum ALB (rs1260326, Pmeta = 3.1×10−9), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP (Pmeta = 1.2×10−14 and 7.1×10−24, respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (Pmeta = 7.2×10−15 and 7.5×10−10, respectively) as well as rs10007186 on 4q21.2 near ANXA3 (Pmeta = 1.3×10−9) also indicated significant associations. Interestingly, TNFRSF13B and TNFSF13 encode a tumor necrosis factor (TNF) receptor and its ligand, which together constitute an important receptor-ligand axis for B-cell homeostasis and immunoglobulin production. Furthermore, three SNPs, rs4985726, rs3803800, and rs11552708 in TNFRSF13B and TNFSF13, were indicated to be associated with serum levels of IgG (P<2.3×10−3) and IgM (P<0.018), while rs3803800 and rs11552708 were associated with IgA (P<0.013). Rs10007186 in 4q21.2 was associated with serum levels of IgA (P = 0.036), IgM (P = 0.019), and IgE (P = 4.9×10−4). Our results should add interesting knowledge about the regulation of major serum components

Methods to identify, study and understand End-user participation in HIT development

<p>Abstract</p> <p>Background</p> <p>Experience has shown that for new health-information-technology (HIT) to be suc-cessful clinicians must obtain <it>positive clinical benefits </it>as a result of its implementation and <it>joint-ownership </it>of the decisions made during the development process. A prerequisite for achieving both success criteria is <it>real </it>end-user-participation. Experience has also shown that further research into developing improved methods to collect more detailed information on social groups participating in HIT development is needed in order to support, facilitate and improve real end-user participation.</p> <p>Methods</p> <p>A case study of an EHR planning-process in a Danish county from October 2003 until April 2006 was conducted using process-analysis. Three social groups (physicians, IT-professionals and administrators) were identified and studied in the <it>local, present </it>perspective. In order to understand the interactions between the three groups, the <it>national, historic </it>perspective was included through a literature-study. Data were collected through observations, interviews, insight gathered from documents and relevant literature.</p> <p>Results</p> <p>In the local, present perspective, the administrator's strategy for the EHR planning process meant that there was no clinical workload-reduction. This was seen as one of the main barriers to the physicians to achieving real influence. In the national, historic perspective, physicians and administrators have had/have different perceptions of the purpose of the patient record and they have both struggled to influence this definition. To date, the administrators have won the battle. This explains the conditions made available for the physicians' participation in this case, which led to their role being reduced to that of clinical consultants - rather than real participants.</p> <p>Conclusion</p> <p>In HIT-development the interests of and the balance of power between the different social groups involved are decisive in determining whether or not the end-users become real participants in the development process. Real end-user-participation is essential for the successful outcome of the process. By combining and developing existing theories and methods, this paper presents an improved method to collect more detailed information on social groups participating in HIT-development and their interaction during the development. This allows HIT management to explore new avenues during the HIT development process in order to support, facilitate and improve real end-user participation.</p

How and why are communities of practice established in the healthcare sector? A systematic review of the literature

Background: Communities of Practice (CoPs) are promoted in the healthcare sector as a means of generating and sharing knowledge and improving organisational performance. However CoPs vary considerably in the way they are structured and operate in the sector. If CoPs are to be cultivated to benefit healthcare organisations, there is a need to examine and understand their application to date. To this end, a systematic review of the literature on CoPs was conducted, to examine how and why CoPs have been established and whether they have been shown to improve healthcare practice. Methods. Peer-reviewed empirical research papers on CoPs in the healthcare sector were identified by searching electronic health-databases. Information on the purpose of establishing CoPs, their composition, methods by which members communicate and share information or knowledge, and research methods used to examine effectiveness was extracted and reviewed. Also examined was evidence of whether or not CoPs led to a change in healthcare practice. Results: Thirty-one primary research papers and two systematic reviews were identified and reviewed in detail. There was a trend from descriptive to evaluative research. The focus of CoPs in earlier publications was on learning and exchanging information and knowledge, whereas in more recently published research, CoPs were used more as a tool to improve clinical practice and to facilitate the implementation of evidence-based practice. Means by which members communicated with each other varied, but in none of the primary research studies was the method of communication examined in terms of the CoP achieving its objectives. Researchers are increasing their efforts to assess the effectiveness of CoPs in healthcare, however the interventions have been complex and multifaceted, making it difficult to directly attribute the change to the CoP. Conclusions: In keeping with Wenger and colleagues' description, CoPs in the healthcare sector vary in form and purpose. While researchers are increasing their efforts to examine the impact of CoPs in healthcare, cultivating CoPs to improve healthcare performance requires a greater understanding of how to establish and support CoPs to maximise their potential to improve healthcare