The economic and quality-of-life burden of Crohn's disease in Europe and the United States, 2000 to 2013: a systematic review.

BACKGROUND: Crohn's disease (CD) is associated with a substantial healthcare burden that affects the patient, healthcare systems and society in general. AIM: To provide a systematic evaluation of published data relating to the economic and health-related quality-of-life (HRQoL) burden of CD in selected European countries (Germany, France, UK, Italy, Spain) and the USA since 2000. METHODS: We undertook a systematic review of publications relating to CD, its economic burden and impact on HRQoL. Research questions focused on the disease costs from a societal perspective and HRQoL burden in adults and pediatric/adolescent patients according to disease stage/severity. Total, direct and indirect costs were identified, as well as the impact of CD on HRQoL measured using both generic and disease-specific instruments. RESULTS: Overall, 61 publications met the research criteria (38 on costs, 23 on HRQoL). CD in the USA and Europe together was associated with annual total costs of nearly 30 billion, more than half due to indirect costs. HRQoL was consistently and statistically significantly lower among CD patients compared with normal populations, due to physical, emotional and social effects. CONCLUSIONS: CD is a global health problem with high societal costs and substantial HRQoL burden. High-value care pathways including cost-effective therapies will help to induce and maintain remission, reduce complications of disease and improve HRQoL.

Phosphatidylinositol phosphate kinase type 1gamma and beta1-integrin cytoplasmic domain bind to the same region in the talin FERM domain.

Talin is an essential component of focal adhesions that couples beta-integrin cytodomains to F-actin and provides a scaffold for signaling proteins. Recently, the integrin beta3 cytodomain and phosphatidylinositol phosphate (PIP) kinase type 1gamma (a phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme) were shown to bind to the talin FERM domain (subdomain F3). We have characterized the PIP kinase-binding site by NMR using a 15N-labeled talin F2F3 polypeptide. A PIP kinase peptide containing the minimal talin-binding site formed a 1:1 complex with F2F3, causing a substantial number of chemical shift changes. In particular, two of the three Arg residues (Arg339 and Arg358), four of eight Ile residues, and one of seven Val residues in F3 were affected. Although a R339A mutation did not affect the exchange kinetics, R358A or R358K mutations markedly weakened binding. The Kd for the interaction determined by Trp fluorescence was 6 microm, and the R358A mutation increased the Kd to 35 microm. Comparison of these results with those of the crystal structure of a beta3-integrin cytodomain talin F2F3 chimera shows that both PIP kinase and integrins bind to the same surface of the talin F3 subdomain. Indeed, binding of talin present in rat brain extracts to a glutathione S-transferase integrin beta1-cytodomain polypeptide was inhibited by the PIP kinase peptide. The results suggest that ternary complex formation with a single talin FERM domain is unlikely, although both integrins and PIP kinase may bind simultaneously to the talin anti-parallel dimer.

Engineering Dictyostelium discoideum myosin II for the introduction of site-specific fluorescence probes.

Dictyostelium discoideum is a useful host for the production of constructs for the analysis of structure-function relationships of myosin. Here we describe the use of myosin II constructs containing a single tryptophan residue, at different locations, for probing events at the nucleotide binding site, the relay loop and the communication path between them. GFP fusions have also been expressed at the N- and C-termini of the myosin motor to provide sensitive probes of the actomyosin dissociation reaction in microscope-based kinetic assays. We report on the fluorescence anisotropy of these constructs in the context of their use as resonance energy transfer probes.