Guideline falls short.

Wendy Barker's article in the July issue of Nursing Older People (26, 6, 18-24) summarised the revised National Health and Care Excellence clinical guideline 161 on falls, published in 2013.

Assessment and prevention of falls in older people.

In June 2013 the National Institute for Health and Care Excellence updated and replaced its 2004 clinical guideline 21 (CG21) on falls with clinical guideline 161 (CG161). Two priorities were outlined in the latter: preventing falls in older people (unchanged from CG21) and preventing falls in older people during a hospital stay (new). CG161 is for health and social care clinicians who care for older people who have fallen or who are at risk of falling. It provides clinicians and commissioners with evidence to implement effective care pathways and recommendations on the assessment and prevention of falls in older people. The amalgamation of the two guidelines has resulted in some disconnection. This article summarises the evidence and supports clinicians in the interpretation of the revised falls guideline.

Dual regulation of metalloproteinase expression in chondrocytes by Wnt-1-inducible signaling pathway protein 3/CCN6.

OBJECTIVE: Wnt-1-inducible signaling pathway protein 3 (WISP-3)/CCN6 is mutated in progressive pseudorheumatoid dysplasia and may have effects on cartilage homeostasis. The aim of this study was to ascertain additional roles for WISP-3/CCN6 by determining its expression in osteoarthritic (OA) cartilage and by investigating its effects on cartilage-relevant metalloproteinase expression in immortalized (C-28/I2) and primary chondrocytes. METHODS: Cartilage steady-state levels of WISP-3/CCN6 messenger RNA and protein production were determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. WISP-3/CCN6 was overexpressed in C-28/I2 cells, and the resultant clones were analyzed by quantitative RT-PCR. The stable clones were analyzed by RT-PCR for metalloproteinase expression, and the signaling pathways involved were investigated using pharmacologic inhibition. The effects of WISP-3/CCN6 on metalloproteinase expression in primary chondrocytes were investigated using a small interfering RNA approach. RESULTS: WISP-3/CCN6 was highly expressed in OA cartilage compared with undamaged cartilage, at both the RNA and protein levels. WISP-3/CCN6 overexpression in C-28/I2 cells resulted in unexpected dual regulation of metalloproteinases; expression of the potent aggrecanase ADAMTS-5 was down-regulated 9-fold, while expression of MMP-10 was up-regulated 14-fold, and these responses were accentuated in the WISP-3/CCN6 clones grown in suspension. MMP-10 up-regulation was dependent on several MAPKs, but WISP-3/CCN6-mediated ADAMTS-5 repression was independent of these pathways and was partially relieved by activation of ß-catenin signaling. WISP-3/CCN6 also suppressed ADAMTS-5 expression in C-28/I2 cells treated with cytokines. In cytokine-treated primary chondrocytes, gene silencing of WISP-3/CCN6 resulted in enhanced ADAMTS-5 expression, while MMP-10 expression was suppressed. CONCLUSION: WISP-3/CCN6 was highly expressed in end-stage OA cartilage, suggesting a role for this growth factor in cartilage homeostasis. WISP-3/CCN6-induced repression of ADAMTS-5 expression and regulation of MMP-10 expression suggest complex and context-dependent roles for WISP-3/CCN6 in cartilage biology.

Phenolic acid composition of sprouted wheats by ultra-performance liquid chromatography (UPLC) and their antioxidant activities.

The phenolic acid profiles of flours from two Canadian wheat classes, Canadian Western Red Spring (CWRS) and Canadian Western Amber Durum (CWAD), were investigated using two different extraction mediums and analysed on an ultra-performance liquid chromatography (UPLC) system at different degrees of sprout damage. A sound (non-sprouted) control sample as well as two different sprouted sub-samples, derived from different germination protocols of the control, were prepared for both the CWAD and CWRS. Free phenolic acids were extracted from the ground whole wheat meal using three repetitive 80% ethanol extractions. Bound phenolic compounds were subsequently released from the residue by alkaline hydrolysis followed by triplicate extraction with diethyl ether:ethyl acetate (1:1, v/v). Twelve phenolic acid standards were clearly resolved and quantified using a short 5min elution gradient. Seven phenolic acids (4-hydroxybenzoic, vanillic, caffeic, syringic, p-coumaric, ferulic and sinapic) were detected in the CWRS and CWAD alcoholic and alkaline extracts. Syringic acid was the main compound in the free phenolic alcoholic extracts of the wheat meal representing 77.0% and 75.3% of the total amount of detected free phenolic compounds for CWRS and CWAD, respectively. However, the major released phenolic compound detected in the alkaline hydrolysed extracts was ferulic acid accounting for 72.3% and 71.0% for CWRS and CWAD respectively total bound phenolics. During germination, syringic acid levels rose as the length of germination time increased, resulting in the increase in total phenolic compound and antioxidant activity of the sprouted wheat flours. There was an increase in total phenolic compounds and the antioxidant activity of the alcoholic extracts from the CWRS and CWAD wheat flours as the germination time was extended. As a result, the sprouted wheats exhibits better nutritional properties than un-germinated wheat and could be used to improve the nutrition value in food products.

Structure of IL-17A in complex with a potent, fully human neutralizing antibody.

IL-17A is a pro-inflammatory cytokine produced by the newly identified Th17 subset of T-cells. We have isolated a human monoclonal antibody to IL-17A (CAT-2200) that can potently neutralize the effects of recombinant and native human IL-17A. We determined the crystal structure of IL-17A in complex with the CAT-2200 Fab at 2.6 A resolution in order to provide a definitive characterization of the epitope and paratope regions. Approximately a third of the IL-17A dimer is disordered in this crystal structure. The disorder occurs in both independent copies of the complex in the asymmetric unit and does not appear to be influenced by crystal packing. The complex contains one IL-17A dimer sandwiched between two CAT-2200 Fab fragments. The IL-17A is a disulfide-linked homodimer that is similar in structure to IL-17F, adopting a cystine-knot fold. The structure is not inconsistent with the previous prediction of a receptor binding cavity on IL-17 family members. The epitope recognized by CAT-2200 is shown to involve 12 amino acid residues from the quaternary structure of IL-17A, with each Fab contacting both monomers in the dimer. All complementarity-determining regions (CDRs) in the Fab contribute to a total of 16 amino acid residues in the antibody paratope. In vitro affinity optimization was used to generate CAT-2200 from a parental lead antibody using random mutagenesis of CDR3 loops. This resulted in seven amino acid changes (three in VL-CDR3 and four in VH-CDR3) and gave an approximate 30-fold increase in potency in a cell-based neutralization assay. Two of the seven amino acids form part of the CAT-2200 paratope. The observed interaction site between CAT-2200 and IL-17A is consistent with data from hydrogen/deuterium exchange mass spectrometry and mutagenesis approaches.