Truncating tau reveals different pathophysiological actions of oligomers in single neurons

Tau protein is involved in maintaining neuronal structure. In Alzheimer's disease, small numbers of tau molecules can aggregate to form oligomers. However, how these oligomers produce changes in neuronal function remains unclear. Previously, oligomers made from full-length human tau were found to have multiple effects on neuronal properties. Here we have cut the tau molecule into two parts: the first 123 amino acids and the remaining 124-441 amino acids. These truncated tau molecules had specific effects on neuronal properties, allowing us to assign the actions of full-length tau to different regions of the molecule. We identified one key target for the effects of tau, the voltage gated sodium channel, which could account for the effects of tau on the action potential. By truncating the tau molecule, we have probed the mechanisms that underlie tau dysfunction, and this increased understanding of tau's pathological actions will build towards developing future tau-targeting therapies

Vertical distribution and diurnal migration of atlantid heteropods

© Inter-Research 201 Understanding the vertical distribution and migratory behaviour of shelled holoplanktonic gastropods is essential in determining the environmental conditions to which they are exposed. This is increasingly important in understanding the effects of ocean acidification and climate change. Here we investigated the vertical distribution of atlantid heteropods by collating data from publications and collections and using the oxygen isotope (? 18 O) composition of single aragonitic shells. Data from publications and collections show 2 patterns of migration behaviour: small species that reside in shallow water at all times, and larger species that make diurnal migrations from the surface at night to deep waters during the daytime. The ? 18 O data show that all species analysed (n = 16) calcify their shells close to the deep chlorophyll maximum. This was within the upper 110 m of the ocean for 15 species, and down to 146 m for a single species. These findings confirm that many atlantid species are exposed to large environmental variations over a diurnal cycle and may already be well adapted to face ocean changes. However, all species analysed rely on aragonite supersaturated waters in the upper < 150 m of the ocean to produce their shells, a region that is projected to undergo the earliest and greatest changes in response to increased anthropogenic CO 2

Visfatin reduces gap junction mediated cell-to-cell communication in proximal tubule-derived epithelial cells

Aim: Associated with obesity, visfatin may have a role in the pathogenesis of diabetic nephropathy in type II diabetes. This study identifies a link between the visfatin, TGF-β1 and reduced cell-to-cell coupling in proximal tubule derived epithelial cells. Methods: Western blot analysis confirmed changes in expression of connexins Cx26, Cx40 and Cx43 in HK2-cells +/- visfatin &/or TGF-β1. Visfatin evoked increases in TGF-β1 secretion were determined by ELISA, and functional intercellular communication assessed via Lucifer yellow dye transfer and paired-whole cell patch clamp electrophysiology. Results: Visfatin (10, 100 and 200ng/mL) decreased expression of Cx26 to 58±11%, 40± 3% and 21±2% and Cx43 to 73±5%, 44± 4% and 29±6% as compared to control at 48hrs (n=3; P<0.01). The effects were not dependent on changes in membrane integrity, cytotoxicity or cell viability as assessed by MTT, crystal-violet and lactate-dehydrogenase assays. Expression of Cx40 was unaffected by the adipocytokine. Visfatin (200ng/ml) increased TGF-β1 secretion by 154% of control (n=3; p<0.01). Visfatin-evoked changes in Cx26 and Cx43 expression were mimicked by exogenous application of TGF-β1 (2-10ng/ml, p<0.001 n=3). Visfatin reduced dye transfer between coupled-cells and decreased functional conductance by 63% as compared to control (n=6; p<0.01). Conclusions: Visfatin reduced connexin expression in HK2-cells, an effect mirrored by a loss in functional conductance between coupled cells. Visfatin increased TGF-β secretion and the pattern of change for connexin expression was mimicked by exogenous application of the pro-fibrotic cytokine. These data suggest that visfatin reduces connexin-mediated intercellular communication in proximal tubule-derived epithelial cells via a TGF-β dependent pathway. This work is supported by a grant from Diabetes UK (BDA: 11/0004215)

Evaluation of demand in a rural English hospital emergency department

The purpose of this article is to analyse the patient demand placed on a rural district general hospital (DGH) emergency department within the context of the Purpose, Process, People (PPP) framework used in the private sector. This analysis was undertaken to inform wider evaluation of the implementation of the enterprise culture—the NHS policy to adopt private sector best practice to produce resource use, quality and efficiency improvements. The article concludes with a view that the PPP framework provides methods of calculating the level of discharge necessary to meet the four-hour wait target. Data describing the characteristics and patterns of attending patients can be used to develop an emergency department’s processes and people to achieve its time-based target

Transforming growth factor and intercellular communication in tubular epithelial cells: a role in diabetic nephropathy.

Aims: Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, including diabetic nephropathy. This study examines a role for glucose-evoked changes in the beta1 isoform of the pro-fibrotic cytokine transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication and hemi-channel mediated ATP release from epithelial cells of the proximal tubule. Methods: Connexin-26 and connexin-43 expression was assessed by immunoblot analysis in human kidney (HK2) tubular epithelial cells treated with TGFβ1 (2-10ng/mL) for 48hrs. Whole cell paired-patch electrophysiology assessed junctional conductance between TGFβ1 treated HK2 cells. Hemi-channel opening was determined by carboxyfluorescein uptake, whilst bio-sensing was used to determine real-time ATP release. Results: Immunoblotting confirmed that TGFβ1 down-regulates connexin-26 to 72.7±13.3%, 71.6±4.8%, and 58.3±5.7% of control and connexin-43 to 61.2±10.4%, 49.5±6.1%, and 48.1±3.8% at 2, 4 and 10 ng/mL respectively. TGFβ1 significantly decreased junctional conductance at 48hrs (1.15±0.9nS compared to 4.5±1.3nS in control cells n=5; P<0.05), whilst carboxyfluorescein uptake increased 346±33% in TGFβ1-treated (10ng/mL) cells. A response inhibited by the hemi-channel blocker carbenoxolone (200µM, 30mins). Bio-sensing confirmed that increased channel opening was paralleled by elevated ATP release following 48hr TGFβ1 treatment (1.99±0.47µM compared to a control 0.29± 0.06µM, P<0.01, n=3). Conclusions: The current study suggests that acute 48hr application of the pro-fibrotic cytokine reduces connexin-mediated intercellular communication in proximal tubular epithelial cells in favour of hemi-channel mediated ATP release. The rise in intercellular ATP may contribute to tubular fibrosis in the diabetic kidney. Acknowledgement: This work is supported by Diabetes UK (BDA:11/0004215, BDA:16/0005427

Does heart rate influence CMR image quality of the coronary vessel wall?

Cardiolog

Mobile health in adults with congenital heart disease: Current use and future needs

Objective Many adults with congenital heart disease (CHD) are affected lifelong by cardiac events, particularly arrhythmias and heart failure. Despite the care provided, the cardiac event rate remains high. Mobile health (mHealth) brings opportunities to enhance daily monitoring and hence timely response in an attempt to improve outcome. However, it is not known if adults with CHD are currently using mHealth and what type of mHealth they may need in the near future. Methods Consecutive adult patients with CHD who visited the outpatient clinic at the Academic Medical Center in Amsterdam were asked to fill out questionnaires. Exclusion criteria for this study were mental impairment or inability to read and write Dutch. Results All 118 patients participated (median age 40 (range 18–78) years, 40 % male, 49 % symptomatic) and 92 % owned a smartphone. Whereas only a small minority (14 %) of patients used mHealth, the large majority (75 %) were willing to start. Most patients wanted to use mHealth in order to receive more information on physical health, and advice on progression of symptoms or signs of deterioration. Analyses on age, gender and complexity of defect showed significantly less current smartphone usage at older age, but no difference in interest or preferences in type of mHealth application for the near future. Conclusion The relatively young adult CHD population only rarely uses mHealth, but the majority are motivated to start using mHealth. New mHealth initiatives are required in these patients with a chronic condition who need lifelong surveillance in order to reveal if a reduction in morbidity and mortality and improvement in quality of life can be achieved