Transfer of innovation on allergic rhinitis and asthma multimorbidity in the elderly (MACVIA-ARIA) - EIP on AHA Twinning Reference Site (GARD research demonstration project).

The overarching goals of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) are to enable European citizens to lead healthy, active and independent lives whilst ageing. The EIP on AHA includes 74 Reference Sites. The aim of this study was to transfer innovation from an app developed by the MACVIA-France EIP on AHA reference site (Allergy Diary) to other reference sites. The phenotypic characteristics of rhinitis and asthma multimorbidity in adults and the elderly will be compared using validated information and communication technology (ICT) tools (i.e. the Allergy Diary and CARAT: Control of Allergic Rhinitis and Asthma Test) in 22 Reference Sites or regions across Europe. This will improve the understanding, assessment of burden, diagnosis and management of rhinitis in the elderly by comparison with an adult population. Specific objectives will be: (i) to assess the percentage of adults and elderly who are able to use the Allergy Diary, (ii) to study the phenotypic characteristics and treatment over a 1-year period of rhinitis and asthma multimorbidity at baseline (cross-sectional study) and (iii) to follow-up using visual analogue scale (VAS). This part of the study may provide some insight into the differences between the elderly and adults in terms of response to treatment and practice. Finally (iv) work productivity will be examined in adults.

Gating and flickery block differentially affected by rubidium in homomeric KCNQ1 and heteromeric KCNQ1/KCNE1 potassium channels.

The voltage-gated potassium channel KCNQ1 associates with the small KCNE1 subunit to form the cardiac IKs delayed rectifier potassium current and mutations in both genes can lead to the long QT syndrome. KCNQ1 can form functional homotetrameric channels, however with drastically different biophysical properties compared to heteromeric KCNQ1/KCNE1 channels. We analyzed gating and conductance of these channels expressed in Xenopus oocytes using the two-electrode voltage-clamp and the patch-clamp technique and high extracellular potassium (K) and rubidium (Rb) solutions. Inward tail currents of homomeric KCNQ1 channels are increased about threefold upon substitution of 100 mM potassium with 100 mM rubidium despite a smaller rubidium permeability, suggesting an effect of rubidium on gating. However, the kinetics of tail currents and the steady-state activation curve are only slightly changed in rubidium. Single-channel amplitude at negative voltages was estimated by nonstationary noise analysis, and it was found that rubidium has only a small effect on homomeric channels (1.2-fold increase) when measured at a 5-kHz bandwidth. The apparent single-channel conductance was decreased after filtering the data at lower cutoff frequencies indicative of a relatively fast "flickery/block" process. The relative conductance in rubidium compared to potassium increased at lower cutoff frequencies (about twofold at 10 Hz), suggesting that the main effect of rubidium is to decrease the probability of channel blockage leading to an increase of inward currents without large changes in gating properties. Macroscopic inward tail currents of heteromeric KCNQ1/KCNE1 channels in rubidium are reduced by about twofold and show a pronounced sigmoidal time course that develops with a delay similar to the inactivation process of homomeric KCNQ1, and is indicative of the presence of several open states. The single channel amplitude of heteromers is about twofold smaller in rubidium than in potassium at a bandwidth of 5 kHz. Filtering at lower cutoff frequencies reduces the apparent single-channel conductance, the ratio of the conductance in rubidium versus potassium is, however, independent of the cutoff frequency. Our results suggest the presence of a relatively rapid process (flicker) that can occur almost independently of the gating state. Occupancy by rubidium at negative voltages favors the flicker-open state and slows the flickering rate in homomeric channels, whereas rubidium does not affect the flickering in heteromeric channels. The effects of KCNE1 on the conduction properties are consistent with an interaction of KCNE1 in the outer vestibule of the channel.

Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives.

The enantiomers of 2-(p-chlorophenoxy)propionic acid (CPP) and of its analogs with substitutions on the asymmetric carbon atom were tested on human ClC-1 channel, the skeletal muscle chloride channel, after heterologous expression in Xenopus laevis oocytes, to gain insight in the mechanism of action of these stereoselective modulators of macroscopic chloride conductance (gCl) of rat striated fibers. By means of two microelectrode voltage clamp recordings, we found that S(-)-CPP shifted the activation curve of the ClC-1 currents toward more positive potentials and decreased the residual conductance at negative membrane potential; both effects probably account for the decrease of gCl at resting potential of native muscle fibers. Experiments on expressed Torpedo marmorata ClC-0 channels and a mutant lacking the slow gate suggest that S(-)-CPP could act on the fast gate of the single protochannels constituting the double-barreled structure of ClC-0 and ClC-1. The effect of S(-)-CPP on ClC-1 was markedly increased at low external pH (pH = 6), possibly for enhanced diffusion through the membrane (i.e., because the compound was effective only when applied to the cytoplasmic side during patch clamp recordings). The R(+)-isomer had little effect at concentrations as high as 1 mM. The CPP analogs with an ethyl, a phenyl, or an n-propyl group in place of the methyl group on the asymmetric center showed a scale of potency and a stereoselective behavior on ClC-1 similar to that observed for blocking gCl in native muscle fibers. The tested compounds were selective toward the ClC-1 channel. In fact, they were almost ineffective on an N-terminal deletion mutant of ClC-2 that is volume- and pH-independent while they blocked wild-type ClC-2 currents only at high concentrations and independently of pH and drug configuration, suggesting a different mechanism of action compared with ClC-1. No effects were observed on ClC-5 that shows less than 30% homology with ClC-1. Thus, CPP-like compounds may be useful both to gain insight into biophysical properties of ClC-1 and for searching tissue-specific therapeutic agents.