Atrial-Selective Approaches for the Treatment of Atrial Fibrillation

Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the treatment of atrial fibrillation (AF). Medical treatment for AF is still more widely applied than interventional therapies but is hampered by several important weaknesses. Besides limited clinical efficacy (cardioversion success and sinus-rhythm maintenance), side effects like ventricular proarrhythmia and negative inotropy are important limitations to present class I and III drug therapy. Although no statistically significant detrimental survival consequences have been documented in trials, constitutional adverse effects might also limit applicability. Cardiac targets for novel atrial-selective antiarrhythmic compounds have been identified, and a large-scale search for safe and effective medications has begun. Several ionic currents (IKACh, IKur) and connexins (Cx-40) are potential targets, because atrial-selective expression makes them attractive in terms of reduced ventricular side-effect liability. Data on most agents are still experimental, but some clinical findings are available. Atrial fibrillation generates a specifically remodeled atrial milieu for which other therapeutic interventions might be effective. Some drugs show frequency-dependent action, whereas others target structurally remodeled atria. This review focuses on potential atrial-selective compounds, summarizing mechanisms of action in vitro and in vivo. It also mentions favorable interventions on the milieu in terms of conventional (such as antifibrotic effects of angiotensin-system antagonism) and innovative gene-therapy approaches that might add to future AF therapeutic options

Rate theory for correlated processes: Double-jumps in adatom diffusion

We study the rate of activated motion over multiple barriers, in particular the correlated double-jump of an adatom diffusing on a missing-row reconstructed Platinum (110) surface. We develop a Transition Path Theory, showing that the activation energy is given by the minimum-energy trajectory which succeeds in the double-jump. We explicitly calculate this trajectory within an effective-medium molecular dynamics simulation. A cusp in the acceptance region leads to a sqrt{T} prefactor for the activated rate of double-jumps. Theory and numerical results agree

Impurity-induced diffusion bias in epitaxial growth

We introduce two models for the action of impurities in epitaxial growth. In the first, the interaction between the diffusing adatoms and the impurities is ``barrier''-like and, in the second, it is ``trap''-like. For the barrier model, we find a symmetry breaking effect that leads to an overall down-hill current. As expected, such a current produces Edwards-Wilkinson scaling. For the trap model, no symmetry breaking occurs and the scaling behavior appears to be of the conserved-KPZ type.Comment: 5 pages(with the 5 figures), latex, revtex3.0, epsf, rotate, multico

Island nucleation in the presence of step edge barriers: Theory and applications

We develop a theory of nucleation on top of two-dimensional islands bordered by steps with an additional energy barrier $\Delta E_S$ for descending atoms. The theory is based on the concept of the residence time of an adatom on the island,and yields an expression for the nucleation rate which becomes exact in the limit of strong step edge barriers. This expression differs qualitatively and quantitatively from that obtained using the conventional rate equation approach to nucleation [J. Tersoff et al., Phys. Rev. Lett.72, 266 (1994)]. We argue that rate equation theory fails because nucleation is dominated by the rare instances when two atoms are present on the island simultaneously. The theory is applied to two distinct problems: The onset of second layer nucleation in submonolayer growth, and the distribution of the sizes of top terraces of multilayer mounds under conditions of strong step edge barriers. Application to homoepitaxial growth on Pt(111) yields the estimate $\Delta E_S \geq 0.33$ eV for the additional energy barrier at CO-decorated steps.Comment: 13 pages, 3 figure

Competing mechanisms for step meandering in unstable growth

The meander instability of a vicinal surface growing under step flow conditions is studied within a solid-on-solid model. In the absence of edge diffusion the selected meander wavelength agrees quantitatively with the continuum linear stability analysis of Bales and Zangwill [Phys. Rev. B {\bf 41}, 4400 (1990)]. In the presence of edge diffusion a local instability mechanism related to kink rounding barriers dominates, and the meander wavelength is set by one-dimensional nucleation. The long-time behavior of the meander amplitude differs in the two cases, and disagrees with the predictions of a nonlinear step evolution equation [O. Pierre-Louis et al., Phys. Rev. Lett. {\bf 80}, 4221 (1998)]. The variation of the meander wavelength with the deposition flux and with the activation barriers for step adatom detachment and step crossing (the Ehrlich-Schwoebel barrier) is studied in detail. The interpretation of recent experiments on surfaces vicinal to Cu(100) [T. Maroutian et al., Phys. Rev. B {\bf 64}, 165401 (2001)] in the light of our results yields an estimate for the kink barrier at the close packed steps.Comment: 8 pages, 7 .eps figures. Final version. Some errors in chapter V correcte

N-Terminal Arginines Modulate Plasma-Membrane Localization of Kv7.1/KCNE1 Channel Complexes

BACKGROUND AND OBJECTIVE: The slow delayed rectifier current (I(Ks)) is important for cardiac action potential termination. The underlying channel is composed of Kv7.1 α-subunits and KCNE1 β-subunits. While most evidence suggests a role of KCNE1 transmembrane domain and C-terminus for the interaction, the N-terminal KCNE1 polymorphism 38G is associated with reduced I(Ks) and atrial fibrillation (a human arrhythmia). Structure-function relationship of the KCNE1 N-terminus for I(Ks) modulation is poorly understood and was subject of this study. METHODS: We studied N-terminal KCNE1 constructs disrupting structurally important positively charged amino-acids (arginines) at positions 32, 33, 36 as well as KCNE1 constructs that modify position 38 including an N-terminal truncation mutation. Experimental procedures included molecular cloning, patch-clamp recording, protein biochemistry, real-time-PCR and confocal microscopy. RESULTS: All KCNE1 constructs physically interacted with Kv7.1. I(Ks) resulting from co-expression of Kv7.1 with non-atrial fibrillation '38S' was greater than with any other construct. Ionic currents resulting from co-transfection of a KCNE1 mutant with arginine substitutions ('38G-3xA') were comparable to currents evoked from cells transfected with an N-terminally truncated KCNE1-construct ('Δ1-38'). Western-blots from plasma-membrane preparations and confocal images consistently showed a greater amount of Kv7.1 protein at the plasma-membrane in cells co-transfected with the non-atrial fibrillation KCNE1-38S than with any other construct. CONCLUSIONS: The results of our study indicate that N-terminal arginines in positions 32, 33, 36 of KCNE1 are important for reconstitution of I(Ks). Furthermore, our results hint towards a role of these N-terminal amino-acids in membrane representation of the delayed rectifier channel complex

Vascular surveillance by haptotactic blood platelets in inflammation and infection

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets

<資料>新西蘭,加奈陀,印度の中央銀行設立計畫

<p><b>Panels A–C,</b> representative images obtained from confocal microscopy of transiently transfected HEK cells. R835Q mutant channels do not appear differently distributed in comparison to WT KCNH2. <b>D</b>, Immunoblots using anti-erg1 (2, 5 µg/mL) of crude membrane extracts from heterologous expression in HEK cells, indicating equal protein expression level. Illustrated below are endoplasmic reticulum and plasma membrane fraction with respective markers of equal protein loading (calnexin for endoplasmic reticulum, spectrin for plasma membranes). Exemplary Western blots of preparations at physiological temperature (37°C) and 40°C (to simulate febrile illness of the index patient’s brother) are shown. No differences were observed in Kv11.1-WT or Kv11.1-R835Q plasma membrane representation of the two proteins under the two conditions. ER: endoplasmic reticulum fraction; PM: plasma-membrane fraction; WT: wild type; NT: non-transfected cells.</p

Problems and needs for improving primary care of osteoarthritis patients: the views of patients, general practitioners and practice nurses

BACKGROUND: Osteoarthritis (OA) is highly prevalent and has substantial impact on quality of life as well as on healthcare costs. The general practitioner (GP) often is the first care provider for patients with this chronic disease. The aim of this study was to identify health care needs of patients with OA and to reveal possible obstacles for improvements in primary care management of OA patients. METHODS: We performed semi-structured interviews with a stratified sample of 20 patients, 20 GPs and 20 practice nurses. RESULTS: Diagnosing OA posed no major problem, but during the course of OA, GPs found it difficult to distinguish between complaints resulting from the affection of the joints and complaints related to a concomitant depression. Patients felt to be well informed about the degenerative nature of the disease and possible side effects of medications, but they lacked information on individual consequences of the disease. Therefore, the most important concerns of many patients were pain and fear of disability which they felt to be addressed by GPs only marginally. Regarding pain treatment, physicians and patients had an ambivalent attitude towards NSAIDs and opiates. Therefore, pain treatment was not performed according to prevailing guidelines. GPs felt frustrated about the impact of counselling regarding life style changes but on the other hand admitted to have no systematic approach to it. Patients stated to be aware of the impact of life style on OA but lacked detailed information e.g. on how to exercise. Several suggestions were made concerning improvement. CONCLUSION: GPs should focus more on disability and pain and on giving information about treatment since these topics are inadequately addressed. Advanced approaches are needed to increase GPs impact on patients' life style. Being aware of the problem of labelling patients as chronically ill, a more proactive, patient-centred care is needed