Views of the self and their ethical implications.

Thesis (M.A.

The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation

Background— The molecular mechanism of increased background inward rectifier current (IK1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated IK,ACh contributes to enhanced basal conductance in chronic AF (cAF). Methods and Results— Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective IK,ACh blocker tertiapin was used for inhibition of IK,ACh. Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated IK,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced IK,ACh in a concentration-dependent manner with greater potency in cAF than in SR (−logIC50: 9.1 versus 8.2; P<0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at −100 mV: cAF, −6.7±1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, −1.7±0.5 pA/pF, n=24/8), suggesting contribution of constitutively active IK,ACh to basal current. In single-channel recordings, constitutively active IK,ACh was prominent in cAF but not in SR (channel open probability: cAF, 5.4±0.7%, n=19/9 versus SR, 0.1±0.05%, n=16/9; P<0.05). Moreover, IK1 channel open probability was higher in cAF than in SR (13.4±0.4%, n=19/9 versus 11.4±0.7%, n=16/9; P<0.05) without changes in other channel characteristics. Conclusions— Our results demonstrate that larger basal inward rectifier K+ current in cAF consists of increased IK1 activity and constitutively active IK,ACh. Blockade of IK,ACh may represent a new therapeutic target in AF

Functional modulation of the transient outward current Ito by KCNE beta-subunits and regional distribution in human non-failing and failing hearts

Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current I,, in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V-0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human I-to while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to It. in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native I-to channel

The feasibility of wireless capsule endoscopy in detecting small intestinal pathology in children under the age of 8 years: a multicentre European study.

Objective: To systematically evaluate the feasibility and methodology to carry out wireless capsule endoscopy (WCE) in children <8 years to define small intestinal pathology. Design: Prospective European multicentre study with negative prior investigation. Patients and interventions: 83 children aged 1.5–7.9 years were recruited. Initially, all were offered “swallowing” (Group 1) for capsule introduction. If this failed endoscopic placement (Group 2) was used and the Roth net, Advance or custom-made introducers were compared. Outcome measures: Primary endpoint: to determine pathology; secondary endpoint: comparison of capsule introduction methods. Results: Capsule introduction: 20 (24%) children aged 4.0–7.9 years (mean, 6.9 years; 14 male) comprising Group 1 were older (p<0.025) than 63 (76%) aged 1.5–7.9 years (mean, 5.25 years; 30 male) forming Group 2. Complications: Roth net mucosal trauma in 50%; no others occurred. The available recording apparatus was inappropriate for those <3 years. Indications: gastrointestinal bleeding: n = 30 (16 positive findings: four ulcerative jejunitis, four polyps, two angiodysplasia, two blue rubber blebs, two Meckel’s diverticula, one anastomotic ulcer, one reduplication); suspected Crohn’s disease: n = 20 (11 had Crohn’s disease); abdominal pain: n = 12 (six positive findings: three Crohn’s disease, two lymphonodular hyperplasia, one blue rubber bleb); protein loss: n = 9 (four lymphangectasia); malabsorption: n = 12 (seven positive findings: six enteropathy, one ascaris). No abnormalities overall: 45%. Conclusion: WCE is feasible and safe down to the age of 1.5 years. 20 children >4 years swallowed the capsule. The Advance introducer proved superior for endoscopic placement. The pathologies encountered showed age specificity and, unlike in adolescents, obscure gastrointestinal bleeding was the commonest indication