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

Caveolin-3 differentially orchestrates cholinergic and serotonergic constriction of murine airways

The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance as inappropriate constriction is a hallmark in asthma and chronic obstructive pulmonary disease. Receptors for acetylcholine and serotonin, two relevant mediators in this context, appear to be incorporated in specialized, cholesterol-rich domains of the plasma membrane, termed caveolae due to their invaginated shape. The structural protein caveolin-1 partly accounts for anchoring of these receptors. We here determined the role of the other major caveolar protein, caveolin-3 (cav-3), in orchestrating cholinergic and serotonergic ASM responses, utilizing newly generated cav-3 deficient mice. Cav-3 deficiency fully abrogated serotonin-induced constriction of extrapulmonary airways in organ baths while leaving intrapulmonary airways unaffected, as assessed in precision cut lung slices. The selective expression of cav-3 in tracheal, but not intrapulmonary bronchial epithelial cells, revealed by immunohistochemistry, might explain the differential effects of cav-3 deficiency on serotonergic ASM constriction. The cholinergic response of extrapulmonary airways was not altered, whereas a considerable increase was observed in cav-3â -/- intrapulmonary bronchi. Thus, cav-3 differentially organizes serotonergic and cholinergic signaling in ASM through mechanisms that are specific for airways of certain caliber and anatomical position. This may allow for selective and site-specific intervention in hyperreactive states

Personality and attention bias in adults with a history of childhood trauma, and attenuating effects of mu-opioid agonist buprenorphine on attention bias

The current study compared personality characteristics and cognitive functioning (specifically, attentional bias) in a sample of adults who had experienced childhood trauma (the Trauma group) and a matched healthy control group. The study also examined the possible effects of the mu-opioid agonist buprenorphine on attentional bias in the Trauma group

Demonstrating the feasibility of standardized application program interfaces that will allow mobile/portable terminals to receive services combining UMTS and DVB-T

Crucial to the commercial exploitation of any service combining UMTS and DVB-T is the availability of standardized API’s adapted to the hybrid UMTS and DVB-T network and to the technical limitations of mobile/portable terminals. This paper describes work carried out in the European Commission Framework Program 5 (FP5) project CONFLUENT to demonstrate the feasibility of such Application Program Interfaces (API’s) by enabling the reception of a Multimedia Home Platform (MHP) based application transmitted over DVB-T on five different terminals with parts of the service running on a mobile phone

The 2-dimensional non-linear sigma-model on a random latice

The O(n) non-linear $\sigma$-model is simulated on 2-dimensional regular and random lattices. We use two different levels of randomness in the construction of the random lattices and give a detailed explanation of the geometry of such lattices. In the simulations, we calculate the mass gap for $n=3, 4$ and 8, analysing the asymptotic scaling of the data and computing the ratio of Lambda parameters $\Lambda_{\rm random}/\Lambda_{\rm regular}$. These ratios are in agreement with previous semi-analytical calculations. We also numerically calculate the topological susceptibility by using the cooling method.Comment: REVTeX file, 23 pages. 13 postscript figures in a separate compressed tar fil

Effect of 475 °C embrittlement on the mechanical properties of duplex stainless steel

The binary iron–chromium alloy embrittles in the temperature range of 280–500 °C limiting its applications to temperatures below 280 °C. The embrittlement is caused by the decomposition of the alloy to chromium-rich phase, α′ and iron-rich phase, α. This phenomenon is termed 475 °C embrittlement as the rate of embrittlement is highest at 475 °C. Primarily the investigations on 475 °C embrittlement were confined to binary iron–chromium alloys and ferritic stainless steels. Duplex stainless steel grades contain varying proportions of ferrite and austenite in the microstructure and the ferritic phase is highly alloyed. Moreover, this grade of steel has several variants depending on the alloy composition and processing route. This modifies the precipitation behaviour and the resulting change in mechanical properties in duplex stainless steels when embrittled at 475 °C as compared to binary iron chromium systems. The precipitation behaviour of duplex stainless steel at 475 °C and the effect on tensile, fracture and fatigue behaviour are reviewed in this article

A three-dimensional model for stage I-crack propagation

The propagation of short fatigue cracks is simulated by means of a three-dimensional model. Under loading conditions in the high cycle fatigue regime the growth of these cracks can determine up to 90% of the lifetime of a component. Stage I-cracks often grow on slip bands and exhibit strong interactions with microstructural features such as grain boundaries. Experimental investigations have shown that the crack propagation rate decreases significantly when the crack tip approaches a grain boundary and even a complete stop of crack propagation is possible. In order to consider the real three-dimensional orientation of a slip plane an existing two-dimensional mechanism-based model (Künkler el al., 2008) is extended to simulate the propagation of a three-dimensional surface crack. The crack geometry is modelled using dislocation loops (Hills et al., 1996), which represent the relative displacement between the crack flanks. To describe the propagation of stage Icracks elastic-plastic material behaviour is considered by allowing a plastic deformation due to slip on the active slip plane. The extension of the plastic zone is blocked by the grain boundary. The crack propagation law is based on the range of the crack tip slide displacement, which is obtained from the plastic solution. Behind the grain boundary the shear stress field is evaluated. Results show that a high twist angle between the slip planes causes a significant decrease in the stresses, which can yield a crack stop

Copeptin Levels Remain Unchanged during the Menstrual Cycle.

BACKGROUND: Copeptin, a surrogate marker for arginin vasopressin production, is evaluated as an osmo-dependent stress and inflammatory biomarker in different diseases. We investigated copeptin during the menstrual cycle and its relationship to sex hormones, markers of subclinical inflammation and estimates of body fluid. METHODS: In 15 healthy women with regular menstrual cycles, blood was drawn on fifteen defined days of their menstrual cycle and was assayed for copeptin, progesterone, estradiol, luteinizing hormone, high-sensitive C-reactive protein, tumor necrosis factor-alpha and procalcitonin. Symptoms of fluid retention were assessed on each visit, and bio impedance analysis was measured thrice to estimate body fluid changes. Mixed linear model analysis was performed to assess the changes of copeptin across the menstrual cycle and the relationship of sex hormones, markers of subclinical inflammation and estimates of body fluid with copeptin. RESULTS: Copeptin levels did not significantly change during the menstrual cycle (p = 0.16). Throughout the menstrual cycle, changes in estradiol (p = 0.002) and in the physical premenstrual symptom score (p = 0.01) were positively related to copeptin, but changes in other sex hormones, in markers of subclinical inflammation or in bio impedance analysis-estimated body fluid were not (all p = ns). CONCLUSION: Although changes in estradiol and the physical premenstrual symptom score appear to be related to copeptin changes, copeptin does not significantly change during the menstrual cycle