Molecular hydrodynamic theory of the velocity autocorrelation function.

The velocity autocorrelation function (VACF) encapsulates extensive information about a fluid's molecular-structural and hydrodynamic properties. We address the following fundamental question: How well can a purely hydrodynamic description recover the molecular features of a fluid as exhibited by the VACF? To this end, we formulate a bona fide hydrodynamic theory of the tagged-particle VACF for simple fluids. Our approach is distinguished from previous efforts in two key ways: collective hydrodynamic modes and tagged-particle self-motion are modeled by linear hydrodynamic equations; the fluid's spatial velocity power spectrum is identified as a necessary initial condition for the momentum current correlation. This formulation leads to a natural physical interpretation of the VACF as a superposition of products of quasinormal hydrodynamic modes weighted commensurately with the spatial velocity power spectrum, the latter of which appears to physically bridge continuum hydrodynamical behavior and discrete-particle kinetics. The methodology yields VACF calculations quantitatively on par with existing approaches for liquid noble gases and alkali metals. Furthermore, we obtain a new, hydrodynamic form of the self-intermediate scattering function whose description has been extended to low densities where the Schmidt number is of order unity; various calculations are performed for gaseous and supercritical argon to support the general validity of the theory. Excellent quantitative agreement is obtained with recent MD calculations for a dense supercritical Lennard-Jones fluid.

Impact of the Hall effect on high-energy-density plasma jets.

Using a 1-MA, 100 ns-rise-time pulsed power generator, radial foil configurations can produce strongly collimated plasma jets. The resulting jets have electron densities on the order of 10(20) cm(-3), temperatures above 50 eV and plasma velocities on the order of 100 km/s, giving Reynolds numbers of the order of 10(3), magnetic Reynolds and Péclet numbers on the order of 1. While Hall physics does not dominate jet dynamics due to the large particle density and flow inside, it strongly impacts flows in the jet periphery where plasma density is low. As a result, Hall physics affects indirectly the geometrical shape of the jet and its density profile. The comparison between experiments and numerical simulations demonstrates that the Hall term enhances the jet density when the plasma current flows away from the jet compared to the case where the plasma current flows towards it.

Central role of PKCα in isoenzyme-selective regulation of cardiac transient outward current Ito and Kv4.3 channels.

The transient outward current I(to) is an important determinant of the early repolarization phase. I(to) and its molecular basis Kv4.3 are regulated by adrenergic pathways including protein kinase C. However, the exact regulatory mechanisms have not been analyzed yet. We here analyzed isoenzyme specific regulation of Kv4.3 and I(to) by PKC. Kv4.3 channels were expressed in Xenopus oocytes and currents were measured with double electrode voltage clamp technique. Patch clamp experiments were performed in isolated rat cardiomyocytes. Unspecific PKC stimulation with PMA resulted in a reduction of Kv4.3 current. Similar effects could be observed after activation of conventional PKC isoforms by TMX. Both effects were reversible by pharmacological inhibition of the conventional PKC isoenzymes (Gö6976). In contrast, activation of the novel PKC isoforms (ingenol) did not significantly affect Kv4.3 current. Whereas TMX-induced PKC activation was not attenuated inhibition of PKCß, inhibition of PKCα with HBDDE prevented inhibitory effects of both PMA and TMX. Accordingly, stimulatory effects of PMA and TMX could be mimicked by the α-isoenzyme selective PKC activator iripallidal. Further evidence for the central role of PKCα was provided with the use of siRNAs. We found that PKCα siRNA but not PKCß siRNA abolished the TMX induced effect. In isolated rat cardiomyocytes, PMA dependent I(to) reduction could be completely abolished by pharmacologic inhibition of PKCα. In summary we show that PKCα plays a central role in protein kinase C dependent regulation of Kv4.3 current and native I(to). These results add to the current understanding of isoenzyme selective ion channel regulation by protein kinases.

Scaling up antiretroviral therapy for HIV-infected children in Côte d'Ivoire: determinants of survival and loss to programme.

OBJECTIVE: To investigate deaths and losses to follow-up in a programme designed to scale up antiretroviral therapy (ART) for HIV-infected children in Côte d'Ivoire. METHODS: Between 2004 and 2007, HIV-exposed children at 19 centres were offered free HIV serum tests (polymerase chain reaction tests in those aged < 18 months) and ART. Computerized monitoring was used to determine: (i) the number of confirmed HIV infections, (ii) losses to the programme (i.e. death or loss to follow-up) before ART, (iii) mortality and loss-to-programme rates during 12 months of ART, and (iv) determinants of mortality and losses to the programme. FINDINGS: The analysis included 3876 ART-naïve children. Of the 1766 with HIV-1 infections (17% aged < 18 months), 124 (7.0%) died, 52 (2.9%) left the programme, 354 (20%) were lost to follow-up before ART, 259 (15%) remained in care without ART, and 977 (55%) started ART (median age: 63 months). The overall mortality rate during ART was significantly higher in the first 3 months than in months 4-12: 32.8 and 6.9 per 100 child-years of follow-up, respectively. Loss-to-programme rates were roughly double mortality rates and followed the same trend with duration of ART. Independent predictors of 12-month mortality on ART were pre-ART weight-for-age z-score < -2, percentage of CD4+ T lymphocytes < 10, World Health Organization HIV/AIDS clinical stage 3 or 4, and blood haemoglobin < 8 g/dl. CONCLUSION: The large-scale programme to scale up paediatric ART in Côte d'Ivoire was effective. However, ART was often given too late, and early mortality and losses to programme before and just after ART initiation were major problems.

CD4+ T-lymphocytes natural decrease in HAART-naïve HIV-infected adults in Abidjan.

OBJECTIVE: To study the CD4 natural decrease and its determinants in sub-Saharan African HIV-infected adults. METHOD: We performed a 7-year prospective cohort study, with biannual CD4 measurement. Follow-up was censored at the first severe morbidity event or at HAART initiation. Changes in CD4 values were studied by jointly modelling (a) the correlation between repeated measures through a linear mixed model and (b) the time to drop-out through a survival model. RESULTS: 690 patients were followed up during 1,382 person-years. Contrasting with the baseline CD4 count and percentage, which were associated with numerous variables, the slopes of both CD4 count and CD4 percentage in the absence of severe morbidity episode were only associated with the follow-up time and with the baseline body mass index (BMI). The mean annual natural decrease in CD4 count (CD4%) was estimated at -81/mm3 (-2.2%), -69/mm3 (-1.7%), and -55/mm3 (-1.2%) for patients with baseline BMI at 16 kg/m2, 20.4 kg/m2, and 25 kg/m2, respectively (p < .001). A steeper decline in the CD4 count was independently associated with a shorter event-free follow-up time. CONCLUSION: These estimates of the CD4 natural decrease in sub-Saharan African patients, while they did not experience any episode of severe morbidity and before they initiate HAART, are in the bracket of those previously reported in industrialized countries. In sub-Saharan African settings with CD4 count being measured less frequently than in industrialized countries, the CD4 should be monitored more closely among adults with low BMI.

Influence of the dielectric property on microwave oven heating patterns: application to food materials.

Patterns of power absorption in a microwave oven for a range of dielectric properties of relevance to food processing were investigated. The governing Maxwell's equations with boundary conditions and a TE10 excitation were solved using a finite element method. Food properties were varied from values at their frozen state to values at high temperatures, as would be typical in a thawing process. For low-loss materials such as frozen foods, the high quality factor makes the heating significantly higher only when the size and shape of the load permit a dielectric cavity resonance in the load. Otherwise, the heating pattern will follow the modal electric field pattern of the oven. For moderate loss materials, the patterns will come from the modes of the dielectric cavity. The bandwidths of these modes are larger than the low-loss situation and their overlap results in a heating pattern that is somewhat more uniform. For high-loss materials, the concept of modes is no longer useful as the very large number of modes strongly overlap. The rapidly decaying field and power loss in the high-loss material can probably be characterized as an exponential decay.

Modulation of K2P 2.1 and K2P 10.1 K(+) channel sensitivity to carvedilol by alternative mRNA translation initiation.

BACKGROUND AND PURPOSE: The ß-receptor antagonist carvedilol blocks a range of ion channels. K2P 2.1 (TREK1) and K2P 10.1 (TREK2) channels are expressed in the heart and regulated by alternative translation initiation (ATI) of their mRNA, producing functionally distinct channel variants. The first objective was to investigate acute effects of carvedilol on human K2P 2.1 and K2P 10.1 channels. Second, we sought to study ATI-dependent modulation of K2P K(+) current sensitivity to carvedilol. EXPERIMENTAL APPROACH: Using standard electrophysiological techniques, we recorded currents from wild-type and mutant K2P 2.1 and K2P 10.1 channels in Xenopus oocytes and HEK 293 cells. KEY RESULTS: Carvedilol concentration-dependently inhibited K2P 2.1 channels (IC50 ,oocytes = 20.3 µM; IC50 , HEK = 1.6 µM) and this inhibition was frequency-independent. When K2P 2.1 isoforms generated by ATI were studied separately in oocytes, the IC50 value for carvedilol inhibition of full-length channels (16.5 µM) was almost 5-fold less than that for the truncated channel variant (IC50 = 79.0 µM). Similarly, the related K2P 10.1 channels were blocked by carvedilol (IC50 ,oocytes = 24.0 µM; IC50 , HEK = 7.6 µM) and subject to ATI-dependent modulation of drug sensitivity. CONCLUSIONS AND IMPLICATIONS: Carvedilol targets K2P 2.1 and K2P 10.1 K(+) channels. This previously unrecognized mechanism supports a general role of cardiac K2P channels as antiarrhythmic drug targets. Furthermore, the work reveals that the sensitivity of the cardiac ion channels K2P 2.1 and K2P 10.1 to block was modulated by alternative mRNA translation initiation.

Acute and subacute effects of the selective serotonin-noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels.

Duloxetine is a selective serotonin-noradrenaline reuptake inhibitor approved for treatment of major depressive disorder. So far, duloxetine has been found to be well tolerated and reported cardiac side effects were negligible. However, pharmacological effects on cardiac hERG channels have not been properly addressed yet. hERG channels were expressed in Xenopus oocytes and a human embryonic kidney (HEK) cell line. Currents were measured using voltage clamp and patch clamp techniques. Channel surface expression was quantified using Western blot analysis. We found that duloxetine inhibits heterologously expressed hERG channels in a concentration-dependent manner, yielding an IC50 of 142.8 µM in Xenopus oocytes. Inhibitory effects were even more pronounced when using a mammalian cell line resulting in a 34 or 59% current decrease by 10 or 30 µM duloxetine, respectively. Duloxetine did not affect channel activation or inactivation kinetics. However, channel deactivation was accelerated by duloxetine. We further showed that inhibition occurs in the open and inactivated, but not closed, states. There was no frequency dependence of block. However, effects of duloxetine were significantly attenuated when using the hERG pore mutants Y652A and F656A. Subacute effects of duloxetine on hERG channel expression were analyzed using the Western blot technique. We found that incubation with duloxetine results in a concentration-dependent decrease of channel surface expression. Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of duloxetine overdose and when administering duloxetine to patients susceptible to drug-induced QT prolongation.

Inhibition of cardiac Kv1.5 and Kv4.3 potassium channels by the class Ia anti-arrhythmic ajmaline: mode of action.

Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For ajmaline, inhibitory effects on a variety of cardiac K(+) channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 µM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of ajmaline.

TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.

BACKGROUND AND PURPOSE: TASK1 (K(2P)3.1) two-pore-domain K(+) channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin-1 (ET-1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET-1-mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET-1. EXPERIMENTAL APPROACH: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record TASK1 currents from hPASMC and Xenopus oocytes. KEY RESULTS: ET-1 inhibited TASK1-mediated I(KN) currents in hPASMC, an effect attenuated by Rho kinase inhibition with Y-27632. In Xenopus oocytes, TASK1 current reduction by ET-1 was mediated by endothelin receptors ET(A) (IC(50) = 0.08 nM) and ET(B) (IC(50) = 0.23 nM) via Rho kinase signalling. TASK1 channels contain two putative Rho kinase phosphorylation sites, Ser(336) and Ser(393) . Mutation of Ser(393) rendered TASK1 channels insensitive to ET(A) - or ET(B)-mediated current inhibition. In contrast, removal of Ser(336) selectively attenuated ET(A) -dependent TASK1 regulation without affecting the ET(B) pathway. CONCLUSIONS AND IMPLICATIONS: ET-1 regulated vascular TASK1 currents through ET(A) and ET(B) receptors mediated by downstream activation of Rho kinase and direct channel phosphorylation. The Rho kinase pathway in PASMC may provide a more specific therapeutic target in pulmonary arterial hypertension treatment.

Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels.

BACKGROUND AND PURPOSE: Human K(2P) 3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K(2P) channels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K(2P) currents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K(2P) 3.1 (hK(2P) 3.1) channels. EXPERIMENTAL APPROACH: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hK(2P) 3.1 currents from Xenopus oocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC). KEY RESULTS: Carvedilol concentration-dependently inhibited hK(2P) 3.1 currents in Xenopus oocytes (IC(50) = 3.8 µM) and in mammalian CHO cells (IC(50) = 0.83 µM). In addition, carvedilol sensitivity of native I(K2P3.1) was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency-dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current-voltage (I-V) relationship by -6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K(2P) currents, was not affected. CONCLUSIONS AND IMPLICATIONS: The antiarrhythmic drug carvedilol targets hK(2P) 3.1 background channels. We propose that cardiac hK(2P) 3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.

Adaptive divergence within and between ecotypes of the terrestrial garter snake, Thamnophis elegans, assessed with F(ST)-Q(ST) comparisons.

Populations of the terrestrial garter snake (Thamnophis elegans) around Eagle Lake in California exhibit dramatic ecotypic differentiation in life history, colouration and morphology across distances as small as a few kilometres. We assayed the role of selection in ecotypic differentiation in T. elegans using F(ST)-Q(ST) analysis and identified selective agents using direct and indirect observations. We extended the conventional implementation of the F(ST)-Q(ST) approach by using three-level analyses of genetic and phenotypic variance to assess the role of selection in differentiating populations both within and between ecotypes. These results suggest that selection has driven differentiation between as well as within ecotypes, and in the presence of moderate to high gene flow. Our findings are discussed in the context of previous correlational selection analyses which revealed stabilizing and correlational selection for some of the traits examined.

Scaling up antiretroviral therapy for HIV-infected children in Côte d'Ivoire: determinants of survival and loss to programme

Objective: To investigate deaths and losses to follow-up in a programme designed to scale up antiretroviral therapy (ART) for HIV- infected children in Cote d'Ivoire. Methods Between 2004 and 2007; HIV-exposed children at 19 centres were offered free HIV serum tests (polymerase chain reaction tests in those aged 18 months) and ART. Computerized monitoring was used to determine: (i) the number of confirmed HIV infections; (ii) losses to the programme (i.e. death or loss to follow-up) before ART; (iii) mortality and loss-to-programme rates during 12 months of ART; and (iv) determinants of mortality and losses to the programme. Findings The analysis included 3876 ART-naive children. Of the 1766 with HIV-1 infections (17aged 18 months); 124 (7.0) died; 52 (2.9) left the programme; 354 (20) were lost to follow-up before ART; 259 (15) remained in care without ART; and 977 (55) started ART (median age: 63 months). The overall mortality rate during ART was significantly higher in the first 3 months than in months 4-12: 32.8 and 6.9 per 100 child-years of follow-up; respectively. Loss-to-programme rates were roughly double mortality rates and followed the same trend with duration of ART. Independent predictors of 12-month mortality on ART were pre-ART weight- for-age z-score -2; percentage of CD4+ T lymphocytes 10; World Health Organization HIV/AIDS clinical stage 3 or 4; and blood haemoglobin 8 g/dl. Conclusion The large-scale programme to scale up paediatric ART in Cote d'Ivoire was effective. However; ART was often given too late; and early mortality and losses to programme before and just after ART initiation were major problems