Modulation of cardiac sodium current by alpha1-stimulation and volatile anesthetics

BACKGROUND: Alpha1-adrenoceptor stimulation is known to produce electrophysiologic changes in cardiac tissues, which may involve modulations of the fast inward Na+ current (I(Na)). A direct prodysrhythmic alpha1-mediated interaction between catecholamines and halothane has been demonstrated, supporting the hypothesis that generation of halothane-epinephrine dysrhythmias may involve slowed conduction, leading to reentry. In this study, we examined the effects of a selective alpha1-adrenergic receptor agonist, methoxamine, on cardiac I(Na) in the absence and presence of equianesthetic concentrations of halothane and isoflurane in single ventricular myocytes from adult guinea pig hearts. METHODS: I(Na) was recorded using the standard whole-cell configuration of the patch-clamp technique. Voltage clamp protocols initiated from two different holding potentials (V(H)) were applied to examine state-dependent effects of methoxamine in the presence of anesthetics. Steady state activation and inactivation and recovery from inactivation were characterized using standard protocols. RESULTS: Methoxamine decreased I(Na) in a concentration- and voltage-dependent manner, being more potent at the depolarized V(H). Halothane and isoflurane interacted synergistically with methoxamine to suppress I(Na) near the physiologic cardiac resting potential of -80 mV. The effect of methoxamine with anesthetics appeared to be additive when using a V(H) of -110 mV, a potential where no Na+ channels are in the inactivated state. Methoxamine in the absence and presence of anesthetics significantly shifted the half maximal inactivation voltage in the hyperpolarizing direction but had no effect on steady-state activation. CONCLUSION: The present results show that methoxamine (alpha1-adrenergic stimulation) decreases cardiac Na+ current in a concentration- and voltage-dependent manner. Further, a form of synergistic interaction between methoxamine and inhalational anesthetics, halothane and isoflurane, was observed. This interaction appears to depend on the fraction of Na+ channels in the inactivated state. (Key words: Anesthetics, volatile: halothane; isoflurane; methoxamine. Patch clamp: whole-cell configuration; sodium current; ventricular guinea pig myocytes.)     

Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion

The membrane protein syntaxin participates in several protein-protein interactions that have been implicated in neurotransmitter release. To probe the physiological importance of these interactions, we microinjected into the squid giant presynaptic terminal botulinum toxin C1, which cleaves syntaxin, and the H3 domain of syntaxin, which mediates binding to other proteins. Both reagents inhibited synaptic transmission yet did not affect the number or distribution of synaptic vesicles at the presynaptic active zone. Recombinant H3 domain inhibited the interactions between syntaxin and SNAP-25 that underlie the formation of stable SNARE complexes in vitro. These data support the notion that syntaxin-mediated SNARE complexes are necessary for docked synaptic vesicles to fuse.     

Polymer characterization by thermal field flow fractionation with a continuous viscosity detector

A sensitive flow viscometer detector has been successfully used with time-delay, exponential-decay thermal field flow fractionation (TDE-TFFF) to produce unique information on polymers. TFFF with a concentration-dependent detector (e.g., refractometer) and a differential capillary viscometer is unable to produce a universal calibration plot that eliminates the necessity of polymer standards for accurate molecular-weight calibration. However, this system directly provides valuable information on the inherent (or intrinsic) viscosity distribution of polymers. Absolute intrinsic viscosity values are measured by TFFF without the need of calibration. Detailed TFFF/inherent-viscosity distribution profiles uniquely describe individual sample differences and are not affected by the experimental conditions used in TFFF separations. These viscosity distributions should be very useful in polymer characterization, since they are closely correlated with polymer end-use and solution properties, as well as to polymer molecule weight.     

Major bridge development in Hong Kong, China-past, present and future

The first “modern” type of vehicular bridge was built in Hong Kong China in the 1920s. The need for an efficient transportation system to cope with population growth and enable economic development has demanded the construction of more and more bridges since the middle of the 20th century. By 2007, Hong Kong had a total of about 1300 vehicular bridges. Four of these bridges, including the Tsing Ma Bridge, Kap Shui Mun Bridge, Ting Kau Bridge, and the cable-stayed bridge on the Hong Kong-Shenzhen Western Corridor, are considered to be major bridges supported by cables. Currently, the Stonecutters Bridge on Route No. 8 is under construction and is expected to be completed in late 2009. At the same time, the Hong Kong-Zhuhai-Macao Bridge will be in its detailed design stage soon. While efforts have been made by bridge builders to construct these giant structures, the upkeeping of these valuable assets at a high standard and ensuring their continuous functioning and performance during their intended lifespans will be another important task for bridge engineers. Wind and structural health monitoring system (WASHMS) will play a key role in this respect.     

Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B

Inhibitory receptors on hemopoietic cells critically regulate cellular function. Despite their expression on a variety of cell types, these inhibitory receptors signal through a common mechanism involving tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM), which engages Src homology 2 (SH2) domain-containing cytoplasmic tyrosine or inositol phosphatases. In this study, we have investigated the proximal signal-transduction pathway of an ITIM-bearing receptor, gp49B, a member of a newly described family of murine NK and mast cell receptors. We demonstrate that the tyrosine residues within the ITIMs are phosphorylated and serve for the association and activation of the cytoplasmic tyrosine phosphatase SHP-1. Furthermore, we demonstrate a physiologic association between gp49B and SHP-1 by coimmunoprecipitation studies from NK cells. To address the mechanism of binding between gp49B and SHP-1, binding studies involving glutathione S-transferase SHP-1 mutants were performed. Utilizing the tandem SH2 domains of SHP-1, we show that either SH2 domain can interact with phosphorylated gp49B. Full-length SHP-1, with an inactivated amino SH2 domain, also retained gp49B binding. However, binding to gp49B was disrupted by inactivation of the carboxyl SH2 domain of full-length SHP-1, suggesting that in the presence of the phosphatase domain, the carboxyl SH2 domain is required for the recruitment of phosphorylated gp49B. Thus, gp49B signaling involves SHP-1, and this association is dependent on tyrosine phosphorylation of the gp49B ITIMs, and an intact SHP-1 carboxyl SH2 domain.     

Demand-side management impact on the transmission and distributionsystem

A project to assess the impact on the transmission and distribution (TD) system due to the implementation of demand-side management (DSM) programs is described. Traditional TD planning methods are reviewed and procedural changes necessary to fully integrate DSM strategy analysis with the system planning process are discussed. Test procedures and results are discussed for a study conducted at a host utility. Several DSM strategies are analyzed to assess the impacts on a TD system serving a large metropolitan area