A decade ago, the administrative costs of health care in United States greatly exceeded those Canada. We investigated whether ascendancy computerization, managed care, and adoption more businesslike approaches to have decreased costs.For Canada, we calculated insurers, employers' benefit programs, hospitals, practitioners' offices, nursing homes, home agencies 1999. analyzed published data, surveys physicians, employment detailed cost reports filed by agencies. In calculating share spending,...

The kinetics of onset rate-dependent depression maximum rate depolarisation (V̇(max) guinea-pig ventricular action potentials were studied for nine Class I anti-arrhythmic drugs using standard microelectrode techniques. found to fall into three well-demarcated subgroups with "fast" (lignocaine, tocainide and mexiletine), "intermediate" (quinidine, disopyramide procainamide) "slow" (flecainide, encainide lorcainide) kinetics. share the ability markedly prolong effective refractory period...

Off-label prescribing is the prescription of a registered medicine for use that not included in product information. The practice common, with rates up to 40% adults and 90% paediatric patients. illegal may sometimes be clinically appropriate, but associated number clinical, safety ethical issues. To date, no explicit guidance has been available help clinicians assess appropriateness off-label prescribing. We describe development guide clinicians, policymakers funders health care evaluating...

Most proteins adopt a well defined three-dimensional structure; however, it is increasingly recognized that some can exist with at least two stable conformations. Recently, class of intracellular chloride ion channel (CLICs) has been shown to in both soluble and integral membrane forms. The structure the form CLIC1 typical glutathione S-transferase superfamily protein but contains glutaredoxin-like active site. In this study we show on oxidation undergoes reversible transition from monomeric...

CLIC1 (NCC27) is a member of the highly conserved class chloride ion channels that exists in both soluble and integral membrane forms. Purified can integrate into synthetic lipid bilayers forming channel with similar properties to those observed <i>in vivo</i>. The structure form has been determined at 1.4-Å resolution. protein monomeric structurally homologous glutathione<i>S</i>-transferase superfamily, it redox-active site resembling glutaredoxin. complex glutathione shows occupies site,...

Ion channels are known to be present on the plasma membrane of virtually all cells and have been found membranes various intracellular organelles. However, until recently they were believed not occur at nuclear membrane. In this study we describe molecular cloning characterization a ion channel protein, designated chloride channel-27 (NCC27), from human myelomonocytic cell line, U937. NCC27 is novel protein that was localize principally nucleus. Its only homologue bovine (p64) internal...

Before Canada's single-payer reform, its payment system, health costs, and number of administrative personnel per capita resembled those the United States. By 1999, administration accounted for 31% U.S. expenditures versus 16.7% in Canada. No recent comprehensive analyses costs are available.To quantify 2017 spending by insurers providers.Analyses government reports, accounting data that providers file with regulators, surveys physicians, census-collected on employment care.United States...

NCC27 is a nuclear chloride ion channel, identified in the PMA-activated U937 human monocyte cell line. mRNA expressed virtually all cells and tissues gene encoding also highly conserved. Because of these factors, we have examined hypothesis that involved cycle regulation. Electrophysiological studies Chinese hamster ovary (CHO-K1) indicated conductance varied according to stage cycle, being only on plasma membrane G2/M phase. We demonstrate Cl- channel blockers known block led arrest CHO-K1...

Drug block of the human <i>ether-à-go-go</i>-related gene K⁺ channel (hERG) is most common cause acquired long QT syndrome, a disorder cardiac repolarization that may result in ventricular tachycardia and sudden death. We investigated open versus inactivated state dependence drug by using hERG mutants N588K N588E, which shift voltage inactivation compared with wild-type but mutated residue remote from drug-binding pocket pore. Four high-affinity drugs (cisapride, dofetilide,...

The voltage- and rate-dependence of the depression maximum rate depolarisation (V̇max) by therapeutic concentrations flecainide lorcainide were studied in guinea-pig ventricle standard microelectrode techniques. At normal resting potentials drugs produced only minor V̇max absence stimulation ("resting block") but trains stimuli at inter-stimulus intervals (ISI) less than 4800 ms led to an exponential decline a new plateau over 20 50 beats. This "rate-dependent block" (RDB) increased with...

Standard microelectrode techniques were used to study the effects of a free radical generating system on action potentials recorded from guinea pig ventricular myocardium. Free radicals generated by mixing xanthine oxidase (0.02-0.04 mu/ml) with superfusate-modified Locke's solution containing purine 2.3 mM. The was validated demonstrating that it could reduce cytochrome C at rate 15.9 +/- 1.5 mol/l/min. This decreased 3.0 0.3 (p less than 0.001) in presence superoxide dismutase (12 mg/100...

The efficacy of sotalol in treating acute atrial fibrillation and flutter after open heart surgery was compared with that a digoxin/disopyramide combination. Forty adult patients postoperative arrhythmias were randomised into either group 1 (sotalol mg/kg bolus intravenously plus 0.2 over 12 hours) or 2 (digoxin 0.75 mg intravenously, then two hours later disopyramide intravenous 0.4 mg/kg/h for 10 hours). In each group, 17 out 20 reverted to sinus junctional rhythm within hours. time...

The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (IV) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced activation. They flow-sensitive alternating inversion recovery (FAIR) scan sequences measure CBF and oxygen level-dependent (BOLD) sensitive T 2 * during stimulation neuronal activation before after saline infusions. Cocaine (0.6 mg/kg IV over 30 seconds) increased heart rate mean pressure decreased...

CLIC1 (NCC27) is an unusual, largely intracellular, ion channel that exists in both soluble and membrane-associated forms. The recombinant protein can be expressed <i>Escherichia coli</i>, a property has made possible detailed electrophysiological studies lipid bilayers examination of the mechanism membrane integration. Soluble<i>E. coli</i>-derived moves from solution into artificial forms chloride-selective channels with essentially identical conductance, pharmacology, opening closing...

Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations high affinity blockade of I Kr (encoded by HERG). In chronic transfection model using CHO‐K1 cells, cisapride inhibited HERG tail currents after step to +25 mV similar potency at room physiological temperatures (IC 50 16.4 n M 20–22°C 23.6 37°C). Channel inhibition exhibited time‐, voltage‐ frequency‐dependence. an envelope...

NCC27 belongs to a family of small, highly conserved, organellar ion channel proteins. It is constitutively expressed by native CHO-K1 and dominantly localized the nucleus nuclear membrane. When cells are transfected with NCC27-expressing constructs, synthesized proteins spill over into cytoplasm activity can then be detected on plasma as well This provided unique opportunity directly compare electrophysiological characteristics one cloned channel, both cytoplasmic membranes. At same time,...

The influence of stimulation rate on the ability mexiletine, disopyramide. and encainide to depress maximum depolarisation (Vmax) intracellular action potentials has been studied in guinea pig ventricular myocardium, using standard microelectrode techniques. Mexiletine disopyramide produced modest depression Vmax even absence (resting block), while did not. All three drugs progressive as was increased over a wide range interstimulus intervals (rate-dependent block). This relationship between...

The effects of Class I antiarrhythmic drugs on the maximum rate depolarization guinea‐pig ventricular action potentials were studied by standard microelectrode techniques. ability seven different to depress in unstimulated tissue (‘resting block’) was found correlate poorly with lipophilicity (log P) compounds and only a little better their molecular weights. Depression stimulated for 11 found, all cases, increase stimulation frequency (‘rate‐dependent block’). rapidity onset rate‐dependent...

Mutations in the pore domain of human ether-a-go-go-related gene (hERG) potassium channel are associated with higher risk sudden death. However, many kindreds clinical presentation is variable, making it hard to predict risk. We hypothesized that vitro phenotyping intrinsic severity individual mutations can assist stratification.We analyzed 2 hERG mutations, G572S and G584S. Similar 90% missense G572S-hERG subunits did not traffic plasma membrane but could coassemble WT resulted a dominant...

The HERG K+ channel has very unusual kinetic behavior that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarization as well in preventing lethal ventricular arrhythmias. Mutagenesis studies have shown the extracellular peptide linker joining fifth transmembrane domain to pore helix is inactivation of channel. This also considerably longer channels, 40 amino acids, than most other voltage-gated channels. In this study we show a synthetic...