Incremental value of isolating the right inferior pulmonary vein during pulmonary vein isolation procedures in patients with paroxysmal atrial fibrillation

Electrical isolation of the left superior, left inferior, and right superior pulmonary veins (PVs) is often, but not always, effective in eliminating paroxysmal atrial fibrillation (PAF). The incremental clinical value of also isolating the right inferior PV has not been well defined. PV isolation by ostial applications of radiofrequency energy guided by PV potentials was performed in 176 consecutive patients (mean age 52 +/- 11 years) with PAF. The left superior, left inferior, and right superior PVs were targeted in 106 patients, and all four PVs were targeted 70 patients. Successful isolation was achieved in 96% of targeted PVs. The mean duration of follow-up was 15 +/- 7 months. At 1-year follow-up, 58% of patients in whom three PVs were isolated were free of recurrent PAF in the absence of antiarrhythmic drug therapy, compared to 73% of patients in whom all four PVs were isolated (P = 0.07). There is a trend towards a better outcome when all four PVs are isolated than when only the three major PVs are isolated. Whenever feasible, the right inferior PV should be isolated along with the other three PVs during the first ablation procedure in patients with PAF.     

Mechanism of immediate recurrences of atrial fibrillation after restoration of sinus rhythm

An immediate recurrence of AF may occur after restoration of sinus rhythm. Although pulmonary vein (PV) isolation has been shown to prevent immediate recurrence of AF, the specific trigger for immediate recurrence of AF has not been described. In 89 consecutive patients (mean age 53 +/- 11 years) who had sinus rhythm restored by spontaneous or transthoracic cardioversion in the course of a PV isolation procedure, electrograms recorded within a PV and in the adjacent left atrium were analyzed to determine the mechanism of initiation of immediate recurrence of AF. Immediate recurrence of AF was defined as a recurrence of AF within 90 seconds after restoration of sinus rhythm. There were 124 episodes of immediate recurrence of AF at a mean of 18 +/- 23 seconds after cardioversion. Recordings within the PV that triggered the immediate recurrence of AF were available in 23 (19%) of the 124 immediate recurrence of AF episodes. Among these 23 episodes of immediate recurrence of AF, all (100%) were triggered by a burst of PV tachycardia (P < 0.001). The coupling interval and prematurity index (coupling interval/preceding sinus cycle length) of the premature depolarizations that did and did not trigger immediate recurrence of AF were 246 +/- 67 ms and 0.30 +/- 0.11 vs 378 +/- 117 ms and 0.49 +/- 0.16, respectively (P < 0.01). Immediate recurrence of AF was abolished by PV isolation. The mechanism of immediate recurrence of AF is a burst of PV tachycardia, not a single premature depolarization. Immediate recurrence of AF identifies patients with AF in whom the PVs may play a major role in the initiation of AF.     

Temporary preservation of beta-cell function by diazoxide treatment in childhood type 1 diabetes

OBJECTIVE: We examined the effect of diazoxide, an ATP-sensitive K(+) channel opener and inhibitor of insulin secretion, on beta-cell function and remission in children at clinical onset of type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 56 subjects (21 girls and 35 boys, age 7-17 years) were randomized to 3 months of active treatment (diazoxide 5-7.5 mg/kg in divided doses) or placebo in addition to multiple daily insulin injections and were followed for 2 years. RESULTS: Diazoxide decreased circulating C-peptide concentrations by approximately 50%. After cessation of the treatment, basal and meal-stimulated C-peptide concentrations increased to a maximum at 6 months, followed by a decline. Meal-stimulated C-peptide concentration was significantly higher at 12 months (0.43 +/- 0.22 vs. 0.31 +/- 0.26 nmol/l, P = 0.018) and tended to fall less from clinical onset to 24 months in the diazoxide- vs. placebo-treated patients (-0.05 +/- 0.24 vs. -0.18 +/- 0.26 nmol/l, P = 0.064). At 24 months, the meal-stimulated C-peptide concentrations were 0.24 +/- 0.20 and 0.20 +/- 0.17 nmol/l, respectively. Side effects of diazoxide were prevalent. CONCLUSIONS: This study demonstrates that partial inhibition of insulin secretion for 3 months at onset of childhood type 1 diabetes suspends the period of remission and temporarily preserves residual insulin production. Further evaluation of the full potential of beta-cell rest will require compounds with less side effects as well as protocols optimized for sustained secretory arrest.     

Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats

Secoisolariciresinol diglucoside (SDG) is an important dietary lignan that is found at very high levels in flaxseed (1-4 %, w/w). Flaxseed lignans have received much research interest in recent years because of reported phyto-oestrogenic, anticarcinogenic, and anti-atherogenic effects. Previously, flaxseed feeding has been shown to decrease vitamin E concentrations in rats despite the antioxidant potential of SDG in vitro. Sesamin, a sesame lignan, on the other hand has been shown to increase vitamin E concentrations in rats. The aim of the present study was to investigate the effect of dietary SDG and its oligomers on vitamin E and cholesterol concentrations in rats. SDG was extracted from defatted flaxseed flour with a dioxane-ethanol mixture and purified by silica column chromatography. The major oligomers with 3-hydroxy-3-methyl glutaric acid, containing a high ratio of SDG to p-coumaric and ferulic acid glucosides, were purified from the extracts by reversed-phase liquid chromatography. When fed to rats at 0.1 % in the diet for 27 d, both SDG and its oligomers had no effect on animal performance but caused an increase in liver cholesterol and a 2-fold reduction in the levels of alpha- and gamma-tocopherols in rat plasma and liver. It is notable that a phenolic antioxidant, such as SDG, causes a vitamin E-lowering effect in rats. This cannot be explained at present, but warrants further investigations with respect to the magnitude, mechanism, and significance of the observed effect for human nutrition.     

Cereal alkylresorcinols elevate gamma-tocopherol levels in rats and inhibit gamma-tocopherol metabolism in vitro

Alkylresorcinols (AR) are a class of amphiphilic phenolic lipids present in high amounts in wheat and rye bran. They have been reported to be both growth retarding and innocuous when fed to rats, and to have a broad range of bioactivities in vitro, suggested to be related to their ability to bind to proteins and modify membranes. This study was designed to test the effects of AR (purified from rye bran) on growth, tocopherol levels, and cholesterol levels in rats. Rats were fed 1 of 4 different levels of AR for 4 wk: 0 (control), 1, 2, and 4 g/kg diet. AR did not affect final body, liver, or lung weights. The AR diets increased the levels of gamma-tocopherol in liver and lungs (P < 0.05). To investigate whether AR could have increased gamma-tocopherol levels via inhibition of tocopherol-omega-hydroxylase, HepG2 cells were incubated with AR and the metabolism of gamma-tocopherol measured. AR significantly inhibited the conversion of gamma-tocopherol to its water-soluble hydroxychroman metabolite in vitro, indicating that AR may increase gamma-tocopherol levels via inhibition of tocopherol metabolism in vivo. The 4 g AR/kg diet decreased liver cholesterol (P < 0.001), but did not affect plasma lipids. AR were detected in the perirenal adipose tissue samples of rats fed AR, indicating that they can accumulate in the fatty tissues of rats. High levels of dietary AR moderately affect gamma-tocopherol, possibly via inhibition of tocopherol metabolism, and decrease liver cholesterol in rats.     

Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ

OBJECTIVE: The aim of this study was to examine the safety and efficacy of risperidone, with or without concomitant psychostimulant use, in the treatment of children with conduct disorder (CD) or other disruptive behavior disorders [oppositional defiant disorder (ODD), disruptive behavior disorder-not otherwise specified (DBD-NOS)], and comorbid attention-deficit hyperactivity disorder (ADHD). METHODS: Data from two 6-week placebo-controlled trials assessing risperidone therapy in children with subaverage IQs and CD, ODD, DBD-NOS were combined, and patients with comorbid ADHD were selected for this post hoc analysis. Patients were grouped according to randomized drug therapy (risperidone or placebo), and then subgrouped according to their use of a concomitant psychostimulant. Safety outcomes included adverse events and weight change, while efficacy outcomes included changes in scores on disruptive behavior and hyperactivity-based subscales of two behavior-rating instruments (Nisonger Child Behavior Rating Form and the Aberrant Behavior Checklist). RESULTS: The analysis included 155 of 208 originally tested children divided into four sub-groups (35-43 patients each). There was no significant difference in the frequency of adverse events in patients who received risperidone alone and those who received risperidone plus a stimulant. The most common adverse events in risperidone-treated patients were somnolence, headache, dyspepsia, rhinitis, and vomiting. Within each randomized treatment group, actual weight gain was comparable, regardless of concomitant stimulant use. Risperidone-treated patients had clinically and statistically significant reductions in both disruptive behavior and hyperactivity subscale scores, compared to placebo, regardless of concomitant stimulant use. The addition of risperidone to a psychostimulant resulted in significantly better control of hyperactivity (p < 0.001) than was achieved with stimulant treatment alone, without causing an increase in adverse events. CONCLUSION: Risperidone was a safe and effective treatment, with or without a combined psychostimulant, for both disruptive behavior disorders and comorbid ADHD in children.     

Formulation, characterization, and in vitro evaluation of silymarin-loaded lipid microspheres

The objective of our study was to incorporate and evaluate Silymarin, a chemically defined natural hepatoprotective agent, in lipid microstructured systems. Various constituents of lipid microspheres—namely, internal oily core; surfactant such as soyabean lecithin; and cosurfactants such as span 20, tween 20, tween 80, and propylene glycol—were tried in different concentrations to optimize the final formulation characteristics such as globule size range, structural integrity, sustainability, and percent drug-holding capacity. The final formulation (formulation A) was characterized with respect to size and morphology using transmission electron microscopy and laser diffraction technique. The enhanced mean percent release of 56.70 ± 2.03% was observed in 36 hr from silymarin-loaded lipid microspheres (formulation A), as compared to 18.67 ± 0.192% with silymarin solution (formulation B). Thus, a stable delivery system having synergistic hepatoprotective effect of silymarin and soyabean lecithin could successively be produced for passive targeting to the liver.     

Lipid raft microdomains: a gateway for compartmentalized trafficking of Ebola and Marburg viruses

Spatiotemporal aspects of filovirus entry and release are poorly understood. Lipid rafts act as functional platforms for multiple cellular signaling and trafficking processes. Here, we report the compartmentalization of Ebola and Marburg viral proteins within lipid rafts during viral assembly and budding. Filoviruses released from infected cells incorporated raft-associated molecules, suggesting that viral exit occurs at the rafts. Ectopic expression of Ebola matrix protein and glycoprotein supported raft-dependent release of filamentous, virus-like particles (VLPs), strikingly similar to live virus as revealed by electron microscopy. Our findings also revealed that the entry of filoviruses requires functional rafts, identifying rafts as the site of virus attack. The identification of rafts as the gateway for the entry and exit of filoviruses and raft-dependent generation of VLPs have important implications for development of therapeutics and vaccination strategies against infections with Ebola and Marburg viruses.